CN104230934A - Compound, and preparation method and application thereof - Google Patents
Compound, and preparation method and application thereof Download PDFInfo
- Publication number
- CN104230934A CN104230934A CN201310229416.6A CN201310229416A CN104230934A CN 104230934 A CN104230934 A CN 104230934A CN 201310229416 A CN201310229416 A CN 201310229416A CN 104230934 A CN104230934 A CN 104230934A
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- Prior art keywords
- formula
- compound
- tynofovir
- impurity
- vitamin
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- 0 CC([C@](C[n]1c2ncnc(N)c2nc1)[U]=C)=* Chemical compound CC([C@](C[n]1c2ncnc(N)c2nc1)[U]=C)=* 0.000 description 3
- RUOJZAUFBMNUDX-UHFFFAOYSA-N CC(CO1)OC1=O Chemical compound CC(CO1)OC1=O RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- HRLPUNCVVCNKBG-UHFFFAOYSA-M CC[U](O)(OCN)OCN Chemical compound CC[U](O)(OCN)OCN HRLPUNCVVCNKBG-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
Abstract
The invention discloses a compound, and a preparation method and an application thereof. A structural formula of the compound is shown as a formula (I). In the formula (I), R represents H. The formula (I) is shown in the description.
Description
Technical field
The present invention relates to pharmaceutical chemistry, particularly relate to a kind of new compound and its production and use.
Background technology
VITAMIN B4, as the moiety of nucleic acid, participates in the synthesis of DNA and RNA in body.Adenosine regulates a series of physiology and pathologic process in human body, as the adjustment of the release of neurotransmitter, steatolysis, leukocyte function.Adenine nucleotide obtains application as efabirenz in antiviral field, as hepatitis B virus resisting medicine adefovir ester and tynofovir like thing.
Tynofovir, chemical name (R)-9-(2-(diethyl phosphonylmethoxy base) propyl group) VITAMIN B4, molecular formula C
9h
14n
5o
4p.Molecular weight 287.08, CAS registration number 147127-20-6, structure is:
Tynofovir
Patent WO9804569 reports that the synthetic method of tynofovir is: with VITAMIN B4 (2) for starting raw material, with R-propylene carbonate (3) react 4,4 react 6,6 be hydrolyzed to obtain tynofovir (1) through bromotrimethylsilane with tolysulfonyl oxygen methyl-phosphorous acid diethyl ester (5).
Ripin etc. report that (Org.Process Res.Dev., 2010,14 (5): 1194-1201) VITAMIN B4 (2) and R-propylene carbonate (3) reaction can produce VITAMIN B4 6-NH
2replace impurity (R)-6-(2'-hydroxypropyl) VITAMIN B4 (7)
can produce on VITAMIN B4 7 N replace impurity 7-(2'-hydroxypropyl) VITAMIN B4 (8) Deng report (Spectrosc.Lett., 1996,29 (6): 1141-1155.) VITAMIN B4 (2) and propylene carbonate reaction
The present inventor's Late Cambrian, it is VITAMIN B4 3 N replace impurity (R)-3-(2'-hydroxypropyl) VITAMIN B4 (formula (Ia)) that VITAMIN B4 (2) and R-propylene carbonate (3) react the major impurity produced, and impurity formula (Ia) structure is confirmed by X-ray monocrystalline.
Impurity formula (Ia) carries out follow-up synthesis tynofovir reaction with compound 4, generates impurity formula (Ib) and impurity formula (Ic).
Impurity formula (Ia) is the major impurity in compound 4, compound 4(crude product) in impurity formula (Ia) account for 8%.VITAMIN B4 3 N replacing impurity is major impurity in tynofovir, has the greatest impact to the quality of tynofovir and yield.Formula (I) impurity of effective control and the upper replacement of removing VITAMIN B4 3 N is the key of tynofovir quality control.The quality control of tynofovir must use formula (I) impurity reference substance to position in the foundation of analytical procedure, and thus formula (I) impurity is the requisite of tynofovir quality control.The validity of the existence meeting havoc tynofovir of impurity, also likely produces serious side reaction simultaneously.Therefore, this area is in the urgent need to effectively identifying the impurity produced in tynofovir synthesis.
Summary of the invention
The present invention aims to provide a kind of new compound and its production and use.
In a first aspect of the present invention, provide the compound of a kind of structure as shown in formula I,
Wherein, R be H,
In a second aspect of the present invention, provide a kind of structure such as formula (I a) shown in the preparation method of compound, described method comprises step: VITAMIN B4 and R-propylene carbonate are obtained by reacting structure such as formula (I a) shown in compound;
In another preference, described reaction is carried out at 120-130 DEG C.
In a third aspect of the present invention, provide a kind of structure such as formula (I a) shown in the purposes of compound, as tynofovir intermediate 4 impurity qualification reference substance or identify for tynofovir impurity
tynofovir intermediate 4.Ester be obtained by reacting structure such as formula (I b) shown in compound;
In another preference, described reaction is carried out at 70-75 DEG C.
In a fifth aspect of the present invention, provide a kind of structure such as formula (I b) shown in the purposes of compound, as tynofovir intermediate 6 impurity qualification reference substance or identify for tynofovir impurity
tynofovir intermediate 6.
In a sixth aspect of the present invention, provide a kind of structure such as formula (I c) shown in the preparation method of compound, described method comprises step: by structure such as formula (I b) shown in compound hydrolysis under strongly-acid reagent exists obtain structure such as formula (I c) shown in compound;
In another preference, described strongly-acid reagent is selected from trimethylammonium halosilanes, Hydrogen bromide.
In another preference, described hydrolysis is carried out at a reflux temperature.
In a seventh aspect of the present invention, provide a kind of structure such as formula (I c) shown in the purposes of compound, as tynofovir impurity qualification reference substance or identify for tynofovir impurity
tynofovir.
In a eighth aspect of the present invention, provide the purposes of a kind of structure compound as shown in formula I, it is characterized in that, as tynofovir impurity qualification reference substance or identify for tynofovir impurity.
Accordingly, the invention provides the impurity produced in effectively qualification tynofovir synthesis.
Accompanying drawing explanation
Fig. 1 is the X-Ray unit figure of formula (Ia) compound.
Fig. 2 is the mass-spectrogram of formula (Ib) compound.
Fig. 3 is the representativeness of formula (Ic) compound
1h NMR composes.
Fig. 4 is the representativeness of formula (Ic) compound
13c NMR composes.
Embodiment
Contriver, through research extensively and profoundly, has found some new compounds, and has found the effect of these new compounds as tynofovir impurity qualification reference substance further.On this basis, the present invention is completed.
Compound
In one aspect of the invention, a kind of formula I compound is provided:
Wherein, R be H,
In one aspect of the invention, formula I compound have formula (I a) structure:
Formula (I X-Ray unit figure a) is shown in accompanying drawing 1, formula (I X-Ray single crystal data a) is as shown in the table:
In one aspect of the invention, formula I compound have formula (I b) structure:
In one aspect of the invention, formula I compound have formula (I c) structure:
The synthesis of compound
Formula I compound described above can use the method combined in the synthetic technology of standard or known technology and literary composition to synthesize.In addition, solvent as mentioned herein, temperature and other reaction conditionss can change.
Formula provided by the invention (synthesis of I a) structural compounds can be undertaken by following flow process:
In an embodiment of the invention, by VITAMIN B4 and the mixing of R-propylene carbonate, be cooled to less than 100 DEG C after backflow and drip toluene, separate out solid, obtain formula (I a) structural compounds; Preferably, after precipitation solid, 0-5 DEG C of crystallization under ice bath, obtains crude product; More preferably, crude product obtains formula (I a) structural compounds purified product through column chromatography.
Formula provided by the invention (synthesis of I b) structural compounds can be undertaken by following flow process:
In an embodiment of the invention, by (R)-3-(2 ˊ-hydroxypropyl) VITAMIN B4 and tolysulfonyl oxygen ylmethyl diethyl phosphonate 60-80 DEG C of mixing, reaction 1.5-3 hour, be cooled to 15-25 DEG C, make pH6-7 concentrated formula (I b) structure oily matter.
Formula provided by the invention (synthesis of I c) structural compounds can be undertaken by following flow process:
By structure such as formula (I b) shown in compound strongly-acid reagent exist under hydrolysis obtain structure such as formula (I c) shown in compound.Strongly-acid reagent can use trimethylammonium halosilanes, Hydrogen bromide.Trimethylammonium halosilanes is trimethylchlorosilane or bromotrimethylsilane, preferred bromotrimethylsilane.
In an embodiment of the invention, by formula (I b) structure oily matter, acetonitrile and bromotrimethylsilane mixing, reflux temperature reaction 4-5 hour, add water except after desolventizing, make water layer pH3-3.5 after extraction, separate out formula (I c) structural compounds; Preferably, formula (I c) structural compounds crude product through water recrystallization purifying.
Term
If without illustrating in addition, for the present patent application, comprising the term in specification sheets and claims, being defined as follows.Must be noted that, in the specification and the appended claims, if Wen Zhongwu clear instruction in addition, singulative " " comprises plural references.If without illustrating in addition, use the ordinary method of mass spectrum, nuclear-magnetism, HPLC and pharmacology.In this application, if without illustrating in addition, use "or" or " with " refer to "and/or".
" formula I compound " refers to that structural formula is (I), and (I a), and (I b), (I compound c).
The structural formula of compound that the present invention relates to and title:
Purposes
Formula I compound can be used as the reference substance in the qualification of tynofovir impurity, such as when carrying out quality monitoring to tynofovir or tenofovir disoproxil, can by formula Ic (I a) compound in contrast product to detect position isomer impurities, ensure that tynofovir purity is greater than 99.9%, the purity meeting tenofovir disoproxil reaches medicinal standard.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature disclosed in specification sheets, anyly can provide identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Major advantage of the present invention is:
1, some new compounds are obtained first.
2, the compound obtained can as the reference substance of impurity in tynofovir or tenofovir disoproxil product quality monitoring.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or number by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
General introduction.
1h-NMR spectrum uses Bruker-400 nuclear magnetic resonance analyser, and interior mark is tetramethylsilane.。The shortenings used illustrates as follows: s, singlet; D, doublet; T, triplet; Q, quartet; Qu, quintet; M, multiplet; Br, spectrum.Mass spectrum uses Waters2795 with the substance quadrupole mass spectrometer of electron spray ionisation (ESI).
Embodiment 1
Formula (the preparation of I a) compound (R)-3-(2 ˊ-hydroxypropyl) VITAMIN B4
By VITAMIN B4 (5.50g, 0.04mol), sodium hydroxide powder (0.12g, 0.003mol) join in 50mL three-necked bottle, add DMF (25mL), R-propylene carbonate (5.70g is added under magnetic agitation, 0.056mol), drip toluene (30mL) after backflow end is chilled to 90 ° of C, separate out solid, 0-5 ° of C crystallization under ice bath, filter, dry, crude product is through CH
2cl
2-MeOH(4:1) twice column chromatography, obtain formula (I a) compound (R)-3-(2 ˊ-hydroxypropyl) VITAMIN B4 (0.62g, 8.2%), mp272.9-273.3 ° of C.MS：194.13[M+1]
+。
1H?NMR(DMSO-d
6)δ：8.20(s,1H),7.74(s,1H),7.86(2H,br),5.15(d,1H,J=4.4Hz),4.35(1H,dd,J=13.2Hz,J=3.2Hz),4.05(1H,dd,J=13.2Hz,J=8.4Hz),4.13(1H,m),1.06(d,3H,J=6.0Hz)。
HPLC method: Promosil C18(250mm × 4.6mm, 5 μm); Moving phase: methyl alcohol: acetonitrile: 0.01mol/L Sodium phosphate dibasic buffering salt (pH5.5)=5:5:90; Column temperature: 40 ° of C; Determined wavelength: 260nm; Flow velocity: 1.0mL/min; Sample concentration: 1mg/mL, sampling volume: 10 μ L; Formula (the retention time of I a) compound: 3.81min; The retention time of tynofovir intermediate 4: 6.02min.
Embodiment 2
Formula (the preparation of I b) compound (R)-3-(2 ˊ-(diethyl phosphonylmethoxy base) propyl group) VITAMIN B4
With formula (I a) compound (R)-3-(2 ˊ-hydroxypropyl) VITAMIN B4 for starting raw material; get this compound 0.5(2.59mmol) join in 25mL three-necked bottle; add 3mL dry DMF; add tert-butyl alcohol magnesium (0.45g; 2.64mmol), nitrogen protection, stirs 1h under 70 ° of C; drip tolysulfonyl oxygen ylmethyl diethyl phosphonate (1.25g, 3.88mmol).React 2h at this temperature and stop heating, when being cooled to 20 ° of C by Glacial acetic acid adjust ph to 6-7, concentrating under reduced pressure obtains brown oil.Add 5mL methylene dichloride, stirred at ambient temperature 0.5h, add 0.5mL water and continue to stir 0.5h, suction filtration removing magnesium salts, filtrate with saturated common salt washing once, anhydrous magnesium sulfate drying, filters to revolve and steams to obtain brown oil formula (I b) compound.MS：344.15[M+1]
+，366.16[M+Na]
+。
1HNMR(DMSO-d
6)δ：8.207（1H，s），7.744（1H，s），7.85（2H，br），4.281-4.405（2H，m），3.708-4.181（7H，m），1.069-1.185（9H，m）。
HPLC method: Promosil C18 post, (250mm × 4.6mm, 5 μm); Moving phase: methyl alcohol: acetonitrile: 0.01mmol/L Sodium phosphate dibasic buffering salt (phosphoric acid is adjusted to pH5.5)=10:10:80; Column temperature: 40 ° of C; Determined wavelength: 260nm; Flow velocity: 1.0mL/min; Sample concentration: 1mg/mL; Sampling volume: 10 μ L; Formula (the retention time of I b) compound: 8.97min; The retention time of tynofovir intermediate 6: 18.32min.
Embodiment 3
Formula (I c) compound (R)-3-[2 ˊ-(phosphonylmethoxy base) propyl group] VITAMIN B4
As above acetonitrile (5mL) is added in gained oily matter, bromotrimethylsilane (4.64g, 30.3mmol), be warming up to back flow reaction 4.5h, remove solvent under reduced pressure, water (3mL) is added in residuum, complete clearly molten, add methylene dichloride (3mL) extraction once, water layer by 50% sodium hydroxide adjust ph to 3.0-3.2, separate out white solid under stirring, stirring at room temperature 1h, under ice bath, stir 5h, suction filtration, filter cake water recrystallization, obtains white solid formula (Ic) compound (0.31g, 41.9%/two step yield).MS：[M+H]
+288.10、[M+Na]
+310.08、[2M+H]
+575.15；
1H?NMR（400MHz，D
2O）δ(ppm)：8.06（1H，s），7.65（1H，s），4.15-4.08（2H，m），3.75（1H，m），3.28-3.10（2H，m），0.96-0.95（3H，d，J=6Hz）；
13C?NMR（100MHz，D
2O）δ(ppm)：16.13、53.86、66.14、67.64、74.81、119.46、145.63、148.60、151.97、155.28。
HPLC method: Promosil C18 post, (250mm × 4.6mm, 5 μm); Moving phase: mobile phase A: 0.05mol/L potassiumphosphate buffering salt (pH6.0); Mobile phase B: 0.05mol/L potassiumphosphate buffering salt (pH6.0): acetonitrile=70:30; Column temperature: 30 ° of C; Determined wavelength: 260nm; Gradient elution: 0-10min100% mobile phase A is to 15% Mobile phase B, and 10-20min, from 15% Mobile phase B to 100% Mobile phase B, keeps 100% Mobile phase B 2min; Flow velocity: 1.5mL/min; Sample concentration: 1mg/mL; Sampling volume: 10 μ L; The retention time of formula (Ic) compound: 6.27min; The retention time of tynofovir 1: 10.77min.
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological context of the present invention, substantial technological content of the present invention is broadly defined in the right of application, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
Claims (8)
1. the compound of structure as shown in formula I,
Wherein, R be H,
2. structure such as formula (I a) shown in the preparation method of compound, it is characterized in that, described method comprises step: VITAMIN B4 and R-propylene carbonate are obtained by reacting structure such as formula (I a) shown in compound.
3. structure such as formula (I a) shown in the purposes of compound, it is characterized in that, as tynofovir intermediate 4 impurity qualification reference substance or identify for tynofovir impurity
tynofovir intermediate 4
。
4. a structure such as formula (I b) shown in the preparation method of compound, it is characterized in that, described method comprises step: by structure such as formula (I a) shown in compound and tolysulfonyl oxygen methyl-phosphorous acid diethyl ester be obtained by reacting structure such as formula (I b) shown in compound.
5. structure such as formula (I b) shown in the purposes of compound, it is characterized in that, as tynofovir intermediate 6 impurity qualification reference substance or identify for tynofovir impurity
tynofovir intermediate 6.
6. structure such as formula (I c) shown in the preparation method of compound, it is characterized in that, described method comprises step: by structure such as formula (I b) shown in compound hydrolysis under strongly-acid reagent exists obtain structure such as formula (I c) shown in compound.
7. structure such as formula (I c) shown in the purposes of compound, it is characterized in that, as tynofovir impurity qualification reference substance or identify for tynofovir impurity
tynofovir
。
8. a purposes for structure compound as shown in formula I, is characterized in that, as tynofovir impurity qualification reference substance or identify for tynofovir impurity.
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| CN201310229416.6A CN104230934B (en) | 2013-06-08 | 2013-06-08 | A kind of compound and its production and use |
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| CN104230934B CN104230934B (en) | 2016-12-28 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294761A (en) * | 2014-07-29 | 2016-02-03 | 浙江九洲药物科技有限公司 | Impurities of tenofovir disoproxil fumarate or tenofovir, and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0052964A1 (en) * | 1980-11-20 | 1982-06-02 | Beecham Group Plc | Adenine derivatives possessing pharmacological activity |
| WO1994003467A2 (en) * | 1992-08-05 | 1994-02-17 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
| CN101239989A (en) * | 1996-07-26 | 2008-08-13 | 吉里德科学公司 | Nucleotide analog |
-
2013
- 2013-06-08 CN CN201310229416.6A patent/CN104230934B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0052964A1 (en) * | 1980-11-20 | 1982-06-02 | Beecham Group Plc | Adenine derivatives possessing pharmacological activity |
| WO1994003467A2 (en) * | 1992-08-05 | 1994-02-17 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
| CN101239989A (en) * | 1996-07-26 | 2008-08-13 | 吉里德科学公司 | Nucleotide analog |
Non-Patent Citations (2)
| Title |
|---|
| ACS: "RN 1378853-06-5", 《STN-REGISTRY》 * |
| S. RAIC, ET AL.: "Acyclic Analogues of Purine Nucleosedes: One- and Two- Dimensional 1H and 13C NMR Evidences for N-9 and N-7 Regioisomers", 《SPECTROSCOPY LETTERS》, vol. 29, no. 6, 31 December 1996 (1996-12-31), pages 1141 - 1155 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294761A (en) * | 2014-07-29 | 2016-02-03 | 浙江九洲药物科技有限公司 | Impurities of tenofovir disoproxil fumarate or tenofovir, and preparation method thereof |
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