CA2206226A1 - Process for the preparation of intermediates useful in the synthesis of cephalosporins - Google Patents

Process for the preparation of intermediates useful in the synthesis of cephalosporins

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Publication number
CA2206226A1
CA2206226A1 CA002206226A CA2206226A CA2206226A1 CA 2206226 A1 CA2206226 A1 CA 2206226A1 CA 002206226 A CA002206226 A CA 002206226A CA 2206226 A CA2206226 A CA 2206226A CA 2206226 A1 CA2206226 A1 CA 2206226A1
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Canada
Prior art keywords
compound
formula
product
defined above
dpm
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.)
Abandoned
Application number
CA002206226A
Other languages
French (fr)
Inventor
Derek Walker
Junning Lee
Charles R. Martin
Haiyan Zhang
Loris Sogli
Ermanno Bernasconi
Vinod P. Menon
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Antibioticos SA
Merck Sharp and Dohme Corp
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Individual
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A process is described for preparing 3-exomethylene cephalosporanic acid derivatives for use in the synthesis of cephalosporin antibiotics such as ceftibuten. The process comprises electrochemical reduction of a compound of formula (IV), wherein: R3 is CH3C(O)-; a is an optional sulfoxide group; n is 2 or 3; R1 is H and R is H or NHR2, where R2 is H or a protecting group selected from C6H5CH2OC(O)-, C6H5C(O)- or C1-C6 alkoxy-C(O)-; or wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-, and produces the desired 3-exomethylene compounds with low levels of the corresponding 3-methyl tautomers.

Description

CA 02206226 l997-05-28 WO 96/17846 PCTrUS9S/15169 PROCESS FOR THE PREPARATrON OF lN l-~ KMFnIATES
USEFUL IN THE ~iYr~l-~SIS OF CEPHALOSPORINS
The present invention provides a process for 5 preparing intermediates useful in the synthesis of cephalosporin type antibiotics.
RAC~GROUND OF THE lN V~N l lON

U.S. Patent No. 4,634,697 describes cephalosporin compounds including Ceftibuten, a commercially important third generation cephalosporin type antibiotic having the chemical formula (I) 2 ~\ ~ ~ ~

H~ O~ ~H
CO2H CO2H (I).
The synthesis of ceftibuten starting from penicillin G is described in Yoshioka, Pure Appl. Chem.. 59, 1041 (1987).
How~ve~, this process is costly and inefficient leaving a current need for a more cost effective and efficient process for the 20 commercial scale preparation of ceftibuten.
The electrochemical transformation of derivatives of cephalosporin C is known. See, Jones, et aZ., J. Pharm.
Pharmac., 20, (Suppl.) 45S-47S (1968), and Hall, J. Pharm. Sci., 62, (6) 980-983 (1973). The formation of 3-exomethylene 25 cephalosporins via eletrochemical reduction is described in Ochiai, et aZ., J. Chem. Soc.. Perkin Trans. I, 258-262 (1974) and U.S. Patent Nos. 3,792,995 and 4,042,472. Baldwin, et aZ., Tetrahedron. 49, (22) 4907-4922 (1993), also describes the electrochemical reduction of cephalosporin C to form an 3-30 exomethylene compound of the formula CA 02206226 1997-0~-28 W O 96/17846 PCTrUS95/15169 NH3+ 0 H S

OOC (CH2)3 H I ~ ~
~N~CH2 In addition, EP 082,656 describes the electrochemical reduction of acetoxymethyl compounds of the formula o\
H H IlJn ' N ~
.~ N~ O~CH3 5 wherein n is 0 or l, and R is H or an acyl group, to form the corresponding 3-exomethylene compounds.
The eletrochemical processes described above are chemically inefficient, requiring dilute reaction concentrations, low current densities and often producing low yields.
10 Moreover, the prior art processes typically produce signiflcant levels of the 3-methyl tautomer of the desired 3-exomethylene compounds. These 3-methyl compounds are essentially useless for the synthesis of cephalosporin type antibiotics and are difficult to remove from the desired 3-exomethylene product.
15 As a result, 3-exomethylene compounds prepared via the prior art electrochemical processes are unsuitable for use in the manufacture of cephalosporin drugs. Consequently, in spite of the potential advantages of electrochemical processes, such as environm~ntal cleanliness and safety, not one is suitable for 20 development into a commercial scale process. There is therefore a need for a robust and efficient electrochemical process which will reliably produce 3-exomethylene cephalosporins in high yield and with low levels (i.e., less than 5%) of 3-methyl tautomers.

CA 02206226 1997-0~-28 : ' .
-2a -Biological methods for the ring expansion of a penicillin into a cephalosporin are provided by European Patent Application 0 366 354 and European Patent Application 0 420 562 (both to Eli Lilly and Company). EPA
0 366 354 describes a deacetoxycephalosporin C synthase from Streptomyces clavvligerus; this enzyme transforms 3-exomethylenecephalosporin C into deacetylcephalosporin C (DAC); in particular, it has expandase activity and can transform penicillin N into DAOC. EPA 0 420 562 describes a deacetoxy-cephalosporin C hydrolase, e.g. from strains of Streptomyces c/avvljgerLIs that produce cephalosporin C and/or cephamycin C. This enzyme converts 10 deacetoxycephalosporin C (DAOC) into deacetylcephalosporin C (DAC) and also 7,13-(a-aminoadipamido)-3-exomethylenecepham-4-carboxyliC acid into deacetylcephalosporin C.
Thus these European Specifications describe enzymes that are useful in the sequential biological transformation of penicillin N into DAC through DAOC.
A biological transformation of that type - by ring-expansion of a penicillin derivative - is acknowledged by Ochiai et al., Tetrahedron Letters, vol. 23, pp.2341-2344 (1972). However, Ochiai etaL describe the development of what was then a novel electrochemical method for the synthesis of 3-methylene-cepham derivatives.
The present invention is concerned with an improved electrochemical method for the synthesis of intermedi~tes useful in the synthesis of cephalosporin-type antibiotics.

A~CED S~

CA 02206226 1997-0~-28 W O96/17846 PCTrUS95/15169 SUMMARY OF THE INVENTION
The present invention solves the problems of the prior art processes by providing an efficient electrochemical process for preparing 3-exomethylene cephalosporins while producing very low levels of the 3-methyl tautomer. More specifically the present invention provides a process for preparing compounds of the formula (II) or (III) and esters thereof ~Rl ~ ~ H S

HOOC tCH2)n H I ~

~N~CH2 co2H (II) R R1 ~ ~ H ¦¦
HOOC ~(CH2)n H I ~

0~ ~CH2 CO2H (III) wherein: n is 2 or 3; Rl is H and R is H or NHR2, where R2 is H
or a protecting group selected from C6HsCH2OC(O)-, C6HsC(O)-or Cl-C6 alkoxy-C(O)-; or wherein R and Rl together with the carbon atom to which they are attached comprise -C(O)-.
Compounds (II) and (III) and the esters thereof are useful as intermediates in the synthesis of ceftibuten (I).
The process of the present invention comprises electrochemically reducing a solution of a compound of the follllula (IV) CA 02206226 l997-0~-28 W O96/17846 PCTrUS95/lS169 /
RVR1 ~ H H

HOOC (CH2)n H ~~ ~

C02H (IV) O
wherein: R3 is CH3C(0)-; ( ) is an optional sulfoxide group;
and n. R and Rl are as defined above, at a concentration of 10-50 g/L, at a pH of 7-10, and at a current density of 10-40 mA/cm2, in the presence of a buffer and in a solvent selected from water, an organic solvent, or a mi~rtl~re of water and a water miscible organic additive, to form a compound of the formula (II) or (III).
The present invention also provides novel compounds of the formula (II) or (III) as defined above, wherein n is 2 or 3; Rl is H and R is H or NHR2, where R2 is C6HsC(0)-;
C6HsCH20C(0)-, or (cH3)2cHcH2oc(o)-; or wherein R and Rl together with the carbon to which they are ~tt~ched comprise -C(0)-, and esters or salts thereof.
In an alternative embodiment, the present invention provides a process for preparing compounds of the formula (V) /o \
R R1 ~ H H
R400C (CH2)n HP ~S~

Co2R4 t CA 02206226 1997-0~-28 W O 96/17846 PCTAUS95/1~169 , .

wherein R4 is diphenylmethyl, and n, ( 11 ), R and Rl are as defined above. In this emborliment the process of the present invention comprises:
(a) electrochemically reducing a compound of the 5 formula (IV~, as defined above, to form a compound of the formula (II) or (III), as defined above, followed by chromatographic purification of the electrochemical reduction product on an adsorbent resin;
(b) esterifying the compound of formula (II) or 10 (III) from step (a) to form a compound of the formula ~VI) R R ~ ~ ( 8 ) Co2R4 ~VI) wherein R4 is diphenylmethyl, and n, ( 11 ), R and Rl are as defined above; and (c) ozonolyzing the compound ~VI) from step (b) to follll a compound of the formula t~l), as defined above.
The present invention further provides a process for preparing the diphenylmethyl ester of 7-amino-3-desacetoxymethylcephalosporanic acid, i.e., a compound of the 20 formula (VII) H H
H2N_~S

~N~o Co2R4 ~VII) wherein R4 is diphenylmethyl, comprising the steps:

CA 02206226 l997-05-28 W O96/17846 PCTrUS9S/15169 (d) reducing a compound of the formula (V) as defined above to form a compound of the formula (VIII) R Rl ~ H _ ( 11 ) R400C (CH2)n HN- ~ ~

0~ ~OH
Co2R4 ~VlII) ~0~
wherein R4, n, R, ~ 1I J and Rl are as defined above;
(e) reacting the product of step (d) with a compound of the formula P-X, wherein P is a sulfonyl activating group and X is Cl, Br or I, in the presence of a tertiary amine base to form a compound of the formula (IX) R400C>~(CH )J~NI -. ~S

~' Co2R4 (I~

wherein P is a sulfonyl activating group, and R4, n, ( 11 ), R and Rl are as defined above; and (f) (i) treating the product of step (e) with PCls in the presence of a tertiary amine base and an alcohol or diol, then with a dialkylamine base; or (ii) treating the product of step (e) with a dialkylamine base or a tertiary amine base, and then with PCls in the presence of a tertiary amine base and an alcohol or diol;

and where an optional ( 11 ) group is present treating with PCl3;

CA 02206226 1997-0~-28 to form a compound of the formula (VII). Compound (~TII) is a key intermediate in the commercial synthesis of ceftibuten (I).

DET~ ~,n DESCR~TION
As used herein, the term:
"alkyl" me~n~ a straight or branched alkyl ch~in.s of 1 to 6 carbon atoms;
"aryl" means a C6-Clo carbocyclic aromatic group, such as phenyl or naphthyl; and "substituted aryl" means an aryl group having 1 to 3 substituents selected from halogeno, Cl-C6 alkyl, NO2 or CF3;
"halogeno" means Cl, Br or I;
"sulfonyl activating group" me~n~s a substituent of the formula -SO2R6, wherein R6 is Cl-C6 alkyl, aryl, substituted aryl or -CF3;
"hydride reducing agent" means NaBH4, LiBH4, NaBH3CN, or a comhin~tion of NaBH4 and LiCl;
"aqueous acid" me~ns an aqueous solution of an acid, such as HCl;
"dialkylamine base" means a compound of the formula HN(alkyl)2, such as diethylamine;
"tertiary amine base" means bases such as pyridine, DMAP, DMA. Et3N or Hunigs base;
"tetra(alkyl)ammonium salts" mean salts comprising a tetra(alkyl)~mmonium cation, such as tetraethylammonium, tetramethylammonium, tetrabutylammonium or tetrapropyl~mmonium, and a suitable counterion such as p-toulenesulfonate or sulfate;
"alcohol" means a Cl-C4 alcohol, such as methanol, ethanol or i-propanol; and "diol" means a C2-C6 diol, such as ethylene glycol, 1,3-propanediol or 1,3-butanediol.
"Buffer" means one or more buffer compounds which are water soluble acids and/or bases, such as LiH2PO4, CA 02206226 1997-0~-28 W O96/17846 PCTrUS95/lS169 KH2PO4, NaH2PO4, Li2HPO4, K2HPO4, Na2HPO4, Li3PO4, K3PO4, Na3PO4, LiHCO3, NaHCO3, KHCO3, Na2CO3, K2CO3, Li2CO3, NaOH, KOH, LiOH, HCl04 and H3BO3, or salts, including borates (such as lithium borate, potassium borate, cesium borate or 5 sodium borate) and ~uaternary ~mmo~ m salts, such as tetra(alkyl)~mmonium salts. The buffer is an individual buffer compound, or two or more such compounds in combin~tion, and is used to maintain constant pH and to facilitate the course of the eletrochemical reduction.
'Water miscible organic additives" are organic compounds which are soluble in water and relatively unsusceptible to electrochemic~1 reduction under the conditions of the present invention, such as EtOAc, iPrOAc, CH3CN, MeOH, EtOH, iPrOH, DMF, formamide, DMSO or urea.
UAdsorbent resin" means a polymeric nonionic macroreticular (i.e., porous) adsorbent capable of selectively adsorbing hydrophobic molecules, such as compounds of the formula (II), (III), (XII), (XIII) and (XIV), from a polar solvent, such as water. Such resins are ty-pically aromatic polymers, such as sty-rene and divinylbenzene coplymers, which may be cross-linked. Such resins are known and are generally prepared by polymerization of the appropriate monomers. (See, e.g. U.S. Patent Nos. 4,224,495 and 4,297,220) A number of such adsorbent resins are readily commercially available, including: Amberlite~ XAD-7, XAD- 11&0, XAD-16 and XAD-1600 (available from Rohm & Haas); XUS-40323.00, XUS-40285.00 and XUS-40283.00 (available from Dow Chemical Co.);
and Diaion HP 10, HP 20, HP 30, HP 40 and HP 50 (available from Mitsubishi Chemical).
As used herein the following reagents and solvents are identified by the abbreviations indicated: methanol (MeOH);
tetrahydrofuran (THF); diethyl ether (Et2O); t-butyl methyl ether (TBME); triethylamine (Et3N); di-isopropylethylamine (Hunigs base); ethyl acetate (EtOAc); iso-propylacetate (iPrOAc); acetic acid (HOAc); ethanol (EtOH);

CA 02206226 1997-0~-28 N,N-dimethylformamide (DMF); dimethylsulfoxide (DMSO);
4-dimethylaminopyridine (DMAP); N,N-dimethyl~niline (DMA);
p-toluenesulfonyl chloride (tosyl chloride or TsCl);
methanesulfonyl chloride (mesyl chloride or MsCl);
5 p-toluenesulfonic acid (p-TSA); iso-propanol (iPrOH).
The present invention comprises a process for preparing a compound of the formula (II) or (III) as shown in Reaction Scheme 1 Reaction Scheme 1 H ( 11 ) H H ( 11 ) S ~ A I ~ ~ (II) ~N ~oR2 .~N~ or CO2H (IV) CO2H

A = R Rl O
HOOC (cH2)n ~--~

In Reaction Scheme 1, a solution comprising a compound of the formula (~V), as defined above, a suitable solvent, and a buffer, is electrochemically reduced to form a compound of the formula (II) or (III) as defined above. The working electrode (cathode) for this reduction is selected from 20 known electrode materials so that hydrogen overpotential is m:~cimi~ed, and includes electrodes made from Ti, In, Cd, Pb, Ga, Zn, Ag, Sn, Bi, Hg, Pt, Mo, Nb, Ta, C, Cu, Fe and Ni, as well as metal alloys such as Pb/Ag, Cu/Hg and steels of various compositions, including those steels described in "Kirk-Othmer 2~ Concise Encyclopedia of Chemical Technology", pp. 1101-1105, John Wiley & Sons, New York (1985). Preferred cathode materials include Ti, In, Cd, Hg, Pb, Ga, Zn, Ag, Sn, Bi and C (in particular C in the form of graphite, graphite felt or reticulated CA 02206226 1997-0~-28 W O96/17846 PCTrUS95/15169 vitreous carbon). Also preferred are cathodes made from C, Pb, Hg, Sn or Zn, with mercury, tin and lead being most preferred.
Preferably the cathode has a high surface area such that the ratio of electrode area to solution volume is optimized. The 5 reduction is preferably carried out at a current density of 10 mA/cm2 to 40 mA/cm2. The solvent is selected from water, suitable organic solvent, or a mixture of water and a water miscible organic additive, and is preferably water or a mixtllre of water and a water miscible organic additive.
The electroch~omic~l reduction is carried out at a temperature of -60~ to 80~C, preferably at -20~ to 30~C,, more preferably at -20~ to 20~C, and most preferably at 0~ to 10~C, at a pH of 7-10. A buffer, or a combination of two or more buffers, is used as needed to maintain the desired pH range. The buffer is present at a concentration of 0.1 M to 2 M, preferably at 0.2 M to 1.5 M, and most preferably at 0.5 M to 1.0 M. The initial concentration of the starting compound (IV) in the reduction solution is from 1 g/L to 100 g/L, preferably at 5 g/L
to 60 g/L and most preferably at 10 g/L to 50 g/L.
The electrochemical reduction is carried out in a suitable electrochemical cell, a large variety of which are known in the art. Preferably the cell is a flow cell wherein the solution comprising the compound to be reduced is circulated through the electrochemical cell from an external reservoir. Also preferred is a two-ch~mhered cell wherein the cathode and anode are contained in separate l~h~mbers. The cathode and anode ch~mhers of such cells are constructed such that fluid contained in one ch~mher is physically separated from the other ch~mher by a suitable divider while maintaining an electrical connection between the ch~mhers. Preferably the divider is a porous material, such as sintered glass, or a suitable ion ~x(~h~nge membrane, such as a Nafiong' membrane. The ch~mher cont~ining the anode will also contain a solution of a buffer in water, which buffer can be the same or different as the buffer in the cathode ~h~mher. Preferably the buffer in the CA 02206226 1997-0~-28 WO 96/17846 PCTIUS95/1~169 anode ch~mher, i.e., the anolyte, is a phosphate salt, perchloric acid or sulfuric acid, with perchloric acid being preferred. The anolyte concentration is preferably 0.2 M to 2 M, and is most preferably about l M.
Compounds of the formula (II), (III) and (~ contain two carboxylic acid groups and therefore exist as anionic species at the preferred pH used for the electrochemical reduction. An ion ~x~h~n~e membrane divider, which is permeable to cations but not anions, can therefore be used to l,levellt migration of compounds (II), (III) and (IV) to the anode, thereby preventing the possibility of side reactions from occurring at that electrode. Preferably the ion ~xch~nge membrane is a perfluorinated ionomer membrane, such as the perfluorinated sulfonic acid or perfluorinated carboxylic acid ionomers described in the "Kirk-Othmer Concise Encyclopedia of Chemical Technology", John Wiley & Sons, p. 843-844 (New York, 1985), herein incorporated by reference. Most preferred are Nafion~ or Flemion(}' membranes, with Nafion(~ membranes being especially preferred.
Compounds of the formula (IV) are known and can be readily prepared via established methods.
The product compounds (II) and (III) from the electrochemical reduction of Reaction Scheme l typically contain several byproducts as impurities. For Example, 2~ electrochemical reduction of a compound of formula (I) having the structural formula (I.l) CO2H ~- ~
~H S

~N ~--OC(O)CH3 (I. 1 ) via the procedure described above produces a compound of the formula (II) having the structural formula (II.l) W O96/17846 PCT~US95/15169 C ~ ~ N ~ ~1.1) along with varying amounts of byproducts of the form~ e (XlI), (X[II) and (XrV).
f 02H H ~ -~S
~ .~N~l~ (XII
o O

OH
I~S~

,OC(O)CH3 ~, N ~1~0C(O)CH3 Purified 3-exomethylene products (II) and (III) offer a number of advantages (including superior performance in subsequent steps of the processes described in Reaction Schemes 2 and 3, 10 below). An efficient method for removal of all. or at least some, of the byproducts from the desired reduction product (II) or (III) is therefore desirable. The instant invention also provides a method for removal of such byproducts comprising chromatography of the crude electrochemical reduction 15 product on a suitable adsorbent resin. Examples of such resins include Amberlite(~ XAD- 16, Amberlite(~ 1 180, Amberlite~

CA 02206226 1997-0~-28 W O96/17846 PCTnUS9~/15169 XAD-7, Amberlite~' XAD-1600, Dianon HP-20, SP-825, XUS-40323.00, XUS-40285.00, and XUS-40283.00, with XAD-16, XAD-1600, XAD-7, HP-20 and XUS-40323 being preferred. Most preferred for removing byproduct impurities of 5 the formula (XlI), (XtII) and (XrV) from a compound of the formula (II.1) is the adsorbent resin XAD-1600.
Adsorbent resin chromatography of the electroch~mic~l reduction product is typically carried out at a temperature of 0~C to 25~C at a colllmn load of about 30 g 10 material/L of resin. The column is preconditioned by w~.~hin~
with methanol followed by deionized water. The electrolytic reduction solution cont~ining the materials to be separated, obtained as described above, is filtered through a filter aid (such as celite(~) then acidified to a pH of 3.5-4.0, and passed through 15 the column, typically at a rate of about 1 column bed volumes/hour (BV/hr.) to load the column. The column is then eluted using a suitable solvent, such as deionized distilled water or a m~ re of deionized distilled water and an alcohol (such as methanol, ethanol or isopropanol), which elution solvent may 20 also contain a buffer to adjust the pH of the solution. The desired compound of formula (II) or (III) is obtained by lyophili7:~tion of the appropriate chromatography fractions.
The present invention also provides a process for preparing compounds of the formula (V) as shown in Reaction 25 Scheme 2.

W O96117846 PCT~US95/15169 Reaction Scheme 2 Step A

H H ( 1~
S ~ A I ~ ~ (Irl) ~N~ oR2 ~N ~CH2 (III) CO2H (IV) CO2H
R R1 ~
HOOC ~(CH2~n NH--5 Step B

~ ~ (11) (II) or (m) ~ S (VI) D--N ~CH2 Co2R4 R Rl O
A~
R400C (CH2)rl NH--Step C
~ ( 1~l ) ozone (VI) ~ A 1~ ~ ~ (V) D--N~'OH
Co2R4 CA 02206226 1997-0~-28 In Step A of Reaction Scheme 2 the starting compound (IV~, as defined above, is eletrochemically reduced to a compound of the formula (II) or (III) via the same procedure described for Reaction Scheme 1. The reduction product (II) 5 or (III) is optionally purified by chromatography on an adsorbent resin as described above.
In Step B, a compound of the formula (II) or (III) is esterified by treating with a suitable esteAryillg agent, such as diphenylrli~omethane, in a suitable solvent, such as water or a 10 mi~rtllre of water and a polar organic solvent, to form the diester ~VI), as defined above.
In Step C, the diester tVI) is treated with ozone in a suitable solvent, such as CH2Cl2, at a temperature of -100~C to 0~C, preferably at -80~ to -20~C, to form an ozonide 15 intermediate, then further treated with a suitable reducing agent, such as P(OC2H3)3 to reduce the ozonide intermediate and form a compound of the formula tV), as defined above.
In an alternative embodiment, the product (II) or (III) of Step A is treated with ozone, using essentially the same 20 procedure as descAbed for Step C (above), to form a compound of the formula (X) (;
ozone - =
(II) or (III) ~ A~ ~S
(X) ~_ N ~ OH

wherein A is as defined above, and the product (~ esteAfied using essentially the same procedure as described for Step B
25 (above) to form a compound of the formula (V), as defined above.
The present invention further provides a process for preparing compounds of the formula (VII) as shown in Reaction Scheme 3.

Reaction Scheme 3 Step D

( 1~l ) hydride reducing (~ ) H agent H H 11 A 1 S ~ (V) ~ -- S (VIII) Co2R4 Co2R4 Al = R Rl O
R4ooc~(cH2)n H--Step E

tertiary amine base ~ ~ ( 11 ) (VIII) , S
A~

Co2R4 Step F
H H
1) PCls & - S
dialkylarnine base H2N~ (VII) 2) PCI5, alcohol ordiol, & tertiaryarnine base 1 0 Co2R4 In Reaction Scheme 3, step D, a compound of the formula tV), as defined above, is treated with a hydride reducing 1~ agent, preferably NaBH4, in the presence of a suitable solvent to form a compound of the formula ~VIII), wherein n, R, Rl, R4 and ( ) are as defined above. Suitable solvents include Et2O, CA 02206226 1997-0~-28 W O96/17846 PCTrUS9~ 169 THF, a Cl-C4 ~lcohol, water, a m~ re of CH2C12 and a Cl-C4 alcohol, or a mi~llre of water and a Cl-C4 alcohol. The reaction is carried out at a temperature of -100~C to 30~C, preferably at -80~C to 0~C, and the specific solvent or solvent mi~rtllre to be used is selected such that the reaction temperature is higher than the freezing point of the mi~rtllre. Preferably the solvent is a mixhlre of CH2C12 and a Cl-C4 alcohol and the reaction temperature is -80~ to -40~C.
Steps E and F of Reaction Scheme 3 are carried out as a "one pot" process, i.e., the required reagents are sequentially added to the reaction mi~ re without workup or isol~tion between steps.
In Step E, the product tVIII) of step D is reacted with a compound of the formula P-X, wherein P and X are as defined above, in a suitable solvent, such as CH2Cl2, in the presence of a tertiary amine base, such as Et3N, to form a mi~rtllre comprising a compound of the formula (IX), wherein P, R3, n, ( 11 ), R and Rl are as defined above, and a tertiary amine base.
In step F, the product mixture from step E is treated sequentially with PCls and a dialkylamine base, such as diethylamine, to form a compound of formula (VII). Tre~ment with PCls in the presence of the tertiary amine base and a Cl-C4 alcohol, preferably methanol, or a C2-C6diol, preferably 1,3-2~ butanediol, serves to cleave the amide side chain to form the free amino group. Additional tertiary amine base is added with the PCls in step F as necessa~. Treatment with dialkylamine base results in elimination of the 3-OP group to form the 3,4 double bond.
The reaction is carried out by adding PCls and an alcohol or diol to the mixture, followed by treatment with a dial~Tlamine base. Alternatively the mi~rtllre is first treated with -W O96/17846 PCTrUS95/15169 the dialkylamine base followed by treatment with PCls and alcohol or diol.

Where an optional ~ 11 ) group is present, step F
further comprises tre~tment with PCl3 to reduce the sulfoxide 5 group to the analogous sulfide.
Compounds of the formula (VII) are readily converted to ceftibuten (I) via known methods.
In an alternative embodiment, the product (X) described above is treated with a hydride reducing agent, using 10 essentially the same procedure as described for Step D (above) to form a compound of the formula (Xl) hydride ( 1~l ) reducing agent H H
(X) ' Al ~ ~
(XI) N~ OH

wherein A is as defined above, and the compound (X~) esterified via essentially the same procedure as described in Step B of 15 Reaction Scheme 2 (above) to form a compound of the formula (VIII), as defined above. The compound tVIII) is then converted to a compound of the formula (VII) via the procedures described for Steps E and F (above).
The following preparations and examples are 20 illustrative of the process of the present invention.

CA 02206226 1997-0~-28 W O 96/17846 PCTrUS95/15169 EXAMPLES

Materials and General Methods:

Electrochemical reductions are carried out in an electrochemical cell with the counter electrode (anode) separated from the working (cathode) and reference electrodes.
The potential can be controlled using a constant voltage source, such as a Princeton Applied Research Model 273 potentiostat, at from -1 to -3 volts, preferably from -1.5 to -2.5 volts.
Nafion(~ membranes for use as dividers are commercially available from a number of sources, e.g. DuPont or Aldrich Chemical Company. The Nafi,on~ membrane is cleaned prior to use by boiling in 3% H2O2 for 30 minutes, followed by immersion in a hot (80~C) solution of 9 M nitric acid for 15 minutes. The membrane is then rinsed in boiling water, sonicated in several aliquots of hot (90~C) water and stored under distilled water until needed.
The counter electrode is a platinum mesh electrode and the reference electrode is an Ag/AgCl electrode. The working electrode is a mercury pool (triple-distilled mercury) electrode; graphite (Johnson Mathey, 99.9995%) electrode;
glassy carbon electrode, lead (Johnson Mathey 99.9999%) electrode, tin foil electrode (Aldrich 99.9% pure), or zinc (Johnson Mathey, 99.95%) rod sealed in Teflon~.
HPLC analysis is performed on a Brownlee HPLC
Analytical Column (RP 18 SPHER I-5, 250 X 4.6 mm) maintained at a temperature of 35~C. The mobile phase is - typically 94:6 0.025 M KH2P04 (aqueous)/CH3CN at a flow rate 30 of 1 mL/min., and a W detector (225 nm) is used.

W O96/17846 PCTAUS95/lS169 F'x~mple Glu H _ S electroch~mic~l Gl ~. H S
N r j j~ ~ leduchon H ~ r ,~ N~CH2 ~N~C~2 CO2H OCOCH3 Co2H

Ho (CH2)3 ssS ~
Dissolve 0.3 g of 7-glutaroyl 7-aminocephalosporanic acid (glutaroyl 7-ACA) in 30 mL of a pH 6.9 aqueous buffer solution of 0.~ M KH2PO4, 0.1 M Na2HP04 and 0.018 M
NaHC03. Eletrolyze the solution at room temperature using a mercury pool working electrode at a potential of -2.2 V for a period of 13 hours to give a 8.5:1 m~ re of the exomethylene product and a 3-methyl compound of the formula o o HO Jl(CH2~J~ N ~ r ~N~CH3 Example lA
Dissolve 0.3 g of glutaroyl 7-ACA in 30 mL of an aqueous buffer solution of 1 M H3BO3 and add NaOH to adjust to 1~ pH 8Ø Eletrolyze as described for Fx~mple 1 at a potential of -2.3 V for a period of 4 3/4 hours to give a 6.8:1 mi~t~lre of the same compounds as for Example 1.

Example 2 Prepare an aqueous electrolysis solution of glutaroyl 7-ACA; 0.05 M KH2PO4: 0.05 M Na2HPO4; 0.08 M boric acid;

-W O 96/17846 PCT~US95/15169 and 0.018 M NaHCO3. Record the initial pH of the solution and electrolyze as described for F~mrle 1 at a pot~nff~l of -2.2 V.
Record the final pH and analyze by HPLC, as described above, to deterrnine the yield and the ratio of 3-exomethylene to 3-5 methyl compound in the product ml~rttlre. Using the startingconcentration of 7-glutaroylcephalosporanic acid indicated, the following results are obt~inefl:
r~ cen~ffon Yield of pH pH Ratio of ~luL~o~l e~c~methylene ~nltial final 3-eso 7-ACA product 3-methyl 1 g/L 52 % 7.3 8.5 9.5:1 5 g/L 50 % 6.8 8.9 lO.l:l 10 g/L 43 % 6.3 8.5 10.6:1 Example 3 Prepare an aqueous electrolysis solution of 5 g/L of glutaroyl 7-ACA and 0.2 M boric acid. Add NaOH to adjust the initial pH of the solution. Using a 2-chambered cell separated by a divider, electrolyze the solution as described for Fx~mple 1 15 at a potential of -2.2 V. Record the final pH and analyze by HPLC, as described above, to determine the yield and the ratio of 3-exomethylene to 3-methyl compound in the product m~ re. At the reaction temperature indicated, the following results are obtained:
I2e~ction Divider Yleld of pH pH Ratio Temp. m~t~j~l e~omethylene initial final 3-e2co product 3-methyl 25~C sintered 4 9 % 8.3 9.4 10.4:1 glass 25~C Nafion~ 64 % 8.3 9.3 10.6:1 0~C Nafion~ 6 7 % 8.7 8.3 13.5:1 CA 02206226 1997-0~-28 W O 96/17846 PCTrUS95115169 Example 4 Prepare an aqueous electrolysis solution of 10 g/L of glutaroyl 7-ACA and 0.5 M boric acid. Add LiOH to adjust the initial pH of the solution to pH = 9. Using a 2-çh~mhered cell separated by a divider, electrolyze the solution as described for F~c~mple 1 at a current density of 15 mA/cm2. Analyze by HPLC, as described above, to determine the yield (80%) and the ratio of 3-exomethylene to 3-methyl compound (20:1) in the product mixture.
Example 5 Prepare an aqueous electrolysis solution of 50 g/L of glutaroyl 7-ACA and 0.5 M boric acid. Add LiOH to adjust the initial pH of the solution to a pH = 9. Using a 2-~h~mhered cell separated by a divider, electrolyze the solution as described for Example 1 at a current density of 15 mA/cm2. Analyze by HPLC, as described above, to determine the yield (75%) and the ratio of 3-exomethylene to 3-methyl compound (30:1) in the product mixtllre.
Example 6 Prepare 20 L of an aqueous electrolysis solution of 30 g/L of 7-glutaroyl 7-aminocephalosporanic acid (glutaroyl 7-ACA) and 0.5 M boric acid. Add LiOH to adjust the initial pH of 2~ the solution to 9.5. Using a 2--~h~mhered cell separated by a divider, electrolyze the solution at a temperature of 6~ to 7~C as described for Example 1 at a current density of 15 mA/cm2.
(The final pH of the solution is 8.2.) Analyze by HPLC, as described above, as well as by NMR, to determine the yield (79% by HPLC, 80% by NMR) and the ratio of 3-exomethylene to 3-methyl compound (25: 1 by HPLC, 37: 1 by NMR) in the product mixture.
Using essentially the same procedure as described for Example 6, 20 L of 50 g/L electrolysis solution was CA 02206226 1997-0~-28 W O 96tl7846 PCTrUS95/15169 electrolyzed to give 70% yield (by HPLC) and an 3-exo to 3-methyl ratio of 28:1 (by HPLC).

F,~mI)le 7 Chromato~raphic Purification of Crude Electrochemical Reduction Product Step A - Adsorbent Resin Column Preconditionin~:
Combine 200 mL of XAD-16 resin (Rohm & Hass) 10 and 1500 mL of deionized distilled water, agitate for 1 hour, then decant the water. Add 1500 mL of MeOH, agitate for 1 hour, then decant the MeOH. Load a~ oxim~tely 155 mL of 'he lesin in a glass chromatography coiumn (2.4 cm X 60 cm) using 250 mL of MeOH. Elute the MeOH (flow rate - 2 BV/hr.), 1~ then elute with 7 L of deionized distilled water (flow rate = 8 BV/hr.). Backwash the column with 2 L of deionized distilled water and allow the resin to settle. Elute the column with 1 L
of 0.5 M NaCL (aqueous) (adjusted to pH = 3.0 with HCl, flow rate = 2 BV/hr.).
Step B - Product Purification:
Load 60 mL of a 50 g/L electrolytic reduction solution cont~ining the crude 3-exomethylene product (prepared according to F,~mple 5) onto the resin column of 25 Step A (flow rate = 1 BV/hr., temp. = 4~-5~C). Elute the column with 60 mL of deiionized distilled water (flow rate 1 BV/hr., temp. = 4~-5~C), then with 700 mL of 0.1 M NaHCO3 (aqueous) (pH = 7.5, flow rate and temp. as above), collecting 50 mL
- fractions. The fractions colected are analyzed by HPLC then 30 ~irlified to pH = 3.5 - 4.0 using dilute HCl (aqueous).
(Analytical results are provided in Table 1 below.) Lyophilize the appropriate fractions to isolate the purified 3-exomethylene product (70% .

W O~6/17846 PCTrUS95/15169 Table 1 Fraction # F~rff~!n pH ~h Re.c~ Of 3~
eso-product 5.11 0 2 5.21 0 3 5.80 0 4 7.69 0 7.48 1.80 %
6 7.46 38.7%
7 7.26 22.2%
8 8.02 15.5%
9 8.30 12.4%
8.16 3.65%
11 7.86 1.28%
12 7.51 <0.5%
13 7.47 <0.5%
14 7.42 <0.5%

Step C - Column Re~eneration:
Slurry the spent resin with 5 BV of 2% NaOH for 45-60 min., decant the aqueous solution and slurry with 5 BV of deionized distilled water for 15 min. Decant the water and slurry with 5 BV of MeOH for 45-60 min. Decant the MeOH and load the resin onto a column using 1 BV of either deionized distilled water or MeOH, then elute the column with 5 BV of deionized distilled water prior to reuse.

Example 8 Precondition a column 120 mL of XAD-1600 resin (Rohm & Haas) via essentially the same procedure as described for Fx~mple 6, Step A, then load 50 mL of a 50 g/L electrolytic reduction solution (pH = 3.0) cont~ining the crude 3-exomethylene product (prepared according to Example 5) WO 96/17846 PCT~US95/15169 onto the column (flow rate = 1 BV/hr., temp. = 4~-5~C). Elute with: 120 mL of deionized distilled water (pH = 3.0, flow rate 1 BV/hr.); 120 mL of de1Oni~ed distilled water (pH = 6.0, flow rate 1 BV/hr.); 500 mL of 0.1 M NaHCO3 (aqueous) (pH = 7.5, 5 flow rate 1 BV/hr.), while collecting 50 mL fractions. Analyze the fr~cticn~ by HPLC, then adjust to pH = 3.5-4.0 using dilute HCl (aqueous). (Analytical results are provided in Table 1 below.) Lyophilize the appropriate fractions to give the purified 3-exomethylene product.
t 0 Table 2 F~ct Qn # Praction pH % Reco~ y of 3-e~o-product 1 5.93 0 2 6.17 0 3 6.16 o 4 5.65 0 4.58 0 6 3.84 0 7 3.78 0 8 3.72 0 9 2.82 0 5.01 0 11 7.01 15.0%
12 7.48 18.8%
13 6.89 18.6%
14 6.15 20.5%
- 15 6.31 22.0%
16 6.49 4.17%
~ 17 6.75 0.40%
18 7.04 0 CA 02206226 1997-0~-28 W O96/17846 PCT~US9S115169 The XAD-1600 resin is regenerated via essentially the same process as described for Example 6, Step C.

~:lmple 9 Step A: Electrochemical Reduction Electrochemically reduce a solution of 1.0 kg of glutaroyl 7-ACA (50 g/L) according to the procedure described for Example 6 to give a 75% solution yield of 3-exomethylene product. Lyophilize the product solution to give the solid product.

Step B: Chromato~aphy:
A column (115 cm X 7.5 cm) was loaded with 20 L
of XAD-1600 resins and preconditioned at 5~C using essentially the same procedure as described for Example 8. Prepare a solution (15 L) of about 300 g of the 3-exomethylene product from Step A (~20 g/L in deionized distilled water), adjust to pH
3.0 with 2 L of 3.7% HCl (aqeuous), and load the column (5~C) at a flow rate of 0.5 BV/h. Elute the column sequentially with 2.5 BV of deionized distilled water (pH = 3.0, flow rate 1 BV/hr.), 3.5 BV of deionized distilled water (pH = 6.0, flow rate 1 BV/hr.); and finally with 4 BV of 0.5 M NaHC03 (aqueous) (pH
= 7.5, flow rate 1 BV/hr.), while collecting fractions (each fraction is 0.25 BV). Analyze the fractions by HPLC, combine the fractions which contain the 3-exomethylene product to give a 93.2% recovery of purified 3-exomethylene compound in 23.3 L of solution (12 g/L).
Concentrate the product solution by reverse osmosis (100 Dalton membrane, pressure = 32 bar, 5~C) to give a concentrated product solution of 11 L (23.0 g/L).
A sample of the 3-exomethylene product is isolated by lyoI-hili~tion. lH NMR (400 MHz, CDCl3): 5.30-5.23 (d of d); 5.12 (d); 4.82 (s); 4.75-4.6 (m); 3.35 (d of d); 2.24-2.18 (m); 2.12-2.05 (m); 1.77-1.68 (m).
Step C: Extractive Esterification O o DPM-O (CH2)J~ H I ~

O O ~ 0~ ~CH2 ~s diazomethane O~o-DPM
HO(CH2~3 ~ ~ ~
~~N ~bCH2 CO2H ( DPM = (C6Hs)2CH~ ) Prepare diphenyldiazomethane from benzophenone hydrazone by oxidation with a m~ re of CH3CO3H, 1,1,3,3-tetramethylguanidine and 1% (w/v) of iodine in CH2Cl2. The oxidation is conducted according to the procedure described in Walker, et al., J.C.S. Perkin I, 2030 (1975) to give a 94% yield of diphenyldiazomethane.
Treat 1 L of the concentrated (23.3 g/L) 3-exo-methylene product solution from Step B (at pH = 3.0-3.4) with 2.5 equivalents of diphenyldiazomethane in CH2Cl2 overnight.
Add an additional 10% (0.25 e~uiv.) of diphenyldiazomethane solution to ensure complete esterification. Concentrate the organic m~ re to a residue and crystallize the residue from i-PrOH to give an 88% yield of the 3-exomethylene bis-diphenylmethyl ester (bis-DPM) product. The purity of the bis-DPM ester product is ~97%. lH NMR (400 MHz, CDCl3):
7.35-7.15 (m, 20H); 6.80 (d, 2H); 6.03 (d, lH); 5.58 (m, lH);
5.3-5.1 (m, 4H); 3.42 (d, lH); 3.0 (d, lH); 2.41 (t, 2H); 2.15 (t, 2H); 1.9 (m, 2H).

-W O96/17846 PCTrUS95/15169 Step D: Ozonolysis o o DPM-O (CH2)3 H-~ ~N~
O O ~
Jl J~ S 0~ ~O-DPM
DPM-O (CH2)3 H- ~ ~

~ N~I~CH2 J~ ( DPM = (C6Hs)2CH-) O O-DPM
Ozonlysis of the bis-DPM ester product of Step C is carried out using standard procedures. The bis-DPM ester (70 5 mmol) is dissolved in EtOAc (ester concentration 80-90 g/L) and cooled to -75~C. Ozone (1.3 equiv.) is added to the mi~rtllre at -78~C by bubbling a stream of ozone in ~2 through the stirred solution. The resulting m~ re is stirred at -75~C for 35-45 min. then treated with P(OC2Hs)3 (to reduce the resulting 10 ozonide intermediate) to give a 90% yield of the 3-hydroxy cephem product.

CA 02206226 l997-05-28 W O 96/17846 PCTrUS95/15169 Step E: Reduction to 3-Hyd~o~ycepham o o DPM-O (CH2)3 H I
j~ ~N~I~
O O
Jl Jl~ H S / O~ ~O-DPM
DPM-O (CH2)3 H ~~ ~

~OH
d~ ( DPM = (C6Hs)2CH- ) O O-DPM
Reduce the 3-hydroxycephem product of Step D by treating with NaBH4 and HOAc in a mi~ re of CH2C12 and MeOH at -50~C for 20 min. Isolate the product to give a 60-70% yield of 7-N-glutaroyl3-hydroxycepham bis-DPM ester.

S~ep F:
~ o DPM-O Jl(CH2)J~ H ~ ~ ~ ~

'~N~OH 0~ X~H

O~O-DPM O O-DPM

( DPM = (C6Hs)2CH- ) The 7-N-glutaroyl-3-hydroxycepham bis-DPM ester product of Step E is converted to 7-amino-3-desacetoxymethyl-cephalosporanic acid DPM ester (7-ADMCA DPM ester) via essentially the same procedure as described in Yoshioka, et al., Pure & Appl. Chem.. 59, (No. 8) 1041-1046 (1987). The 15 Yoshioka, et al., process is for conversion of a 7-N-phenylacetyl DPM ester to 7-ADMCA DPM ester, and is substantially the same as the process described in Reaction Scheme 3, Steps E and F, CA 02206226 1997-0~-28 W O 96/17846 PCTrUS95/15169 shown above. The 7-ADMCA DPM ester product is isolated in 70-80% yield and can be analyzed by HPLC (Brownlee RP18 column, diode array detector at 220 nm, eluant - 65% CH3CN/
35% aqueous phosphate buffer (0.02 M, pH = 4.2), flow rate 2.0 mL/min.) lH NMR (300 MHz, CDC13): 7.5-7.4 (m, 2H); 7.38-7.2 (m, 8H); 6.95 (s, lH); 6.6 (d of d, lH); 4.85 (d of d, 2H);
3.65-3.35 (m, 2H); 1.76 (br s, 2H).

Example 10 The extractive esterification of Example 9, Step B
can be carried out on a 40-50 g/L solution of the 3-exo-methylene starting material. At such higher concentrations the reaction proceeds more rapidly (it is complete in 6 to 7 hours) and requires less diphenyldiazomethane (typically 2.5 equivalents).

Example 11 Prepare an aqueous electrolysis solution of 10 g/L of glutaroyl 7-ACA and 0.2 M boric acid. Add LiOH to adjust the initial pH of the solution to pH = 9. Using a lead cathode (working electrode) in a 2-ch~mbered cell separated by a divider, electrolyze the solution as described for Example 1 at a current density of 24 mA/cm2. A total of 1200 C of charge was passed during the electrolysis. Analyze by HPLC, as described above, to deterrnine the yield (54%) and the ratio of 3-exomethylene to 3-methyl compound (72:1) in the product mi~ re.

Example 12 Prepare 10 mL of an aqueous electrolysis solution of 10 g/L of glutaroyl 7-ACA and 0.15 M sodium phosphate buffer (pH = 7). Using a tin cathode (working electrode) in a two rh~mhered cell separated by a divider, at a temperature of 5~C
electrolyze the solution as described for Example 1 at a current density of 15 mA/cm2. A total of 2016 C of charge was passed W O96/17846 PCTrUS95/15169 during the electrolysis. Analyze by HPLC, as described above, to determine the yield (72%) and the ratio of 3-exomethylene to 3-methyl compound (30:1) in the product mi~ re.

Example 13 Prepare 10 mL of an aqueous electrolysis solution of 10 g/L of glutaroyl 7-ACA and 0.15 M sodium phosphate buffer (pH = 7). Using a tin cathode (working electrode) in a two ch~mhered cell separated by a divider, at a temperature of 5~C
electrolyze the solution as described for Example 1 at a current density of 30 mA/cm2. Analyze by HPLC, as described above, to determine the yield (70%) and the ratio of 3-exomethylene to 3-methyl compound (36:1) in the product mi~tllre.

1~ Example 14 Prepare 10 mL of an aqueous electrolysis solution of 10 g/L of glutaroyl 7-ACA and 0.5 M boric acid. Adjust the solution to pH = 9.5 with LiOH. Using a tin cathode (working electrode) in a 2-ch~mhered cell separated by a divider, at a temperature of 5~C electrolyze the solution as described for Example 1 at a current density of 30 mA/cm2. Analyze by HPLC, as described above, to determine the yield (67%) and the ratio of 3-exomethylene to 3-methyl compound (20:1) in the product mixture.

W O96/17846 PCTrUS95/15169 Example 15 H H

~r o N ~

0~ O-CH(C6H5)2 Step A: Extractive Esterification o o DPM-O (CH2)J~ N ~ ~ ~

HOJl(cH2)J~H~ ~ ~ diazomethane ~ O-DPM
~N ~CH2 co2H ( DPM = (C6Hs) CH- ) Add a solution of 34.2 g of diphenyldiazomethane in CH2Cl2 to a 1 L solution of 21.0 g (0.064 mole) of 7-~-(carboxy-but~n~mido)-3-exomethylene-3-cepham-4-carboxylic acid. Cool the mixture to 0~-5~C and slowly add (dropwise) 18% HCl (aqueous) to adjust to pH = 3. Warm to room temperature and stir for 6 hours, then add HCl to lower the pH to 2-2.5 and stir for 1 hr. Separate the phases and extract the aqueous phase with CH2Cl2 (2 X 50 mL). Wash the combined organic phases with 500 mL of water, then concentrate in vacuo to a volume of ~70 mL. Add 300 mL of iPrOH and distill off the r~m~ining CH2Cl2 at 45~C. Cool the m~ re to 25~C, add seed crystals of the product and stir for 4 hrs. Cool to 0~-5~C and stir for 0.5 hrs. Collect the product by filtration and dry in a vacuum oven at 35~C to give 34 g of the diester product. lH NMR (CDC13, 200 MHz): 1.98 (m, 2H); 2.23 (t, 2H); 2.5 (t, 2H); 3.09-3.50 (AB quartet, 2H, J=13 Hz, J=9 Hz); 5.21-5.24 (s, 2H); 5.32 (s, lH); 5.35 (d, lH, J=4.3 Hz); 5.64 (d of d, lH, J=4.3 Hz, J=9.2 Hz); 6.10 (d, lH, J=9.2 Hz); 6.86-6.88 (s, 2H); 7.23-7.37 (br.
s, 20H).

Step B: Ozonolysis O O

DPM-O (CH2)3 N -. ~S ~

oJ-- ~OH

Jl Jl~ s O~O-DPM
DPM-O (CH2)3 N I ~
,~N~CH2 J~ ( DPM = (C6Hs)2CH~ ) O O-DPM
Dissolve 46.26 g (0.070 mole) of the bis-DPM ester product from Step A in 500 mL of EtOAc and cool to -75~C.
Bubbled a stream of ozone (~2.7 mmol/min.) through the stirred solution at -75~C for 35 min. Remove excess ozone by bubbling oxygen through the m~ re for 5 minutes, then nitrogen for 15 min. Slowly add 25 mL (0.143 mole) of P(OC2Hs)3 over a 20 min. period while maint~ining the temperature at <-65~C, then stir for 1 hr. Pour the mixt~re into 105 mL of 5% HCl (aqueous) and stir at 15~-20~C for 1 hr. Wash the organic phase with 5% NaCl (aqueous) (2 X 250 mL), then concentrate in va~uo to a residue. Triturate the residue with n-pentane to give a 90% yield of the 3-hydroxy cephem product.
lH NMR (CDCl3, 300 MHz): 2.01 (m, 2H); 2.30 (t, 2H); 2.53 (t, 2H); 3.27-3.45 (AB quartet, 2H, J=17 Hz); 5.01 (d, lH, J=4.5 Hz); 5.71 (d of d, lH, J=4.5 Hz, J=8.5 Hz); 6.37 (d, lH, J=8.5 Hz); 6.89-6.91 (s, 2H); 7.23-7.45 (br. s, 20H); 11.68 (s, lH) .

W O96117846 PCTrUS95/15169 Step C: Reduction to 3-Hvdroxycepham o O

DPM-O Jl(CH2~ N ~

~o~L X~OH
Jl ~11~ s O O-DPM
DPM-O (CH2)3 N I ~

~N~OH
1 ( DPM =(C6H5)2c H-) O O-DPM
Combine 10.6 g (0.016 mole) of the 3-hydroxy-cephem product of Step B, 8.2 mL of ~l~Ci~l HOAc, 90 mL of MeOH and 180 mL of CH2Cl2 and cool to -55~C. Add 1.84 g (0.049 mole) of NaBH4 and stir at -50~C for 20 min. Pour the reaction mlxtllre into a m~ re of 300 mL of CH2Cl2 and 105 mL of 7% NaHCO3 (aqueous) at room temperature and stir for 15 min. Wash the organic phase with 5% NaCl (aqueous) (2 X
10 200 mL), then concentrate in vacL~o to a residue. Crystallize the residue from 100 mL of toluene by stirring at 5~C to 12 hrs. to give 6.4 g of the product. lH NMR (DMSO-d6, 300 MHZ): 1.96 (m, 2H); 2.23 (t, 2H); 2.48 (t, 2H); 2.61-2.98 (AB of ABX, 2H, JAB=13 8 HZ. JAX=10 0 HZ. JBX=3.5 HZ); 3.32 (d, 1H, J=7.8 1~ Hz); 4.08 (m, lH, J=10.0 Hz, J=7.8 Hz, J=6.0 HZ); 4.84 (d, lH, J=6.0 HZ); 5.07 (d, 1H, J=4.0 HZ); 5.53 (d of d, 1H, J=9.0 Hz, J=4.0 Hz); 6.51 (d, lH, J=9.0 Hz); 6.87-6.92 (S, 2H); 7.2-7.4 (br. s, 20 H).

Step D - Mesylate Preparation:
o o DPM O ~ CH2) ~ N ~ S l j~ O 'r Os02CH3 ~ ~ H H / O O-DPM
DPM-O ~(CH2)3 N ~ S ~
o ~ N ~ OH( DPM =(C6H5)2CH-) O O-DPM
Combine 12.0 g (0.018 mole) of the product of Step C, 2.7 mL of methanesulfonyl chloride and 800 mL of CH2Cl2, cool to -20~C and add 320 mL of a 1.2% solution of Et3N in CH2Cl2 over a period of 20 min. with the temperature at <-20~C.
Warm to -10~C and stir for 1 hr., then pour the mixtllre into 1 L
of chilled 5% NaCl (aqueous). Wash the organic phase with 5%
NaCl (aqueous), then concentrate u7 vacuo (temperature <35~C) to a residue. C~stallize the residue from MeOH to give 11.4 g of the product. lH NMR (CDCl3, 300 MHz): 2.00 (m, 2H); 2.27 (t, 2H); 2.49 (t, 2H); 2.68 (s, 3H); 2.83-3.51 (AB or ABX, 2H, JAB=13.5 Hz, JAX=10-5 Hz, JBX=3.3 Hz); 5.04 (m, 2H); 5.25 (d, lH, J=4.4 Hz); 5.50 (d of d, lH, J=4.4 Hz, J=9.0 Hz); 6.55 (d, lH, J=9.0 Hz); 6.89-6.95 (s, 2H); 7.2-7.4 (br. s, 20 H).

Step E - Side Chain cleav~e:

DPM-O ~(~H2)3~ N - S H -1 o ~ OSOzCH3 ~ ~ OSOzCH3 (DPM =(C6H5)~CH-) ~ O-DPM O~' O-DPM

Combine 14.3 g (0.019 mole) of the product of Step D and 1.26 L of CH2Cl2 and cool to -50~C. Add 6.4 mL of pyridine and 8.3 g of PCls, raise the temperature to -10~C and stir for 2 hrs. Very slowly add 135 mL of MeOH while maint~inin~ the temperature at <0~C. Stir for 2 hrs. at 0~-5~C, then add 1.2 L of water and add saturated Na2CO3 (aqueous) to adjust to pH=7. Wash the organic phase twice with 5% NaCl 5 (aqueous), then concentrate in vacuo at 30~-35~C to a residue.
Crystallize the residue from iPrOAc to give 6.7 g of the product.
lH NMR (DMSO-d6, 300 MHz): 3.05 (s, 3H); 3.16-3.23 (AB of ABX, 2H, JAB=13.8 Hz, JAX=7.2 Hz, JBX=2.7 Hz); 4.93 (d, lH, J=4.3 Hz); 5.15 (d, lH, J=4.3 Hz); 5.20 (d, lH, J=5.7 Hz);
5.37 (m, lH, J=5.7 Hz, J=7.2 Hz, J=2.7 Hz); 6.92 (s, lH); 7.3-7.6 (br. s, 10 H); 9.34 (br. s, 2H).

Step F - Elimin~tion:
NH2 S ~ S

o~ ~ oSo2cH3 o O ~ O-DPM O ~ O-DPM
(DPM =(C~H5)2CH-) Combine 6.4 g (0.014 mole) of the product of Step E and 950 mL of CH2Cl2 and cool to -55~C. Slowly add 13.7 g of diethylamine while keeping the temperature <-50~C. Warm the mi~rtllre to -10~C and stir for 3-4 hrs. Pour the reaction mixture into 200 mL of 10 % H3PO4 (aqueous), separate the layers and wash the organic phase sequentially with 5% NaCl (aqueous), 10% NaHCO3 (aqueous) and 5% NaCl (aqueous). Concentrate in vacuo to a residue, then crystallize by adding 50 mL of iPrOAc and concentrating to a volume of 15-20 mL to give 4.8 g of the title compound. lH NMR (CDC13,300 MHz): 1.78 (br. s, 2H);
3.41-3.59 (AB of ABX, 2H, JAB=19.3 HZ, JAX=6.4 Hz, JBX=2.7 Hz); 4.80-4.91 (d, 2H, J=5.3 Hz); 6.63 (d of d, lH, J=6.4 Hz, J=2.7 Hz); 6.95 (S,1H); 7.2-7.4 (br. s, 10 H).

W O 96117846 PCTrUS95/lS169 Step G - Alternative Fiimin~tion:

DPM-G ~(CH2)3 N

DPM-O CH~3 N ~ ~ ~

o~N~ OS02CH3 o- O-DPM
O O-DPM ( DPM =(C6H5kCH-) Combine 12.4 g (0.017 mole) of the product of Step D and 1.10 L of CH2Cl2 and cool to -50~C, then add 17.2 mL of 5 diethyl~mine. Warm the mi~ re to -10~C and stir for 1 hr.
Pour the cold reaction mi~rtllre into 1 L of 5 % HCl(aqueous), while keeping the temperature <10~C. Wash the organic phase with 5% NaCl (aqueous), then coml~ine with 500 mL of water and adjust to pH=6.5 with 7% NaHCO3 (aqueous). Wash the 10 organic phase with 5% NaCl (aqueous), then concentrate in va~uo to a residue and crystallize to give 8.6 g of the product.
lH NMR (CDC13, 300 MHz): 2.03 (m, 2H); 2.27 (t, 2H); 2.53 (t, 2H); 3.38-3.59 (AB of ABX, 2H); 4.94 (d, lH); 5.90 (d of d, lH); 6.14 (d, lH); 6.66 (d of d, lH); 6.89-6.96 (s, 2H); 7.2-7.5(br.s,20H).

Step H - Alternative Side Chain cleavage:

DPM-O~(CH~ ? NH~

O O-DPM ~ O-DPM
( DPM =(C6H5)~CH-) Combine 13.2 g (0.02 mole) of the product of Step G and 1.5 L of CH2Cl2, cool to -50~C, then add 6.6 mL of pyridine and 8.5 g of PCls. Very slowly add 150 mL of MeOH
while maint~ining the temperature at <0~C. Stir for 2 hrs. at W O96/17846 PCTrUS95/15169 -10~C, then add 300 mL of water and stir at <0~C for 2 hrs. Add 7% NaHCO3 (aqueous) to adjust to pH=6.5, wash the organic phase with 5% NaCl (aqueous), then concentrate u~ va~uo to a residue. Crystallize the residue from iPrOAc to give 6.6 g of the title compound.

Example 1 6 ~ ~ S 3C ~ O
HO (CH2)3 H ~ o CO2H

A 10 g/L solution of the sulfoxide analog of 7-glutaroyl ACA in 0.5 M boric acid (aqueous) adjusted to pH 9.5 with LiOH is electrochemically reduced at 5~C, 15 mA/cm2, using essentially the same procedures as described for F~r~mple 4, to give a 95% yield of the 3-exomethylene product. None of the 3-methyl product was detected.

Claims (14)

We Claim:
1. A process for preparing a compound of the formula or wherein: n is 2 or 3; R1 is H and R is H or NHR2, where R2 is H
or a protecting group selected from C6H5CH2OC(O)-, C6H5C(O)-or C1-C6 alkoxy-C(O)-; or wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-, comprising electrochemically reducing a solution of a compound of the formula wherein: R3 is CH3C(O)-; is an optional sulfoxide group;
and n, R and R1 are as defined above, at a concentration of 10-50 g/L, at a pH of 7-10, at a current density of 10-40 mA/cm2, in the presence of a buffer and in a solvent selected from water, an organic solvent, or a mixture of water and a water miscible organic additive.
2. The process of claim 1 wherein the electrochemical reduction is carried out at a temperature of -20° to 20°C.
3. The process of claims 1, or 2 wherein the solvent is a water and the electrochemical reduction is conducted at a temperature of 0°C to 10°C.
4. The process of claims 1, 2 or 3 further comprising purification of the compound prepared by the electrochemical reduction by chromatography using column comprising an adsorbent resin.
5. The process of claims 1, 2, 3 or 4 wherein the electrochemical reduction is performed using a 2-chambered cell wherein the chambers are separated by an ion exchange membrane.
6. The process of claim 5 wherein the ion exchange membrane is a perfluorinated sulfonic acid or perfluorinated carboylic acid ionomer membrane and wherein the membrane is permeable to cations but not permeable to anions.
7. The process of claims 1, 2, 3, 4, 5 or 6 wherein the electrochemical reduction is carried out using a cathode which is selected from a titanium, indium, cadmium, lead, gallium, zinc, silver, tin, bismuth, mercury, platinum, molybdenum, niobium, tantalum, carbon, copper, iron or nickel electrode, or an electrode comprising a metal alloy selected from lead/silver alloy, copper/mercury alloy or steel.
8. The process of claim 9 wherein the cathode is titanium, indium, cadmium, mercury, lead, gallium, zinc, silver, tin, bismuth or carbon, wherein the carbon is in the form of graphite, graphite felt or reticulated vitreous carbon.
9. The process of claims 1, 2, 3, 4, 5, 6, 7 or 8 wherein the electrochemical reduction is carried out at a pH of from 8 to 9.5, and a cathode selected from a tin, mercury or lead electrode.
10. A process for preparing a compound of the formula wherein: R4 is diphenylmethyl; is an optional sulfoxide group; n is 2 or 3; R1 is H and R is H or NHR2, where R2 is H, C6H5C(O)-, C6H5CH2OC(O)- or C1-C6 alkoxy-C(O)-; or R and R1 together with the carbon atom to which they are attached comprise -C(O)-, comprising the steps:
(a) electrochemically reducing a compound of the formula wherein: R3 is CH3C(O)-; and , n, R and R1 are as defined above, to form a compound of the formula, wherein , n, R and R1 are as defined above, followed by chromatographic purification of the electrochemical reduction product on an adsorbent resin;
(b) esterifying the product of step (a) to form a compound of the formula wherein R4 is diphenylmethyl, and n, , R and R1 are as defined above; and (c) ozonolyzing the product of step (b).
11. A process for preparing compounds of the formula wherein: R4 is diphenylmethyl, comprising the steps;
(a) electrochemically reducing a compound of the formula 12. A compound of the formula wherein: n is 2 or 3; R1 is H and R is H or NHR2, where R2 is a protecting groupselected from C6H5CH2OC(O)-, C6H5C(O)- or C1-C6 alkoxy-C(O)-; or wherein R
and R1 together with the carbon atom to which they are attached comprise -C(O)-,or a salt thereof.
13. The compound of claim 12 wherein R1 and R are both H.
14. The compound of claim 12 wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-.
15. A compound of the formula wherein: n is 2 or 3; R1 is H and R is H or NHR2, where R2 is H or a protecting group selected from C6H5CH2OC(O)-, C6H5C(O)- or C1-C6 alkoxy-C(O)-; or wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-, or a salt thereof.
16. The compound of claim 15 wherein R1 and R are both H.
17. The compound of claim 15 wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-.
18. The compound of claim 15 having the formula .

wherein R4 is diphenylmethyl, and n, , R and R1 are as defined above;
(c) ozonolyzing the product of step (b) to form a compound of the formula wherein R4, n, , R and R1 are as defined above;
(d) reducing the product of step (c) with a hydride reducing agent to form a compound of the formula (VIII) wherein R4, n, , R and R1 are as defined above;
(e) reacting the product of step (d) with a compound of the formula P-X, wherein P is a sulfonyl activating group and X is Cl, Br or I, in the presence of a tertiary amine base to form a compound of the formula (IX) (IX) wherein P is a sulfonyl activating group, and R4, n, , R and R are as defined above; and (f) (i) treating the product of step (e) first with PCl5 in the presence of a tertialy amine base and an alcohol or diol, and then with a dialkylamine base; or (ii) treating the product of step (e) first with a dialkylamine base and then with PCl5 in the presence of a tertiary amine base and an alcohol or diol;
and where an optional group is present treating with PCl3 to form the compound of the formula wherein R4 is as defined above.
12. A compound of the formula wherein: n is 2 or 3; R1 is H and R is H or NHR2, where R2 is H
or a protecting group selected from C6H5CH2OC(O)-, C6H5C(O)-or C1-C6 alkoxy-C(O)-; or wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-, or a salt thereof.
13. The compound of claim 12 wherein R1 and R are both H.
14. The compound of claim 12 wherein R and R1 together with the carbon atom to which they are attached comprise -C(O)-.
CA002206226A 1994-12-09 1995-12-06 Process for the preparation of intermediates useful in the synthesis of cephalosporins Abandoned CA2206226A1 (en)

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EP0720611A1 (en) * 1994-07-22 1996-07-10 Antibioticos S.P.A. Glutaryl 7-aca derivatives and processes for obtaining them
CN1184071C (en) 1996-05-15 2005-01-12 松下电器产业株式会社 Method of controlling screen printing machine
JP4418043B2 (en) 1998-10-07 2010-02-17 大塚化学株式会社 Process for producing β-hydroxyester
JP4215132B2 (en) * 2007-03-05 2009-01-28 学校法人慶應義塾 Electrochemical analysis method using boron-doped conductive diamond electrode
CN102617600A (en) * 2012-02-23 2012-08-01 苏州中联化学制药有限公司 Synthesizing method of 7-amino-3-nor-3-cephem-4-carboxylic acid
CN103374018A (en) * 2012-04-26 2013-10-30 黄山市歙县宏辉化工有限公司 Novel method for preparing ceftibuten parent nucleus 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (7-NACABH)
CN103588791A (en) * 2013-11-29 2014-02-19 中国科学院长春应用化学研究所 Preparation method of p-nitrobenzyl-7-phenoxyacetamido-3-hydroxycephem-4-carboxylate-1-beta-oxide

Family Cites Families (17)

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Publication number Priority date Publication date Assignee Title
NL241315A (en) * 1958-07-18
US3275626A (en) * 1962-07-31 1966-09-27 Lilly Co Eli Penicillin conversion via sulfoxide
CS183696B2 (en) * 1971-02-25 1978-07-31 Robert R Chauvette Method for producing derivatives of 3-methyl-delta up3-cephem-4-carboxylic acid
JPS515396B1 (en) * 1971-04-05 1976-02-19
US4008228A (en) * 1971-12-06 1977-02-15 Eli Lilly And Company Process for preparing 3-methyl-3-cephem antibiotics
US4060688A (en) * 1972-11-28 1977-11-29 Eli Lilly And Company Cephalosporin intermediates
US4052387A (en) * 1974-12-24 1977-10-04 Eli Lilly And Company Method of preparation of 3-methylenecephams
US4042472A (en) * 1976-04-12 1977-08-16 Eli Lilly And Company Electrolytic process for 7-methoxy-3-exomethylenecepham compounds
US4379739A (en) * 1980-03-31 1983-04-12 Eli Lilly And Company Electrolytic reduction of cephalosporin p-nitrobenzyl esters
CA1200543A (en) * 1981-12-21 1986-02-11 Eli Lilly And Company 7-epi-3-exomethylenecepham derivatives
AU575854B2 (en) * 1983-10-04 1988-08-11 Shionogi & Co., Ltd. 7beta-(carboxyalkenamido) cephalosporins
US4939249A (en) * 1988-09-16 1990-07-03 Eli Lilly And Company Process for 1-carba(dethia) cephalosporins
US5082772A (en) * 1988-10-24 1992-01-21 Eli Lilly And Company Process for preparing deacetylcephalosporin c
IL95764A (en) * 1989-09-26 1995-03-15 Lilly Co Eli Deacetoxycephalosporin c hydroxylase.
US5126446A (en) * 1991-01-04 1992-06-30 Eli Lilly And Company Process for 3-exomethylenecepham sulfoxide esters
GB9203327D0 (en) * 1992-02-17 1992-04-01 Erba Carlo Spa Process for the synthesis of exomethylenecephams
JP2554990B2 (en) * 1994-04-15 1996-11-20 塩野義製薬株式会社 3-Acyloxy-7β-aminocepham-4-carboxylic acid diphenylmethyl ester and process for producing the same

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US5847116A (en) 1998-12-08

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