ZA200205990B - Process for the preparation acetyl-amidiniophenylalanyl-cyclohexylglycul-pyridinioalaninamides. - Google Patents
Process for the preparation acetyl-amidiniophenylalanyl-cyclohexylglycul-pyridinioalaninamides. Download PDFInfo
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- ZA200205990B ZA200205990B ZA200205990A ZA200205990A ZA200205990B ZA 200205990 B ZA200205990 B ZA 200205990B ZA 200205990 A ZA200205990 A ZA 200205990A ZA 200205990 A ZA200205990 A ZA 200205990A ZA 200205990 B ZA200205990 B ZA 200205990B
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- South Africa
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- formula
- compound
- salt
- acid
- reaction
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- 238000000034 method Methods 0.000 title claims description 68
- 230000008569 process Effects 0.000 title claims description 56
- 238000002360 preparation method Methods 0.000 title claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 203
- 150000003839 salts Chemical class 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 239000002253 acid Substances 0.000 claims description 45
- 238000005984 hydrogenation reaction Methods 0.000 claims description 45
- 150000001450 anions Chemical class 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 239000003054 catalyst Substances 0.000 claims description 33
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 27
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 22
- 239000010948 rhodium Substances 0.000 claims description 19
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 18
- 101150096839 Fcmr gene Proteins 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 11
- 229960003237 betaine Drugs 0.000 claims description 11
- 229910052703 rhodium Inorganic materials 0.000 claims description 11
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 10
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 8
- 150000001718 carbodiimides Chemical class 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
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- 239000000203 mixture Substances 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 43
- 238000003756 stirring Methods 0.000 description 43
- 239000000047 product Substances 0.000 description 40
- -1 methanesuifonate Chemical compound 0.000 description 39
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
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- 239000001257 hydrogen Substances 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 22
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- 238000010168 coupling process Methods 0.000 description 20
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- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 19
- 230000008878 coupling Effects 0.000 description 19
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
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- 239000007858 starting material Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 150000001409 amidines Chemical class 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 10
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
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- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 229910052723 transition metal Inorganic materials 0.000 description 7
- 150000003624 transition metals Chemical class 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
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- 238000001914 filtration Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
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- 159000000000 sodium salts Chemical class 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
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- 230000002378 acidificating effect Effects 0.000 description 5
- 125000000909 amidinium group Chemical group 0.000 description 5
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 230000006196 deacetylation Effects 0.000 description 5
- 238000003381 deacetylation reaction Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
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- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- MVTHUEOHHHQQKY-QMMMGPOBSA-N (2s)-2-(diaminomethylideneamino)-3-phenylpropanoic acid Chemical compound NC(N)=N[C@H](C(O)=O)CC1=CC=CC=C1 MVTHUEOHHHQQKY-QMMMGPOBSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
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- FQHNTAUBDWKWHC-ZETCQYMHSA-O (2s)-2-(pyridin-1-ium-1-ylamino)propanamide Chemical compound NC(=O)[C@H](C)N[N+]1=CC=CC=C1 FQHNTAUBDWKWHC-ZETCQYMHSA-O 0.000 description 3
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 description 3
- WTKYBFQVZPCGAO-LURJTMIESA-N (2s)-2-(pyridin-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CN=C1 WTKYBFQVZPCGAO-LURJTMIESA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- HWCZNXXRUZTNNE-UHFFFAOYSA-N 2-[acetyl(cyclohexyl)amino]acetic acid Chemical compound OC(=O)CN(C(=O)C)C1CCCCC1 HWCZNXXRUZTNNE-UHFFFAOYSA-N 0.000 description 3
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- 150000008064 anhydrides Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
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- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229910017052 cobalt Inorganic materials 0.000 description 3
- GSOLWAFGMNOBSY-UHFFFAOYSA-N cobalt Chemical compound [Co][Co][Co][Co][Co][Co][Co][Co] GSOLWAFGMNOBSY-UHFFFAOYSA-N 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
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- 238000004817 gas chromatography Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
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- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- GKXPOWGXHMTRPS-AWEZNQCLSA-N (2s)-2-(phenylmethoxycarbonylamino)-3-pyridin-3-ylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CN=C1 GKXPOWGXHMTRPS-AWEZNQCLSA-N 0.000 description 2
- VZTWJWFMCMTPJP-SFHVURJKSA-N (2s)-2-[[2-acetamido-3-(4-cyanophenyl)prop-2-enoyl]amino]-2-cyclohexylacetic acid Chemical compound N([C@@H](C1CCCCC1)C(O)=O)C(=O)C(NC(=O)C)=CC1=CC=C(C#N)C=C1 VZTWJWFMCMTPJP-SFHVURJKSA-N 0.000 description 2
- MONMGLBZOWLFBG-UITAMQMPSA-N (4z)-2-methyl-4-(pyridin-3-ylmethylidene)-1,3-oxazol-5-one Chemical compound O=C1OC(C)=N\C1=C/C1=CC=CN=C1 MONMGLBZOWLFBG-UITAMQMPSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- GIWJJSHNDIKWOB-JZGIKJSDSA-N CC1=CC=C(S([O-])(=O)=O)C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1.C[N+]1=CC=CC(C[C@H]([NH3+])C(N)=O)=C1 Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1.C[N+]1=CC=CC(C[C@H]([NH3+])C(N)=O)=C1 GIWJJSHNDIKWOB-JZGIKJSDSA-N 0.000 description 2
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical compound OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229940068911 chloride hexahydrate Drugs 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
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- KTBROLPHLXUYSN-JTQLQIEISA-N methyl (2s)-2-acetamido-3-pyridin-3-ylpropanoate Chemical compound COC(=O)[C@@H](NC(C)=O)CC1=CC=CN=C1 KTBROLPHLXUYSN-JTQLQIEISA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical class OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BFMKBYZEJOQYIM-WXGMZPBLSA-N tert-butyl (2r,4r)-4-diphenylphosphanyl-2-(diphenylphosphanylmethyl)pyrrolidine-1-carboxylate Chemical compound C([C@H]1C[C@H](CN1C(=O)OC(C)(C)C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 BFMKBYZEJOQYIM-WXGMZPBLSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 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
- C07K5/08—Tripeptides
-
- 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
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Catalysts (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10003586 | 2000-01-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200205990B true ZA200205990B (en) | 2003-04-30 |
Family
ID=7628946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200205990A ZA200205990B (en) | 2000-01-28 | 2002-07-26 | Process for the preparation acetyl-amidiniophenylalanyl-cyclohexylglycul-pyridinioalaninamides. |
Country Status (30)
| Country | Link |
|---|---|
| US (2) | US20010031858A1 (pt) |
| EP (1) | EP1254159B9 (pt) |
| JP (1) | JP4778181B2 (pt) |
| KR (1) | KR100758141B1 (pt) |
| CN (1) | CN1176104C (pt) |
| AR (1) | AR027246A1 (pt) |
| AT (1) | ATE325810T1 (pt) |
| AU (1) | AU779722B2 (pt) |
| BR (1) | BR0107804A (pt) |
| CA (1) | CA2398497C (pt) |
| CZ (1) | CZ20022583A3 (pt) |
| DE (1) | DE60119491T2 (pt) |
| DK (1) | DK1254159T3 (pt) |
| EE (1) | EE200200410A (pt) |
| ES (1) | ES2262632T3 (pt) |
| HK (1) | HK1051866A1 (pt) |
| HR (1) | HRP20020631A2 (pt) |
| HU (1) | HUP0301986A2 (pt) |
| IL (2) | IL150897A0 (pt) |
| MX (1) | MXPA02006762A (pt) |
| NO (1) | NO20023577L (pt) |
| NZ (1) | NZ520427A (pt) |
| PL (1) | PL356801A1 (pt) |
| PT (1) | PT1254159E (pt) |
| RU (1) | RU2250212C2 (pt) |
| SK (1) | SK10842002A3 (pt) |
| TW (1) | TWI236481B (pt) |
| WO (1) | WO2001055175A2 (pt) |
| YU (1) | YU51202A (pt) |
| ZA (1) | ZA200205990B (pt) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH695999A5 (de) | 2002-02-28 | 2006-11-15 | Wilex Ag | Verfahren zur Herstellung von 3- Amidinophenylalanin-Derivaten. |
| EP1968999A2 (en) * | 2005-12-07 | 2008-09-17 | Technische Universität München | Small peptidic and peptido-mimetic affinity ligands for factor viii and factor viii-like proteins |
| CN101774942B (zh) * | 2010-01-27 | 2012-08-22 | 宁波武盛化学有限公司 | 制备n-乙酰基-dl-环己基甘氨酸的方法 |
| WO2011133651A1 (en) * | 2010-04-20 | 2011-10-27 | Chiral Quest , Inc. | An enantioselective process for cycloalkenyl b-substituted alanines |
| EP2646150A4 (en) * | 2010-11-29 | 2014-10-08 | Takasago Perfumery Co Ltd | CATALYST FOR ASYMMETRIC HYDROGENATION AND METHOD FOR PRODUCING AN OPTICALLY ACTIVE CARBONYL COMPOUND THEREWITH |
| CN115068469B (zh) * | 2022-07-08 | 2024-02-27 | 深圳市小分子新药创新中心有限公司 | Tigit抑制剂及其应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2916711A1 (de) | 1979-04-25 | 1980-11-06 | Behringwerke Ag | Blutgerinnungsfaktoren und verfahren zu ihrer herstellung |
| US4623717A (en) * | 1980-03-05 | 1986-11-18 | Miles Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
| US4440679A (en) * | 1980-03-05 | 1984-04-03 | Cutter Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
| US5849510A (en) | 1994-04-26 | 1998-12-15 | Selectide Corporation | Factor Xa inhibitors |
| KR100380124B1 (ko) * | 1994-04-26 | 2003-08-02 | 셀렉타이드 코포레이션 | 인자Xa억제제 |
| WO1997022712A1 (en) * | 1995-12-20 | 1997-06-26 | Hoechst Marion Roussel, Inc. | NOVEL PROCESS FOR PREPARING N-ACETYL(L)-4-CYANOPHENYLALANINE Ac-(L)-Phe(4-CN)-OH AND N-ACETYL-(L)-p-AMIDINOPHENYLALANINE-CYCLOHEXYLGLYCINE-β-(3-N-METHYLPYRIDINIUM)-ALANINE Ac-(L)-pAph-Chg-PalMe(3)-NH¿2? |
| DE19856443A1 (de) | 1998-12-08 | 2000-06-21 | Centeon Pharma Gmbh | Stabilisiertes Antithrombin III-Präparat |
-
2001
- 2001-01-18 SK SK1084-2002A patent/SK10842002A3/sk unknown
- 2001-01-18 KR KR1020027009583A patent/KR100758141B1/ko not_active IP Right Cessation
- 2001-01-18 ES ES01911497T patent/ES2262632T3/es not_active Expired - Lifetime
- 2001-01-18 AR ARP010100225A patent/AR027246A1/es unknown
- 2001-01-18 NZ NZ520427A patent/NZ520427A/en unknown
- 2001-01-18 YU YU51202A patent/YU51202A/sh unknown
- 2001-01-18 PL PL01356801A patent/PL356801A1/xx unknown
- 2001-01-18 AU AU40516/01A patent/AU779722B2/en not_active Ceased
- 2001-01-18 EE EEP200200410A patent/EE200200410A/xx unknown
- 2001-01-18 CN CNB018041523A patent/CN1176104C/zh not_active Expired - Fee Related
- 2001-01-18 PT PT01911497T patent/PT1254159E/pt unknown
- 2001-01-18 BR BR0107804-6A patent/BR0107804A/pt not_active Application Discontinuation
- 2001-01-18 CZ CZ20022583A patent/CZ20022583A3/cs unknown
- 2001-01-18 IL IL15089701A patent/IL150897A0/xx active IP Right Grant
- 2001-01-18 MX MXPA02006762A patent/MXPA02006762A/es active IP Right Grant
- 2001-01-18 DE DE60119491T patent/DE60119491T2/de not_active Expired - Lifetime
- 2001-01-18 AT AT01911497T patent/ATE325810T1/de active
- 2001-01-18 EP EP01911497A patent/EP1254159B9/en not_active Expired - Lifetime
- 2001-01-18 JP JP2001561027A patent/JP4778181B2/ja not_active Expired - Fee Related
- 2001-01-18 HU HU0301986A patent/HUP0301986A2/hu unknown
- 2001-01-18 DK DK01911497T patent/DK1254159T3/da active
- 2001-01-18 CA CA2398497A patent/CA2398497C/en not_active Expired - Fee Related
- 2001-01-18 RU RU2002123046/04A patent/RU2250212C2/ru not_active IP Right Cessation
- 2001-01-18 WO PCT/EP2001/000523 patent/WO2001055175A2/en not_active Application Discontinuation
- 2001-01-26 US US09/769,487 patent/US20010031858A1/en not_active Abandoned
- 2001-03-07 TW TW090101207A patent/TWI236481B/zh not_active IP Right Cessation
-
2002
- 2002-07-24 IL IL150897A patent/IL150897A/en not_active IP Right Cessation
- 2002-07-25 HR HRP20020631 patent/HRP20020631A2/hr not_active Application Discontinuation
- 2002-07-26 ZA ZA200205990A patent/ZA200205990B/en unknown
- 2002-07-26 NO NO20023577A patent/NO20023577L/no unknown
-
2003
- 2003-06-11 HK HK03104146A patent/HK1051866A1/xx not_active IP Right Cessation
-
2004
- 2004-06-17 US US10/869,076 patent/US7084250B2/en not_active Expired - Lifetime
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