CA2398497C - Process for the preparation of acetyl-amidiniophenylalanyl-cyclohexylglycyl-pyridinioalaninamides - Google Patents
Process for the preparation of acetyl-amidiniophenylalanyl-cyclohexylglycyl-pyridinioalaninamides Download PDFInfo
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- CA2398497C CA2398497C CA2398497A CA2398497A CA2398497C CA 2398497 C CA2398497 C CA 2398497C CA 2398497 A CA2398497 A CA 2398497A CA 2398497 A CA2398497 A CA 2398497A CA 2398497 C CA2398497 C CA 2398497C
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- 238000000034 method Methods 0.000 title claims abstract description 72
- 230000008569 process Effects 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 67
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 150000001450 anions Chemical class 0.000 claims abstract description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 204
- 238000005984 hydrogenation reaction Methods 0.000 claims description 45
- 239000002253 acid Substances 0.000 claims description 44
- 239000003054 catalyst Substances 0.000 claims description 33
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 22
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 15
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 11
- 229960003237 betaine Drugs 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
- 150000001718 carbodiimides Chemical class 0.000 claims description 6
- 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 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- MHMNQHQEAPWCEF-CEXZUDLPSA-N [Rh+].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 Chemical compound [Rh+].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 MHMNQHQEAPWCEF-CEXZUDLPSA-N 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 23
- 238000010168 coupling process Methods 0.000 abstract description 21
- 230000008878 coupling Effects 0.000 abstract description 20
- 239000007858 starting material Substances 0.000 abstract description 15
- 239000000543 intermediate Substances 0.000 abstract description 13
- 150000001409 amidines Chemical class 0.000 abstract description 11
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 abstract description 9
- 208000007536 Thrombosis Diseases 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 5
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 abstract description 2
- VZTWJWFMCMTPJP-UHFFFAOYSA-N 2-[[2-acetamido-3-(4-cyanophenyl)prop-2-enoyl]amino]-2-cyclohexylacetic acid Chemical compound C1CCCCC1C(C(O)=O)NC(=O)C(NC(=O)C)=CC1=CC=C(C#N)C=C1 VZTWJWFMCMTPJP-UHFFFAOYSA-N 0.000 abstract description 2
- XVWHDXISTYTFDL-UHFFFAOYSA-O 2-amino-3-(1-methylpyridin-1-ium-3-yl)propanamide Chemical class C[N+]1=CC=CC(CC(N)C(N)=O)=C1 XVWHDXISTYTFDL-UHFFFAOYSA-O 0.000 abstract description 2
- HQMLIDZJXVVKCW-REOHCLBHSA-N L-alaninamide Chemical compound C[C@H](N)C(N)=O HQMLIDZJXVVKCW-REOHCLBHSA-N 0.000 abstract description 2
- 101000655609 Streptomyces azureus Thiostrepton Proteins 0.000 abstract description 2
- DVLNTYJJQFFQGW-UHFFFAOYSA-N 2-[[2-acetamido-3-[4-[amino(azaniumylidene)methyl]phenyl]propanoyl]amino]-2-cyclohexylacetate Chemical compound C1CCCCC1C(C(O)=O)NC(=O)C(NC(=O)C)CC1=CC=C(C(N)=N)C=C1 DVLNTYJJQFFQGW-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 239000000203 mixture Substances 0.000 description 50
- 239000000243 solution Substances 0.000 description 43
- 238000003756 stirring Methods 0.000 description 43
- 239000000047 product Substances 0.000 description 40
- -1 2-[2-acetylamino-3-(4-amidinophenyl)propionylamino]-cyclohexylacetic acid Chemical compound 0.000 description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 25
- 239000001257 hydrogen Substances 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 22
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 239000000725 suspension Substances 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 15
- 239000008367 deionised water Substances 0.000 description 14
- 229910021641 deionized water Inorganic materials 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 238000001556 precipitation Methods 0.000 description 14
- 239000010948 rhodium Substances 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 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
- 239000002585 base Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 238000005897 peptide coupling reaction Methods 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 7
- 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 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [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
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- 238000002425 crystallisation Methods 0.000 description 6
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- 230000002255 enzymatic effect Effects 0.000 description 6
- 230000007717 exclusion Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000011987 methylation Effects 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 108010016626 Dipeptides Proteins 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 125000000909 amidinium group Chemical group 0.000 description 5
- 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 229910052703 rhodium Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 150000003512 tertiary amines Chemical class 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
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- CLWRFNUKIFTVHQ-UHFFFAOYSA-N [N].C1=CC=NC=C1 Chemical group [N].C1=CC=NC=C1 CLWRFNUKIFTVHQ-UHFFFAOYSA-N 0.000 description 4
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- 238000010992 reflux Methods 0.000 description 4
- 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
- DVLNTYJJQFFQGW-IRXDYDNUSA-N (2s)-2-[[(2s)-2-acetamido-3-(4-carbamimidoylphenyl)propanoyl]amino]-2-cyclohexylacetic acid Chemical compound C([C@H](NC(=O)C)C(=O)N[C@@H](C1CCCCC1)C(O)=O)C1=CC=C(C(N)=N)C=C1 DVLNTYJJQFFQGW-IRXDYDNUSA-N 0.000 description 3
- FVYLUSZAYQYPSS-ROUUACIJSA-N (2s)-2-[[(2s)-2-acetamido-3-(4-cyanophenyl)propanoyl]amino]-2-cyclohexylacetic acid Chemical compound C([C@H](NC(=O)C)C(=O)N[C@@H](C1CCCCC1)C(O)=O)C1=CC=C(C#N)C=C1 FVYLUSZAYQYPSS-ROUUACIJSA-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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108010074860 Factor Xa Proteins 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
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- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910000856 hastalloy Inorganic materials 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WCYJQVALWQMJGE-UHFFFAOYSA-M hydroxylammonium chloride Chemical compound [Cl-].O[NH3+] WCYJQVALWQMJGE-UHFFFAOYSA-M 0.000 description 1
- VGYYSIDKAKXZEE-UHFFFAOYSA-L hydroxylammonium sulfate Chemical compound O[NH3+].O[NH3+].[O-]S([O-])(=O)=O VGYYSIDKAKXZEE-UHFFFAOYSA-L 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- 229940102396 methyl bromide 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
- 125000000896 monocarboxylic acid group Chemical group 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
- 229920001155 polypropylene Polymers 0.000 description 1
- 150000003112 potassium compounds Chemical class 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
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000005086 pumping Methods 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium 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 (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10003586.8 | 2000-01-28 | ||
| DE10003586 | 2000-01-28 | ||
| PCT/EP2001/000523 WO2001055175A2 (en) | 2000-01-28 | 2001-01-18 | Process for the preparation of acetyl-amidiniophenylalanyl-cyclohexylglycyl-pyridinioalaninamides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2398497A1 CA2398497A1 (en) | 2001-08-02 |
| CA2398497C true CA2398497C (en) | 2011-04-26 |
Family
ID=7628946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2398497A Expired - Fee Related CA2398497C (en) | 2000-01-28 | 2001-01-18 | Process for the preparation of acetyl-amidiniophenylalanyl-cyclohexylglycyl-pyridinioalaninamides |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US20010031858A1 (enExample) |
| EP (1) | EP1254159B9 (enExample) |
| JP (1) | JP4778181B2 (enExample) |
| KR (1) | KR100758141B1 (enExample) |
| CN (1) | CN1176104C (enExample) |
| AR (1) | AR027246A1 (enExample) |
| AT (1) | ATE325810T1 (enExample) |
| AU (1) | AU779722B2 (enExample) |
| BR (1) | BR0107804A (enExample) |
| CA (1) | CA2398497C (enExample) |
| CZ (1) | CZ20022583A3 (enExample) |
| DE (1) | DE60119491T2 (enExample) |
| DK (1) | DK1254159T3 (enExample) |
| EE (1) | EE200200410A (enExample) |
| ES (1) | ES2262632T3 (enExample) |
| HR (1) | HRP20020631A2 (enExample) |
| HU (1) | HUP0301986A2 (enExample) |
| IL (2) | IL150897A0 (enExample) |
| MX (1) | MXPA02006762A (enExample) |
| NO (1) | NO20023577L (enExample) |
| NZ (1) | NZ520427A (enExample) |
| PL (1) | PL356801A1 (enExample) |
| PT (1) | PT1254159E (enExample) |
| RU (1) | RU2250212C2 (enExample) |
| SK (1) | SK10842002A3 (enExample) |
| TW (1) | TWI236481B (enExample) |
| WO (1) | WO2001055175A2 (enExample) |
| YU (1) | YU51202A (enExample) |
| ZA (1) | ZA200205990B (enExample) |
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. |
| WO2007065691A2 (en) * | 2005-12-07 | 2007-06-14 | 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 |
| US9000192B2 (en) | 2010-11-29 | 2015-04-07 | Takasago International Corporation | Catalyst for asymmetric hydrogenation and method for manufacturing optically active carbonyl compound using the same |
| 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 (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2916711A1 (de) | 1979-04-25 | 1980-11-06 | Behringwerke Ag | Blutgerinnungsfaktoren und verfahren zu ihrer herstellung |
| US4440679A (en) | 1980-03-05 | 1984-04-03 | Cutter Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
| US4623717A (en) | 1980-03-05 | 1986-11-18 | Miles Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
| SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
| DE69426897T2 (de) * | 1993-10-15 | 2001-07-05 | Rhone-Poulenc Rorer Pharmaceuticals, Inc. | Antithrombotisch wirkende azacycloalkyl-alkanoyl-peptide und-pseudopeptide |
| US5849510A (en) | 1994-04-26 | 1998-12-15 | Selectide Corporation | Factor Xa inhibitors |
| DK0758341T3 (da) * | 1994-04-26 | 2004-06-28 | Aventis Pharma Inc | Faktor Xa-inhibitorer |
| CN1087349C (zh) * | 1995-12-20 | 2002-07-10 | 阿温蒂斯药物公司 | N－乙酰基－(L)－4－氰基苯丙氨酸Ac-(L)-Phe(4－CN)－OH与N－乙酰基－(L)－对脒基苯丙氨酸－环己基甘氨酸－β－（3－N－甲基吡啶鎓）－丙氨酸AC－（L）－PAPh－chg－PaIMe(3)-NH2的新颖的制备方法 |
| DE19856443A1 (de) | 1998-12-08 | 2000-06-21 | Centeon Pharma Gmbh | Stabilisiertes Antithrombin III-Präparat |
-
2001
- 2001-01-18 ES ES01911497T patent/ES2262632T3/es not_active Expired - Lifetime
- 2001-01-18 DK DK01911497T patent/DK1254159T3/da active
- 2001-01-18 MX MXPA02006762A patent/MXPA02006762A/es active IP Right Grant
- 2001-01-18 PL PL01356801A patent/PL356801A1/xx unknown
- 2001-01-18 KR KR1020027009583A patent/KR100758141B1/ko not_active Expired - Fee Related
- 2001-01-18 HU HU0301986A patent/HUP0301986A2/hu unknown
- 2001-01-18 CZ CZ20022583A patent/CZ20022583A3/cs unknown
- 2001-01-18 AU AU40516/01A patent/AU779722B2/en not_active Ceased
- 2001-01-18 CA CA2398497A patent/CA2398497C/en not_active Expired - Fee Related
- 2001-01-18 YU YU51202A patent/YU51202A/sh unknown
- 2001-01-18 EE EEP200200410A patent/EE200200410A/xx unknown
- 2001-01-18 EP EP01911497A patent/EP1254159B9/en not_active Expired - Lifetime
- 2001-01-18 RU RU2002123046/04A patent/RU2250212C2/ru not_active IP Right Cessation
- 2001-01-18 PT PT01911497T patent/PT1254159E/pt unknown
- 2001-01-18 HR HRP20020631 patent/HRP20020631A2/hr not_active Application Discontinuation
- 2001-01-18 SK SK1084-2002A patent/SK10842002A3/sk unknown
- 2001-01-18 JP JP2001561027A patent/JP4778181B2/ja not_active Expired - Fee Related
- 2001-01-18 WO PCT/EP2001/000523 patent/WO2001055175A2/en not_active Ceased
- 2001-01-18 DE DE60119491T patent/DE60119491T2/de not_active Expired - Lifetime
- 2001-01-18 BR BR0107804-6A patent/BR0107804A/pt not_active Application Discontinuation
- 2001-01-18 AR ARP010100225A patent/AR027246A1/es unknown
- 2001-01-18 AT AT01911497T patent/ATE325810T1/de active
- 2001-01-18 CN CNB018041523A patent/CN1176104C/zh not_active Expired - Fee Related
- 2001-01-18 NZ NZ520427A patent/NZ520427A/en unknown
- 2001-01-18 IL IL15089701A patent/IL150897A0/xx active IP Right Grant
- 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
- 2002-07-26 ZA ZA200205990A patent/ZA200205990B/en unknown
- 2002-07-26 NO NO20023577A patent/NO20023577L/no unknown
-
2004
- 2004-06-17 US US10/869,076 patent/US7084250B2/en not_active Expired - Lifetime
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20170118 |