CN103483420B - A kind of Telaprevir intermediate in B crystal form and synthetic method thereof - Google Patents
A kind of Telaprevir intermediate in B crystal form and synthetic method thereof Download PDFInfo
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- cyclohexyl
- pyrazinylcarbonyl
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- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 title claims abstract description 108
- 108010017101 telaprevir Proteins 0.000 title claims abstract description 106
- 229960002935 telaprevir Drugs 0.000 title claims abstract description 105
- 239000013078 crystal Substances 0.000 title claims abstract description 97
- 238000010189 synthetic method Methods 0.000 title claims abstract description 23
- BZUKJNKTPCZNPM-LSDHHAIUSA-N (2s)-2-[[(2s)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoic acid Chemical compound N([C@H](C(=O)N[C@@H](C(C)(C)C)C(O)=O)C1CCCCC1)C(=O)C1=CN=CC=N1 BZUKJNKTPCZNPM-LSDHHAIUSA-N 0.000 claims abstract description 64
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 10
- 239000013557 residual solvent Substances 0.000 claims abstract description 4
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 3
- 230000005855 radiation Effects 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000010992 reflux Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 238000005352 clarification Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 238000010009 beating Methods 0.000 claims description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000005755 formation reaction Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- 238000003821 enantio-separation Methods 0.000 description 4
- 150000005826 halohydrocarbons Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000005233 alkylalcohol group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229940084039 incivek Drugs 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229940067107 phenylethyl alcohol Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000004799 α-ketoamides Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a kind of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl)-glycyl-3-methyl-L-Valine B crystal form and synthetic method thereof, belong to technical field of medicine synthesis.This Telaprevir intermediate in B crystal form uses Cu-Ka radiation, represents that X-ray powder diffraction has characteristic peak 5.5 ± 0.2,7.4 ± 0.2,10.7 ± 0.2,16.7 ± 0.2,17.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,19.2 ± 0.2,20.5 ± 0.2,21.5 ± 0.2,22.1 ± 0.2 with 2 θ angles; White solid, fusing point is 221.6 ~ 229.3 DEG C, water content 0.1% ~ 0.5%, residual solvent 8% ~ 12%; And provide the synthetic method of this intermediate B crystal formation.This crystal formation outward appearance is good, and water content is few, and temperature and humidity good stability, purity is high.
Description
Technical field
The present invention relates to a kind of Telaprevir intermediate and synthetic method thereof, be specifically related to a kind of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form and synthetic method thereof, belong to technical field of medicine synthesis.
Background technology
VX-960 (TVR); chemical name: (1S; 3aR; 6aS)-(2S)-2-cyclohexyl-N-(carbonyl pyrazine)-glycyl-3-methyl-L-valyl-N-(1S)-1-[(cyclopropylamino)-oxoacetyl] butyl-octahydro ring penta [c] pyrroles-1-methane amide; CAS registration number: 402957-28-2; be that one has restraining effect to HCV gene 1 type NS3/4A serine protease, the medicine that HCV copies can be stopped.By preventing its propagation in conjunction with virus thus play the effect of protease inhibition.VX-960 structural formula is as follows:
In May, 2011, the VX-960 listing of U.S. FDA approved Vertex drugmaker, commodity are called Incivek, for accepting the invalid or untreated of interferon therapy before, and suffer from the third liver adult patients of other hepatopathys.In July, 2011, to EU Committee, European Union's FAD advises that the interferon A MP.AMp.Amp alPHa of approval VX-960 and PEGization and ribavirin combination use, the curative ratio of the third hepatopath can be significantly improved, and can significantly shorten treatment the course for the treatment of, the course for the treatment of foreshortened to 24 weeks by 48 weeks of standard.In August, 2011, Incivek also gets the Green Light in Canada.Janssen pharmacy obtains the approval listing VX-960 of European Union, and commodity are called Incivo, can use, be used for the treatment of the third liver adult patients in each member states of European Union.
Because this medicine security is high, and administration time is short, can reduce the untoward reaction that long-term prescription brings to patient, is therefore since two thousand one the most effective HCV therapy medicine.
And (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine intermediate that to be VX-960 important, CAS registration number: 402958-96-7, structural formula is as follows:
About the document of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine has in prior art:
As pct international patent (publication number: WO2011103932A1) and Anass Znabet, (the A highly efficient synthesis of telaprevir bystrategic use of biocatalysis and multicomponent reactions of the people such as Marloes M.Polak, The RoyalSociety of Chemistry46 (2010) 7918-7920), they all relate to synthesis Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, and concrete synthetic route is as follows:
And for example U.S. patent Nos (publication number: US201029686), it relate to the synthetic method of a kind of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, and concrete synthetic route is as follows:
And for example Yvonne Yip, (P4and P1 ' the optimization of bicycloproline P2bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors of the people such as Frantz Victor, Bioorganic & MedicinalChemistry Letters14 (2004) 5007-5011) in also disclose a kind of method of synthesis Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, concrete synthetic route is as follows:
Although above-mentioned three kinds of synthetic methods have finally all synthesized Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, but synthesize the Telaprevir intermediate obtained and be white solid (white solid), purity is not high, and be not all described the crystal formation of this intermediate and some other physical properties in above-mentioned three kinds of documents, and these all may affect the drug effect of the finished product.
Summary of the invention
The present invention is directed to the above-mentioned problems in the prior art, the crystal formation of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine is being carried out to a large amount of favorite outer discoveries of system experimentation research, Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine is synthesized certain crystallized form can make it more stable, and the research not about Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine crystal formation in prior art is reported.The invention provides a kind of temperature and humidity good stability, the new crystal of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine that purity is high, i.e. B crystal form for this reason.
Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, use Cu-Ka radiation, represent that X-ray powder diffraction has characteristic peak 5.5 ± 0.2,7.4 ± 0.2,10.7 ± 0.2,16.7 ± 0.2,17.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,19.2 ± 0.2,20.5 ± 0.2,21.5 ± 0.2,22.1 ± 0.2 with 2 θ angles.
The X-ray powder diffraction test of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form has measured under envrionment temperature and ambient moisture." envrionment temperature " is generally 0-40 DEG C; " ambient moisture " is generally the relative humidity of 30%-80%.
The representational X-ray powder diffraction of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is shown in accompanying drawing 1." representational X-ray powder diffraction " refers to the overall pattern of this collection of illustrative plates of X-ray powder diffraction feature compound display of this crystal formation, be understandable that in test process, owing to being subject to the impact of many factors, as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc., the X-ray powder diffraction measured by same crystal formation go out peak position or peak intensity has certain difference.Therefore, the X-ray powder diffraction of Telaprevir intermediate in B crystal form of the present invention, the experimental error of its diffraction peak 2 θ value is generally ± and 0.2.
Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form of the present invention, its DSC scanning has first endotherm(ic)peak between 150 ~ 180 DEG C, particularly has maximum endotherm(ic)peak at about 172.19 DEG C.Second endotherm(ic)peak, between 215 ~ 250 DEG C, particularly has maximum endotherm(ic)peak at about 203.05 DEG C.And second endotherm(ic)peak is obviously better than first endotherm(ic)peak.The DSC spectrogram of Telaprevir intermediate in B crystal form of the present invention is shown in Fig. 2.
The outward appearance of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is white solid, fusing point is 221.6 ~ 229.3 DEG C, water content 0.1% ~ 0.5%, residual solvent 8% ~ 12%.Wherein, described residual solvent comprises for halohydrocarbon, anhydrous saturated alkane class, anhydrous ester class, one or more in anhydrous ethers.Further preferably, described halohydrocarbon comprises methylene dichloride, ethylene dichloride, and described anhydrous saturated alkane class is normal heptane, and described anhydrous ester class comprises ethyl acetate, and described anhydrous ethers comprises methyl tertiary butyl ether, ether, isopropyl ether.
The chemical shift of the proton nmr spectra of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is 12.5 (bs, 1H), 9.2 (d, J=1.6Hz, 1H), 8.91 (d, J=2.4Hz, 1H), 8.77 (dd, J=1.2Hz, 2.4Hz, 1H), 8.51 (d, J=10.8Hz, 1H), 8.22 (d, J=8.8Hz, 1H), 4.69 (dd, J=6.8Hz, 9.2Hz, 1H), 4.11 (d, J=8.8Hz, 1H), 1.58 ~ 1.81 (m, 6H), 1.08 ~ 1.11 (m, 18H).The proton nmr spectra spectrogram of Telaprevir intermediate in B crystal form of the present invention is shown in Fig. 3.
The chiral purity of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is 100.00%, and its chiral chromatography spectrogram is shown in Fig. 5.
Liquid phase-the mass spectrum of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is LC/MS=377(M
++ 1), 399(M
++ Na), its liquid phase-mass spectrogram is shown in Fig. 6.
Another object of the present invention is the synthetic method providing above-mentioned Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, described synthetic method comprises following method, but is not limited to following method:
Method one: Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine is added in good solvent, be heated to the reflux temperature of good solvent to solution clarification, solution is concentrated into dry, then add poor solvent and carry out making beating process, collected by suction crystal after leaving standstill, drying, obtains Telaprevir intermediate in B crystal form.
Method two: under stirring, good solvent is added in Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, the reflux temperature being heated to good solvent all dissolves to Telaprevir intermediate, then add poor solvent all to separate out to solid, leave standstill after stirring, collected by suction crystal, dry, obtain Telaprevir intermediate in B crystal form.
Method three: under stirring, poor solvent is added in Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, be heated to the reflux temperature of poor solvent, reflux after 5 ~ 8 hours and stir, collected by suction crystal, drying, obtains Telaprevir intermediate in B crystal form.
Method four: under stirring, good solvent is added in Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine A crystal formation, be heated to the reflux temperature of good solvent to solution clarification, solution is concentrated into dry, add poor solvent again to pull an oar, collected by suction crystal after making beating, dry, obtain Telaprevir intermediate in B crystal form.
The crystallization condition of same compound is different, and especially recrystallisation solvent is different, and the crystal habit obtained also may be different.The present invention, by screening the recrystallisation solvent of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, optimizes the crystallization method and recrystallisation solvent that are applicable to forming Telaprevir intermediate in B crystal form.
In the synthetic method of above-mentioned four kinds of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, as preferably, described good solvent is alkyl alcohol, aromatic alcohol, alkyl acid, ketone, or tetrahydrofuran (THF), acetonitrile, DMF, one or more in methyl-sulphoxide.Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine has higher solubleness in described good solvent, can reduce the consumption of solvent, cost-saving.Further preferably, described alkyl alcohol comprises methyl alcohol, ethanol, propyl alcohol, and described aromatic alcohol comprises phenylcarbinol, phenylethyl alcohol, and described alkyl acid comprises formic acid, acetic acid, and described ketone comprises acetone, butanone, Propiophenone.
In the synthetic method of above-mentioned four kinds of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, as preferably, described poor solvent is halohydrocarbon, anhydrous saturated alkane class, anhydrous ester class, one or more in anhydrous ethers.These poor solvent polarity are little, low to the solubleness of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine.Further preferably, described halohydrocarbon comprises methylene dichloride, ethylene dichloride, and described anhydrous saturated alkane class comprises normal heptane, and described anhydrous ester class comprises ethyl acetate, and described anhydrous ethers comprises methyl tertiary butyl ether, ether, isopropyl ether.
Wherein, described Telaprevir intermediate A crystal formation is by following two kinds of methods synthesis:
Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine is joined in good solvent, slowly drip poor solvent under reflux to separate out to solid, cooling, leave standstill, collected by suction crystal, dry Telaprevir intermediate A crystal formation.
Or Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine is joined in poor solvent, slowly drip good solvent after reflux just to dissolve to solid, cooling, suction filtration after leaving standstill, dry Telaprevir intermediate A crystal formation.
Wherein, in the synthetic method of above-mentioned Telaprevir intermediate A crystal formation, described good solvent is selected from one or more in methyl alcohol, ethanol, phenylcarbinol, phenylethyl alcohol, formic acid, acetic acid, acetone, tetrahydrofuran (THF), acetonitrile, DMF, methyl-sulphoxide.Described poor solvent is alkyl alcohol and water, aromatic alcohol and water, alkyl acid and water, and a kind of mixed solvent in ketone and water, in described mixed solvent, the mass percent of water is 50% ~ 100%.
In addition, the B crystal form that Telaprevir intermediate of the present invention remains containing solvent α is also dissolved in solvent α by the B crystal form residual containing solvent β being scattered in, and after the heated at reflux temperature of solvent α refluxes 5 ~ 8 hours, cooling suction filtration obtains.Wherein, as preferably, described solvent α and solvent β is selected from anhydrous saturated alkane class respectively, anhydrous ester class, the one in anhydrous ethers.Further preferably, described anhydrous saturated alkane class is selected from the one in normal heptane, normal hexane, Skellysolve A, described anhydrous ester class is selected from the one in ethyl acetate, isopropyl acetate, and described anhydrous ethers is selected from the one in methyl tertiary butyl ether, isopropyl ether.
The present invention has the following advantages:
1, the outward appearance of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is good, and water content is few, and temperature and humidity good stability, purity is high.
2, the synthetic method of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is simple to operate, used time is shorter, industrial production operation is convenient, quality controllable, is conducive to save energy.
Accompanying drawing explanation
Fig. 1 is the powder x-ray diffraction figure that Telaprevir intermediate in B crystal form does not add monochromator and obtains, and length axis represents diffracted intensity, and axis of abscissa represents diffraction angle (2 θ).
Fig. 2 is the DSC spectrogram of Telaprevir intermediate in B crystal form.
Fig. 3 is the proton nmr spectra spectrogram of Telaprevir intermediate in B crystal form.
Fig. 4 is the liquid chromatography spectrogram of Telaprevir intermediate in B crystal form.
Fig. 5 is the chiral chromatography spectrogram of Telaprevir intermediate in B crystal form.
Fig. 6 is the liquid phase-mass spectrogram of Telaprevir intermediate in B crystal form.
The liquid chromatography spectrogram of the Telaprevir intermediate that Fig. 7 obtains for pct international patent (publication number: WO2011103932A1) in conventionally.
Embodiment
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearly understand, illustrating below in conjunction with specific embodiments and the drawings, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
In accompanying drawing of the present invention illustrates, Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form relevant in Fig. 1-7 contains 0.17% moisture content, 10% residual methyl tert-butyl ether solvent.
Embodiment 1
10g Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine is joined in 25mL dehydrated alcohol, at 80 DEG C after reflux to solution clarification, be concentrated into dry under the condition of 40 DEG C, then add after 50mL ethyl acetate pulls an oar 4 hours, leave standstill, collected by suction crystal, dry, obtain 9.3g Telaprevir intermediate in B crystal form (containing a small amount of ethyl acetate solvent in lattice).Purity is 99.10%, and chiral purity is 100%.
Embodiment 2
Under stirring, 30mL dehydrated alcohol is added in 10g Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, at 80 DEG C, be heated to Telaprevir intermediate all dissolve forming reactions liquid, add normal heptane when reaction solution being cooled to 30 DEG C all to separate out to solid, stir after 4 hours and leave standstill, collected by suction crystal, dry, obtain 8.7 grams of VX-960 intermediate B crystal formations.Purity is 99.36%, and chiral purity is 99.86%.
Embodiment 3
Under stirring, 40mL methylene dichloride is added in 5g Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, at 40 DEG C, reflux is after 3 hours, naturally cool to room temperature, collected by suction crystal, drying, obtains 4.2g Telaprevir intermediate in B crystal form.Purity is 99.30%, and chiral purity is 99.62%.
Embodiment 4
20g Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine (purity 98.4%) is joined in the Virahol of 60mL, the mixed solvent of 35mL acetone and 70mL water is dripped under reflux to just having solid to separate out at 85 DEG C, after naturally cooling to room temperature, leave standstill, collected by suction crystal, dried overnight under the condition of 50 DEG C, obtains 17.8g Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine A crystal formation;
Under stirring, 30mL dehydrated alcohol is added in above-mentioned obtained 10g Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine A crystal formation, reflux molten clear after, be concentrated into dry, add again 50mL methyl tertiary butyl ether at room temperature pull an oar 4 hours after collected by suction crystal, drying, obtains 9.5g Telaprevir intermediate in B crystal form (containing a small amount of methyl tert-butyl ether solvent in lattice).Purity is 99.8%, and chiral purity is 100%.
Embodiment 5
Under stirring, the VX-960 B crystal form obtained in 3.0g embodiment 1 (in lattice containing ethyl acetate solvent) is added to after in the methyl tertiary butyl ether of 30mL, reflux is pulled an oar 5 hours, naturally cool to room temperature, collected by suction crystal, drying, obtains 2.8g VX-960 B crystal form (containing methyl tert-butyl ether solvent in lattice).Purity is 99.64%, and chiral purity is 100%.
Comparative example
In prior art, Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine in pct international patent (publication number: WO2011103932A1), its purity 98.4%, fusing point 185.1 ~ 185.5 DEG C, water content 0.23%.
Randomly draw Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form sample in the embodiment of the present invention and Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine in comparative example carries out stability contrast experiment.Carried out high-temperature stability test (12h, 48h, 72h) at 75 DEG C, test result is as shown in table 1.
Table 1: the stability test result of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine in Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form and comparative example
As can be drawn from Table 1, Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form has better high-temperature stability than (2S) of the prior art-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine.
The Telaprevir intermediate randomly drawed in Telaprevir intermediate in the embodiment of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form sample and comparative example is detected by liquid chromatography.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatograph;
Chromatographic column: Luna C18,4.6mm × 250mm, 5 μm;
Column temperature: 25 DEG C;
Flow velocity: 1.0mL/min;
Determined wavelength: 210nm;
Sampling volume: 5.0 μ L;
Moving phase: acetonitrile: 0.1% phosphate aqueous solution=60:40 (v/v);
Working time: 30min.
Detect the liquid chromatography spectrogram of Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form sample in the rear embodiment of the present invention as shown in Figure 4; Analytical results is as shown in table 2.
Table 2: Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form sample liquid analysis of hplc result in the embodiment of the present invention
After detecting, the liquid chromatography spectrogram of comparative example as shown in Figure 7; Analytical results is as shown in table 3.
Table 3: the liquid-phase chromatographic analysis result of Telaprevir intermediate sample in comparative example
From Fig. 4 and 7, table 2 and table 3 can be found out: the purity of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form is higher, reach 99.86%, and in comparative example, the purity of Telaprevir intermediate is only 98.3959%.
Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form sample extracted in the embodiment of the present invention is detected by chiral chromatography immediately.As shown in Figure 5, analytical results is as shown in table 4 for chiral chromatography spectrogram after detection.
Table 4: the chiral chromatographic analysis result of Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form sample
As can be seen from Fig. 5 and table 4, Telaprevir intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form chiral purity is high, reaches 100.00%.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (5)
1. Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, it is characterized in that, described Telaprevir intermediate in B crystal form: use Cu-Ka radiation, represent that X-ray powder diffraction has characteristic peak 5.5 ± 0.2,7.4 ± 0.2,10.7 ± 0.2,16.7 ± 0.2,17.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,19.2 ± 0.2,20.5 ± 0.2,21.5 ± 0.2,22.1 ± 0.2 with 2 θ angles; DSC scanning has first endotherm(ic)peak between 150 ~ 180 DEG C, and second endotherm(ic)peak is between 215 ~ 250 DEG C; Its outward appearance is white solid, and fusing point is 221.6 ~ 229.3 DEG C, water content 0.1% ~ 0.5%, residual solvent 8% ~ 12%; The chemical shift of proton nmr spectra is 12.5 (bs, 1H), 9.2 (d, J=1.6Hz, 1H), 8.91 (d, J=2.4Hz, 1H), 8.77 (dd, J=1.2Hz, 2.4Hz, 1H), 8.51 (d, J=10.8Hz, 1H), 8.22 (d, J=8.8Hz, 1H), 4.69 (dd, J=6.8Hz, 9.2Hz, 1H), 4.11 (d, J=8.8Hz, 1H), 1.58 ~ 1.81 (m, 6H), 1.08 ~ 1.11 (m, 18H).
2. the synthetic method of Telaprevir intermediate as claimed in claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, it is characterized in that, this synthetic method comprises the following steps: join in good solvent by Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, be heated to the reflux temperature of good solvent to solution clarification, solution is concentrated into dry, then add poor solvent and carry out making beating process, collected by suction crystal after leaving standstill, dry, obtain Telaprevir intermediate in B crystal form, described good solvent is methyl alcohol, ethanol, one or more in propyl alcohol, described poor solvent is methylene dichloride, ethylene dichloride, normal heptane, ethyl acetate, methyl tertiary butyl ether, ether, one or more in isopropyl ether.
3. the synthetic method of Telaprevir intermediate as claimed in claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, it is characterized in that, this synthetic method comprises the following steps: under stirring, good solvent is added in Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, be heated to the reflux temperature of good solvent to all dissolving, then add poor solvent all to separate out to solid, leave standstill after stirring, collected by suction crystal, dry, obtain Telaprevir intermediate in B crystal form, described good solvent is methyl alcohol, ethanol, one or more in propyl alcohol, described poor solvent is methylene dichloride, ethylene dichloride, normal heptane, ethyl acetate, methyl tertiary butyl ether, ether, one or more in isopropyl ether.
4. the synthetic method of Telaprevir intermediate as claimed in claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, it is characterized in that, this synthetic method comprises the following steps: under stirring, poor solvent is added in Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, be heated to the reflux temperature of poor solvent, reflux after 5 ~ 8 hours and stir, collected by suction crystal, dry, obtain Telaprevir intermediate in B crystal form, described poor solvent is methylene dichloride or ethylene dichloride.
5. the synthetic method of Telaprevir intermediate as claimed in claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine B crystal form, it is characterized in that, this synthetic method comprises the following steps: under stirring, good solvent is added in Telaprevir intermediate A crystal formation, be heated to the reflux temperature of good solvent to solution clarification, solution is concentrated into dry, add poor solvent again to pull an oar, collected by suction crystal after making beating, dry, obtain Telaprevir intermediate in B crystal form, described good solvent is methyl alcohol, ethanol, one or more in propyl alcohol, described poor solvent is ethyl acetate, methyl tertiary butyl ether, ether, one or more in isopropyl ether, wherein, the synthetic method of described Telaprevir intermediate A crystal formation is: join in Virahol by Telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinylcarbonyl) glycyl-3-methyl-L-Valine, under reflux, slowly dropping acetone and water mixed solvent mixed solvent are separated out to solid, cooling, leave standstill, collected by suction crystal, dry, obtain Telaprevir intermediate A crystal formation.
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| CN102875649A (en) * | 2012-09-26 | 2013-01-16 | 深圳翰宇药业股份有限公司 | Method for preparing telaprevir and intermediate thereof and intermediate |
| CN103113288A (en) * | 2013-02-04 | 2013-05-22 | 苏州永健生物医药有限公司 | Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative |
| WO2013131978A1 (en) * | 2012-03-07 | 2013-09-12 | Dipharma Francis S.R.L. | Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor |
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| WO2013131978A1 (en) * | 2012-03-07 | 2013-09-12 | Dipharma Francis S.R.L. | Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor |
| CN102875649A (en) * | 2012-09-26 | 2013-01-16 | 深圳翰宇药业股份有限公司 | Method for preparing telaprevir and intermediate thereof and intermediate |
| CN103113288A (en) * | 2013-02-04 | 2013-05-22 | 苏州永健生物医药有限公司 | Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative |
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| A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions;Anass Znabet et al;《Chem Commun》;20100920;第46卷;全文 * |
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