CN1263726C - 制备拉坦前列素的方法和中间体 - Google Patents
制备拉坦前列素的方法和中间体 Download PDFInfo
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- CN1263726C CN1263726C CNB028144368A CN02814436A CN1263726C CN 1263726 C CN1263726 C CN 1263726C CN B028144368 A CNB028144368 A CN B028144368A CN 02814436 A CN02814436 A CN 02814436A CN 1263726 C CN1263726 C CN 1263726C
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 239000000543 intermediate Substances 0.000 title claims abstract description 12
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 title description 9
- 229960001160 latanoprost Drugs 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000011541 reaction mixture Substances 0.000 claims abstract description 15
- 229910052796 boron Inorganic materials 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 230000002829 reductive effect Effects 0.000 claims description 25
- -1 cationic amine Chemical class 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 14
- 150000002576 ketones Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 229910000085 borane Inorganic materials 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 229960004418 trolamine Drugs 0.000 claims description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims 4
- 150000001638 boron Chemical class 0.000 claims 4
- PSEHHVRCDVOTID-NAVXHOJHSA-N chloro-bis[(1s,3s,4r,5s)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@@H]([C@H]1C)B(Cl)[C@@H]2[C@@H](C)[C@@]3(C[C@](C2)(C3(C)C)[H])[H])[C@]2([H])C(C)(C)[C@@]1([H])C2 PSEHHVRCDVOTID-NAVXHOJHSA-N 0.000 abstract 1
- 239000008139 complexing agent Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 23
- 239000012071 phase Substances 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 150000002561 ketenes Chemical class 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000002002 slurry Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- CPVNCBJFUQQXSU-UHFFFAOYSA-N 5-triphenylphosphaniumylpentanoate Chemical class C1(=CC=CC=C1)[P+](CCCCC(=O)[O-])(C1=CC=CC=C1)C1=CC=CC=C1 CPVNCBJFUQQXSU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Natural products CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- HNPFPERDNWXAGS-NFVOFSAMSA-N latanoprost free acid Chemical compound C([C@@H](O)CCC=1C=CC=CC=1)C[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O HNPFPERDNWXAGS-NFVOFSAMSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/54—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
Abstract
本发明是新颖的中间体式(VI)化合物及其盐。另外,本发明包括15(S)-前列腺素中间体化合物(VI)和(XVIII)的制备方法,包含(1)使对应的烯酮与(-)-氯代二异松蒎醇基硼烷接触,同时保持反应混合物的温度在约-50℃至约0℃的范围内,和(2)使步骤(1)的反应混合物与硼配合剂接触。
Description
发明背景
发明领域
本发明是制备拉坦前列素的方法,包括中间体,它是可用于治疗眼科病症的药物。
相关技术的说明
美国专利5,422,368公开了拉坦前列素(实施例2)及其作为眼科药物的有用性。该专利公开了制备拉坦前列素和两种密切相关的化合物的方法(实施例2)。
利用氯代二异松蒎醇基硼烷还原α,β-不饱和烯酮的实例数量非常有限。J.Am.Chem.Soc.,110(5),1539-46(1988)描述了利用氯代二异松蒎醇基硼烷还原无环族芳基烯酮4-苯基-3-丁烯-2-酮的一个实例,产生81%的对映体选择性,没有简单的无环族非芳基共轭烯酮的实例。
Bull.Korean Chem.Soc.,15(12),1033-4(1994)致力于使用氯代二异松蒎醇基硼烷的1,2对1,4还原问题,但是没有讨论还原作用的对映选择性或非对映选择性。
Tetrahedron Letters 1067-1070(1976)公开了一种环戊烷二醇酸,其中侧链不含任何芳族官能度。
发明概述
所公开的有式(VI)化合物
其中:
(1)R3是-H,R4是-H,
(2)R3是-H,R4是-O-CH3和
(3)R3和R4一起构成与苯基环3-与4-位连接的五元环,其中从R3-位至R4-位的第二个环是-CH-CH-O-和
其中是单键或双键,
及其药学上可接受的盐。
也公开了式(VI)化合物的可药用盐,其中盐的阳离子选自钠、钾、锂、铯和R1R2R3N+-H,其中R1、R2和R3相同或不同,且选自C1-C4烷基、α-甲基苄胺、吡啶、C1-C4烷基取代的吡啶,苄胺和β-苯乙胺,其中特别优选阳离子胺为三乙胺或吡啶。
所公开的还有15(S)-前列腺素中间体的制备方法,该中间体选自由化合物(IV)
其中R3、R4和是如上所定义的,X11是苯基或被一至三个C1-C4烷基、一至三个C1-C4烷氧基、一个苯基、一至三个-F、-Cl、-Br和-I取代的苯基,
和化合物(XVIII)组成的组,
其中X11是如上所定义的,
该方法包含:
(1)使一种化合物与(-)-氯代二异松蒎醇基硼烷接触,该化合物选自由化合物(III)
其中R3、R4、X11和分别是如上或化合物(XVII)所定义的,
和化合物(XVII)组成的组,
其中11是如上所定义的,
同时保持反应混合物的温度在约-50℃至约0℃范围内,和
(2)使步骤(1)反应混合物与硼配合剂接触。
发明的详细说明
拉坦前列素(XVI)是已知的,见美国专利5,422,368实施例2。
本发明的方法如图表A与B和实施例1-12所述。
烯酮(III)以及其他本发明化合物在底部侧链的苯基环上具有三种取代的可能性。它们是这样的,其中R3和R4:
(1)R3是-H,R4是-H,这得到苯基,
(2)R3是-H,R4是-O-CH3,这得到4-甲氧基苯基和
(3)R3和R4一起构成与苯基环3-与4-位连接的五元环,其中从R3-位至R4-位的第二个环是-CH=CH-O-,
其中是单键或双键,
其中X11是苯基或被一至三个C1-C4烷基、一至三个C1-C4烷氧基、一个苯基、一至三个-F、-Cl和-Br取代的苯基。优选的是R3和R4都是-H。优选的是X11是苯基。
烯酮(III)必须在C-11位被保护,正如本领域技术人员所知。优选的是关于保护基团-CO-X11,X11是苯基或被一至三个C1-C4烷基、一至三个C1-C4烷氧基、-个苯基、一至三个-F、-Cl和-Br取代的苯基。关于α,β-不饱和烯酮(III)的(-)-氯代二异松蒎醇基硼烷还原作用,该还原作用可以在任意化学惰性溶剂中进行,该溶剂充分地溶解烯酮(III)。适合的溶剂包括THF、二氯甲烷和DME,和它们的混合物。单独的MTBE和甲苯不是可行的。助溶剂的使用不是必要的,例如己烷、庚烷、异辛烷或相似的烃,但是是优选的。这一点是重要的,因为(-)-氯代二异松蒎醇基硼烷是商业上可得到的在这些溶剂中的溶液。MTBE和甲苯可以用作助溶剂。溶剂的性质事实上对产物中的15(S)/15(R)比例没有影响。优选的是使用约3至约4当量的(-)-氯代二异松蒎醇基硼烷;更优选的是使用至少3.5当量的(-)-氯代二异松蒎醇基硼烷。更少的当量数使反应不完全;更多的当量数也不会有速率或选择性的提高。当使(-)-氯代二异松蒎醇基硼烷与α,β-不饱和烯酮(III)接触时,温度应当保持低于0℃。优选的是温度保持在低于-20℃;更优选的是温度保持在约-35至约-45℃范围内。温度在-35℃以上,选择性降低,在约-45℃以下,速率变得太慢以致无法实施。
当反应完全时,必须利用硼配合剂破坏过量的(-)-氯代二异松蒎醇基硼烷,它选自由水、C1-C6醇与二醇、乙醇胺、二乙醇胺、三乙醇胺和它们的混合物组成的组。优选的是硼配合剂是水和二乙醇胺;更优选的是配合剂是水。
优选的是在步骤(2)之前,使步骤(1)反应混合物与容易还原的醛或酮接触。优选的是容易还原的醛或酮选自由C1-C6醛与酮和苯甲醛组成的组;更优选的是容易还原的醛或酮是丙酮或甲乙酮。在加入硼配合剂时,优选的是也加入一种碱。优选的是碱选自由碳酸盐、碳酸氢盐、单-、二-与三-C1-C6烷基胺、吡啶和被C1-C4烷基取代的吡啶;更优选的是碱是碳酸氢盐或碳酸盐。进而更优选的是碱是碳酸氢盐。
在步骤(2)之前或之后,优选地使反应混合物温热至约15至约25℃。优选的是使反应混合物温热约1至约3小时。
拉坦前列素(XVI)已知可用作眼科药物,见美国专利5,296,504和5,422,368。另外,国际专利公报WO 98/30900公开了拉坦前列素(XVI)可用于治疗另一种眼科病症近视。
图表B(和实施例11与12)的方法始于已知的烯酮(XVII),再转化为15-醇(XVIII)中间体,已知可用于制备药学上有用的前列腺素,见Tetrahedron Letters,1076-1070(1976)和J.Am.Chem.Soc.92,397-8(1970)。非芳基α,β-不饱和酮(XVII)的还原方法类似于芳基α,β-不饱和酮(III)的还原作用。
其中R3是-H且R4是-O-CH3和其中R3和R4一起构成与苯基环3-与4-位连接的五元环(其中从R3-位至R4-位的第二个环是-CH=CH-O-)的产物已知也是有用的药物。这两种药物也能够借助本发明的方法加以制备。
定义和约定
下列定义和解释用在本文始终,包括说明书和权利要求书。
定义
所有温度均为摄氏度。
拉坦前列素(XVI)表示(5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]-5-庚烯酸1-甲基乙基酯。已知也称为17-苯基-18,19,20-三降-PF2α异丙基酯。
MTBE表示甲基叔丁基醚。
TLC表示薄层色谱。
THF表示四氢呋喃。
THP表示四氢吡喃基。
盐水表示饱和氯化钠水溶液。
色谱(柱色谱和快速色谱)表示化合物的纯化/分离,以(载体,洗脱剂)表示。不言而喻的是汇集适当的部分,浓缩,得到所需的化合物。
CMR表示C-13磁共振光谱,按照从TMS下移的ppm(δ)报告化学漂移。
NMR表示核(质子)磁共振光谱,按照从四甲基硅烷下移的ppm(δ)报告化学漂移。
TMS表示三甲代甲硅烷基。
-φ表示苯基(C6H5)。
MS表示质谱,以m/e、m/z或质量/电荷单位表示。[M+H]+表示母体加氢原子的正离子。EI表示电子碰撞。CI表示化学电离。FAB表示快速原子轰击。
HRMS表示高分辨率质谱。
药学上可接受的盐表示这样的性质和/或物质,从药理学/毒理学观点来看它们是患者可接受的,从关于组成、制剂、稳定性、患者可接受性和生物利用度的物理/化学观点来看它们是制造药物的化学人员可接受的。
psi表示磅每平方英寸。
当使用溶剂对时,所用溶剂的比例是体积/体积(v/v)。
当使用固体在溶剂中的溶解度时,固体与溶剂的比例是重量/体积(wt/v)。
DIBAL表示氢化二异丁基铝。
THAM表示三(羟甲基)氨基甲烷。
实施例
毋庸赘述,相信本领域技术人员利用前述说明能够实施本发明至最完全的程度。下列详细实施例描述如何制备各种本发明化合物和/或进行各种本发明方法,仅被解释为说明性的,决不是前述公开内容的限制。本领域技术人员将从这些工艺迅速确认关于反应剂和反应条件与技术的适当变化。
制备例1 5-(三苯基亚膦基)戊酸钾
搅拌溴化4-羧基丁基三苯基鏻盐(2.91g)与THF(10ml),将浆液冷却至0℃。将叔丁醇钾的THF溶液(20%w/v,7.6ml)冷却至0℃。向浆液滴加丁醇化物溶液,保持温度在0至5℃,然后搅拌1小时。然后将所得内鎓盐溶液冷却至-10℃。
实施例1[3aR-[3aα,4α(E),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-氧代-5-苯基-1-戊烯基)-2H-环戊二烯并[b]呋喃-2-酮(III)
将氯化锂(2.6g)溶于THF(170ml)。加入(2-氧代-4-苯基丁基)膦酸二甲酯(II,7.87g)和三乙胺(4.3ml)。将混合物搅拌,冷却至-10℃。历经3小时向反应混合物加入Corey醛苯甲酸酯(1S,5R,6R,7R)-6-甲酰基-7-(苄氧基)-2-氧杂二环并[3.3.0]辛-3-酮(I,8.42g)的THF(75ml)溶液。将所得混合物在-10℃下搅拌18小时。该阶段结束时,加入MTBE(100ml),使混合物温热至0至+20℃。加入亚硫酸氢钠(38%,100ml),将两相混合物搅拌10分钟。分离各相,有机相用饱和碳酸氢钠水溶液(100ml)洗涤。分离有机相,在减压下浓缩至体积<100ml。加入乙酸乙酯(200ml),将混合物浓缩至体积为50ml。加入MTBE(100ml),使混合物冷却至20-25℃达1小时。然后将混合物冷却至-20℃达2小时。将固体过滤,用MTBE洗涤,在氮压机上干燥,得到标题化合物,
mp=117-118°;NMR(CDCl3,400MHz)δ7.82,7.41,7.28,7.10,7.02,6.49,6.04,5.12,4.91,2.72和2.5-2.1;CMR(CDCl3,100.6MHz)δ198.5,175.7,165.8,143.0,140.8,133.5,131.4,129.4,128.5,126.2,83.0,78.4,54.0,42.5,37.8,34.8和29.9。
实施例2[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-羟基-5-苯基-1-戊烯基)-2H-环戊二烯并[b]呋喃-2-酮(IV)
将[3aR-[3aα,4α(E),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-氧代-5-苯基-1-戊烯基)-2H-环戊二烯并[b]呋喃-2-酮(III,实施例1,10.0g,0.0247mol)在THF(100ml)中的混合物冷却至-38至-42℃。向烯酮(III)混合物加入(-)-氯代二异松蒎醇基硼烷溶液(2M己烷溶液,43ml),保持内部温度低于-35℃。当加入完全时,将混合物在-38至-42℃下搅拌18小时。此时加入丙酮(12.7ml),使混合物温热至20-25℃,搅拌2小时。加入MTBE(100ml),然后加入碳酸氢钠(10g)的水(150ml)溶液。将两相混合物搅拌15分钟。分离各相,有机相用水(100ml)洗涤。在减压下浓缩有机相。加入MTBE(300ml),然后浓缩混合物。加入乙腈(100ml),再次浓缩混合物。加入乙腈(150ml)和庚烷(100ml)。将两相混合物搅拌5分钟,然后使其沉降。分离各相。乙腈相用庚烷萃取(3×100ml)。浓缩乙腈相。取出-部分浓缩物,经过色谱纯化(硅胶230-400目,庚烷/乙酸乙酯1/1),得到标题化合物,mp=78-81℃;NMR(CDCl3,400MHz)δ7.77,7.32,7.19,7.04,6.94,5.45,5.37,5.01,4.79,3.88,2.61-2.23,2.01和1.60;CMR(CDCl3,100.6MHz)δ176.5,166.0,141.7,136.0,133.3,129.5,128.4,125.8,83.3,79.2,71.2,53.9,42.6,38.7,37.5,34.9和31.5。
实施例3[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-羟基-5-苯基-1-戊基)-2H-环戊二烯并[b]呋喃-2-酮(V)
将[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-羟基-5-苯基-1-戊烯基)-2H-环戊二烯并[b]呋喃-2-酮(IV,实施例2)溶于THF(125ml)。加入披铂碳催化剂(5%,1g)和三乙胺(3.4ml)。将混合物用氮净化,然后在20±5℃的5psi氢下剧烈搅拌。根据HPLC的测量,当反应完全时,用氮净化反应。通过C盐过滤混合物。在减压下浓缩滤液,得到粗产物。取出一部分产物,经过色谱纯化(硅胶230-400目,庚烷/乙酸乙酯1/1),得到标题化合物,mp=68-70℃;
NMR(CDCl3,400MHz)δ7.91,7.47,7.36,7.19,7.10,5.18,4.99,3.56,2.84-2.57,2.44-2.26,1.71-1.16;CMR(CDCl3,100.6MHz)δ176.9,166.0,141.8,133.2,129.6,128.4,125.9,84.4,80.1,70.8,52.6,43.5,39.0,37.7,36.2,35.1,32.0和29.5;MS
计算值m/z=408实测值m/z=409(m+1)。
实施例4 2-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]乙酸(VI)
向[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-羟基-5-苯基-1-戊基)-2H-环戊二烯并[b]呋喃-2-酮(V,实施例3)加入氢氧化钾(10g)在甲醇(300ml)与水(5ml)中的混合物。将混合物搅拌,在80℃油浴中加热约2小时。当反应完全时,在减压下浓缩混合物。加入水(100ml)和MTBE(100ml),将混合物在20-25℃下搅拌15分钟。使各相分离。产物在含水相中,取出有机相,弃去。加入盐酸(3N,需要约60ml),调节含水相的pH至1至1.5。在20-25℃下搅拌溶液。30分钟后,加入MTBE(100ml),将混合物在20-25℃下搅拌约12小时。分离各相,含水相用MTBE(50ml)萃取一次。合并MTBE相,用碳酸钠(1N,50ml)洗涤。将MTBE混合物与氢氧化钾(2.8g,42.5mmol)的水(100ml)溶液搅拌30分钟。分离各相,在20-25℃下将含水相加入到枸橼酸一水合物(8.90g)与乙酸乙酯(100ml)的浆液中。将混合物搅拌15分钟,分离各相。含水相用乙酸乙酯萃取(5×50ml)。合并有机相,经无水硫酸钠(8.90g)干燥15分钟。在减压下浓缩乙酸乙酯萃取液至体积为100ml,保持内部温度低于30℃。加入乙酸乙酯(200ml),再次浓缩混合物至体积为100ml。将所得浆液在0-5℃下搅拌30分钟。将固体过滤,用庚烷/乙酸乙酯(1/1,35ml)洗涤,然后在氮压机上干燥,得到标题化合物。
实施例5[3aR-[3aα,4α(R*),5β,6aα]]-六氢-5-羟基-4-(3-羟基-5-苯基戊基)-2H-环戊二烯并[b]呋喃-2-酮(VII)
搅拌2-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]乙酸(VI,实施例4,4.80g)和甲苯(100ml),将浆液加热至回流达30分钟。30分钟后,在大气压下缓慢蒸馏甲苯,以除去水。蒸馏约1小时后,全部羟基酸都已溶解。然后蒸馏溶液至体积为约50ml。然后将混合物冷却至约80℃,加入乙酸乙酯(25ml)。然后将混合物冷却至约30℃,加入庚烷(20ml)。向混合物接种少量标题化合物。将混合物在约30℃下搅拌10分钟,在此期间发生大量结晶。产物已经结晶后,历经15分钟加入庚烷(30ml)。将浆液冷却至20-25℃,搅拌1小时。将产物过滤,在氮下干燥,得到标题化合物,mp=69-71℃;
NMR(CDCl3,400MHz)δ7.35,7.26,5.00,4.06,3.68,2.89-2.55,2.34-2.07和1.87-1.34;CMR(CDCl3,100.6MHz)δ177.8,141.9,128.4,125.9,84.0,71.2,53.9,43.1,41.4,39.1,36.0,35.2,32.0和28.9。
实施例6(3aR,4R,5R,6aS)-5-(1-乙氧基乙氧基)-4-[(3R)-3-(1-乙氧基乙氧基)-5-苯基戊基]六氢-2H-环戊二烯并[b]呋喃-2-酮(X)
将[3aR-[3aα,4α(R*),5β,6aα]]-六氢-5-羟基-4-(3-羟基-5-苯基戊基)-2H-环戊二烯并[b]呋喃-2-酮(VII,实施例5,1.0g,3.3mmol)溶于二氯甲烷(3ml),将混合物置于可密封的压力试管内。加入1.0ml三氯乙酸(0.27g)在二氯甲烷(10ml)中的混合物,然后加入乙基乙烯基醚(6.3ml)。将压力试管密封,在油浴中加热至45℃达约8小时。此时加入三乙胺(0.12ml),将混合物搅拌10分钟。然后在减压下浓缩混合物。
实施例7(3aR,4R,5R,6aS)-5-(1-乙氧基乙氧基)-4-[(3R)-3-(1-乙氧基乙氧基)-5-苯基戊基]六氢-2H-环戊二烯并[b]呋喃-2-醇(XI)
将(3aR,4R,5R,6aS)-5-(1-乙氧基乙氧基)-4-[(3R)-3-(1-乙氧基乙氧基)-5-苯基戊基]六氢-2H-环戊二烯并[b]呋喃-2-酮(X,实施例6)溶于THF(14ml),将混合物冷却至-40℃。利用注射器泵,历经15分钟加入DIBAL(1.0M甲苯溶液,3.78ml),保持内部温度低于-30℃。加入完全后,将混合物搅拌15分钟,然后加入乙酸乙酯(0.38ml)。将混合物倒入酒石酸钠钾(10g)的水(30ml)溶液中,温热至20-25℃。将两相混合物加热至45℃达1小时,然后冷却。分离各相,浓缩有机相。
实施例87-[(1R,2R,3R,5S)-3-(1-乙氧基乙氧基)-5-羟基-2-[(3R)-3-(1-乙氧基乙氧基)-5-苯基戊基]环戊基]-5-庚烯酸(XII)
将(3aR,4R,5R,6aS)-5-(1-乙氧基乙氧基)-4-[(3R)-3-(1-乙氧基乙氧基)-5-苯基戊基]六氢-2H-环戊二烯并[b]呋喃-2-醇(XI,实施例7)溶于无水THF(10ml),在-10℃至-5℃下加入到含有5-(三苯基亚膦基)戊酸钾(制备例1)溶液的混合物中。将所得混合物在低于-5℃下搅拌约3小时。历经10分钟加入水(30ml,0℃),然后加入乙酸乙酯(20ml)和THAM水溶液(10ml)。分离各相,有机相用THAM水溶液洗涤(15%,2×15ml)。合并含水相,用乙酸乙酯(15ml)洗涤一次。向所合并的含水相加入MTBE(50ml)。将混合物用含水磷酸(40%)酸化至pH=3。分离有机相,在减压下浓缩至20ml。有固体(5-二苯膦基戊酸)结晶出来。加入MTBE(50ml),在减压下浓缩浆液至体积为20ml。将固体过滤,用MTBE(100ml)洗涤。在减压下浓缩滤液,得到标题化合物。
实施例9拉坦前列素酸;(5Z)-7-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]-5-庚烯酸(XV)
将7-[(1R,2R,3R,5S)-3-(1-乙氧基乙氧基)-5-羟基-2-[(3R)-3-(1-乙氧基乙氧基)-5-苯基戊基]环戊基]-5-庚烯酸(XII,实施例8)溶于THF(30ml)。加入水(15ml)和磷酸(85wt%,0.67ml),将混合物加热至回流达约2小时。将混合物冷却,加入MTBE(30ml)。分离各相。有机相用盐水(100ml)洗涤一次。在减压下浓缩有机相。加入MTBE(3×50ml),在减压下浓缩,得到标题化合物。
实施例10拉坦前列素;(5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]-5-庚烯酸1-甲基乙基酯(XVI)
将拉坦前列素酸(XV,实施例9)溶于DMF(10ml),加入到碳酸铯(1.6g)的DMF(10ml)浆液中。加入2-碘丙烷(0.49ml),将浆液加热至45℃达约6小时。当反应完全时,加入MTBE(40ml)和水(50ml),将混合物搅拌15分钟。分离各相,含水相用MTBE(20ml)洗涤。合并有机相,浓缩。浓缩液经过色谱纯化(硅胶,150g,230-400目),用MTBE洗脱。汇集适当的部分,浓缩,得到标题化合物。
实施例112-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-1-辛烯基]环戊基]乙酸(XIX)
将(-)氯代二异松蒎醇基硼烷(27.0g)溶于THF(90ml),冷却至-35℃。加入[3aR-[3aα,4α(E),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-氧代-1-辛烯基)-2H-环戊二烯并[b]呋喃-2-酮(XVII,J.Am.Chem.Soc.,96(18),5865-76(1974),7.4g)在THF(30ml)中的混合物,保持混合物的内部温度<-35℃。将混合物在-35至-40℃下搅拌18小时。加入丙酮(12.3ml),将溶液在20-25℃下搅拌2小时。加入MTBE(50ml)和饱和碳酸氢钠水溶液(50ml),将两相混合物搅拌5分钟。分离有机相,用水(50ml)洗涤一次,然后在减压下浓缩。将混合物在回流下与甲醇(75ml)、水(7.5ml)和氢氧化钾(4.76g)搅拌2小时。在减压下浓缩混合物。使浓缩液在水(75ml)与MTBE(75ml)之间分配。分离含水相,用MTBE萃取(2×50ml)。将含水相的pH用盐酸(3M)调至约1.2,搅拌2.5小时。将混合物用氯化钠饱和,然后用MTBE萃取(4×75ml)。合并MTBE混合物,用碳酸钠溶液洗涤(1M,2×50ml)。碳酸钠溶液用MTBE反萃取(2×50ml)。合并MTBE萃取液,浓缩至体积约100ml,然后与氢氧化钾(3.29g)的水(30ml)溶液搅拌1小时。分离含水相,加入到无水枸橼酸(9.68g)的乙酸乙酯(100ml)溶液中。分离各相,含水相用乙酸乙酯萃取(4×50ml)。合并乙酸乙酯萃取液,通过无水硫酸钠(约10g)过滤。在减压下浓缩滤液(温度最高30℃)至体积约100ml。加入乙酸乙酯(100ml),在减压下浓缩混合物(温度最高30℃)至体积约80ml。将所得浆液冷却至-20℃达1小时,然后过滤,得到标题化合物,mp=105-107℃;
NMR(d6-DMSO,400MHz)δ5.37-5.49,4.61,4.58,4.06,3.94,3.76,2.48,2.35,2.11-2.16,1.8,1.27-1.51和0.94;CMR(d6-DMSO,100.6MHz)δ174.48,136.33,131.21,75.65,71.40,69.37,53.79,44.42,44.31,37.80,31.82,31.64,25.16,22.49和14.23。
实施例12(3aS,4S,5S,6aR)-六氢-5-羟基-4-[(1E,3R)-3-羟基-1-辛烯基]-2H-环戊二烯并[b]呋喃-2-酮(XX)
搅拌2-[(1R,2R,3R,5S)-3,5-二羟基-2-[(3R)-3-羟基-1-辛烯基]环戊基]乙酸(XIX,实施例11,2.55g)与MTBE(100ml)和三氯乙酸(0.102g)。将浆液加热至回流达1小时以上。然后加入三乙胺(0.2ml)。将混合物冷却,用水(50ml)洗涤一次。将混合物经无水颗粒状硫酸钠干燥,然后在减压下浓缩,得到标题化合物,
NMR(CDCl3,400MHz)δ5.58,5.43,4.88,4.03,3.92,3.55,2.8,2.71,2.3-2.5,2.22,1.9,1.2-1.6和0.89;CMR(CDCl3,100.6MHz)δ176.94,136.79,130.20,82.41,76.27,72.78,56.12,42.34,39.61,37.05,33.98,31.60,25.06,22.52和13.94。
图A
图B
Claims (23)
2、根据权利要求1的化合物,其中该盐的阳离子选自由钠、钾、锂、铯、R1R2R3N+-H组成的组,其中R1、R2和R3是相同或不同的,是C1-C4烷基、α-甲基苄胺、吡啶、被C1-C4烷基取代的吡啶、苄胺和β-苯乙胺。
3、根据权利要求2的化合物,其中该阳离子的胺是三乙胺或吡啶。
5、15(S)-前列腺素中间体的制备方法,该中间体选自由化合物(IV)
其中:
(1)R3是-H,R4是-H,
(2)R3是-H,R4是-O-CH3和
(3)R3和R4一起构成与苯基环3-与4-位连接的五元环,其中从R3-位至R4-位的第二个环是-CH=CH-O-,
其中
是单键或双键和
其中X11是苯基或被一至三个C1-C4烷基、一至三个C1-C4烷氧基、一个苯基、一至三个-F、-Cl、-Br和-I取代的苯基,和化合物(XVIII)组成的组,
其中X11是如上所定义的,
该方法包含:
(1)使一种化合物与(-)-氯代二异松蒎醇基硼烷接触,该化合物选自化合物(III)
其中R3、R4、X11和
分别是如上所定义的或化合物(XVII),
其中X11是如上所定义的,
同时保持反应混合物的温度在-50℃至0℃范围内,和
(2)使步骤(1)反应混合物与硼配合剂接触,其中硼配合剂选自由水、C1-C6醇和二醇、乙醇胺、二乙醇胺、三乙醇胺及其混合物组成的组。
6、根据权利要求5的方法,其中反应混合物的温度低于-20℃。
7、根据权利要求6的方法,其中反应混合物的温度为-35至-45℃。
8、根据权利要求5的方法,其中使用3至4当量的(-)-氯代二异松蒎醇基硼烷。
9、根据权利要求8的方法,其中使用至少3.5当量的(-)-氯代二异松蒎醇基硼烷。
10、根据权利要求5的方法,其中在步骤(2)之前,使步骤(1)的反应混合物与容易还原的醛或酮接触。
11、根据权利要求10的方法,其中该容易还原的醛或酮选自由C1-C6醛与酮和苯甲醛组成的组。
12、根据权利要求11的方法,其中该容易还原的醛或酮是丙酮或甲乙酮。
13、根据权利要求5的方法,其中该硼配合剂选自由水、C1-C6醇与二醇、乙醇胺、二乙醇胺、三乙醇胺和它们的混合物组成的组。
14、根据权利要求13的方法,其中该硼配合剂选自由水和二乙醇胺组成的组。
15、根据权利要求14的方法,其中该硼配合剂是水。
16、根据权利要求15的方法,其中随着该硼配合剂加入一种碱。
17、根据权利要求16的方法,其中该碱选自由碳酸盐、碳酸氢盐、单-、二-或三-C1-C6烷基胺、吡啶和被C1-C4烷基取代的吡啶组成的组。
18、根据权利要求17的方法,其中该碱是碳酸氢盐或碳酸盐。
19、根据权利要求5的方法,其中在步骤(2)之前或之后,使反应混合物温热至15至25℃。
20、根据权利要求19的方法,其中使反应混合物温热1至3小时。
21、根据权利要求5的方法,其中X11是苯基。
22、根据权利要求5的方法,其中该15(S)-前列腺素中间体是化合物(IV)
已知它是[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-羟基-5-苯基-1-戊烯基)-2H-环戊二烯并[b]呋喃-2-酮。
23、根据权利要求5的方法,其中该15(S)-前列腺素中间体是化合物(XVIII)
已知它是[3aR-[3aα,4α(E),5β,6aα]]-5-(苯甲酰氧基)六氢-4-(3-羟基-1-辛烯基)-2H-环戊二烯并[b]呋喃-2-酮。
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KR100437873B1 (ko) | 2001-05-08 | 2004-06-26 | 연성정밀화학(주) | 프로스타글란딘 유도체의 제조방법 및 그의 입체특이적출발물질 |
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GB0329379D0 (en) * | 2003-12-19 | 2004-01-21 | Johnson Matthey Plc | Prostaglandin synthesis |
US7109371B2 (en) * | 2004-01-05 | 2006-09-19 | Johnson Matthey Public Limited Company | Prostaglandin synthesis |
CN103755737A (zh) * | 2006-02-07 | 2014-04-30 | 株式会社·R-技术上野 | 用于制备前列腺素衍生物的方法 |
JP2008037782A (ja) * | 2006-08-04 | 2008-02-21 | Daiichi Fine Chemical Co Ltd | プロスタグランジン誘導体の製造方法 |
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CN101555221B (zh) * | 2008-04-09 | 2013-01-23 | 明德国际仓储贸易(上海)有限公司 | 一种前列腺素f型衍生物的制造方法 |
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IT1392492B1 (it) | 2008-12-24 | 2012-03-09 | Ind Chimica Srl | Processo per la purificazione del latanoprost, analogo sintetico della prostaglandina pgf2alfa. |
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- 2002-06-24 KR KR1020047000521A patent/KR100581647B1/ko not_active IP Right Cessation
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Also Published As
Publication number | Publication date |
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KR100602549B1 (ko) | 2006-07-20 |
CA2453631A1 (en) | 2003-01-30 |
PL366372A1 (en) | 2005-01-24 |
TWI242551B (en) | 2005-11-01 |
BR0211204A (pt) | 2004-07-13 |
HK1065781A1 (en) | 2005-03-04 |
RU2005123682A (ru) | 2007-01-27 |
JP2007016050A (ja) | 2007-01-25 |
US6689901B2 (en) | 2004-02-10 |
KR20060006980A (ko) | 2006-01-20 |
KR100581647B1 (ko) | 2006-05-22 |
EP1406854A1 (en) | 2004-04-14 |
JP2004535465A (ja) | 2004-11-25 |
CN1533372A (zh) | 2004-09-29 |
ZA200400163B (en) | 2005-01-10 |
IL159632A0 (en) | 2004-06-01 |
RU2004101053A (ru) | 2005-06-27 |
KR20040018457A (ko) | 2004-03-03 |
WO2003008368A1 (en) | 2003-01-30 |
MXPA04000473A (es) | 2004-12-06 |
US20030045571A1 (en) | 2003-03-06 |
AR034797A1 (es) | 2004-03-17 |
RU2267480C2 (ru) | 2006-01-10 |
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