CN1053431A - 膦酸酯的非对映选择制备 - Google Patents
膦酸酯的非对映选择制备 Download PDFInfo
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- CN1053431A CN1053431A CN91100404A CN91100404A CN1053431A CN 1053431 A CN1053431 A CN 1053431A CN 91100404 A CN91100404 A CN 91100404A CN 91100404 A CN91100404 A CN 91100404A CN 1053431 A CN1053431 A CN 1053431A
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- diastereomer
- described method
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- hydrogen
- alkyl group
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- 150000003008 phosphonic acid esters Chemical class 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000013507 mapping Methods 0.000 title description 2
- -1 halogen ester Chemical class 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012973 diazabicyclooctane Substances 0.000 claims abstract description 6
- 229960001880 fosinopril sodium Drugs 0.000 claims abstract description 4
- TVTJZMHAIQQZTL-WATAJHSMSA-M sodium;(2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylate Chemical compound [Na+].C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C([O-])=O)CCCC1=CC=CC=C1 TVTJZMHAIQQZTL-WATAJHSMSA-M 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 12
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 11
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000284 extract Substances 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims 2
- 229960002429 proline Drugs 0.000 abstract description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 abstract description 5
- 229930182821 L-proline Natural products 0.000 abstract description 5
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 abstract description 3
- 239000002220 antihypertensive agent Substances 0.000 abstract description 3
- 229940127088 antihypertensive drug Drugs 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 238000001640 fractional crystallisation Methods 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960002490 fosinopril Drugs 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 1
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BTJRKNUKPQBLAL-UHFFFAOYSA-N hydron;4-methylmorpholine;chloride Chemical compound Cl.CN1CCOCC1 BTJRKNUKPQBLAL-UHFFFAOYSA-N 0.000 description 1
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3264—Esters with hydroxyalkyl compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Cosmetics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
在4-甲基吗啉、二氮杂双环辛烷、奎宁环、1-甲
基吡咯烷或辛可尼定存在下来进行下式所示膦酸酯
与下式所示卤代酯类的反应,则会使非对映选择性增
加。除去R3保护基并分级结晶以后,可以拆分得到
的所需的非对映异构体对,并且所需的异构体可以偶
合到4-取代的L-脯氨酸上,得到具有血管紧张肽转
变酶抑制活性的化合物。本发明的方法特别适用于
以高产率生产抗高血压药fosinopril钠。
Description
Fosinopril钠,即[1[S*(R*)],2α,4β]-4-环己基-1-[[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酰基]-L-脯氨酸单钠盐,具有下述结构式,目前认为是一种抗高血压药。
Petrillo,Jr.在美国专利4337 201和4 381 124中公开了各种膦酰基-链烷酰基取代的脯氨酸类,包括有Fosinopril,具有血管紧张肽转变酶抑制活性。
Petrillo,Jr.等人在美国专利4 873 356中公开了一种制备fosinopril的方法,其中下式所示膦酸酯
式中R3是苄基或取代的苄基,n是0或1,R1是低级烷基,芳基,芳烷基,环烷基或环烷基烷基,
与下式所示卤代酯类反应,
式中Hal是Cl或Br,X是氢,低级烷基或苯基,y是氢,低级烷基,苯基或烷氧基,
生成下式所示的膦酸二酯,
已经公开了这一反应在有机碱[如三乙胺(较好)、吡啶、三丙胺、二氮杂双环十一烯或任意其它普通有机碱]和有机溶剂[如甲苯(较好)、乙腈、二氯甲烷、乙醚、四氢呋喃或二噁烷]存在下,并且最好在催化剂[如硫酸四丁铵和碘化钠)存在下进行。
然后将所得到的膦酸二酯氢化,生成一对外消旋混合物,通过分级结晶将其分离成单个外消旋混合物。这一外消旋混合物用拆分试剂处理,例如L-辛可尼定或其它旋光活性胺,分离出所需要的中间体。
式中R1是苯基丁基,n是0,R2是氢,y是乙基,x是异丙基的这一中间体然后在一种偶合剂存在下偶合到4-反-环己基-L-脯氨酸盐酸盐上,得到fosinopril。
本发明涉及制备抗高血压药fosinopril和有关化合物方法的效率的改进。按照这一改进方法,下式所示膦酸酯
与下式所示卤代酯在4-甲基吗啉(较好)、二氮杂双环辛烷、奎宁环、1-甲基吡咯烷或辛可尼定存在下进行反应
该反应在有机溶剂例如甲苯(较好)、乙腈、二氯甲烷、二甲苯、四氢呋喃或二噁烷中,在大约40℃至约138℃、最好在大约95℃进行,得到4种异构体的混合物。
然后将所得异构体氢化,通过在催化剂例如钯/碳存在下与氢反应除去R3酯基,得到两个非对映异构体对的混合物。所需要的非对映异构体对含有
和
不需要的非对映异构体对含有
在本方法中使用4-甲基吗啉、二氮杂双环辛烷、奎宁环、1-甲基吡咯烷或辛可尼定,结果使异构体比ⅢA/B对ⅢC/D从使用三乙胺时的约1.2增加到大约1.5。在生产所需的非对映体对ⅢA/B中,这种增加使得生产所需最终产物的总效率增加。
式Ⅰ至Ⅲ中所用的符号具有下面的意义:
R1是低级烷基,环烷基,芳基,芳基低级烷基或环烷基-低级烷基。
n是0或1。
R2是氢,低级烷基或芳基低级烷基。
R3是
R4是低级烷基,低级烷氧基,苯基, ,或二(低级烷基)氨基,
x是氢,低级烷基,或苯基,
y是氢,低级烷基,低级烷氧基或苯基。
该申请各处所用的术语“低级烷基”,不论单独存在还是作为较大基团的一部分,都是指含1-7个碳原子的直链和支链基团,较好的是含1-4个碳原子的直链和支链,如甲基、乙基、正丙基、异丙基、正丁基、叔丁基等等。
该申请各处所用的术语“环烷基”不论单独存在还是作为较大基团的一部分,都是指含3-7个碳原子的饱和环,即环丙基、环丁基、环戊基、环己基和环庚基。
该申请各处所用的术语“芳基”,不论单独存在还是作为较大基团的一部分,都是指苯基、1-萘基、2-萘基、和带有一个、两个或三个选自含1-4个碳原子的低级烷基、含1-4个碳原子的低级烷氧基、含1-4个碳原子的低级烷硫基、羟基、硝基、氨基、二(含1-4个碳原子的低级烷基)氨基、羟基、Cl、Br、F或CF3的取代基的苯基、1-萘基或2-萘基。苯基和单取代的苯基是较好的芳基。
该申请各处所用的术语“低级烷氧基”和“低级烷硫基”是指在O或S上连接有低级烷基。
说明书各处所用的术语“芳基-低级烷基”和“环烷基-低级烷基”是指连接有上述低级烷基的上述芳基和环烷基,即
本发明涉及制备由Petrillo,Jr.在美国专利4 337 201和4 384 123中公开的血管紧张肽转变酶抑制剂的一种改进方法。本发明特别涉及到制备方法的改进。当R1是
n是o、R2是氢、y是-C2H5、x是-CH(CH3)2时,这种酯是制备fosinopril的中间体。
按照本发明的改进方法,式Ⅰ所示的膦酸酯,特别是当R3是苄基时,与式Ⅱ所示的卤代酯在有机溶剂中、在4-甲基吗啉、二氮杂双环辛烷、奎宁环、1-甲基吡咯烷或辛可尼定存在下进行反应,并且然后氢化除去R3酯基,得到ⅢA、ⅢB、ⅢC和ⅢD的混合物,其中混合物中非对映体对ⅢA/B对ⅢC/D的比大约是1.5。
所用的膦酸酯Ⅰ对卤代酯Ⅱ的摩尔比为大约0.1∶1到大约1∶1,最好是0.2∶1到0.3∶1,反应温度为大约40℃-约138℃,最好是约95℃,反应时间为约18-约96小时。
通过氢解反应除去保护基以后,然后使ⅢA和ⅢB的外消旋混合物与一种拆分试剂例如L-辛可尼定(较好)或其它常规拆分试剂例如旋光活性胺,在有机溶剂例如乙酸乙酯、乙醇或四氢呋喃存在下进行反应。这一步的反应温度是大约25℃-约80℃,反应时间为约2-12小时,并且所用拆分试剂与ⅢA和ⅢB的外消旋混合物的摩尔比为约2∶1至约0.2∶1,最好是约1∶1至约0.5∶1,得到具有如下结构的拆分的盐
用一种强酸如盐酸或硫酸或者一种酸式盐如硫酸氢钾处理,得到不含ⅢB的ⅢA。
在偶合剂如N,N′-二环己基碳化二亚胺存在下,使拆分的酸ⅢA(其中R1是
n是0,R2是氢,y是-C2H5,x是-CH(CH3)2)偶合到下式所示的4-取代的L-脯氨酸盐酸盐,得到fosinopril。
或者,将式ⅢA的酸转变为活化形式,例如混合酸酐、酰氯等,然后偶合到式Ⅴ所示的4-取代的L-脯氨酸或其酯。
进行ⅢA和V的偶合反应采用的ⅢA对Ⅴ摩尔比为约0.5∶1到约2∶1,所用的反应温度为约-20℃到约30℃,反应时间为约2至约12小时。
本发明方法中所用的式Ⅰ所示的膦酸酯原料的实例包括(但不限于):
本发明方法中所用的式Ⅱ所示的卤代酯类原料的实例包括(但不限于):
用下述实施例说明本发明。
实施例
[1(S*(R*)],2α,4β]-4-环己基-1-[[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酰基]-L-脯氨酸,单钠盐
a)[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酸(非对映体对)
将[羟基(4-苯基丁基)膦酰基]乙酸苯基甲基酯(100克,0.29摩尔)、4-甲基吗啉(59.3克,0.58摩尔)和甲苯(150毫升)放在带有搅拌器、冷凝器和加热外套的500毫升三口圆底烧瓶中。将该混合物搅拌15分钟保证溶解。
加入丙酸1-氯-2-甲基丙酯(104.6克,0.58摩尔)并将混合物加热到95℃。在此温度搅拌反应液,直到HPLC测定结果表明烷基化反应已经完成(18-19小时)。
将溶液冷至25℃,通过烧结玻璃漏斗(中等孔隙度,250毫升)真空过滤,用甲苯洗涤4-甲基吗啉氢氯化物饼(100毫升,25℃)。
合并滤液和洗涤液,置于带有气体分散管、机械搅拌器、冷凝器、45℃水浴和一个气体出口管的500毫升三口圆底烧瓶中。混合物在625转/分下搅拌,将氮气吹入溶液15分钟。
往溶液中加入钯/碳(5%,2.5克干品,或5.0克50%湿品),于1psi下鼓入氢气。由HPLC测定出3小时后氢解反应完成。往溶液中吹入氮气,清除多余的氢。用Hyflo(4克,7厘米布氏漏斗)过滤溶液,滤饼用甲苯25(毫升)洗涤。合并洗涤液和滤液,用一批5%碳酸氢钠水溶液提取(20克碳酸氢钠在380毫升水中)。用浓盐酸33毫升酸化含水提取液至pH3.0,并用甲基异丁基酮(400毫升,一次提取)提取。将甲基异丁基酮溶液的体积减少到200毫升(40℃,最高),然后在30℃用所需的非对映体对接种。浆液在30℃搅拌2小时,用1小时慢慢冷至0℃。然后将浆液冷至-10℃。在-10℃保持2小时后,真空过滤收集产品并用冷的(-10℃)甲基异丁基酮(30毫升,三批)洗涤。
将产品溶解在70-80℃的75毫升甲基异丁基酮中进行重结晶。将溶液进行热过滤并用纯产品在50°进行接种。然后用2小时冷至0℃,在此温度下使溶液保持3小时。真空过滤分出晶体,用冷(0°)甲基异丁基酮(30毫升,两批)洗涤,空气干燥15分钟。在真空下于26℃干燥16小时后,固体[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酸的总收率为49克(大约44%,按三次操作平均值计算)。
分析计算C19H29O6P:C,59.36;H,7,60;P,8.06
实验值:C,59.60;H,7,86;P,8.07
b)[R-(R*,S*)]-[[2-甲基-1-(1-氧代丙氧基)丙氧基]-(4-苯基丁基)膦酰基]乙酸
往l-辛可尼定(980克,3.33摩尔)在6升乙酸乙酯中保持在45℃的剧烈搅拌的悬浮液中逐步加入(a)步所得的非对映体产品(1275.5克,3.33摩尔),再继续搅拌2.5小时,同时所得盐悬浮液逐步加热到70℃,这时完全溶解。用Hyflo滤除小量不溶物质后,将溶液接种并冷却。将分离的结晶产物过滤并用1200毫升乙酸乙酯∶异丙醚(1∶1)洗涤,真空干燥后得到1897.2克富集了所需异构体的辛可尼定盐;熔点106-109℃;[α]D=-59.3°(C=1,甲醇);[α]365=-237.6°(C=1,甲醇)。将此物质与136.8克用类似方法制备的物质合并,用10.18升煮沸的乙酸乙酯将其总量(2014克)重结晶,过滤并用1500毫升前面所用的同样溶剂混合物洗涤以及真空干燥以后,得到1162克所需的异构体辛可尼定盐;熔点120-122°(分解),[α]D=-45.2°(C=1,甲醇);[α]365=-185.5°(C=1,甲醇)。将样品(10克用乙腈重结晶两次,并用乙酸乙酯重结晶3次,得一分析样品[R-(R*,S*)[-[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酸,辛可尼定盐(1∶1);熔点125-126°(分解);[α]D=-42.2°(C=1,甲醇);[α]365=-178.8°(C=1,甲醇)。
分析计算C19H29O6P·C19H22N2O:
C,67.23;H,7.57;N,4.13
实验值:C,67.17;H,7.62;N,4.14。
往该辛可尼定盐(406.8克,0.6摩尔)在乙酸乙酯(4800毫升)和水(2700毫升)的混合物中的搅拌悬浮液中滴入硫酸氢钾(180克)在水(700)中的溶液,至pH为2.3。分出有机层,用盐水(1×1000毫升)洗涤,用硫酸镁干燥2小时。合并的水相用乙酸乙酯(3×1500毫升)再提取,并按上述方法处理。将合并的乙酸乙酯洗涤液过滤并真空浓缩。残留物用甲苯共沸(3×1300毫升),然后真空干燥三天,得到230.4克[R-(R*,S*)]-[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酸。
c).[1[S*(R*)],2α,4β]-4-环己基-1-[[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酰基]-L-脯氨酸,单钠盐。
将(b)中的游离酸产物(230.4克,0.6摩尔)和羟基苯并三唑水合物(在80℃真空干燥24小时,101.1克,0.66摩尔)在Burdick and Jackson二氯甲烷(分子筛干燥,6升)中的浆液冷却(冰/丙酮浴)并用N,N′-二环己基碳化二亚胺(136克,0.66摩尔)处理。使混合物升至室温,搅拌3小时。然后混合物在冰/丙酮中冷却并用(反)-4-环己基-L-脯氨酸单盐酸盐(154.2克,0.66摩尔)、然后用二异丙基乙基胺(170.7克,1.32摩尔)处理。反应混合物在室温搅拌18小时。然后冷却并用水(1升)处理,真空浓缩除去二氯甲烷。残留物用乙醚(3600毫升)和水(3600毫升)稀释,然后过滤。用10%盐酸将滤液调至pH=1.8。分出醚层,水层用乙酸乙酯(3×2升)洗涤。合并的有机层用5%KHSO4(3×1升)洗涤,再用水(3×1升)和盐水(1升)洗涤,用硫酸镁干燥,真空浓缩,得到398.9克粗产品。
将该粗品溶解于丙酮(4393毫升)中,用2-乙基己酸钠盐(117.3克)在丙酮(1468毫升)中的溶液处理,然后在室温搅拌过夜。过滤收集所得沉淀,用丙酮(3×400毫升)和己烷(1升)洗涤,然后真空干燥,得277克[1[S*(R*)],2α,4β]-4-环己基-1-[[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酰基]-L-脯氨酸单钠盐;熔点195℃-196℃;[α]D=-5.1°(C=2,甲醇)。
分析计算C30H45NO7P·Na:
C,61.53;H,7.75;N,2.39;P,5.29
实验值:C,61.69;H,7.89;N,2.34;P,5.1。
Claims (11)
1、制备含有下述结构式所示化合物的所需非对映异构体的方法,
相对于含下述结构式所示化合物的不需要的非对映体对,上述所需产品收率增加,
该方法包括
a)使下式所示膦酸酯
与下式所示卤代酯类
在4-甲基吗啉、二氮杂双环辛烷、奎宁环、1-甲基吡咯烷或辛可尼定存在下,在有机溶剂中,在大约40℃至约138℃温度下反应,得到含有4个异构体的混合物的中间体;
b)将来自(a)步的4种异构体的混合物氢化,除去R3酯基,以提高了的收率得到所需的非对映体对,分出不需要的非对映体对,式中:
R1是低级烷基,环烷基,芳基,芳基低级烷基或环烷基低级烷基;
n是0或1;
R2是氢,低级烷基或芳基低级烷基;
R3是
R4是低级烷基,低级烷氧基,苯基,
Hal是Br或Cl;
x是氢,低级烷基或苯基;以及
y是氢,低级烷基,低级烷氧基或苯基。
3、权利要求2所述的方法,其中(a)步的反应是在4-甲基吗啉存在下进行的,所需非对映体对与不需要的非对映体对的比为大约1.5。
4、权利要求3所述的方法,其中(a)步的反应是在甲苯中、在大约95℃温度下进行大约18至19小时,(b)步的氢化反应是在1psi压力下往反应液中鼓入氢气、在钯/碳存在下进行。
5、以提高的产率制备fosinopril钠的方法,包括
a)在4-甲基吗啉、二氮杂双环辛烷、奎宁环、1-甲基吡咯烷或辛可尼定存在下,在有机溶剂中,在大约40℃-约138℃温度下,使下式所示膦酸酯
与下式所示卤代酯反应
得到含4种异构体混合物的中间体;
b)氢化由(a)步得到的4种异构体混合物,以提高的产率得到含下述结构式所示化合物的非对映体对,
产率高是相对于含下述结构式所示化合物的非对映体对
和
c)用甲基异丁基酮提取(b)步产物,将所需要的非对映体对与不需要的非对映体对分离;
d)用旋光活性胺处理(c)步中得到的所需的非对映体对形成盐进行拆分,并用强酸或酸式盐处理所需异构体的盐,得到下式所示化合物,
e)将(d)步所得的产品酸偶合到(反)-4-环己基-L-脯氨酸单盐酸盐,然后用钠离子源处理,得到fosinopril钠。
6、权利要求5所述的方法,其中(a)步反应是在4-甲基吗啉存在下进行的,所需非对映体对与不需要的非对映体对的比为约1.5。
7、权利要求6所述的方法,其中(a)步反应在甲苯中,在大约95℃温度下进行约18-19小时,(b)步的氢化反应是通过在钯/碳存在下在1psi压力下往反应液中通入氢气进行的。
8、权利要求7所述的方法,其中(d)步的拆分试剂是l-辛可尼定。
9、权利要求8所述的方法,其中(e)步的偶合反应在偶合剂存在下进行的。
10、权利要求9所述的方法,其中(e)步的偶合剂是N,N′-二环己基碳化二亚胺,钠离子源是2-乙基己酸钠盐。
11、权利要求8所述的方法,其中由(d)步拆分得的酸产品在进行(e)步偶合反应之前转变为活化形式。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US467,451 | 1990-01-19 | ||
US07/467,451 US5008399A (en) | 1990-01-19 | 1990-01-19 | Diastereoselective preparation of phosphinate esters |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1053431A true CN1053431A (zh) | 1991-07-31 |
CN1026791C CN1026791C (zh) | 1994-11-30 |
Family
ID=23855753
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN91100404A Expired - Lifetime CN1026791C (zh) | 1990-01-19 | 1991-01-19 | 膦酸酯的非对映选择制备 |
Country Status (19)
Country | Link |
---|---|
US (1) | US5008399A (zh) |
EP (1) | EP0437799B1 (zh) |
JP (1) | JP2846484B2 (zh) |
KR (2) | KR0179368B1 (zh) |
CN (1) | CN1026791C (zh) |
AT (1) | ATE118779T1 (zh) |
AU (1) | AU623562B2 (zh) |
CA (1) | CA2032900C (zh) |
DE (1) | DE69017183T2 (zh) |
DK (1) | DK0437799T3 (zh) |
ES (1) | ES2068321T3 (zh) |
FI (1) | FI101539B1 (zh) |
HU (1) | HU208142B (zh) |
IE (1) | IE67354B1 (zh) |
IL (1) | IL96838A (zh) |
NO (1) | NO179915C (zh) |
PT (1) | PT96519B (zh) |
RU (1) | RU2044740C1 (zh) |
ZA (1) | ZA9196B (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9304619D0 (en) * | 1993-03-06 | 1993-04-21 | Ciba Geigy Ag | Esters |
US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
CA2411876A1 (en) * | 2001-04-30 | 2002-11-07 | Lupin Laboratories Limited | A process for manufacture of fosinopril sodium |
CN100488969C (zh) * | 2005-10-27 | 2009-05-20 | 上海医药工业研究院 | 光学活性的取代氧膦基乙酸盐及其用途 |
CN100497335C (zh) * | 2005-10-27 | 2009-06-10 | 上海医药工业研究院 | 取代氧膦基乙酸的光学拆分方法 |
IT1394407B1 (it) * | 2009-05-25 | 2012-06-15 | Dipharma Francis Srl | Procedimento per la preparazione di fosinopril e suoi intermedi |
IT1406151B1 (it) | 2010-12-06 | 2014-02-14 | Dipharma Francis Srl | Procedimento per la preparazione di fosinopril e suoi intermedi |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4384123A (en) * | 1980-12-04 | 1983-05-17 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted prolines |
US4337201A (en) * | 1980-12-04 | 1982-06-29 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted prolines |
US4873356A (en) * | 1987-09-30 | 1989-10-10 | E. R. Squibb & Sons, Inc. | Method for preparing phosphinic acids used in preparing ace inhibitors and intermediates produced thereby |
-
1990
- 1990-01-19 US US07/467,451 patent/US5008399A/en not_active Expired - Lifetime
- 1990-12-20 AU AU68319/90A patent/AU623562B2/en not_active Expired
- 1990-12-20 CA CA002032900A patent/CA2032900C/en not_active Expired - Lifetime
- 1990-12-21 ES ES90125061T patent/ES2068321T3/es not_active Expired - Lifetime
- 1990-12-21 DK DK90125061.3T patent/DK0437799T3/da active
- 1990-12-21 EP EP90125061A patent/EP0437799B1/en not_active Expired - Lifetime
- 1990-12-21 AT AT90125061T patent/ATE118779T1/de not_active IP Right Cessation
- 1990-12-21 DE DE69017183T patent/DE69017183T2/de not_active Expired - Lifetime
- 1990-12-31 IL IL9683890A patent/IL96838A/en not_active IP Right Cessation
-
1991
- 1991-01-04 ZA ZA9196A patent/ZA9196B/xx unknown
- 1991-01-07 IE IE4791A patent/IE67354B1/en not_active IP Right Cessation
- 1991-01-16 FI FI910231A patent/FI101539B1/fi active
- 1991-01-18 PT PT96519A patent/PT96519B/pt not_active IP Right Cessation
- 1991-01-18 HU HU91179A patent/HU208142B/hu unknown
- 1991-01-18 NO NO910214A patent/NO179915C/no not_active IP Right Cessation
- 1991-01-18 RU SU914894275A patent/RU2044740C1/ru active
- 1991-01-18 KR KR1019910000782A patent/KR0179368B1/ko not_active IP Right Cessation
- 1991-01-18 JP JP3019468A patent/JP2846484B2/ja not_active Expired - Lifetime
- 1991-01-19 CN CN91100404A patent/CN1026791C/zh not_active Expired - Lifetime
-
1998
- 1998-09-28 KR KR1019980040259A patent/KR0179470B1/ko not_active IP Right Cessation
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