WO2014033667A1 - Process for the preparation of telaprevir - Google Patents
Process for the preparation of telaprevir Download PDFInfo
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- WO2014033667A1 WO2014033667A1 PCT/IB2013/058130 IB2013058130W WO2014033667A1 WO 2014033667 A1 WO2014033667 A1 WO 2014033667A1 IB 2013058130 W IB2013058130 W IB 2013058130W WO 2014033667 A1 WO2014033667 A1 WO 2014033667A1
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- telaprevir
- hydroxy
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- carried out
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- 229960002935 telaprevir Drugs 0.000 title claims abstract description 37
- 108010017101 telaprevir Proteins 0.000 title claims abstract description 37
- 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 22
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 pyrazin-2-yl- carbonyl Chemical group 0.000 claims abstract description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 11
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims abstract 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- KVHFSHWXHLFZRT-JMCLDYEDSA-N (3s,3as,6ar)-n-[(3s)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxamide Chemical compound OC([C@@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1)CCC)C(=O)NC1CC1 KVHFSHWXHLFZRT-JMCLDYEDSA-N 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012317 TBTU Substances 0.000 claims description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 229940086542 triethylamine Drugs 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- LOWMYOWHQMKBTM-UHFFFAOYSA-N 1-butylsulfinylbutane Chemical compound CCCCS(=O)CCCC LOWMYOWHQMKBTM-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 2
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 2
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DRNGSSWBFKDSEE-JAMMHHFISA-N (3s)-3-amino-n-cyclopropyl-2-hydroxyhexanamide Chemical compound CCC[C@H](N)C(O)C(=O)NC1CC1 DRNGSSWBFKDSEE-JAMMHHFISA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- NAUGUUNRDWGECM-UHFFFAOYSA-N 2,6-ditert-butyl-n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 NAUGUUNRDWGECM-UHFFFAOYSA-N 0.000 description 1
- CNEFRTDDIMNTHC-UHFFFAOYSA-N 2-cyano-2-hydroxyiminoacetic acid Chemical compound ON=C(C#N)C(O)=O CNEFRTDDIMNTHC-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BZUKJNKTPCZNPM-LSDHHAIUSA-N CC(C)(C)[C@@H](C(O)=O)NC([C@H](C1CCCCC1)NC(c1nccnc1)=O)=O Chemical compound CC(C)(C)[C@@H](C(O)=O)NC([C@H](C1CCCCC1)NC(c1nccnc1)=O)=O BZUKJNKTPCZNPM-LSDHHAIUSA-N 0.000 description 1
- PZJGEEGFSUTIMI-SSUIOXDUSA-N CCC[C@@H](C(C(NC1=CC1)=O)O)NC([C@H](C(CCC1)C1C1)N1C([C@H](C1(C)C2=C1C2)NC([C@H](C1CCCCC1)NC(c1nccnc1)=O)=O)=O)=O Chemical compound CCC[C@@H](C(C(NC1=CC1)=O)O)NC([C@H](C(CCC1)C1C1)N1C([C@H](C1(C)C2=C1C2)NC([C@H](C1CCCCC1)NC(c1nccnc1)=O)=O)=O)=O PZJGEEGFSUTIMI-SSUIOXDUSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940122055 Serine protease inhibitor Drugs 0.000 description 1
- 101710102218 Serine protease inhibitor Proteins 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- KPFBUSLHFFWMAI-HYRPPVSQSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-6-formyl-3-methoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@@H]2[C@](CCC(OC)=C3)(C)C3=C(C=O)C[C@H]2[C@@H]2CC[C@](OC(C)=O)(C(C)=O)[C@]21C KPFBUSLHFFWMAI-HYRPPVSQSA-N 0.000 description 1
- RKTBAMPZUATMIO-MXZHIVQLSA-N [[(e)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N\OC(N(C)C)=[N+](C)C RKTBAMPZUATMIO-MXZHIVQLSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
Definitions
- the present invention provides a process for the preparation of telaprevir wherein (1 S,3aR,6aS)-N-[(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3- yl]octahydrocyclopenta[c]pyrrole- 1-carboxamide and N- ⁇ (2S)-2-cyclohexyl-2-[(pyrazin- 2-yl-carbonyl)amino]acetyl ⁇ -3-methyl-L-valine are condensed to form hydroxy telaprevir, which is then converted into telaprevir.
- Telaprevir is chemically known as (lS,3aR,6aS)-2-[(2S)-2-( ⁇ (2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino]acetyl ⁇ amino)-3,3-dimethylbutanoyl]-N-[(3S)- 1 - (cyclopropylamino)- l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole- 1-carboxamide, and has the structure depicted by Formula I:
- Telaprevir is a serine protease inhibitor disclosed in PCT Publication No. WO 02/18369. Processes for the preparation of telaprevir are disclosed in U.S. Patent No. 7,776,887; U.S. Publication No. 2010/0298568; PCT Publication Nos. WO 02/18369, WO 2008/090819, and WO 201 1/153423; and Chemical Communications 46(42):7918-7920 (2010).
- PCT Publication No. WO 02/18369 discloses a process for the preparation of telaprevir which involves condensing (l S,3aR,6aS)-2-[(2S)-2-( ⁇ (2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino)acetyl ⁇ amino]-3,3-dimethylbutanoyl]-3,3a,4,5,6,6a- hexahydro-lH-cyclopenta[c]pyrole- l-carboxylic acid with (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide in the presence of dichloromethane, PyBOP ([benzotriazole- 1 -yl- oxy]-tripyrrolidinophosphonium hexafluorophosphate), and N,N-diisopropylethylamine leading to the formation of hydroxy telaprevir, which is
- the present invention provides a process for the preparation of telaprevir of Formula I, comprising the steps of:
- N- ⁇ (2S)-2-cyclohexyl-2-[(pyrazin-2-yl-carbonyl)amino]acetyl ⁇ -3-methyl-L-valine of Formula IV may be prepared by following the process disclosed in PCT Publication No. WO 02/18369.
- the condensation in step a) is carried out in the presence of a coupling agent, a base, and a solvent.
- a coupling agent examples include HATU (2-(lH-7- azabenzotriazol- 1 -yl) ⁇ 1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate
- HBTU Bisbenzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate
- HDBTU (2-(3,4-dihydro-4-oxo- l,2,3-benzotriazin-3-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
- HOTU (0-[(Ethoxycarbonyl)
- the base may be selected from weak organic or inorganic bases which facilitate the coupling reagent in carrying out the peptide synthesis.
- organic bases include ⁇ , ⁇ -diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2- propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7- ene, or mixtures thereof.
- inorganic bases include sodium bicarbonate and potassium bicarbonate.
- the reaction is carried out in the presence of an organic base.
- the organic base is selected from N,N-diisopropylethylamine, 4- dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine.
- the solvent is selected from the group comprising of nitriles, chlorinated solvents, amides, dialkylsulfoxides, or mixtures thereof.
- nitriles include acetonitrile, propionitrile, butyronitrile, or valeronitrile.
- chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, or chloroform.
- amides include dimethylformamide, dimethylacetamide, or N-methyl formamide.
- dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, or dibutylsulfoxide.
- the solvent is selected from dichloromethane, acetonitrile, or
- the condensation is carried out at about 0°C to about 20°C. Preferably, the condensation is carried out at about 0°C to about 15°C.
- the temperature of the reaction mixture may be maintained at about 20°C to about 40°C for about 2 hours to about 20 hours. Preferably, the temperature of the reaction mixture is maintained at about 20°C to about 25°C for about 5 hours to about 10 hours.
- Isolation of the hydroxy telaprevir of Formula II may be carried out by filtration, concentration, decantation, or combinations thereof. Preferably, the isolation of the hydroxy telaprevir of Formula II is carried out by concentration.
- the oxidation in step b) is carried out in the presence of an oxidizing agent and a solvent. Examples of oxidizing agents include Dess-Martin Periodinane, oxalyl chloride, chromium trioxide, or potassium permanganate.
- the oxidizing agents may be used in combination with a catalyst such as TEMPO ((2,2,6,6- tetramethylpiperidin- 1 -yl)oxy), or TPAP (tetrapropylammonium perruthenate).
- TEMPO ((2,2,6,6- tetramethylpiperidin- 1 -yl)oxy
- TPAP tetrapropylammonium perruthenate
- the oxidation is carried out in the presence of Dess-Martin Periodinane.
- the solvent is selected from the group comprising of nitriles, aromatic hydrocarbons, chlorinated solvents, dialkylsulfoxides, water, or mixtures thereof.
- nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
- aromatic hydrocarbons include toluene and xylene.
- chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
- dialkylsulfoxides examples include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide.
- the solvent is selected from dichloromethane or toluene.
- the oxidation is carried out at about 0°C to about 20°C, preferably at about 0°C to about 10°C.
- the reaction mixture is stirred at the same temperature for about 30 minutes to about 20 hours.
- the reaction mixture is maintained at about 0°C to about 5°C for about 1 hour to about 5 hours.
- Isolation of telaprevir of Formula I may be carried out by filtration, concentration, decantation, or a combination thereof.
- the isolation of telaprevir of Formula I is carried out by concentration.
- dichloromethane layer was concentrated to obtain hydroxy telaprevir as a solid residue.
- telaprevir Form II; 1.05 g
- dichloromethane 25 mL
- Dess-Martin Periodinane was added at about 5°C.
- the reaction mixture was stirred at about 0°C to about 5°C for about 2 hours.
- the progress of the reaction was monitored by thin layer chromatography.
- the reaction mixture was quenched with sodium thiosulphate solution and washed with sodium bicarbonate solution (20 mL).
- the dichloromethane layer was concentrated under reduced pressure to obtain telaprevir as a solid residue.
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- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed herein is a process for the preparation of telaprevir wherein (1S,3aR,6a S)-N-[(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl] octahydrocyclopenta[c]pyrrole-1-carboximide and N-{(2S)-2-cyclohexyl-2-[(pyrazin-2-yl- carbonyl)amino]acetyl}-3-methyl-L-valine are condensed to form hydroxy telaprevir, which is then converted into telaprevir.
Description
PROCESS FOR THE PREPARATION OF TELAPREVIR
Field of the Invention
The present invention provides a process for the preparation of telaprevir wherein (1 S,3aR,6aS)-N-[(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3- yl]octahydrocyclopenta[c]pyrrole- 1-carboxamide and N- {(2S)-2-cyclohexyl-2-[(pyrazin- 2-yl-carbonyl)amino]acetyl}-3-methyl-L-valine are condensed to form hydroxy telaprevir, which is then converted into telaprevir.
Background of the Invention
Telaprevir is chemically known as (lS,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino]acetyl} amino)-3,3-dimethylbutanoyl]-N-[(3S)- 1 - (cyclopropylamino)- l,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole- 1-carboxamide, and has the structure depicted by Formula I:
Formula I
Telaprevir is a serine protease inhibitor disclosed in PCT Publication No. WO 02/18369. Processes for the preparation of telaprevir are disclosed in U.S. Patent No. 7,776,887; U.S. Publication No. 2010/0298568; PCT Publication Nos. WO 02/18369, WO 2008/090819, and WO 201 1/153423; and Chemical Communications 46(42):7918-7920 (2010).
PCT Publication No. WO 02/18369 discloses a process for the preparation of telaprevir which involves condensing (l S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2- [(pyrazin-2-ylcarbonyl)amino)acetyl}amino]-3,3-dimethylbutanoyl]-3,3a,4,5,6,6a- hexahydro-lH-cyclopenta[c]pyrole- l-carboxylic acid with (3S)-3-amino-N-cyclopropyl-2- hydroxyhexanamide in the presence of dichloromethane, PyBOP ([benzotriazole- 1 -yl- oxy]-tripyrrolidinophosphonium hexafluorophosphate), and N,N-diisopropylethylamine
leading to the formation of hydroxy telaprevir, which is further oxidized using Dess Martin Periodinane to obtain telaprevir.
Chemical Communications 46(42):7918-7920 (2010) discloses the following process of preparation of telaprevir:
K2C03,MeOH
Telaprevir
There remains a need for development of an alternative process for the preparation of telaprevir, which is easier, more economical, and results in a final product with higher purity.
Summary of the Invention
The present invention provides a process for the preparation of telaprevir of Formula I, comprising the steps of:
a) condensing (l S,3aR,6aS)-N-[(3S)-l-(cyclopropylamino)-2-hydroxy- l- oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1 -carboxamide of Formula III
Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2ylcarbonyl)amino]acetyl}-3-methyl-L-valine of Formula IV
Formula IV to obtain hydroxy telaprevir of Formula II; and
Formula II
b) oxidizing the hydroxy telaprevir of Formula II to obtain telaprevir of Formula I.
Formula I
Detailed Description of the Invention
(l S,3aR,6aS)-N-[(3S)- l-(cyclopropylamino)-2-hydroxy-l-oxohexan-3- yl]octahydrocyclopenta[c]pyrrole-l-carboxamide of Formula III may be prepared by the methods disclosed in U.S. Patent No. 8,188,137, and U.S. Publication No. 2010/0292219.
N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-yl-carbonyl)amino]acetyl}-3-methyl-L-valine of Formula IV may be prepared by following the process disclosed in PCT Publication No. WO 02/18369.
The condensation in step a) is carried out in the presence of a coupling agent, a base, and a solvent. Examples of coupling agents include HATU (2-(lH-7- azabenzotriazol- 1 -yl)~ 1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate
methanaminium); HBTU (0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate); HDBTU (2-(3,4-dihydro-4-oxo- l,2,3-benzotriazin-3-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate; HOTU (0-[(Ethoxycarbonyl)
cyanomethylenamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOBT (N- hydroxybenzotriazole); EDC (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide); EDC. HC1 (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride); BOP
((benzotriazole- 1 -yloxy)tris(dimethylamino) phosphonium hexafluorophosphate); PyBOP (benzotriazole- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate); DEPBT (3- (diethoxy-phosphoryloxy)-3H-benzo[d] [ 1 ,2,3]triazin-4-one); Oxyma (ethyl
(hydroxyimino)cyanoacetate); COMU ((1 -cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate); TNTU (2-(endo-5- norborene-2,3-dicarboxyamido)-l,l,3,3-tetramethyluronium tetrafluoroborate; TPTDP (S-
(l-oxo-2-pyridyl)-thio- l,3-dimethylpropyleneuronium tetrafluoroborate); TPTU (0-[l,2- dihydro-2-oxo-l-pyridyl]-N,N, Ν',Ν'-tetramethyluronium tetrafluoroborate); TBTU (O- (Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate); DIC (Ν,Ν'- diisopropylcarbodiimide); DCC (NN'-dicyclohexylcarbodiimide); or mixtures thereof. Preferably, the coupling reagent is selected from HOBT, HATU, HBTU, TBTU, EDC, EDC HC1, or mixtures thereof.
The base may be selected from weak organic or inorganic bases which facilitate the coupling reagent in carrying out the peptide synthesis. Examples of organic bases include Ν,Ν-diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2- propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7- ene, or mixtures thereof. Examples of inorganic bases include sodium bicarbonate and potassium bicarbonate. Preferably, the reaction is carried out in the presence of an organic base. Preferably, the organic base is selected from N,N-diisopropylethylamine, 4- dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine.
The solvent is selected from the group comprising of nitriles, chlorinated solvents, amides, dialkylsulfoxides, or mixtures thereof. Examples of nitriles include acetonitrile, propionitrile, butyronitrile, or valeronitrile. Examples of chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, or chloroform. Examples of amides include dimethylformamide, dimethylacetamide, or N-methyl formamide. Examples of dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, or dibutylsulfoxide.
Preferably, the solvent is selected from dichloromethane, acetonitrile, or
dimethylformamide .
The condensation is carried out at about 0°C to about 20°C. Preferably, the condensation is carried out at about 0°C to about 15°C. The temperature of the reaction mixture may be maintained at about 20°C to about 40°C for about 2 hours to about 20 hours. Preferably, the temperature of the reaction mixture is maintained at about 20°C to about 25°C for about 5 hours to about 10 hours.
Isolation of the hydroxy telaprevir of Formula II may be carried out by filtration, concentration, decantation, or combinations thereof. Preferably, the isolation of the hydroxy telaprevir of Formula II is carried out by concentration.
The oxidation in step b) is carried out in the presence of an oxidizing agent and a solvent. Examples of oxidizing agents include Dess-Martin Periodinane, oxalyl chloride, chromium trioxide, or potassium permanganate. Additionally, for rapid oxidation, the oxidizing agents may be used in combination with a catalyst such as TEMPO ((2,2,6,6- tetramethylpiperidin- 1 -yl)oxy), or TPAP (tetrapropylammonium perruthenate).
Preferably, the oxidation is carried out in the presence of Dess-Martin Periodinane.
The solvent is selected from the group comprising of nitriles, aromatic hydrocarbons, chlorinated solvents, dialkylsulfoxides, water, or mixtures thereof.
Examples of nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile. Examples of aromatic hydrocarbons include toluene and xylene. Examples of chlorinated solvents include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
Examples of dialkylsulfoxides include dimethylsulfoxide, diethylsulfoxide, and dibutylsulfoxide. Preferably, the solvent is selected from dichloromethane or toluene.
The oxidation is carried out at about 0°C to about 20°C, preferably at about 0°C to about 10°C. The reaction mixture is stirred at the same temperature for about 30 minutes to about 20 hours. Preferably, the reaction mixture is maintained at about 0°C to about 5°C for about 1 hour to about 5 hours.
Isolation of telaprevir of Formula I may be carried out by filtration, concentration, decantation, or a combination thereof. Preferably, the isolation of telaprevir of Formula I is carried out by concentration.
The processes disclosed above are further illustrated in the examples below. These examples are provided as illustrations only, and therefore should not be construed as limiting of the scope of the invention. Thus, specific embodiments, certain modifications, and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
EXAMPLES
Example la: Preparation of Hydroxy Telaprevir (Formula II)
N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3-methyl-L-valine (Formula IV; 1.16 g) was dissolved in dichloromethane (30 mL). To this solution, TBTU (1.2 g) was added at 12°C. (l S,3aR,6aS)-N-(3S)- l-(cyclopropylamino)-2-hydroxy-l-
oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-l-carboxamide (Formula III; 1.0 g) and N,N-diisopropylethylamine (0.56 mL) were added at 0°C to 5°C. After the addition, the temperature of the reaction mixture was raised from about 23°C to about 25°C, and the reaction mixture was stirred at the same temperature for about 7 hours. The reaction mixture was washed with IN HC1 and 5% sodium bicarbonate solution. The
dichloromethane layer was concentrated to obtain hydroxy telaprevir as a solid residue.
Yield: 1.7 g
Example lb: Preparation of Hydroxy Telaprevir (Formula II)
N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3-methyl-L-valine (Formula IV; 1.45 g) was dissolved in dichloromethane (25 mL). To this solution, HOBT (0.5 g) and EDC. HC1 (0.9 g) were added at 12°C. (l S,3aR,6aS)-N-[(3S)-l- (cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]octahydrocyclopenta[c]pyrrole- 1 - carboxamide (Formula III; 1.25 g) and N,N-diisopropylethylamine (1.5 mL) were added at 0°C to 5°C. After the addition, the temperature of the reaction mixture was raised from about 23°C to about 25°C, and the reaction mixture was stirred at the same temperature for about 8 hours. The reaction mixture was washed with IN HC1 and 5% sodium
bicarbonate solution. The dichloromethane layer was concentrated to obtain hydroxy telaprevir as a solid residue.
Yield: 1.8 g
Example II: Preparation of Telaprevir (Formula I)
Hydroxy telaprevir (Formula II; 1.05 g) was dissolved in dichloromethane (25 mL). To the resulting solution, Dess-Martin Periodinane was added at about 5°C. The reaction mixture was stirred at about 0°C to about 5°C for about 2 hours. The progress of the reaction was monitored by thin layer chromatography. After the reaction was complete, the reaction mixture was quenched with sodium thiosulphate solution and washed with sodium bicarbonate solution (20 mL). The dichloromethane layer was concentrated under reduced pressure to obtain telaprevir as a solid residue.
Yield: 0.7 g
Claims
1. A process for the preparation of telaprevir of Formula I
Formula I
comprising the steps of:
a) condensing (1 S,3aR,6aS)-N-[(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1-
Formula III
oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1 -carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}-3- methyl-L-valine of Formula IV
Formula IV
to obtain hydroxy telaprevir of Formula II; and
Formula II
b) oxidizing the hydroxy telaprevir of Formula II to obtain telaprevir of Formula I.
2. The process according to claim 1, wherein the condensation of (l S,3aR,6aS)-N- [(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1-carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino]acetyl}-3-methyl-L-valine of Formula IV is carried out in the presence of a coupling agent.
3. The process according to claim 2 wherein the coupling agent is selected from the group consisting of HOBT, HATU, HBTU, TBTU, EDC, EDC HCl, or mixtures thereof.
4. The process according to claim 1, wherein the condensation of (l S,3aR,6aS)-N- [(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1-carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino]acetyl}-3-methyl-L-valine of Formula IV is carried out in the presence of a base selected from Ν,Ν-diisopropylethylamine, 4-dimethylaminopyridine, triethyl amine, or N,N-2-trimethyl-2-propanamine.
5. The process according to claim 1, wherein the condensation of (l S,3aR,6aS)-N- [(3S)- 1 -(cyclopropylamino)-2-hydroxy- 1 -oxohexan-3-yl]-octahydrocyclopenta[c]pyrrole- 1-carboxamide of Formula III with N- {(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl) amino]acetyl}-3-methyl-L-valine of Formula IV is carried out in the presence of a solvent selected from nitriles, chlorinated solvents, amides, dialkylsulfoxides, or mixtures thereof.
6. The process according to claim 4, wherein the solvent is dichloromethane.
7. The process according to claim 1 , wherein the oxidation of the hydroxy telaprevir of Formula II is carried out in the presence of an oxidizing agent selected from Dess-
Martin Periodinane, oxalyl chloride, chromium trioxide, or potassium permanganate.
8. The process according to claim 1, wherein the oxidation is carried out in the presence of a solvent selected from the group comprising of nitriles, aromatic hydrocarbons, chlorinated solvents, dialkylsulfoxides, water, or mixtures thereof.
9. The process according to claim 7, wherein the solvent is dichloromethane.
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