CN1026791C - 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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- CN1026791C CN1026791C CN91100404A CN91100404A CN1026791C CN 1026791 C CN1026791 C CN 1026791C CN 91100404 A CN91100404 A CN 91100404A CN 91100404 A CN91100404 A CN 91100404A CN 1026791 C CN1026791 C CN 1026791C
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- diastereomer
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- 238000002360 preparation method Methods 0.000 title claims description 7
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical class [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 title description 2
- -1 phosphinic acid ester Chemical class 0.000 claims abstract description 25
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 17
- 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
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 11
- 150000003008 phosphonic acid esters Chemical class 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012973 diazabicyclooctane Substances 0.000 abstract description 4
- 239000002220 antihypertensive agent Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 229960001880 fosinopril sodium Drugs 0.000 abstract description 2
- 238000001640 fractional crystallisation Methods 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 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 abstract description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 abstract 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 abstract 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 abstract 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 abstract 1
- 229940030600 antihypertensive agent Drugs 0.000 abstract 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 abstract 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 abstract 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 abstract 1
- 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
- 125000000217 alkyl group Chemical group 0.000 description 19
- 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
- 125000003118 aryl group Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000002431 hydrogen Chemical group 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 7
- 229960002429 proline Drugs 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
- 125000003545 alkoxy group Chemical group 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- 229930182821 L-proline Natural products 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 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
- 239000000284 extract Substances 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
- 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 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
- 150000001412 amines Chemical class 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 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
- 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
- 238000005859 coupling reaction Methods 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
- 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
- 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
- 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
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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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件对，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）：
X Y Hal
-CH（CH3）2-CH（CH3）2Cl
H -OCH3Cl
-C2H5 
Cl
-CH（CH3）2-C2H5Cl
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
-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 (1)
1、制备所需式Ⅰ和式Ⅱ表示的非对映体，且收率比所含不需要的式Ⅲ和式Ⅳ表示的非对映体高的方法，
该方法包括，
a)在甲苯中在4-甲基吗啉存在下，通过Ⅴ所示的膦酸酯与通式Ⅵ所示的氯代酯于约95℃反应约18-19小时
得到含四种异构体混合物的中间体；
b)在正压下在钯/碳存在下，通氢气于反应混合物中，氢化来自步骤a)的四种异构体的混合物，除去苄酯基；和
c)用甲基异丁基酮提取步骤b)的产物，从不需要的非对映体中分离出所需的非对映体。
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| US07/467,451 US5008399A (en) | 1990-01-19 | 1990-01-19 | Diastereoselective preparation of phosphinate esters |
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| CN1053431A CN1053431A (zh) | 1991-07-31 |
| CN1026791C true CN1026791C (zh) | 1994-11-30 |
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| 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 |
| JP2004520440A (ja) * | 2001-04-30 | 2004-07-08 | ルピン ラボラトリーズ リミティド | フォシノプリルナトリウムの製造方法 |
| 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 |
| 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 |
| 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 |
|---|---|---|---|---|
| US4337201A (en) * | 1980-12-04 | 1982-06-29 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted prolines |
| US4384123A (en) * | 1980-12-04 | 1983-05-17 | 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 |
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1990
- 1990-01-19 US US07/467,451 patent/US5008399A/en not_active Expired - Lifetime
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1991
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1998
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