CA2029787C - Method for preparation of taxol using an oxazinone - Google Patents
Method for preparation of taxol using an oxazinone Download PDFInfo
- Publication number
- CA2029787C CA2029787C CA002029787A CA2029787A CA2029787C CA 2029787 C CA2029787 C CA 2029787C CA 002029787 A CA002029787 A CA 002029787A CA 2029787 A CA2029787 A CA 2029787A CA 2029787 C CA2029787 C CA 2029787C
- Authority
- CA
- Canada
- Prior art keywords
- aryl
- hydrogen
- alkenyl
- alkynyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/84—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing rings with more than eight members
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Process for the preparation of a taxol intermediate comprising contacting an alcohol with an oxazinone having the formula:
(see formula 1) wherein R1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR7 wherein R7 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl alkenyl, alkynyl, aryl, heteroaryl, and OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
(see formula 1) wherein R1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR7 wherein R7 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl alkenyl, alkynyl, aryl, heteroaryl, and OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
Description
METHCD FOR PREPARATION OF TAXOL USING AN OXAZINONE
BACKGROUND OF THE INVENTION
The present invention is directed to a novel oxazinone, a process for its preparation, and a process for the preparation of taxol invclving the use cf such oxazinone.
The taxane fami'_y of tsrpenes, of which taxol~M is a membe:, has attracted considerable inzares't in both the biological and chemical arts. Taro:. is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic i0 and tumcr-inhibit inc act iTrit;r haul n w _~.~ ~::e .O lCwi ?'lg +...,. r,~ a.
s~.Lac - r_.
OAc C~isCONH Ig ~ O
12 lI 10 9 I
Qi",~~ I3 13?T! 16~ 8 14 I ., OH ~ 3 4 3 OH = H;''~p OAc OCOC6Hs IG Because of this promi si.~.g activi ty, ta:~oi is currently under;oing clinical trials in both rcar.ce and the United States.
The supply of taxol °cr these clinical trials is present 1=r be i ng provided by the bar ~ f rom several spec i as of yew. However, taxcl is found only ~n minute cuantities in the bark of t;;es2 s_ew growing evergreens, causing considerable concern that the limi;.?d supply of taxol will not meet the demand. Consequently, chemists in recent ysars -la-the bark of these slow growing evergreens, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently, chemists in recent years have expended their energies in trying to find a viable synthet is route for the preparation of taxols. So far, the results have not been entirely satisfactory.
One synthetic route that has been proposed is directed to the synthesis of the tetracyclic taxane nucleus from commodity chemicals. A synthesis of the taxol congener taxusin has been reported by Holton, et al. in JACS ~, 6558 (1988). Despite the progress made in this approach, the final total synthesis of taxol is, nevertheless, likely to be a multi-step, tedious, and costly process.
An alternate approach to the preparation of taxol has been described by Greene, et al. in JACS 7~, 5917 (1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure shown below:
HOnmK h~,._ V !
Ho Ph~AcO
\\O
10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the leaves of Taxus baccata. According to the method of Greene et al., 10-deacetyl baccatin III is converted to taxol by attachment of the C10 acetyl group and by attachment of the C13 f3-amido ester side chain through the esterification of the C-13 alcohol with a f3-amido carboxylic acid unit. Although this approach requires relatively few steps, the synthesis of the f3-amido ~oz978~
BACKGROUND OF THE INVENTION
The present invention is directed to a novel oxazinone, a process for its preparation, and a process for the preparation of taxol invclving the use cf such oxazinone.
The taxane fami'_y of tsrpenes, of which taxol~M is a membe:, has attracted considerable inzares't in both the biological and chemical arts. Taro:. is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic i0 and tumcr-inhibit inc act iTrit;r haul n w _~.~ ~::e .O lCwi ?'lg +...,. r,~ a.
s~.Lac - r_.
OAc C~isCONH Ig ~ O
12 lI 10 9 I
Qi",~~ I3 13?T! 16~ 8 14 I ., OH ~ 3 4 3 OH = H;''~p OAc OCOC6Hs IG Because of this promi si.~.g activi ty, ta:~oi is currently under;oing clinical trials in both rcar.ce and the United States.
The supply of taxol °cr these clinical trials is present 1=r be i ng provided by the bar ~ f rom several spec i as of yew. However, taxcl is found only ~n minute cuantities in the bark of t;;es2 s_ew growing evergreens, causing considerable concern that the limi;.?d supply of taxol will not meet the demand. Consequently, chemists in recent ysars -la-the bark of these slow growing evergreens, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently, chemists in recent years have expended their energies in trying to find a viable synthet is route for the preparation of taxols. So far, the results have not been entirely satisfactory.
One synthetic route that has been proposed is directed to the synthesis of the tetracyclic taxane nucleus from commodity chemicals. A synthesis of the taxol congener taxusin has been reported by Holton, et al. in JACS ~, 6558 (1988). Despite the progress made in this approach, the final total synthesis of taxol is, nevertheless, likely to be a multi-step, tedious, and costly process.
An alternate approach to the preparation of taxol has been described by Greene, et al. in JACS 7~, 5917 (1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure shown below:
HOnmK h~,._ V !
Ho Ph~AcO
\\O
10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the leaves of Taxus baccata. According to the method of Greene et al., 10-deacetyl baccatin III is converted to taxol by attachment of the C10 acetyl group and by attachment of the C13 f3-amido ester side chain through the esterification of the C-13 alcohol with a f3-amido carboxylic acid unit. Although this approach requires relatively few steps, the synthesis of the f3-amido ~oz978~
carboxylic acid unit is a multi-step process which proceeds in low yield, and the coupling reaction is tedious and also proceeds in low yield. However, this coupling reaction is a key step which is required in every contemplated synthesis of taxol or biologically active derivative of taxol, since it has been shown by Wani, et al. in JACS Q~, 2325 (1971) that the presence of the f3-amido ester side chain at C13 is required for anti-tumor activity.
A major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of a readily available unit which could be easily attached to the C13 oxygen to provide the f3-amido ester side chain. Development of such a unit and a process for its attachment in high yield would facilitate the synthesis of taxol as well as related anti-tumor agents having a modified set of nuclear substituents or a modified C13 side chain. This need has been fulfilled by the discovery of a new, readily available, side chain precursor chemical unit and an efficient process for its attachment at the C13 oxygen.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a side chain precursor for the synthesis of taxols, and the provision of a process for the attachment of the side chain precursor in relatively high yield to provide a taxol intermediate.
Briefly, therefore, the present invention is directed to a side chain precursor, an oxazinone 1 of the formula:
~Q 2 9787 Ri O
Rz \ RS
Rs Rs wherein R1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR7 wherein R7 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and -OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
The present invention is also directed to a process for the preparation of a taxol intermediate comprising contacting an alcohol with an oxazinone 1 in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a ,Q-amido ester which may be used as an intermediate in the synthesis of taxol.
The present invention is also directed to a process for the preparation of taxol which comprises contacting an alcohol with oxazinone 1 in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a ,Q-amido ester taxol intermediate.
The intermediate is then used in the synthesis of taxol.
According to one aspect of the present invention there is provided an oxazinone of the formula:
- 4a -Rl O O
N 3 4 s ~~~~~'ORg wherein R1 is C6_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl--or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, 06_15 aryl or heteroaryl; R8 is a hydroxyl protecting group; and R3 is hydrogen, C6-15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, or alkynyl.
According to a further aspect of the present invention there is provided a process for the preparation of a taxol intermediate having the formula:
O V U O 1g 12 -11 1~ 9 ,...819 '/'3 2 1 17 W N O""" 13 is ,, g 7 14 1' ~~'216 3 6 OX3 4 s 2 0 K . . ....... E
F
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
30 G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or - 4b -G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, or alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and X1, X2, and X3, are independently, hydroxyl protecting groups;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, or C6_15 aryl, or substituted 6_15 aryl; and W is C6-15 aryl, substituted or unsubstituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy; the process comprising contacting an alcohol with an oxazinone having the formula:
Ri O
\ RS
wherein R1 is C6-15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6_15 aryl, heteroaryl, or -OR8 wherein R8 is alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl, or a hydroxyl ~oZ9~s~
- 4c -protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, 06_15 aryl substituted or unsubstituted C6_15 and heteroaryl;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a ,Q-amido ester which is suitable for use as an intermediate in the synthesis of taxol.
According to another aspect of the present invention there is provided a process for the preparation of taxol which comprises contacting an alcohol with an oxazinone of the formula:
~~'ORg wherein R1 is 06_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, 06_15 aryl or heteroaryl; R$ is ethoxyethyl, 2,2,2-trichloroethoxymethyl or other hydroxyl protecting group; and R3 is hydrogen, C6_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, or alkynyl;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a ~i-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
._ ~p 2 9787 - 4d -According to a still further aspect of the present invention there is provided a process for the preparation of a taxol having the formula:
1S ~1, 0 ~ U ~ 12 -1 ~,1~ 9 ~~~~.$19 L
/'3 2 1 17 N ~ ~~~ ~ m ~ 114 15 ~~,,,.16 8 7 K ., ~~~~~~E
M
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo;
~~ ~ 9787 - 4e -K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or P and Q together form an oxo;
S is hydroxy;
T is hydrogen;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, C6_15 aryl or heteroaryl; and W is 06_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy; comprising:
contacting an oxazinone of the formula:
Ri O
\ RS
wherein R1 06_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl; R5 is hydrogen, R2 is -OR8 wherein R8 is a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6_15 aryl and heteroaryl;
with an alcohol of the formula:
.. ~~ ~ 9787 - 4f -1 s 1"1 A
n 13 15 ,., 8 7 14 1 ~~'16 3 JGM
.....g wherein said A, B, E, F, G, I, J, K, and M are as defined above, and X1 and X2 are, independently, hydroxyl protecting groups, the contacting of said oxazinone and said alcohol being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a ~3-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
According to another aspect of the present invention there is provided an oxazinone having the formula:
\ RS
wherein R1 is C6-15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl, and -OR8 wherein R8 is 2~ ~ 97 87 4g alkyl, alkenyl, alkynyl, 06_15 aryl or heteroaryl, or a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, 06_15 aryl and heteroaryl.
According to a further aspect of the present invention there is provided a process for preparing an oxazinone as defined in the preceding paragraph wherein R1, R2, R3, R5 and R6 are as defined therein, which process comprises reacting a compound of formula 33 R ' 'N
1 ~ ~OH
wherein R1, R2, R3, R5 and R6 are as defined above, with an alkali metal t-butoxide to form a first intermediate, reacting the first intermediate with sulfonyl chloride to form a second intermediate and cyclizing the second intermediate to form the oxazinone.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
1F 'e?
~~29787 DETAILED DESCRIPTION
The present invention is directed to an oxazinone 1 and its derivatives, the structure of which is depicted hereinbelow.
R~
MINI' R2 ' R
Rs R3 5 as noted above, Rl is aryl, heteroaryl, alkyl, alkenyl, alkynyl or-ORS wherein R~ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and -OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
Preferably, the oaazinone l has the structure R~~ a /~~~~~bRe lA
wherein R1, R3 and R8 are as previously defined. Most preferably R8 is ethoxyethyl or 2,2,2-trichloroethoxy-methyl. Thus, the structure of the most preferred oxazinone in which R1 and R3 are phenyl, R5 is hydrogen and R2 is-OR8 with R8 being ethoxyethyl is shown below:
Ph~ a ' ~~~~~~bEE
Ph According to IUPAC rules, the name of oxazinone 2 is 2,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one.
In accordance with the present invention, a process is provided for preparing taxol intermediates, natural taxol and non-naturally occurring taxols having the following structural formula:
o ~U o ">
pnum I
H T S
wherein J G_ M _F
A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
~A~g7~87 _7_ E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane ring or M and F together form an oxetane ring;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy ar P and Q together form an oxo; and S and T are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or S and T together form an oxo; and U and V are independently hydrogen or lower alkyl, alkenyl, alkynyl, aryl, or substituted aryl; and W is aryl, substituted aryl, lower alkyl, alkenyl, alkynyl, alkoxy or aryloxy.
The taxol alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, ~0 ~ 97 87 _7a_ isopropyl, butyl, isobutyl, tent-butyl, aryl, hexyl, and the like.
The taxol alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 10 carbon ~~~8787 s atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
The taxol alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
Exemplary alkanoyloxy include acetate, propionate, butyrate, valarate, isobutyrate and the like. The more preferred alkanoyloxy is acetate.
The taxol aryl moieties, either alone or with various substituents contain from 6 to 10 carbon atoms and include phenyl, a-naphthyl or t3-naphthyl, etc.
Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc.
Phenyl is the more preferred aryl.
As defined herein, the term "aryloyloxy"
includes aromatic heterocyclic moieties the term "aryl"
includes any compound having an aromatic ring of which no hetero atom is a member, and the term "heteroaryl"
includes any compound having an aromatic ring which comprises a hetero atom.
Preferred values of the substituents A, B, D, L, E, F, G, M, I, J, K, P, Q, S, T, U, V, and W are enumerated below in Table I.
20297~'~
z n xo n n n V~ H
O
xV ~ ox xx n n o n n n n C~ ~ ~- c~ Ei C H
O ro x O ~ (Y., H
O p O O n o ~
n x v~H a>
,:
v ~a H
P4 ~ ~
C,"
O .L," S-1 A"'y ", f0 ~ O
~ O V n V
' m xo ~ v~~ Vx o a ox wx n n n o o n n n n n n n n w w c~ .~.~~ x w cn w ~ E
o, o ~.
N
w ~ b ~
.
~ a C ~ o ~
V E x O x V rx N s.a o w v~N OV GL Vx O 05C xo x~
n n n o o n n n n n n n n n a~ n n n ~ca a wow c~~~- ~~, x wa v~H x> 3 ..
a~
b a o o o w w v x ~ x o h o xo xo w x w a n n i n n a n n n n n n n a~ n i ~m ao ww ~~v H x a.~o~c~H ~~ 3 N w v CT O N ~ ~
O O
o ~a x o o ~a ~a ~ O V .~-~ ~
o o n m c ~ as H
~
b x .~ a c ~
~
xo xo ~ h ~ ~s ~ xrx x ~ ~
o n n n n n n o o n a n ~ w a o w ~. c~ H a4 w cn x > 3 w w ~r, o '~ c N
2p~9?87 to Exemplary compounds within the generic formula are depicted hereinbelow:
O Ar O ~ O Ph O O
~ ~,,~ OH ~..~ ~ ~,,~ OH
Ph~N~Onnm "~ Ar ~~O~~nui I _ an,, I
H OH H OH
HO = H HO
O
Ph Ac0 ~ Ph Ac0 O O
O Ar O ~ O Ph O O
~,,~ ~ ~,,~ OH ~ ~
R ~N~Onnm R~~O~nnn u,~~~~~ I
_ ~~
I
H OH H OH
HO ~ H ' 1"~j ~ H
Ph ' O ' AcO~ Ph Ac0 - O O
oAC OAc O R O ~ O R O - O
~,,~ ~ ~ OH ~..~ ~ ~
PhOnnu "~~~~ Ar ~~Onnni p_ I r~i ~~~
H OH H OH
HO = H ~ HO-Ph ' ~, Ac0'~ Ph Ac0 O O
~1 Ar O - O O Ph O - O
OCOR ~~"l ~ OCOR
Ph N Onmii ,~~~ At Olnim , I ono I _ ~n H OH _ H OH
HO = H ' HO o Ph ~
~~ AcO~ Ph~ ACO
O ~~O
lU 11 O Ar O ~ O Ph O O
~~ ~ OCOR ~ ~ ~,.~
~~~
. 'N' Y " Onon 'Ontun ~~,~n~ R
I _ I _ H OH H OH
HO
O
Ph ~ Ph~ Ac0 \\ Ac0 O \\
O
O Ac O ~ O Ph O O
R~~Omnn n R~~O~mm I - " ~n = ' ini H OH ~ H OH
HO ~ H HO ' H
Ph O
Ac0 ~ Ph Ac0 O O
~p~g787 O R O ~ O R O O
Ph~N~Onnn Ar ~~OI'nm n",rrrr I _ ~~oi",~~
I
H OH _ H OH
HO a Ph~AcO' ' Ph O Ac0\
~~O
O
Ar O - O O Ph O - O
OCOR ~ ~ OCOR
Ph N O~I~~~~~ Ar ~ Olnna ~~n"~"i _ ~~~~~iiii _ I
I
H OH H OH
'-'~~ ~ '~~~
Ph~AcO Ph AcO
~~O
O
OAc O ph O O
O Ar O
~ ~ ~~.,~ OCOR
R~~Onno R~~Onnn I _ I _ ~np~,~~
H OH H OH
F Ph O Ac O' O
O
~~~g~87 O Ar O ~ O Ph O
R~N~Ounui ~~n", R~~Omnn ,", i ii I
H OH _ H OH _ HO F.~p H
'OCOR ph~ OCOR
~~O \\O
O R O ~ O R O O
..
Ph~~Onnm iy ~ Ar ~~O~unn nips I _ nn I in H OH H OH
~r HO ~ H % HO = H
F'h~ OCOR ph~ OCOR
\O ~~O
O
O Ar O
~,,~ ~ ~,,~ OCOR
Ph~N~Onnm "n Ar I
H OH
Ph~ 11/~ /OCOR r~ ~..,.R
~~O O
~p ~ 87 87 O Ar O O Ph O
R ~N~Onnm R~~Omn I I
H OH H OH
F -- \~ JCOR Yn JCOR
O O
In accordance with the process of the present invention, oxazinones 1 are converted to f3-amido esters in the presence of an alcohol and an activating agent, preferably a tertiary amine such as triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidazole, and 4-dimethylaminopyridine (DMAP). For example, oxazinones 1 react with compounds having the taxane tetracyclic nucleus and a C13 hydroxyl group, in the presence of 4-dimethyl- aminopyridine (DMAP), to provide substances having a f3-amido ester group at C13.
Most preferably, the alcohol is 7-O-triethylsilyl baccatin III which can be obtained as described by Greene, et al. in JACS ~Q, 5917 (1988) or by other routes. As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl baccatin III according to the following reaction scheme:
OR ~Q OSi(C2H5)3 OH / O OH / ; CH3 ,.
' ; CHg ~3 10 HO-__-~3 ~~3 ~ ~ HO__ '~ g ~ ~ ~n __ ~ _ OCOCH3 ' OCOCH3 ococ6H5 sect, cSHsN
1. (CH, H3 )3 30 2. CH3COC1, CsHsN
a, R=H
b~ I~=COCH3 10 Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2H5)3SiC1 at 23oC under an argon atmosphere for 20 hours in the presence of 50 mL of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (31a) as a reaction product in 84-86% yield after purification. The reaction product is then acetylated with 5 equivalents of CH3COC1 and 25 mL of pyridine/mmol of 31a at 0oC under an argon atmosphere for 48 hours to provide 86%
yield of 7-0-triethylsilyl baccatin III (31b). Greene, et al. in JACS 110, 5917 at 5918 (1988).
As shown in the following reaction scheme, 7-O-triethylsilyl baccatin III 31b may be reacted with an oxazinone of the present invention at room temperature to provide a taxol intermediate in which the C-7 and C-2' hydroxyl groups are protected with triethylsilyl and ethoxyethyl protecting groups, respectively. These groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxol substituents. The synthesis of taxol from oxazinone 2 is carried out as follows ~~~9~87 Ac Ac O Ph O O
_ OTLS Ph ( 1 ) DM1P. OH
~ymm . ~y~~ Ph N e~ CZ) HCl I
OtE H Np HO Ph HO
PhC00 Ac0 PhC~11c0 31b 2 TA~OL
Although the present scheme is directed to the synthesis of the natural product taxol, it can be used with modifications in either the oxazinone or the tetracyclic alcohol, which can be derived from natural or unnatural sources, to prepare other synthetic taxols contemplated within the present invention.
Alternatively, an oxazinone 1 may be converted to a f3-amido ester in the presence of an activating agent and an alcohol other than 7-O-triethylsilyl baccatin III to form a taxol intermediate. Synthesis of taxol may then proceed using the taxol intermediate under an appropriate reaction scheme.
The oxazinone alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.
The oxazinone alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms.
They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
The oxazinone alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
Exemplary oxazinone alkanoyloxy include acetate, propionate, butyrate, valarate, isobutyrate and the like. The more preferred alkanoyloay is acetate.
The oxazinone aryl moieties described, either alone or with various substituents contain from 6 to 15 carbon atoms and include phenyl, a-naphthyl or f3-naphthyl, etc. Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
As noted above, R2 and R5 of oxazinone 1 may be - OR8 with R8 being alkyl, acyl, ketal, ethoxyethyl ("EE"), 2,2,2-trichloroethozymethyl, or other hydroxyl protecting group such as acetals and ethers, i.e., methoxymethyl ("MOM"), benzyloxymethyl; esters, such as acetates;
carbonates, such as methyl carbonates; and the like. A
variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John wiley and Sons, 1981. The hydroxyl protecting group selected should be easily removed under conditions that are sufficiently mild so as not to disturb the ester linkage or other substituents of the taxol intermediate. However, RS is preferably ethoxyethyl or 2,2,2-trichloroethoxymethyl, and most preferably ethoxyethyl.
Preferred values of the oxazinone substituents R1, R2, R3, R5, R6, R~, and R8 are enumerated herein below:
~~~g'~87 x x ri M
x a x x ro ro n n rl M
N
x U
N O
W -n ro N
,'fir '~ O ,?'., s~ t.~U
N ~ U
x x ~ M
ro ro ~ U
n n a n rl M I~
fx P4 Lx LY
r~
ri r~
x x ro ro ro n n a a M l~ 00 x x ac x w a~
O O
a~ a~ ~, x x o 1 I ~ V
w w ro O
n a n n r-I M t~ Cfl ~r ~,'GL' C
O
x x n n n n -i M I~ CD
CL' L~ fx CL
x x x ~ ~ w 0 o w x x ro w n n n n n n n N M U'1~O l~ CD
LL' L1: L1.'LY,p4 ~: RS
~~~g~787 Since the oxazinone 1 has several asymmetric carbons, it is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.
The oxazinones 1 can be prepared from readily available materials according to the following reaction scheme:
O R O
RW 3 Ri ~ \
R H KO~ a CIi~80~C1 Re s H gz R~ N\s /
Rj R~ ~ Rs Carboxylic acid 33 may alternatively be prepared according to the method described in Greene et al. , JACS l~l , 5917 (1988). 13-lactams 32 can be prepared from readily available materials, as illustrated in the followinn reaction scheme in which Rl and R3 are phenyl, R5 and R~
are hydrogen and R2 is-OR8 with R8 being ethoxyethyl:
~p~9~87 O \
\ ~ N~ 2 C1 + / 4 3 O ~ ~ OAc O
H~ H\
a N z c d Ni a 4 3 ~ 4 3 ~ 4 3 OEE ~ ~ OEE ~ 1 OAc w w w reagents: (a) triethylamine, CH2C12, 25°C, 18h; (b) 4 equiv ceric ammonium nitrate, CH3CN, -10 °C, 10 min; (c) KOH, ~~ 5 THF, H20, O °C, 30 min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), O °C, 1.5h; (e) CH3Li, ether, -78 °C, 10 min; benzoyl chloride, -78 °C, lh.
The starting materials are readily available.
a-Acyloxy acetyl chloride is prepared from glycolic acid, 10 and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones.
The p-methoxyphenyl group can be readily r_emoveo through oxidation with ceric ammonium nitrate, and the 15 acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones.
A ~ 9787 The 3-hydroxyl group may be protected with a variety of standard protecting groups such as the 1-ethoxyethyl group. Preferably, the racemic 3-hydroxy-4-arylazetidin-2-one is resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters and only the dextrorotatory enantiomer is used in the preparation of taxol. In any event, the 3-(1-ethoxy-ethoxy)-4-phenylazetidin-2-one can be converted to !3-lactam 32, by treatment with a base, preferably n-butyllithium, and an aroyl chloride at -78 °C or below.
The following examples illustrate the invention.
PREPARATION OF CIS-2,4-DIPHENYL
A major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of a readily available unit which could be easily attached to the C13 oxygen to provide the f3-amido ester side chain. Development of such a unit and a process for its attachment in high yield would facilitate the synthesis of taxol as well as related anti-tumor agents having a modified set of nuclear substituents or a modified C13 side chain. This need has been fulfilled by the discovery of a new, readily available, side chain precursor chemical unit and an efficient process for its attachment at the C13 oxygen.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a side chain precursor for the synthesis of taxols, and the provision of a process for the attachment of the side chain precursor in relatively high yield to provide a taxol intermediate.
Briefly, therefore, the present invention is directed to a side chain precursor, an oxazinone 1 of the formula:
~Q 2 9787 Ri O
Rz \ RS
Rs Rs wherein R1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR7 wherein R7 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and -OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
The present invention is also directed to a process for the preparation of a taxol intermediate comprising contacting an alcohol with an oxazinone 1 in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a ,Q-amido ester which may be used as an intermediate in the synthesis of taxol.
The present invention is also directed to a process for the preparation of taxol which comprises contacting an alcohol with oxazinone 1 in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a ,Q-amido ester taxol intermediate.
The intermediate is then used in the synthesis of taxol.
According to one aspect of the present invention there is provided an oxazinone of the formula:
- 4a -Rl O O
N 3 4 s ~~~~~'ORg wherein R1 is C6_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl--or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, 06_15 aryl or heteroaryl; R8 is a hydroxyl protecting group; and R3 is hydrogen, C6-15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, or alkynyl.
According to a further aspect of the present invention there is provided a process for the preparation of a taxol intermediate having the formula:
O V U O 1g 12 -11 1~ 9 ,...819 '/'3 2 1 17 W N O""" 13 is ,, g 7 14 1' ~~'216 3 6 OX3 4 s 2 0 K . . ....... E
F
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
30 G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or - 4b -G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, or alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and X1, X2, and X3, are independently, hydroxyl protecting groups;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, or C6_15 aryl, or substituted 6_15 aryl; and W is C6-15 aryl, substituted or unsubstituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy; the process comprising contacting an alcohol with an oxazinone having the formula:
Ri O
\ RS
wherein R1 is C6-15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6_15 aryl, heteroaryl, or -OR8 wherein R8 is alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl, or a hydroxyl ~oZ9~s~
- 4c -protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, 06_15 aryl substituted or unsubstituted C6_15 and heteroaryl;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a ,Q-amido ester which is suitable for use as an intermediate in the synthesis of taxol.
According to another aspect of the present invention there is provided a process for the preparation of taxol which comprises contacting an alcohol with an oxazinone of the formula:
~~'ORg wherein R1 is 06_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, 06_15 aryl or heteroaryl; R$ is ethoxyethyl, 2,2,2-trichloroethoxymethyl or other hydroxyl protecting group; and R3 is hydrogen, C6_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, or alkynyl;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a ~i-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
._ ~p 2 9787 - 4d -According to a still further aspect of the present invention there is provided a process for the preparation of a taxol having the formula:
1S ~1, 0 ~ U ~ 12 -1 ~,1~ 9 ~~~~.$19 L
/'3 2 1 17 N ~ ~~~ ~ m ~ 114 15 ~~,,,.16 8 7 K ., ~~~~~~E
M
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo;
~~ ~ 9787 - 4e -K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or P and Q together form an oxo;
S is hydroxy;
T is hydrogen;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, C6_15 aryl or heteroaryl; and W is 06_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy; comprising:
contacting an oxazinone of the formula:
Ri O
\ RS
wherein R1 06_15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl; R5 is hydrogen, R2 is -OR8 wherein R8 is a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6_15 aryl and heteroaryl;
with an alcohol of the formula:
.. ~~ ~ 9787 - 4f -1 s 1"1 A
n 13 15 ,., 8 7 14 1 ~~'16 3 JGM
.....g wherein said A, B, E, F, G, I, J, K, and M are as defined above, and X1 and X2 are, independently, hydroxyl protecting groups, the contacting of said oxazinone and said alcohol being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a ~3-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
According to another aspect of the present invention there is provided an oxazinone having the formula:
\ RS
wherein R1 is C6-15 aryl, substituted C6_15 aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl, and -OR8 wherein R8 is 2~ ~ 97 87 4g alkyl, alkenyl, alkynyl, 06_15 aryl or heteroaryl, or a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, 06_15 aryl and heteroaryl.
According to a further aspect of the present invention there is provided a process for preparing an oxazinone as defined in the preceding paragraph wherein R1, R2, R3, R5 and R6 are as defined therein, which process comprises reacting a compound of formula 33 R ' 'N
1 ~ ~OH
wherein R1, R2, R3, R5 and R6 are as defined above, with an alkali metal t-butoxide to form a first intermediate, reacting the first intermediate with sulfonyl chloride to form a second intermediate and cyclizing the second intermediate to form the oxazinone.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
1F 'e?
~~29787 DETAILED DESCRIPTION
The present invention is directed to an oxazinone 1 and its derivatives, the structure of which is depicted hereinbelow.
R~
MINI' R2 ' R
Rs R3 5 as noted above, Rl is aryl, heteroaryl, alkyl, alkenyl, alkynyl or-ORS wherein R~ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and -OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.
Preferably, the oaazinone l has the structure R~~ a /~~~~~bRe lA
wherein R1, R3 and R8 are as previously defined. Most preferably R8 is ethoxyethyl or 2,2,2-trichloroethoxy-methyl. Thus, the structure of the most preferred oxazinone in which R1 and R3 are phenyl, R5 is hydrogen and R2 is-OR8 with R8 being ethoxyethyl is shown below:
Ph~ a ' ~~~~~~bEE
Ph According to IUPAC rules, the name of oxazinone 2 is 2,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one.
In accordance with the present invention, a process is provided for preparing taxol intermediates, natural taxol and non-naturally occurring taxols having the following structural formula:
o ~U o ">
pnum I
H T S
wherein J G_ M _F
A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
~A~g7~87 _7_ E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane ring or M and F together form an oxetane ring;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy ar P and Q together form an oxo; and S and T are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or S and T together form an oxo; and U and V are independently hydrogen or lower alkyl, alkenyl, alkynyl, aryl, or substituted aryl; and W is aryl, substituted aryl, lower alkyl, alkenyl, alkynyl, alkoxy or aryloxy.
The taxol alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, ~0 ~ 97 87 _7a_ isopropyl, butyl, isobutyl, tent-butyl, aryl, hexyl, and the like.
The taxol alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 10 carbon ~~~8787 s atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
The taxol alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
Exemplary alkanoyloxy include acetate, propionate, butyrate, valarate, isobutyrate and the like. The more preferred alkanoyloxy is acetate.
The taxol aryl moieties, either alone or with various substituents contain from 6 to 10 carbon atoms and include phenyl, a-naphthyl or t3-naphthyl, etc.
Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc.
Phenyl is the more preferred aryl.
As defined herein, the term "aryloyloxy"
includes aromatic heterocyclic moieties the term "aryl"
includes any compound having an aromatic ring of which no hetero atom is a member, and the term "heteroaryl"
includes any compound having an aromatic ring which comprises a hetero atom.
Preferred values of the substituents A, B, D, L, E, F, G, M, I, J, K, P, Q, S, T, U, V, and W are enumerated below in Table I.
20297~'~
z n xo n n n V~ H
O
xV ~ ox xx n n o n n n n C~ ~ ~- c~ Ei C H
O ro x O ~ (Y., H
O p O O n o ~
n x v~H a>
,:
v ~a H
P4 ~ ~
C,"
O .L," S-1 A"'y ", f0 ~ O
~ O V n V
' m xo ~ v~~ Vx o a ox wx n n n o o n n n n n n n n w w c~ .~.~~ x w cn w ~ E
o, o ~.
N
w ~ b ~
.
~ a C ~ o ~
V E x O x V rx N s.a o w v~N OV GL Vx O 05C xo x~
n n n o o n n n n n n n n n a~ n n n ~ca a wow c~~~- ~~, x wa v~H x> 3 ..
a~
b a o o o w w v x ~ x o h o xo xo w x w a n n i n n a n n n n n n n a~ n i ~m ao ww ~~v H x a.~o~c~H ~~ 3 N w v CT O N ~ ~
O O
o ~a x o o ~a ~a ~ O V .~-~ ~
o o n m c ~ as H
~
b x .~ a c ~
~
xo xo ~ h ~ ~s ~ xrx x ~ ~
o n n n n n n o o n a n ~ w a o w ~. c~ H a4 w cn x > 3 w w ~r, o '~ c N
2p~9?87 to Exemplary compounds within the generic formula are depicted hereinbelow:
O Ar O ~ O Ph O O
~ ~,,~ OH ~..~ ~ ~,,~ OH
Ph~N~Onnm "~ Ar ~~O~~nui I _ an,, I
H OH H OH
HO = H HO
O
Ph Ac0 ~ Ph Ac0 O O
O Ar O ~ O Ph O O
~,,~ ~ ~,,~ OH ~ ~
R ~N~Onnm R~~O~nnn u,~~~~~ I
_ ~~
I
H OH H OH
HO ~ H ' 1"~j ~ H
Ph ' O ' AcO~ Ph Ac0 - O O
oAC OAc O R O ~ O R O - O
~,,~ ~ ~ OH ~..~ ~ ~
PhOnnu "~~~~ Ar ~~Onnni p_ I r~i ~~~
H OH H OH
HO = H ~ HO-Ph ' ~, Ac0'~ Ph Ac0 O O
~1 Ar O - O O Ph O - O
OCOR ~~"l ~ OCOR
Ph N Onmii ,~~~ At Olnim , I ono I _ ~n H OH _ H OH
HO = H ' HO o Ph ~
~~ AcO~ Ph~ ACO
O ~~O
lU 11 O Ar O ~ O Ph O O
~~ ~ OCOR ~ ~ ~,.~
~~~
. 'N' Y " Onon 'Ontun ~~,~n~ R
I _ I _ H OH H OH
HO
O
Ph ~ Ph~ Ac0 \\ Ac0 O \\
O
O Ac O ~ O Ph O O
R~~Omnn n R~~O~mm I - " ~n = ' ini H OH ~ H OH
HO ~ H HO ' H
Ph O
Ac0 ~ Ph Ac0 O O
~p~g787 O R O ~ O R O O
Ph~N~Onnn Ar ~~OI'nm n",rrrr I _ ~~oi",~~
I
H OH _ H OH
HO a Ph~AcO' ' Ph O Ac0\
~~O
O
Ar O - O O Ph O - O
OCOR ~ ~ OCOR
Ph N O~I~~~~~ Ar ~ Olnna ~~n"~"i _ ~~~~~iiii _ I
I
H OH H OH
'-'~~ ~ '~~~
Ph~AcO Ph AcO
~~O
O
OAc O ph O O
O Ar O
~ ~ ~~.,~ OCOR
R~~Onno R~~Onnn I _ I _ ~np~,~~
H OH H OH
F Ph O Ac O' O
O
~~~g~87 O Ar O ~ O Ph O
R~N~Ounui ~~n", R~~Omnn ,", i ii I
H OH _ H OH _ HO F.~p H
'OCOR ph~ OCOR
~~O \\O
O R O ~ O R O O
..
Ph~~Onnm iy ~ Ar ~~O~unn nips I _ nn I in H OH H OH
~r HO ~ H % HO = H
F'h~ OCOR ph~ OCOR
\O ~~O
O
O Ar O
~,,~ ~ ~,,~ OCOR
Ph~N~Onnm "n Ar I
H OH
Ph~ 11/~ /OCOR r~ ~..,.R
~~O O
~p ~ 87 87 O Ar O O Ph O
R ~N~Onnm R~~Omn I I
H OH H OH
F -- \~ JCOR Yn JCOR
O O
In accordance with the process of the present invention, oxazinones 1 are converted to f3-amido esters in the presence of an alcohol and an activating agent, preferably a tertiary amine such as triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidazole, and 4-dimethylaminopyridine (DMAP). For example, oxazinones 1 react with compounds having the taxane tetracyclic nucleus and a C13 hydroxyl group, in the presence of 4-dimethyl- aminopyridine (DMAP), to provide substances having a f3-amido ester group at C13.
Most preferably, the alcohol is 7-O-triethylsilyl baccatin III which can be obtained as described by Greene, et al. in JACS ~Q, 5917 (1988) or by other routes. As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl baccatin III according to the following reaction scheme:
OR ~Q OSi(C2H5)3 OH / O OH / ; CH3 ,.
' ; CHg ~3 10 HO-__-~3 ~~3 ~ ~ HO__ '~ g ~ ~ ~n __ ~ _ OCOCH3 ' OCOCH3 ococ6H5 sect, cSHsN
1. (CH, H3 )3 30 2. CH3COC1, CsHsN
a, R=H
b~ I~=COCH3 10 Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2H5)3SiC1 at 23oC under an argon atmosphere for 20 hours in the presence of 50 mL of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (31a) as a reaction product in 84-86% yield after purification. The reaction product is then acetylated with 5 equivalents of CH3COC1 and 25 mL of pyridine/mmol of 31a at 0oC under an argon atmosphere for 48 hours to provide 86%
yield of 7-0-triethylsilyl baccatin III (31b). Greene, et al. in JACS 110, 5917 at 5918 (1988).
As shown in the following reaction scheme, 7-O-triethylsilyl baccatin III 31b may be reacted with an oxazinone of the present invention at room temperature to provide a taxol intermediate in which the C-7 and C-2' hydroxyl groups are protected with triethylsilyl and ethoxyethyl protecting groups, respectively. These groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxol substituents. The synthesis of taxol from oxazinone 2 is carried out as follows ~~~9~87 Ac Ac O Ph O O
_ OTLS Ph ( 1 ) DM1P. OH
~ymm . ~y~~ Ph N e~ CZ) HCl I
OtE H Np HO Ph HO
PhC00 Ac0 PhC~11c0 31b 2 TA~OL
Although the present scheme is directed to the synthesis of the natural product taxol, it can be used with modifications in either the oxazinone or the tetracyclic alcohol, which can be derived from natural or unnatural sources, to prepare other synthetic taxols contemplated within the present invention.
Alternatively, an oxazinone 1 may be converted to a f3-amido ester in the presence of an activating agent and an alcohol other than 7-O-triethylsilyl baccatin III to form a taxol intermediate. Synthesis of taxol may then proceed using the taxol intermediate under an appropriate reaction scheme.
The oxazinone alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.
The oxazinone alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms.
They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
The oxazinone alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
Exemplary oxazinone alkanoyloxy include acetate, propionate, butyrate, valarate, isobutyrate and the like. The more preferred alkanoyloay is acetate.
The oxazinone aryl moieties described, either alone or with various substituents contain from 6 to 15 carbon atoms and include phenyl, a-naphthyl or f3-naphthyl, etc. Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
As noted above, R2 and R5 of oxazinone 1 may be - OR8 with R8 being alkyl, acyl, ketal, ethoxyethyl ("EE"), 2,2,2-trichloroethozymethyl, or other hydroxyl protecting group such as acetals and ethers, i.e., methoxymethyl ("MOM"), benzyloxymethyl; esters, such as acetates;
carbonates, such as methyl carbonates; and the like. A
variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John wiley and Sons, 1981. The hydroxyl protecting group selected should be easily removed under conditions that are sufficiently mild so as not to disturb the ester linkage or other substituents of the taxol intermediate. However, RS is preferably ethoxyethyl or 2,2,2-trichloroethoxymethyl, and most preferably ethoxyethyl.
Preferred values of the oxazinone substituents R1, R2, R3, R5, R6, R~, and R8 are enumerated herein below:
~~~g'~87 x x ri M
x a x x ro ro n n rl M
N
x U
N O
W -n ro N
,'fir '~ O ,?'., s~ t.~U
N ~ U
x x ~ M
ro ro ~ U
n n a n rl M I~
fx P4 Lx LY
r~
ri r~
x x ro ro ro n n a a M l~ 00 x x ac x w a~
O O
a~ a~ ~, x x o 1 I ~ V
w w ro O
n a n n r-I M t~ Cfl ~r ~,'GL' C
O
x x n n n n -i M I~ CD
CL' L~ fx CL
x x x ~ ~ w 0 o w x x ro w n n n n n n n N M U'1~O l~ CD
LL' L1: L1.'LY,p4 ~: RS
~~~g~787 Since the oxazinone 1 has several asymmetric carbons, it is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.
The oxazinones 1 can be prepared from readily available materials according to the following reaction scheme:
O R O
RW 3 Ri ~ \
R H KO~ a CIi~80~C1 Re s H gz R~ N\s /
Rj R~ ~ Rs Carboxylic acid 33 may alternatively be prepared according to the method described in Greene et al. , JACS l~l , 5917 (1988). 13-lactams 32 can be prepared from readily available materials, as illustrated in the followinn reaction scheme in which Rl and R3 are phenyl, R5 and R~
are hydrogen and R2 is-OR8 with R8 being ethoxyethyl:
~p~9~87 O \
\ ~ N~ 2 C1 + / 4 3 O ~ ~ OAc O
H~ H\
a N z c d Ni a 4 3 ~ 4 3 ~ 4 3 OEE ~ ~ OEE ~ 1 OAc w w w reagents: (a) triethylamine, CH2C12, 25°C, 18h; (b) 4 equiv ceric ammonium nitrate, CH3CN, -10 °C, 10 min; (c) KOH, ~~ 5 THF, H20, O °C, 30 min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), O °C, 1.5h; (e) CH3Li, ether, -78 °C, 10 min; benzoyl chloride, -78 °C, lh.
The starting materials are readily available.
a-Acyloxy acetyl chloride is prepared from glycolic acid, 10 and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones.
The p-methoxyphenyl group can be readily r_emoveo through oxidation with ceric ammonium nitrate, and the 15 acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones.
A ~ 9787 The 3-hydroxyl group may be protected with a variety of standard protecting groups such as the 1-ethoxyethyl group. Preferably, the racemic 3-hydroxy-4-arylazetidin-2-one is resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters and only the dextrorotatory enantiomer is used in the preparation of taxol. In any event, the 3-(1-ethoxy-ethoxy)-4-phenylazetidin-2-one can be converted to !3-lactam 32, by treatment with a base, preferably n-butyllithium, and an aroyl chloride at -78 °C or below.
The following examples illustrate the invention.
PREPARATION OF CIS-2,4-DIPHENYL
5-(1-ETHOXYETHOXY)-4,5-DIHYDRO-1,3-OXAZIN-6-ONE 2 cis-1-p-enethozpphenyl-3-acetozp-4-phenplazetidin-2-one. To a solution of 962 mg (4.56 mmol) of the imine derived from benzaldehyde and p-methoay aniline, and 0.85 mL (6.07 mmol) of triethylamine in 15 mL of CH2C12 at -20°C was added dropwise a solution of 413 mg (3.04 mmol) of a-acetoxy acetyl chloride in 15 mL of CH2C12. The reaction mixture was allowed to warm to 25°C over an 18 h period. The reaction mixture was then diluted with 100 mL of CH2C12 and the solution was extracted with 30 mL of 10% aqueous HC1.
The organic layer was washed with 30 mL of water and 30 mL
of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to provide a solid mass. ThP
solid was triturated with 50 mL of hexane and. the mixture was filtered. The remaining solid was recrystallized from ethyl acetate/hexane to give 645 mg (68%) of cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one as white crystals, m.p. 163°C.
cis-3-acetoay-4-phenylazetidin-2-one. To a solution of 20.2 g of cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin -2-one in 700 mL of acetonitrile at -10°C was slowly added a solution of csric ammonium nitrate in 450 mL of water over a 1 h period. The mixture was stirred for 30 min at -10°C and diluted with 500 mL of ether. The aqueous layer was extracted with two 100 mL portions of ether, and the combined organic layer was washed with two 100 mL portions of water, two 100 mL portions of saturated aqueous sodium bisulfite, two 100 mL portions of saturated aqueous sodium bicarbonate and concentrated to give 18.5 g of a solid.
Recrystallization of the solid from acetone/hexane gave 12.3 g (92%) of cis-3-acetoxy-4-phenylazetidin-2-one as white crystals, m.p. 152-154°C.
cis-3-hydroay-4-phenylazetidin-2-one. To a mixture of 200 mL of THF and 280 mL of 1 M aqueous potassium hydroxide solution at 0°C was added a solution of 4.59 g (22.4 mmol) of cis-3-acetoxy-4-phenylazetidin-2-one in 265 mL of THF
via a dropping funnel over a 40 min period. The solution was stirred at 0°C for 1 h and 100 mL of water and 100 mL
of saturated sodium bicarbonate were added. The mixture was extracted with four 200 mL portions of ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to give 3.54 g (97%) of racemic cis-3-hydroxy-4-phenylazetidin-2-one as white crystals, m.p. 147-149°C. This material was resolved into its enantiomers by recrystallization of its 2-methoxy-2-(trifluoromethyl)phenylacetic ester from hexane/acetone followed by hydrolysis [x]25Hg177°.
cis-3-(1-ethozyethoay)-4-phenylazetidin-2-one. To a solution of 3.41 g (20.9 mmol) of cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL of THF at 0°C was added 5 mL
of ethyl vinyl ether and 20 mg (0.2 mmol) of methane-~~~9'~8~
sulfonic acid. The mixture was stirred at 0°C for 20 min, diluted with 20 mL of saturated aqueous sodium bicarbonate, and extracted with three 40 mL portions of ethyl acetate.
The combined ethyl acetate layers wre dried over sodium sulfate and concentrated to give 4.87 g (99%) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one as a colorless oil.
cis-1-benzoyl-3-(1-ethoayethoay)-4-phenylazetidin-2-one.
To a solution of 2.35 g (10 mmol) of cis-3-(1-ethoxyethoxy) -4-phenylazetidin-2-one in 40 mL of THF at -78°C was added 6.1 mL (10.07 mmol) of a 1.65 M solution of n-butyllithium in hexane. The mixture was stirred for 10 min at -78°C and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78°c for 1 h and diluted with 70 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to give 3.45 g of an oil. Chromatography of the oil on silica gel eluted with ethyl acetate/hexane gave 3.22 g (95%) of cis-1-benzoyl-3-(1-ethoayethoxy)-4-phenylazetidin-2-one as a colorless oil.
2R,3S-R-benzopl-O-(1-ethozyethyl)-3-phenylisoserine. To a solution of 460 mg (1.36 mmol) of cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one in 20 mL of THF at 0°C
was added 13.5 mL of a 1M aqueous solution (13.5 mmol) of potassium hydroxide. The mixture was stirred at 0°C fir 10 min and the THF was evaporated. The mixture was partitioned between 12 mL of a 1N aqueous HC1 solution and 30 mL of chloroform. The aqueous layer was extracted with two additional 30 mL portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and concentrated to provide 416 mg (86%) of 2R,3S-N-benzoyl-~,~~g787 O-(1-ethoxyethyl)-3-phenylisoserine (formula 33 in which R1 and R3 are phenyl and R2 is ethoxyethyl).
cis-2,4-diphenpl-5-(1-ethoayethoap)-4,5-dihydro-1,3-oaazin-6 -one 2. To a solution of 416 mg (1.16 mmol) of 2R,3S-N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred at 25°C for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25°C for 1.5 h. The mixture was diluted with 80 mL of hexane and ethyl acetate and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase was dried over sodium sulfate and concentrated to give 256 mg (65%) of cis-2,4-diphenyl-5-(1-ethoayethoxy)-4,5-dihydro-1,3-oxazin-6-one 2 as a colorless oil, [a]25Hg -22° (CHC13, c 1.55).
PREPARATION OF TAXOL
To a small reaction vessel was added 77 mg (0.218 mmol) of (-)-cis-2,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oaazin-6-one 2, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine.
The mixture was stirred at 25°C for 12 h and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hexane followed by recrystal-lization from ethyl acetate/hexane gave 46 mg (77°~) of ~.A29787 Ph 2'-O-(1-ethoxyethyl)-7-O-triethylsilyl taxol as a ca. 2:1 mixture of diastereomers and 9.3 mg (23%) of 7-O-tri-ethylsilyl baccatin III. The yield based on consumed 7-O-triethylsilyl baccatin III was quantitative.
5 A 5 mg sample of 2'-(1-ethoxyethyl)-7-O-triethylsilyl taxol was dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution was added. The mixture was stirred at 0°C for 30 h and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of 10 saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluted with ethyl acetate/hexane to provide 3.8 mg (ca. 90%) of taxol, which was identical with an authentic sample in all respects.
PREPARATION OF N-DEBENZOYL-N-TERTBUTOXYCARBONYL TAXOL
Ac0 tHuO~ O ~ O O
OL~E 1~' OH
t Hu0 ~ i pl ~ t Hu0 ~ O~~m ~CO~H OEE ~ OH
H ~ ~
~S !~\
O Ac G
2-tertbutoap-4-phenyl-5-(1-ethoaxethoay)-4,5-dihydro-J_,3-oaazin-6-one. To a solution of 409 mg (1.16 mmol) of 20 N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3-phenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25°C
~ozs78~
for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25°C for 1.5 hour. The mixture is diluted with 80 mL of hexane an ethyl acetate and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 235 mg (70%) of 2-tertbutoxy-4-phenyl-5-(1-ethoxy-ethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
N-debenzoyl-1~1-tertbutoaycarbonyl taaol. To a small reaction vessel is added 73 mg (0.218 mmol) of 2-tertbutoxy-4-phenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine. The mixture is stirred at 25°C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/heaane followed by recrystallization from ethyl acetate/hexane gives 44 mg (73%) of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethoayethoxy)-7-O-triethylsilyl taxol as a ca. 1:1 mixture of diastereomers and 9.3 mg (23%) of 7-O-triethylsilyl baccatin III.
A 5 mg sample of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethoxyethoxy)-7-O-triethylsilyl taxol is dissolved irr 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution is added. The mixture is stirred at 0°C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and ~p29~8 concentrated. The residue is purified by column chromatography on silica gel eluted with ethyl acetate/
hexane to provide 3.8 mg (ca. 90%) of N-debenzoyl-N-tert-butoxycarbonyl taxol.
PREPARATION OF N-DEBENZOYL-N-TERTBUTOXY
CARBONYL-2'-(1-ETHOXYETHYL)-3'-PHENYL-TAXOL
a Huo~ ~ f~ ~ O'1 OEE ~( u t Hu0\/~ NI t Hu0 N~/~Omro ~\~O=H OELr H O' H
'OI ~ ~ ~ ~ \
O
Ac O
Ph 2-tertbutozp-4,4-Biphenyl-5-(1-ethozyethozy)-4,5-dihydro-1,3-oaazin-6-one. To a solution of 497 mg (1.16 mmol) of N-tertbutoaycarbonyl-O-(1-ethoxyethyl)-3,3-diphenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoaide and the mixture is stirred at 25°C
for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25°C for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate, and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 243 mg (59%) of 2-tertbutoxy-4,4-Biphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
~~~~8~
N-debenzoyl-N-tertbutoaycarbonyl-3'-phenyl taaol. To a small reaction vessel is added 90 mg (0.218 mmol) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine. The mixture is stirred at 25°C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hezane followed by recrystallization from ethyl acetate/hexane gives 44 mg (66%) of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethozyethyl)3'-phenyl-7-0-triethylsilyl taxol as a ca. 3:1 mixture of diastereomers.
A 5 mg sample of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethoxyethyl)3'-phenyl-7-O-triethylsilyl taxol is dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution is added. The mixture is stirred at 0°C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel eluted with ethyl acetate/
hexane to provide 4.0 mg (ca. 90%) of N-debenzoyl-N-tert-butozycarbonyl-3'-phenyl taxol.
~~ ~ ~ '~ g 7 29 PREPARATION OF 2,4-DIPHENYL-5-(1-ETHOXYETHOXY) 5-METHYL-4,5-DIHYDRO-1,3-OXAZIN-6-ONE
Ac O
O ~ O O
OEE OH
~~N nmn O H
OEE H OH
O ~ ~ HO ~~, OAcO
To a solution of 430 mg (1.16 mmol) of N-benzoyl-0-(1-ethoxyethyl)-2-methyl-3-phenylisoserine in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25°C for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL
of THF is added and the mixture is stirred at 25°C for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 270 mg (76%) of 2,4-diphenyl-5-(1-ethoxyethoxy)-5-methyl-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
3'-METHYL TAXOL
To a small reaction vessel is added 77 mg (0.218 mmol) of 2,4-diphenyl-5-(1-ethoxyethoxy)-5-methyl-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine.
The mixture is stirred at 25°C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hexane followed by recrystallization from ethyl acetate/hexane gives 32 mg (53%) of 2'-(1-ethoxy- ethyl)-3'-methyl-7-O-triethylsilyl taxol as a ca. 1:1 mixture of diastereomers.
A 5 mg sample of 2'-(1-ethoxyethyl)-3'-methyl-7-0-triethylsilyl taxol is dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution is added. The mixture is stirred at 0°C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue is puz~ified by column chromatography on silica gel eluted with ethyl acetate/hexane to provide 3.9 mg (ca. 90%) of 3'-methyl taxol.
In view of the above, it will be seen that the several objects of the invention are achieved.
As various changes could be made in the above compositions and processes without departing from the scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense.
The organic layer was washed with 30 mL of water and 30 mL
of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to provide a solid mass. ThP
solid was triturated with 50 mL of hexane and. the mixture was filtered. The remaining solid was recrystallized from ethyl acetate/hexane to give 645 mg (68%) of cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one as white crystals, m.p. 163°C.
cis-3-acetoay-4-phenylazetidin-2-one. To a solution of 20.2 g of cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin -2-one in 700 mL of acetonitrile at -10°C was slowly added a solution of csric ammonium nitrate in 450 mL of water over a 1 h period. The mixture was stirred for 30 min at -10°C and diluted with 500 mL of ether. The aqueous layer was extracted with two 100 mL portions of ether, and the combined organic layer was washed with two 100 mL portions of water, two 100 mL portions of saturated aqueous sodium bisulfite, two 100 mL portions of saturated aqueous sodium bicarbonate and concentrated to give 18.5 g of a solid.
Recrystallization of the solid from acetone/hexane gave 12.3 g (92%) of cis-3-acetoxy-4-phenylazetidin-2-one as white crystals, m.p. 152-154°C.
cis-3-hydroay-4-phenylazetidin-2-one. To a mixture of 200 mL of THF and 280 mL of 1 M aqueous potassium hydroxide solution at 0°C was added a solution of 4.59 g (22.4 mmol) of cis-3-acetoxy-4-phenylazetidin-2-one in 265 mL of THF
via a dropping funnel over a 40 min period. The solution was stirred at 0°C for 1 h and 100 mL of water and 100 mL
of saturated sodium bicarbonate were added. The mixture was extracted with four 200 mL portions of ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to give 3.54 g (97%) of racemic cis-3-hydroxy-4-phenylazetidin-2-one as white crystals, m.p. 147-149°C. This material was resolved into its enantiomers by recrystallization of its 2-methoxy-2-(trifluoromethyl)phenylacetic ester from hexane/acetone followed by hydrolysis [x]25Hg177°.
cis-3-(1-ethozyethoay)-4-phenylazetidin-2-one. To a solution of 3.41 g (20.9 mmol) of cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL of THF at 0°C was added 5 mL
of ethyl vinyl ether and 20 mg (0.2 mmol) of methane-~~~9'~8~
sulfonic acid. The mixture was stirred at 0°C for 20 min, diluted with 20 mL of saturated aqueous sodium bicarbonate, and extracted with three 40 mL portions of ethyl acetate.
The combined ethyl acetate layers wre dried over sodium sulfate and concentrated to give 4.87 g (99%) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one as a colorless oil.
cis-1-benzoyl-3-(1-ethoayethoay)-4-phenylazetidin-2-one.
To a solution of 2.35 g (10 mmol) of cis-3-(1-ethoxyethoxy) -4-phenylazetidin-2-one in 40 mL of THF at -78°C was added 6.1 mL (10.07 mmol) of a 1.65 M solution of n-butyllithium in hexane. The mixture was stirred for 10 min at -78°C and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78°c for 1 h and diluted with 70 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to give 3.45 g of an oil. Chromatography of the oil on silica gel eluted with ethyl acetate/hexane gave 3.22 g (95%) of cis-1-benzoyl-3-(1-ethoayethoxy)-4-phenylazetidin-2-one as a colorless oil.
2R,3S-R-benzopl-O-(1-ethozyethyl)-3-phenylisoserine. To a solution of 460 mg (1.36 mmol) of cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one in 20 mL of THF at 0°C
was added 13.5 mL of a 1M aqueous solution (13.5 mmol) of potassium hydroxide. The mixture was stirred at 0°C fir 10 min and the THF was evaporated. The mixture was partitioned between 12 mL of a 1N aqueous HC1 solution and 30 mL of chloroform. The aqueous layer was extracted with two additional 30 mL portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and concentrated to provide 416 mg (86%) of 2R,3S-N-benzoyl-~,~~g787 O-(1-ethoxyethyl)-3-phenylisoserine (formula 33 in which R1 and R3 are phenyl and R2 is ethoxyethyl).
cis-2,4-diphenpl-5-(1-ethoayethoap)-4,5-dihydro-1,3-oaazin-6 -one 2. To a solution of 416 mg (1.16 mmol) of 2R,3S-N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred at 25°C for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25°C for 1.5 h. The mixture was diluted with 80 mL of hexane and ethyl acetate and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase was dried over sodium sulfate and concentrated to give 256 mg (65%) of cis-2,4-diphenyl-5-(1-ethoayethoxy)-4,5-dihydro-1,3-oxazin-6-one 2 as a colorless oil, [a]25Hg -22° (CHC13, c 1.55).
PREPARATION OF TAXOL
To a small reaction vessel was added 77 mg (0.218 mmol) of (-)-cis-2,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oaazin-6-one 2, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine.
The mixture was stirred at 25°C for 12 h and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hexane followed by recrystal-lization from ethyl acetate/hexane gave 46 mg (77°~) of ~.A29787 Ph 2'-O-(1-ethoxyethyl)-7-O-triethylsilyl taxol as a ca. 2:1 mixture of diastereomers and 9.3 mg (23%) of 7-O-tri-ethylsilyl baccatin III. The yield based on consumed 7-O-triethylsilyl baccatin III was quantitative.
5 A 5 mg sample of 2'-(1-ethoxyethyl)-7-O-triethylsilyl taxol was dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution was added. The mixture was stirred at 0°C for 30 h and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of 10 saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluted with ethyl acetate/hexane to provide 3.8 mg (ca. 90%) of taxol, which was identical with an authentic sample in all respects.
PREPARATION OF N-DEBENZOYL-N-TERTBUTOXYCARBONYL TAXOL
Ac0 tHuO~ O ~ O O
OL~E 1~' OH
t Hu0 ~ i pl ~ t Hu0 ~ O~~m ~CO~H OEE ~ OH
H ~ ~
~S !~\
O Ac G
2-tertbutoap-4-phenyl-5-(1-ethoaxethoay)-4,5-dihydro-J_,3-oaazin-6-one. To a solution of 409 mg (1.16 mmol) of 20 N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3-phenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25°C
~ozs78~
for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25°C for 1.5 hour. The mixture is diluted with 80 mL of hexane an ethyl acetate and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 235 mg (70%) of 2-tertbutoxy-4-phenyl-5-(1-ethoxy-ethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
N-debenzoyl-1~1-tertbutoaycarbonyl taaol. To a small reaction vessel is added 73 mg (0.218 mmol) of 2-tertbutoxy-4-phenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine. The mixture is stirred at 25°C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/heaane followed by recrystallization from ethyl acetate/hexane gives 44 mg (73%) of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethoayethoxy)-7-O-triethylsilyl taxol as a ca. 1:1 mixture of diastereomers and 9.3 mg (23%) of 7-O-triethylsilyl baccatin III.
A 5 mg sample of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethoxyethoxy)-7-O-triethylsilyl taxol is dissolved irr 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution is added. The mixture is stirred at 0°C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and ~p29~8 concentrated. The residue is purified by column chromatography on silica gel eluted with ethyl acetate/
hexane to provide 3.8 mg (ca. 90%) of N-debenzoyl-N-tert-butoxycarbonyl taxol.
PREPARATION OF N-DEBENZOYL-N-TERTBUTOXY
CARBONYL-2'-(1-ETHOXYETHYL)-3'-PHENYL-TAXOL
a Huo~ ~ f~ ~ O'1 OEE ~( u t Hu0\/~ NI t Hu0 N~/~Omro ~\~O=H OELr H O' H
'OI ~ ~ ~ ~ \
O
Ac O
Ph 2-tertbutozp-4,4-Biphenyl-5-(1-ethozyethozy)-4,5-dihydro-1,3-oaazin-6-one. To a solution of 497 mg (1.16 mmol) of N-tertbutoaycarbonyl-O-(1-ethoxyethyl)-3,3-diphenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoaide and the mixture is stirred at 25°C
for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25°C for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate, and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 243 mg (59%) of 2-tertbutoxy-4,4-Biphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
~~~~8~
N-debenzoyl-N-tertbutoaycarbonyl-3'-phenyl taaol. To a small reaction vessel is added 90 mg (0.218 mmol) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine. The mixture is stirred at 25°C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hezane followed by recrystallization from ethyl acetate/hexane gives 44 mg (66%) of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethozyethyl)3'-phenyl-7-0-triethylsilyl taxol as a ca. 3:1 mixture of diastereomers.
A 5 mg sample of N-debenzoyl-N-tertbutoxycarbonyl-2'-(1-ethoxyethyl)3'-phenyl-7-O-triethylsilyl taxol is dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution is added. The mixture is stirred at 0°C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel eluted with ethyl acetate/
hexane to provide 4.0 mg (ca. 90%) of N-debenzoyl-N-tert-butozycarbonyl-3'-phenyl taxol.
~~ ~ ~ '~ g 7 29 PREPARATION OF 2,4-DIPHENYL-5-(1-ETHOXYETHOXY) 5-METHYL-4,5-DIHYDRO-1,3-OXAZIN-6-ONE
Ac O
O ~ O O
OEE OH
~~N nmn O H
OEE H OH
O ~ ~ HO ~~, OAcO
To a solution of 430 mg (1.16 mmol) of N-benzoyl-0-(1-ethoxyethyl)-2-methyl-3-phenylisoserine in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25°C for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL
of THF is added and the mixture is stirred at 25°C for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 270 mg (76%) of 2,4-diphenyl-5-(1-ethoxyethoxy)-5-methyl-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
3'-METHYL TAXOL
To a small reaction vessel is added 77 mg (0.218 mmol) of 2,4-diphenyl-5-(1-ethoxyethoxy)-5-methyl-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine.
The mixture is stirred at 25°C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hexane followed by recrystallization from ethyl acetate/hexane gives 32 mg (53%) of 2'-(1-ethoxy- ethyl)-3'-methyl-7-O-triethylsilyl taxol as a ca. 1:1 mixture of diastereomers.
A 5 mg sample of 2'-(1-ethoxyethyl)-3'-methyl-7-0-triethylsilyl taxol is dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HC1 solution is added. The mixture is stirred at 0°C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue is puz~ified by column chromatography on silica gel eluted with ethyl acetate/hexane to provide 3.9 mg (ca. 90%) of 3'-methyl taxol.
In view of the above, it will be seen that the several objects of the invention are achieved.
As various changes could be made in the above compositions and processes without departing from the scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense.
Claims (15)
1. A process for the preparation of a taxol TM
intermediate having the formula:
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, or alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and X1, X2, and X3, are independently, hydroxyl protecting groups;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6-15 aryl; and W is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy with at least one heteroatom;
the process comprising contacting an alcohol of the formula:
wherein said A, B, E, F, G, I, J, K, and M are as defined above, and X1 and X2 are, independently, hydroxyl protecting groups;
with an oxazinone having the formula:
wherein R1 is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl with at least one heteroatom, and -OR8 wherein R8 is alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl with at least one heteroatom, or a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6-15 aryl, and heteroaryl with at least one heteroatom;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a taxol derivative having a C-13 .beta.-amido ester group which is suitable for use as an intermediate in the synthesis of taxol.
intermediate having the formula:
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, or alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and X1, X2, and X3, are independently, hydroxyl protecting groups;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6-15 aryl; and W is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy with at least one heteroatom;
the process comprising contacting an alcohol of the formula:
wherein said A, B, E, F, G, I, J, K, and M are as defined above, and X1 and X2 are, independently, hydroxyl protecting groups;
with an oxazinone having the formula:
wherein R1 is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom; R2 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl with at least one heteroatom, and -OR8 wherein R8 is alkyl, alkenyl, alkynyl, C6-15 aryl, heteroaryl with at least one heteroatom, or a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6-15 aryl, and heteroaryl with at least one heteroatom;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a taxol derivative having a C-13 .beta.-amido ester group which is suitable for use as an intermediate in the synthesis of taxol.
2. The process of claim 1 wherein alkyl is C1-15 alkyl, alkenyl is C2-15 alkenyl, and alkynyl is C2-15 alkynyl.
3. The process of claim 1 or 2 wherein the hydroxyl protecting group is selected from acetals, ethers, esters, and carbonates.
4. The process of any one of claims 1 to 3 wherein R1 is C6-15 aryl, R2 is -OR8 with R8 being ethoxyethyl or 2,2,2-trichloroethoxymethyl and R3 is C6-15 aryl.
5. The process of any one of claims 1 to 4 wherein the alcohol has the formula:
wherein R4 is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl.
wherein R4 is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl.
6. The process of claim 5 wherein R4 is selected from ethers, esters, carbonates and silyl groups.
7. The process of any one of claims 1 to 6 wherein the activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidazole, or 4-dimethyl-aminopyridine.
8. A process for the preparation of taxol which comprises contacting an alcohol of the formula:
wherein;
A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, or alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
and X1 and X2 are, independently, hydroxyl protecting groups, with an oxazinone of the formula:
wherein R1 is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom; R8 is ethoxyethyl, 2,2,2-trichloroethoxymethyl or other hydroxyl protecting group; and R3 is hydrogen, or C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, or alkynyl;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a taxol derivative having a C-13 .beta.-amido ester group which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
wherein;
A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, or alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
and X1 and X2 are, independently, hydroxyl protecting groups, with an oxazinone of the formula:
wherein R1 is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom; R8 is ethoxyethyl, 2,2,2-trichloroethoxymethyl or other hydroxyl protecting group; and R3 is hydrogen, or C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, or alkynyl;
the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a taxol derivative having a C-13 .beta.-amido ester group which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
9. The process of claim 8 wherein alkyl is C1-15 alkyl, alkenyl is C2-15 alkenyl, and alkynyl is C2-15 alkynyl.
10. The process of claim 8 er 9 wherein the alcohol has the formula:
wherein R4 is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl.
wherein R4 is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl.
11. A process for the preparation of a taxol having the formula:
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo;
K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or P and Q together form an oxo;
S is hydroxy;
T is hydrogen;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom;
or substituted C6-15 aryl; and W is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy with at least one heteroatom; comprising:
contacting an oxazinone of the formula:
wherein R1 is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom; R5 is hydrogen, R2 is -OR8 wherein R8 is a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6-15 aryl and heteroaryl with at least one heteroatom; with an alcohol of the formula:
wherein said A, B, E, F, G, I, J, K, and M are as defined above, and X1 and X2 are, independently, hydroxyl protecting groups, the contacting of said oxazinone and said alcohol being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a taxol derivative having a C-13 .beta.-amido ester group which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane;
J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo;
K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or P and Q together form an oxo;
S is hydroxy;
T is hydrogen;
U and V are independently hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom;
or substituted C6-15 aryl; and W is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy with at least one heteroatom; comprising:
contacting an oxazinone of the formula:
wherein R1 is C6-15 aryl, substituted C6-15 aryl, heteroaryl with at least one heteroatom, alkyl, alkenyl, alkynyl or -OR7 wherein R7 is alkyl, alkenyl, alkynyl, C6-15 aryl or heteroaryl with at least one heteroatom; R5 is hydrogen, R2 is -OR8 wherein R8 is a hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C6-15 aryl, substituted C6-15 aryl and heteroaryl with at least one heteroatom; with an alcohol of the formula:
wherein said A, B, E, F, G, I, J, K, and M are as defined above, and X1 and X2 are, independently, hydroxyl protecting groups, the contacting of said oxazinone and said alcohol being carried out in the presence of a sufficient amount of a tertiary amine activating agent to cause the oxazinone to react with the alcohol to form a taxol derivative having a C-13 .beta.-amido ester group which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.
12. The process of claim 11 wherein said activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidazole, or 4-dimethyl-aminopyridine.
13. The process of claim 11 or 12 wherein said alcohol has the following formula:
wherein R4 is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl.
wherein R4 is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl.
14. The process of claim 13 wherein R1 and R3 are phenyl, and R6 is hydrogen.
15. The process of claim 14 wherein said activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidazole, or 4-dimethyl-aminopyridine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002347588A CA2347588C (en) | 1989-11-14 | 1990-11-13 | An oxazinone used in preparing taxol and process for preparation thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/436,235 US5015744A (en) | 1989-11-14 | 1989-11-14 | Method for preparation of taxol using an oxazinone |
| US07/436,235 | 1989-11-14 | ||
| US07/603,041 US5136060A (en) | 1989-11-14 | 1990-10-30 | Method for preparation of taxol using an oxazinone |
| US07/603,041 | 1990-10-30 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002347588A Division CA2347588C (en) | 1989-11-14 | 1990-11-13 | An oxazinone used in preparing taxol and process for preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2029787A1 CA2029787A1 (en) | 1991-05-15 |
| CA2029787C true CA2029787C (en) | 2001-10-09 |
Family
ID=27030868
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002347588A Expired - Fee Related CA2347588C (en) | 1989-11-14 | 1990-11-13 | An oxazinone used in preparing taxol and process for preparation thereof |
| CA002029787A Expired - Fee Related CA2029787C (en) | 1989-11-14 | 1990-11-13 | Method for preparation of taxol using an oxazinone |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002347588A Expired - Fee Related CA2347588C (en) | 1989-11-14 | 1990-11-13 | An oxazinone used in preparing taxol and process for preparation thereof |
Country Status (28)
| Country | Link |
|---|---|
| US (3) | US5136060A (en) |
| EP (1) | EP0428376B1 (en) |
| JP (1) | JP2507830B2 (en) |
| KR (1) | KR0161499B1 (en) |
| CN (1) | CN1043528C (en) |
| AT (1) | ATE132860T1 (en) |
| AU (1) | AU633375B2 (en) |
| BG (1) | BG60478B1 (en) |
| CA (2) | CA2347588C (en) |
| CZ (2) | CZ283581B6 (en) |
| DE (1) | DE69024757T2 (en) |
| DK (1) | DK0428376T3 (en) |
| EG (1) | EG19641A (en) |
| ES (1) | ES2083438T3 (en) |
| FI (1) | FI104487B (en) |
| GR (1) | GR3019192T3 (en) |
| HU (1) | HU209299B (en) |
| IE (2) | IE76279B1 (en) |
| IL (3) | IL96304A (en) |
| MY (1) | MY106071A (en) |
| NO (1) | NO177902C (en) |
| NZ (1) | NZ235993A (en) |
| OA (1) | OA09327A (en) |
| PL (1) | PL167898B1 (en) |
| PT (1) | PT95870B (en) |
| RO (1) | RO110491B1 (en) |
| RU (1) | RU2033994C1 (en) |
| YU (1) | YU48232B (en) |
Families Citing this family (101)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY110249A (en) * | 1989-05-31 | 1998-03-31 | Univ Florida State | Method for preparation of taxol using beta lactam |
| US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
| US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
| US5380916A (en) * | 1990-11-02 | 1995-01-10 | University Of Florida | Method for the isolation and purification of taxane derivatives |
| US5475120A (en) * | 1990-11-02 | 1995-12-12 | University Of Florida | Method for the isolation and purification of taxol and its natural analogues |
| CA2071160A1 (en) * | 1991-07-31 | 1993-02-01 | Vittorio Farina | Asymmetric synthesis of taxol side chain |
| US6028205A (en) * | 1991-09-23 | 2000-02-22 | Florida State University | C2 tricyclic taxanes |
| US6011056A (en) | 1991-09-23 | 2000-01-04 | Florida State University | C9 taxane derivatives and pharmaceutical compositions containing them |
| US6521660B2 (en) | 1991-09-23 | 2003-02-18 | Florida State University | 3′-alkyl substituted taxanes and pharmaceutical compositions containing them |
| US5721268A (en) * | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
| US6335362B1 (en) | 1991-09-23 | 2002-01-01 | Florida State University | Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them |
| US5998656A (en) | 1991-09-23 | 1999-12-07 | Florida State University | C10 tricyclic taxanes |
| US5654447A (en) * | 1991-09-23 | 1997-08-05 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III |
| US5728850A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
| US5728725A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | C2 taxane derivaties and pharmaceutical compositions containing them |
| US5710287A (en) * | 1991-09-23 | 1998-01-20 | Florida State University | Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them |
| US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
| US5350866A (en) * | 1991-09-23 | 1994-09-27 | Bristol-Myers Squibb Company | 10-desacetoxytaxol derivatives |
| US5274124A (en) * | 1991-09-23 | 1993-12-28 | Florida State University | Metal alkoxides |
| US6794523B2 (en) | 1991-09-23 | 2004-09-21 | Florida State University | Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them |
| US5739362A (en) * | 1991-09-23 | 1998-04-14 | Florida State University | Taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
| US5283253A (en) * | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
| US6018073A (en) * | 1991-09-23 | 2000-01-25 | Florida State University | Tricyclic taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
| US6005138A (en) | 1991-09-23 | 1999-12-21 | Florida State University | Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
| US5489601A (en) * | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
| ES2214665T3 (en) * | 1991-09-23 | 2004-09-16 | Florida State University | METAL ALCOXIDS. |
| US5284865A (en) * | 1991-09-23 | 1994-02-08 | Holton Robert A | Cyclohexyl substituted taxanes and pharmaceutical compositions containing them |
| US6495704B1 (en) | 1991-09-23 | 2002-12-17 | Florida State University | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
| US5714513A (en) * | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
| US7074945B2 (en) * | 1991-09-23 | 2006-07-11 | Florida State University | Metal alkoxide taxane derivatives |
| ES2230790T3 (en) * | 1992-01-15 | 2005-05-01 | E.R. SQUIBB & SONS, INC. | ENZYMATIC PROCEDURES FOR THE RESOLUTION OF ENANTIOMERIC BLENDS OF USEFUL COMPOUNDS AS INTERMEDIATES IN THE PREPARATION OF TAXANES. |
| US5272171A (en) * | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
| US5254703A (en) * | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
| US5254580A (en) * | 1993-01-19 | 1993-10-19 | Bristol-Myers Squibb Company | 7,8-cyclopropataxanes |
| US5294637A (en) * | 1992-07-01 | 1994-03-15 | Bristol-Myers Squibb Company | Fluoro taxols |
| US5614549A (en) * | 1992-08-21 | 1997-03-25 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| FR2696458B1 (en) * | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
| FR2696463B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for obtaining 10-deacetyl baccatin III. |
| FR2696462B1 (en) * | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for obtaining 10-deacetyl baccatin III. |
| FR2697752B1 (en) * | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Antitumor compositions containing taxane derivatives. |
| NZ258044A (en) * | 1992-11-27 | 1995-12-21 | Faulding F H & Co Ltd | Pharmaceutical composition comprising taxol, solubilising agent, an acid and an organic solvent |
| ES2119996T3 (en) * | 1992-11-27 | 1998-10-16 | Napro Biotherapeutics Inc | INJECTABLE COMPOSITION INCLUDING FACLITAXEL. |
| US5380751A (en) * | 1992-12-04 | 1995-01-10 | Bristol-Myers Squibb Company | 6,7-modified paclitaxels |
| FR2698871B1 (en) | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and the pharmaceutical compositions containing them. |
| MX9307777A (en) | 1992-12-15 | 1994-07-29 | Upjohn Co | 7-HALO-Y 7ß, 8ß-METHANE-TAXOLES, ANTINEOPLASTIC USE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
| US5973160A (en) * | 1992-12-23 | 1999-10-26 | Poss; Michael A. | Methods for the preparation of novel sidechain-bearing taxanes |
| US5646176A (en) * | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
| US6339164B1 (en) | 1993-01-29 | 2002-01-15 | Florida State University | C2 substituted phenyl taxane derivatives and pharmaceutical compositions containing them |
| US6187916B1 (en) * | 1993-02-01 | 2001-02-13 | Research Foundation Of State University Of New York | Process for the preparation of taxane derivatives and β-lactam intermediates therefor |
| US6593482B2 (en) | 1993-02-01 | 2003-07-15 | Aventis Pharma S.A. | Methods for preparing new taxoids and pharmaceutical compositions containing them |
| US5684175A (en) * | 1993-02-05 | 1997-11-04 | Napro Biotherapeutics, Inc. | C-2' hydroxyl-benzyl protected, N-carbamate protected (2R, 3S)- 3-phenylisoserine and production process therefor |
| NZ262030A (en) * | 1993-02-05 | 1997-10-24 | Bryn Mawr College | Process for preparing a taxol intermediate |
| CA2157114C (en) * | 1993-03-05 | 2003-12-16 | Robert A. Holton | Process for the preparation of 9-desoxotaxanes |
| US6710191B2 (en) | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
| TW467896B (en) * | 1993-03-19 | 2001-12-11 | Bristol Myers Squibb Co | Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes |
| SG68049A1 (en) * | 1993-03-22 | 2001-08-21 | Univ Florida State | Taxanes having alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing same |
| CA2161328A1 (en) * | 1993-06-11 | 1994-12-22 | Robert C. Kelly | Delta 6,7-taxols antineoplastic use and pharmaceutical compositions containing them |
| TW397866B (en) * | 1993-07-14 | 2000-07-11 | Bristol Myers Squibb Co | Enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes |
| US6005120A (en) | 1993-07-20 | 1999-12-21 | Florida State University | Tricyclic and tetracyclic taxanes |
| US5442065A (en) * | 1993-09-09 | 1995-08-15 | Board Of Regents, The University Of Texas System | Synthesis of tetrahydroquinoline enediyne core analogs of dynemicin |
| US5965566A (en) * | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| WO1995011020A1 (en) * | 1993-10-20 | 1995-04-27 | Enzon, Inc. | 2'- and/or 7- substituted taxoids |
| US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| US6441026B1 (en) | 1993-11-08 | 2002-08-27 | Aventis Pharma S.A. | Antitumor compositions containing taxane derivatives |
| IL127597A (en) * | 1994-01-28 | 2003-07-31 | Upjohn Co | Iso-taxol analogs |
| US5508447A (en) * | 1994-05-24 | 1996-04-16 | Board Of Regents, The University Of Texas System | Short synthetic route to taxol and taxol derivatives |
| CA2170661A1 (en) | 1995-03-22 | 1996-09-23 | John K. Thottathil | Novel methods for the preparation of taxanes using oaxzolidine intermediates |
| US5560872A (en) * | 1995-05-18 | 1996-10-01 | Lever Brothers Company | Compositions comprising oxazolidine and tetrahydrooxazine amide surfactants |
| US5675025A (en) * | 1995-06-07 | 1997-10-07 | Napro Biotherapeutics, Inc. | Paclitaxel synthesis from precursor compounds and methods of producing the same |
| US5840748A (en) * | 1995-10-02 | 1998-11-24 | Xechem International, Inc. | Dihalocephalomannine and methods of use therefor |
| US5807888A (en) * | 1995-12-13 | 1998-09-15 | Xechem International, Inc. | Preparation of brominated paclitaxel analogues and their use as effective antitumor agents |
| US5854278A (en) * | 1995-12-13 | 1998-12-29 | Xechem International, Inc. | Preparation of chlorinated paclitaxel analogues and use thereof as antitumor agents |
| US6177456B1 (en) | 1995-10-02 | 2001-01-23 | Xechem International, Inc. | Monohalocephalomannines having anticancer and antileukemic activity and method of preparation therefor |
| US5654448A (en) * | 1995-10-02 | 1997-08-05 | Xechem International, Inc. | Isolation and purification of paclitaxel from organic matter containing paclitaxel, cephalomannine and other related taxanes |
| US6107497A (en) * | 1996-02-29 | 2000-08-22 | Napro Biotherapeutics, Inc. | Intermediate for use in docetaxel synthesis and production method therefor |
| US5688977A (en) * | 1996-02-29 | 1997-11-18 | Napro Biotherapeutics, Inc. | Method for docetaxel synthesis |
| FR2745814B1 (en) * | 1996-03-06 | 1998-04-03 | Rhone Poulenc Rorer Sa | NOVEL TAXOIDS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| JP2000510470A (en) | 1996-05-06 | 2000-08-15 | フロリダ・ステイト・ユニバーシティ | 1-Deoxybaccatin III, 1-deoxytaxol and 1-deoxytaxol analogs, and methods for their preparation |
| US5750737A (en) * | 1996-09-25 | 1998-05-12 | Sisti; Nicholas J. | Method for paclitaxel synthesis |
| DE19726146A1 (en) * | 1997-06-19 | 1998-12-24 | Basf Ag | New ß-amino and ß-azidopcarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists |
| US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
| US6111144A (en) * | 1997-08-21 | 2000-08-29 | Florida State University | Method for the synthesis of a taxane intermediate |
| US6150537A (en) * | 1997-12-12 | 2000-11-21 | Emory University | Methods for the esterification of alcohols and compounds useful therefor as potential anticancer agents |
| US6156789A (en) * | 1998-03-17 | 2000-12-05 | Rhone-Poulenc Rorer S.A. | Method for treating abnormal cell proliferation in the brain |
| US6025516A (en) * | 1998-10-14 | 2000-02-15 | Chiragene, Inc. | Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes |
| WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US6452024B1 (en) | 2000-02-22 | 2002-09-17 | Chaichem Pharmaceuticals International | Process for extraction and purification of paclitaxel from natural sources |
| WO2002024179A2 (en) | 2000-09-22 | 2002-03-28 | Bristol-Myers Squibb Company | Method for reducing toxicity of combined chemotherapies |
| EP1337273A2 (en) | 2000-11-28 | 2003-08-27 | Transform Pharmaceuticals, Inc. | Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof |
| US6479679B1 (en) | 2001-04-25 | 2002-11-12 | Napro Biotherapeutics, Inc. | Two-step conversion of protected taxane ester to paclitaxel |
| US6452025B1 (en) | 2001-04-25 | 2002-09-17 | Napro Biotherapeutics, Inc. | Three-step conversion of protected taxane ester to paclitaxel |
| PL368945A1 (en) * | 2001-11-30 | 2005-04-04 | Bristol-Myers Squibb Company | Paclitaxel solvates |
| DE60327651D1 (en) * | 2002-10-09 | 2009-06-25 | Chatham Biotec Ltd | THIO ANALOGUES OF PACLITAXEL AND THEIR PREPARED PRODUCTS |
| US6759539B1 (en) | 2003-02-27 | 2004-07-06 | Chaichem Pharmaceuticals International | Process for isolation and purification of paclitaxel from natural sources |
| US7202370B2 (en) * | 2003-10-27 | 2007-04-10 | Conor Medsystems, Inc. | Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III |
| WO2006116532A2 (en) * | 2005-04-28 | 2006-11-02 | University Of Massachusetts Lowell | Synthesis of oligo/poly(catechins) and methods of use |
| WO2007143839A1 (en) * | 2006-06-12 | 2007-12-21 | 6570763 Canada Inc. | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
| US7847111B2 (en) | 2006-06-19 | 2010-12-07 | Canada Inc. | Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
| CA2723654A1 (en) * | 2008-05-07 | 2009-11-12 | Ivax Research, Llc | Processes for preparation of taxanes and intermediates thereof |
| KR101014438B1 (en) * | 2008-09-26 | 2011-02-14 | 동아제약주식회사 | The process for preparing taxane derivatives |
| WO2012000118A1 (en) | 2010-07-02 | 2012-01-05 | Angiochem Inc. | Short and d-amino acid-containing polypeptides for therapeutic conjugates and uses thereof |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4521599A (en) * | 1983-07-11 | 1985-06-04 | The Upjohn Company | Process for the preparation of 1,3-oxazine-4-ones |
| US4631340A (en) * | 1984-09-06 | 1986-12-23 | Pennwalt Corporation | 1,4-oxazinone derivatives |
| US4549014A (en) * | 1984-09-06 | 1985-10-22 | Pennwalt Corporation | Adamantyl containing 1,4-oxazinone derivatives |
| US4552585A (en) * | 1984-10-04 | 1985-11-12 | Fmc Corporation | Herbicidal 2-(aminophenyl)methyl derivatives of 3-isoxazolidinones or 3-oxazinones |
| FR2601675B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2601676B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL |
| US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
| GB8803114D0 (en) * | 1988-02-11 | 1988-03-09 | Bp Chem Int Ltd | Bleach activators in detergent compositions |
| FR2629818B1 (en) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF TAXOL |
| FR2629819B1 (en) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF BACCATIN III AND DESACETYL-10 BACCATIN III DERIVATIVES |
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
-
1990
- 1990-10-30 US US07/603,041 patent/US5136060A/en not_active Expired - Lifetime
- 1990-11-07 NZ NZ235993A patent/NZ235993A/en unknown
- 1990-11-08 AU AU65904/90A patent/AU633375B2/en not_active Ceased
- 1990-11-11 IL IL9630490A patent/IL96304A/en not_active IP Right Cessation
- 1990-11-11 IL IL10924690A patent/IL109246A/en not_active IP Right Cessation
- 1990-11-12 IE IE960720A patent/IE76279B1/en not_active IP Right Cessation
- 1990-11-12 MY MYPI90001993A patent/MY106071A/en unknown
- 1990-11-12 IE IE406190A patent/IE74154B1/en not_active IP Right Cessation
- 1990-11-13 NO NO904923A patent/NO177902C/en unknown
- 1990-11-13 DE DE69024757T patent/DE69024757T2/en not_active Expired - Fee Related
- 1990-11-13 CA CA002347588A patent/CA2347588C/en not_active Expired - Fee Related
- 1990-11-13 FI FI905609A patent/FI104487B/en not_active IP Right Cessation
- 1990-11-13 CA CA002029787A patent/CA2029787C/en not_active Expired - Fee Related
- 1990-11-13 AT AT90312366T patent/ATE132860T1/en not_active IP Right Cessation
- 1990-11-13 EP EP90312366A patent/EP0428376B1/en not_active Expired - Lifetime
- 1990-11-13 ES ES90312366T patent/ES2083438T3/en not_active Expired - Lifetime
- 1990-11-13 DK DK90312366.9T patent/DK0428376T3/en active
- 1990-11-13 PT PT95870A patent/PT95870B/en not_active IP Right Cessation
- 1990-11-14 RO RO146329A patent/RO110491B1/en unknown
- 1990-11-14 HU HU907131A patent/HU209299B/en not_active IP Right Cessation
- 1990-11-14 BG BG93228A patent/BG60478B1/en unknown
- 1990-11-14 PL PL90287757A patent/PL167898B1/en not_active IP Right Cessation
- 1990-11-14 EG EG68490A patent/EG19641A/en active
- 1990-11-14 KR KR1019900018425A patent/KR0161499B1/en not_active IP Right Cessation
- 1990-11-14 CZ CS905634A patent/CZ283581B6/en not_active IP Right Cessation
- 1990-11-14 OA OA59891A patent/OA09327A/en unknown
- 1990-11-14 YU YU216090A patent/YU48232B/en unknown
- 1990-11-14 CZ CZ953136A patent/CZ283539B6/en not_active IP Right Cessation
- 1990-11-14 JP JP2308463A patent/JP2507830B2/en not_active Expired - Fee Related
- 1990-11-14 RU SU904831946A patent/RU2033994C1/en not_active IP Right Cessation
- 1990-11-14 CN CN90109112A patent/CN1043528C/en not_active Expired - Fee Related
-
1992
- 1992-06-15 US US07/898,438 patent/US5384399A/en not_active Expired - Lifetime
-
1994
- 1994-04-07 IL IL10924694A patent/IL109246A0/en unknown
- 1994-11-07 US US08/335,495 patent/US5532363A/en not_active Expired - Lifetime
-
1996
- 1996-03-05 GR GR960400595T patent/GR3019192T3/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2029787C (en) | Method for preparation of taxol using an oxazinone | |
| US5015744A (en) | Method for preparation of taxol using an oxazinone | |
| US5175315A (en) | Method for preparation of taxol using β-lactam | |
| US5336785A (en) | Method for preparation of taxol | |
| EP0568203B1 (en) | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones | |
| RU2098413C1 (en) | Metal alcoholates | |
| JP3469237B2 (en) | Preparation of substituted isoserine esters using metal alkoxides and β-lactams | |
| PT100883B (en) | PROCESS FOR THE PREPARATION OF TAXANE DERIVATIVES USING METALIC AND B-LACTAMAN ALCOXIDES |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |