CN111018766B - Method for synthesizing bimatoprost - Google Patents
Method for synthesizing bimatoprost Download PDFInfo
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- CN111018766B CN111018766B CN201811178292.2A CN201811178292A CN111018766B CN 111018766 B CN111018766 B CN 111018766B CN 201811178292 A CN201811178292 A CN 201811178292A CN 111018766 B CN111018766 B CN 111018766B
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- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 title claims abstract description 25
- 229960002470 bimatoprost Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000002194 synthesizing effect Effects 0.000 title claims description 20
- 238000000926 separation method Methods 0.000 claims abstract description 15
- 238000000746 purification Methods 0.000 claims abstract description 10
- 238000001308 synthesis method Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 32
- 230000035484 reaction time Effects 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 230000009471 action Effects 0.000 claims description 17
- -1 alkyl silicon Chemical compound 0.000 claims description 17
- 239000003638 chemical reducing agent Substances 0.000 claims description 17
- 239000008346 aqueous phase Substances 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012448 Lithium borohydride Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000085 borane Inorganic materials 0.000 claims description 3
- PSEHHVRCDVOTID-VMAIWCPRSA-N chloro-bis[(1r,3r,4s,5r)-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-VMAIWCPRSA-N 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005708 Sodium hypochlorite Chemical group 0.000 claims description 2
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical group [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 59
- 238000007086 side reaction Methods 0.000 abstract description 4
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 abstract 2
- 229960001389 doxazosin Drugs 0.000 abstract 2
- 238000002360 preparation method Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 57
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 238000010189 synthetic method Methods 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 5
- 208000010412 Glaucoma Diseases 0.000 description 5
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 4
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- 201000004569 Blindness Diseases 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000004410 intraocular pressure Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- RIAKDKCWGIVRRH-UHFFFAOYSA-N 2-bromopentanoic acid triphenylphosphane Chemical compound CCCC(Br)C(O)=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIAKDKCWGIVRRH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FTUAIEDAAMWBHD-UHFFFAOYSA-N Coriolide Natural products CCCCCC(O)C=CC=C/CCCCCCC=C=O FTUAIEDAAMWBHD-UHFFFAOYSA-N 0.000 description 2
- 206010030043 Ocular hypertension Diseases 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 210000001742 aqueous humor Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
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- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
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Classifications
-
- 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
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of bimatoprost, belonging to the technical field of chemical synthesis. The method adopts the following synthetic route different from the conventional technology to synthesize doxazosin, provides a new synthetic route for the preparation of doxazosin, has the advantages of simple conditions, few side reactions, simple and convenient separation and purification, high yield and high stereoselectivity, and can simply and efficiently obtain bemeprost.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a method for synthesizing bimatoprost.
Background
Glaucoma is the second most common cause of blindness, irreversible blindness, worldwide. Glaucoma is a group of diseases characterized by atrophy and depression of optic papilla, visual field loss and visual deterioration, pathological increased intraocular pressure and insufficient blood supply of optic nerve are primary risk factors of the onset of the diseases, and the tolerance of optic nerve to pressure damage is also related to the occurrence and development of the glaucoma. Obstruction of any ring in the aqueous humor circulatory pathway can lead to pathological changes caused by elevated intraocular pressure, but some patients also present with normal tension glaucoma. Glaucoma is one of three major blinding diseases causing blindness in humans, with a total incidence of 1% and 2% after age 45. Clinically, glaucoma is classified into three major categories, primary, secondary and congenital, according to etiology, angle of the atrium, tonography and the like.
Bemeprost (bimatoprost), with the chemical name of (Z) -7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2 [ (1E,3S) -3-hydroxy-5-phenylpenten-1-yl ] cyclopentyl ] -N-ethylheptylamide-5-ene, is an analogue of prostaglandin fatty acid amide developed by Allergan corporation, is popular after first marketing in the United states in 2001, and is now a first-line drug for treating open-angle glaucoma and ocular hypertension in Europe and America. Bimatoprost is used to lower intraocular pressure in patients with open angle glaucoma and ocular hypertension who are intolerant or inadequately sensitive to other ocular hypotensive agents. Moreover, bimatoprost is believed to lower intraocular pressure by increasing both outflow pathways of aqueous humor through the trabecular meshwork and uveoscleral.
In the existing method for synthesizing bimatoprost, the stability of a synthetic intermediate is poor due to the existence of hydroxyl, side reactions are easy to occur, the yield of each step is low, and the purification is difficult. Even if the hydroxyl group is protected, the phenomena of low reaction yield and more byproducts generally exist, so that the total yield of the bimatoprost is not high.
Disclosure of Invention
Based on the method, the invention provides a method for synthesizing bemeprostat with high stereoselectivity and high yield.
The specific technical scheme is as follows:
a method for synthesizing bimatoprost comprises the following steps:
wherein: r1Is alkyl silicon base; x1、X2Is halogen;
step A: (A1) compounds 1 and R1X1Reacting under the action of a solvent A and an alkali A; (A2) performing suction filtration, and reacting the filtrate under the action of acid A;
and B: the compound 2 reacts under the action of a solvent B and an oxidant B;
and C: reacting the compound 3 with beta-carbonyl dimethoxy butyl phenyl phosphate under the action of a solvent C and a base C;
step D: reacting the compound 4 under the action of a solvent D, a reducing agent D and a catalyst D;
step E: the compound 5 reacts under the action of a solvent E and a reducing agent E;
step F: compound 6 and Ph3P(CH2)4CO2NHEtX2Reacting under the action of a solvent F and an alkali F;
step G: the compound 7 is reacted under the action of the solvent G and the acid G.
In one of the embodiments, the first and second electrodes are,
the R is1Selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl or tert-butyldiphenylsilyl;
said X1、X2Each independently selected from chlorine, bromine or iodine.
In one of the embodiments, the first and second electrodes are,
in the step A, the base A is selected from imidazole, triethylamine, diethyl isopropylamine and piperidine; the acid A is selected from hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, hydrochloric acid methanol solution, and trifluoroacetic acid;
in the step B, the oxidant B is selected from Dess-Martin reagent, activated manganese dioxide, sodium hypochlorite, PCC or PDC;
in step C, the base C is selected from potassium carbonate, sodium hydride, potassium tert-butoxide, tert-butyllithium, imidazole, triethylamine, diisopropylethylamine, piperidine, lutidine, sodium hexamethyldisilazane, potassium hexamethyldisilazane, N-methylmorpholine, 1, 4-diazabicyclo [2.2.2] octane or pyridine;
in the step D, the reducing agent D is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, borane, lithium tri-sec-butylborohydride or (-) -diisopinocampheylchloroborane; the catalyst D is selected from p-toluenesulfonic acid;
in the step E, the reducing agent E is selected from lithium borohydride, sodium borohydride, potassium borohydride, diisopropylaluminum hydride or lithium aluminum hydride;
in step F, the base F is selected from sodium hydride, potassium tert-butoxide, n-butyllithium, sodium hexamethyldisilazane or potassium hexamethyldisilazane;
in the step G, the acid G is selected from trifluoroacetic acid, aluminum trichloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoric acid, sulfuric acid or nitric acid.
4. The method for synthesizing bimatoprost according to claim 1, wherein the solvent A, B, C, D, E, F, G is selected from dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1, 2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, n-hexane and diethyl ether.
In one of the embodiments, the first and second electrodes are,
in step A1, the compound 1 and R1X1The molar ratio of (A) to (B) is 1: 1-10; the reaction temperature is 0-50 ℃, and the reaction time is 1-10 hours; in the step A2, the reaction temperature is 0-50 ℃, and the reaction time is 1-10 hours;
in the step B, the molar ratio of the compound 2 to the oxidant B is 1: 1-5; the reaction temperature is 0-50 ℃; the reaction time is 1-20 hours;
in the step C, the molar ratio of the compound 3, the beta-carbonyl dimethoxy butyl phenyl phosphate and the base C is 1: 1-5; the reaction temperature is 0-50 ℃; the reaction time is 1-10 hours;
in step D, the compound 4, a reducing agent D, catalysts D and R1X1The molar ratio of (a) to (b) is 1: 1-5: 0.05-0.5: 1-5; the reaction temperature is-78-0 ℃; the reaction time is 1-20 hours;
in the step E, the molar ratio of the compound 5 to the reducing agent E is 1: 1-5; the reaction temperature is-78-0 ℃; the reaction time is 1-10 hours;
in step F, the compound 6, a base F and Ph3P(CH2)4CO2NHEtX2In a molar ratio of 1:1 to 5: 1-5; the reaction temperature is-78-0 ℃; the reaction time is 1-10 hours;
in the step G, the molar ratio of the compound 7 to the acid G is 1: 1-5; the reaction temperature is 0-40 ℃; the reaction time is 1 to 10 hours.
In one of the embodiments, the first and second electrodes are,
in step A1, the compound 1 and R1X1The molar ratio of (A) to (B) is 1: 1-5; the reaction temperature is 20-50 ℃, and the reaction time is 5-10 hours; in the step A2, the reaction temperature is 20-50 ℃, and the reaction is carried outThe time of (3) to (7) hours;
in the step B, the molar ratio of the compound 2 to the oxidant B is 1: 1-3; the reaction temperature is 20-40 ℃; the reaction time is 6-12 hours;
in the step C, the molar ratio of the compound 3 to the beta-carbonyl dimethoxy butyl phenyl phosphate and the base C is 1: 1-3: 2-5; the reaction temperature is 20-40 ℃; the reaction time is 1 to 3 hours;
in step D, the compound 4, a reducing agent D, catalysts D and R1X1The molar ratio of (a) to (b) is 1: 2-4: 0.05-0.2: 1-5; the temperature of the reaction is-78 to-30 ℃; the reaction time is 4-8 hours;
in the step E, the molar ratio of the compound 5 to the reducing agent E is 1: 2-4; the temperature of the reaction is-40 to-10 ℃; the reaction time is 2-6 hours;
in step F, the compound 6 is reacted with Ph3P(CH2)4CO2NHEtX2And alkali F in a molar ratio of 1: 1-3: 1-3; the reaction temperature is-78-20 ℃; the reaction time is 5 to 8 hours;
in the step G, the molar ratio of the compound 7 to the acid G is 1: 1-5; the reaction temperature is 20-40 ℃; the reaction time is 6 to 10 hours.
In one embodiment, the reaction described in step F and step C is carried out under an inert gas blanket.
In one embodiment, step A, B, C, D, E, F, G includes a separation and purification step after the reaction is completed.
In one embodiment, the separation and purification steps are: quenching the reaction with a quenching agent, adding an organic solvent and water, standing for layering, extracting the aqueous phase with the organic solvent, combining the organic phases, drying and concentrating.
In one embodiment, the quenching agent is an aqueous ammonium chloride solution, and the organic solvent is ethyl acetate, chloroform or dichloromethane.
Compared with the prior art, the invention has the following beneficial effects:
(1) the inventor of the invention finds that, in the synthesis process of the bemepiride, when a specific alkyl silicon base is selected to protect the hydroxyl group of the synthetic starting material, the chemical properties of the synthetic intermediate obtained in each step are stable, side reactions are not easy to occur, and the yield and the purity of the reaction are improved; in addition, the synthetic intermediate 4 reacts under the action of a specific solvent, a reducing agent and a catalyst, the stereoselectivity of the reaction is high, the obtained target product is of a single configuration, the yield and the purity of the synthetic intermediate 5 are improved, and the separation and purification process is simplified.
(3) Furthermore, the method for synthesizing bemepiride has the advantages of simple conditions of all steps, simple and convenient operation and good substrate expansibility, and can be applied to synthesizing analogues of bemepiride. In the synthesis process, the side reaction of each step is less, the yield is high, and the separation and purification after the reaction are simplified. In the method for synthesizing bemepiride, the target product with higher purity can be obtained by only concentrating or further recrystallizing each synthetic intermediate and bemepiride, so that the heavy column chromatography process in the traditional technology is avoided, the product loss in the separation and purification process is reduced, the yield is further improved, and the purification cost is saved.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1: synthesis of bimatoprost
Taking the lactone (1) in the family as a raw material to synthesize bemeprostinil, wherein the reaction route is shown as follows:
(1) synthesis of Compound 2a
TBSCl (52.6g,350mmol,3.0eq) and imidazole (25.0g,360mmol, 3.0eq) were added to a solution of coriolide (20g,116.2mmol) in dichloromethane (200mL), reacted at room temperature for 8h, suction filtered, a 10% hydrochloric acid solution (80mL) was added to the organic phase, then reacted at room temperature for 5h, quenched with a saturated ammonium chloride solution (150mL), concentrated, dichloromethane (200mL) and water (200mL) were added, allowed to stand for separation, the aqueous phase was extracted with dichloromethane (150mL x 3), washed with a saturated saline solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized with ethyl acetate (180mL) to give compound 2(27.4g, 83%) as a white solid.1H NMR(400MHz,CDCl3):δ4.35(brs,OH),4.25(dd,J＝9.3Hz,J＝2.4Hz,1H),3.65(m,1H),3.61(m,1H),3.41(m,1H),2.38-2.20(m,3H),1.80-1.83(m,2H),1.45(m,1H),0.98(s,9H),0.19(s,6H)ppm.MS(m/z):287(M++1)。
(2) Synthesis of Compound 3a
Dess-Martin oxidant (38.2g,90mmol,1.5eq) was added to a solution of Compound 2(17.06g,60mmol) in dichloromethane (200ml) at a temperature of 0 deg.C, reacted overnight at room temperature, quenched with saturated ammonium chloride solution (200ml), concentrated, dichloromethane (100ml) and water (100ml) were added, allowed to stand for separation, the aqueous phase was extracted with dichloromethane (100 ml. times.3), washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 2 as a yellow solid (16.38g, 96%).1H NMR(400MHz,CDCl3):δ9.73(s,1H),4.27(dd,J＝9.6Hz,J＝2.6Hz,1H),3.68(m,1H),2.41-2.18(m,4H),2.05-1.83(m,2H),1.45(m,1H),0.99(s,9H),0.18(s,6H)ppm.MS(m/z):285(M++1)。
(3) Synthesis of Compound 4a
The mixture was sequentially added to anhydrous THF (100ml) under an argon atmosphereDimethoxybutylphenyl β -carbonylphosphate (13.60g,60.0mmol, 1.0eq) and potassium carbonate (25.0g, 180mmol, 3.0eq) were added and reacted at room temperature for 1 hour, followed by dropwise addition of a THF (75ml) solution of Compound 3(17.04g, 60mmol, 1eq) at-20 ℃ overnight, concentration, addition of ethyl acetate (150ml) and water (80ml), standing for layering, extraction of the aqueous phase with ethyl acetate (150 ml. times.2), washing with saturated brine (70ml), drying over anhydrous sodium sulfate, and concentration to give compound 4a (19.62g, 86%) as a white solid.1H NMR(400MHz,CDCl3):δ7.29-7.16(m,5H),5.68-5.55(m,2H),3.25-3.17(m,2H),2.62(t,J＝6.8Hz,2H),2.11-1.75(m,8H),0.99(s,18H),0.22(s,12H)ppm.MS(m/z):415(M++1)。
(4) Synthesis of Compound 5a
Under argon protection at-50 ℃, sodium borohydride (1.71g,45.0mmol, 3.0eq), TBSCl (22.6g,15mmol,1.0eq), p-toluenesulfonic acid (0.1g) were added dropwise to a THF (100ml) solution of compound 4(5.7g,15mmol,1.0eq), reacted at-50 ℃ for 6h, quenched with a saturated ammonium chloride solution (50ml), concentrated, ethyl acetate (100ml) and water (50ml) were added, the layers were allowed to stand, the aqueous phase was extracted with ethyl acetate (100ml × 2), washed with saturated brine (50ml), dried over anhydrous sodium sulfate, and concentrated to give compound 5a (6.60g, 83%).1H NMR(400MHz,CDCl3):δ7.29-7.16(m,5H),5.68-5.55(m,2H),4.18(m,1H),3.25-3.17(m,2H),2.62(t,J＝6.8Hz,2H),2.11-1.75(m,8H),0.99(s,18H),0.22(s,12H)ppm.MS(m/z):531(M++1)。
(5) Synthesis of Compound 6a
To a solution of compound 5(5.1g,10mmol,1.0eq) in toluene (70ml) was added a solution of diisopropylaluminum hydride in tetrahydrofuran (4M,7.5ml,3.0eq) at-20 ℃ under argon protection for 3h, the reaction was quenched with a saturated solution of ammonium chloride (50ml), concentrated, and ethyl acetate was addedEthyl acetate (100ml) and water (50ml) were allowed to stand for separation, and the aqueous phase was extracted with ethyl acetate (100 ml. times.2), washed with saturated brine (50ml), dried over anhydrous sodium sulfate, and concentrated to give Compound 6a (4.92g, 96%).1H NMR(400MHz,CDCl3):δ7.28-7.15(m,5H),5.66-5.53(m,3H),4.18(m,1H),3.23-3.16(m,2H),2.61(t,J＝6.8Hz,2H),2.09-1.72(m,8H),0.98(s,18H),0.21(s,12H)ppm.MS(m/z):533(M++1)。
(6) Synthesis of Compound 7a
To a solution of compound 6(5.12g,10.0mmol) in THF (100ml) was added successively bromovaleric acid triphenylphosphine salt (6.65,15.0mmol), potassium tert-butoxide (3.36g,30mmol,2.0eq), -78 ℃ for 7h, quenched with saturated ammonium chloride solution (20ml), concentrated, added ethyl acetate (50ml) and water (20ml), allowed to stand for layering, the aqueous phase extracted with ethyl acetate (50ml 2), washed with saturated brine (20ml), dried over anhydrous sodium sulfate, and concentrated to give compound 7(5.20g, 87%).1H NMR(400MHz,CDCl3):δ7.29-7.16(m,5H),5.67-5.42(m,3H),5.35(m,1H),4.15-4.07(m,2H),3.88(t,J＝8.5Hz,1H),3.21-3.14(m,2H),2.75-2.61(m,2H),2.42-1.58(m,13H),1.48(tt,J＝10.2,4.8Hz,1H),1.12(t,J＝7.3Hz,3H)0.98(s,18H),0.21(s,12H)ppm.MS(m/z):644(M++1)。
(7) Synthesis of Compound 8
To a solution of compound 7a (2.99g,5.0mmol) in dichloromethane (50ml) was added p-hydrofluoric acid (10ml) under argon protection, reacted at room temperature for 8h, quenched with saturated ammonium chloride solution (20ml), allowed to stand for separation, the aqueous phase was extracted with dichloromethane (20 ml. times.2), the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, and concentrated to give compound 8(1.84g, 100%).1H NMR(400MHz,CDCl3):δ7.27-7.14(m,5H),5.65-5.41(m,3H),5.33(m,1H),4.13-4.05(m,2H),3.86(t,J＝8.5Hz,1H),3.19-3.13(m,2H),2.73-2.60(m,2H),2.39-1.57(m,13H),1.46(tt,J＝10.2,4.8Hz,1H),1.10(t,J＝7.3Hz,3H)ppm.13C NMR(100MHz,CDCl3):173.3,142.0,135.1,133.2,129.6,129.1,128.4,128.3,125.7,77.6,72.2,72.2,55.4,50.1,42.9,38.7,35.8,34.3,31.8,26.6,25.6,25.3,14.7ppm.MS(m/z):416(M++1)。
Example 2: synthesis of bimatoprost
(1) Synthesis of Compound 2a
TBSCl (52.6g,350mmol,3.0eq) and potassium carbonate (49.6g,360mmol, 3.0eq) were added to a solution of coriolide (20g,116.2mmol) in dichloromethane (200mL), reacted at room temperature for 8h, suction filtered, a 10% hydrochloric acid solution (80mL) was added to the organic phase, then reacted at room temperature for 5h, quenched with a saturated ammonium chloride solution (150mL), concentrated, dichloromethane (200mL) and water (200mL) were added, allowed to stand for separation, the aqueous phase was extracted with dichloromethane (150mL x 3), washed with a saturated saline solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized with ethyl acetate (180mL) to give compound 2 as a white solid (24.7g, 75%).
(2) Synthesis of Compound 3a
PCC oxidant (31.1g,90mmol,1.5eq) was added to a solution of compound 2(17.06g,60mmol) in toluene (200ml) at 0 ℃, the reaction was allowed to react overnight at room temperature, the reaction was quenched with saturated ammonium chloride solution (200ml), concentrated, dichloromethane (100ml) and water (100ml) were added, the mixture was allowed to stand for separation, the aqueous phase was extracted with dichloromethane (100ml × 3), the saturated brine (100ml) was washed, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2(14.8g, 87%) as a yellow body.
(3) Synthesis of Compound 4a
Under the protection of nitrogen, β -carbonyl dimethoxybutylphenyl phosphate (13.60g,60.0mmol, 1.0eq) and piperidine (18.0g, 180mmol, 3.0eq) were added to anhydrous THF (100ml) in this order to react at room temperature for 1 hour, then a solution of compound 3(17.04g, 60mmol, 1eq) in THF (75ml) was added dropwise, reacted at-20 ℃ overnight, concentrated, ethyl acetate (150ml) and water (80ml) were added, the mixture was allowed to stand for layering, the aqueous phase was extracted with ethyl acetate (150ml × 2), washed with saturated brine (70ml), dried over anhydrous sodium sulfate, and concentrated to give compound 4a as a white solid (18.3g, 80%).1H NMR(400MHz,CDCl3):δ7.29-7.16(m,5H),5.68-5.55(m,2H),3.25-3.17(m,2H),2.62(t,J＝6.8Hz,2H),2.11-1.75(m,8H),0.99(s,18H),0.22(s,12H)ppm.MS(m/z):415(M++1)。
(4) Synthesis of Compound 5a
Under argon protection at-50 ℃, sodium borohydride (1.71g,45.0mmol, 3.0eq), TBSCl (22.6g,15mmol,1.0eq), p-toluenesulfonic acid (0.1g) were added dropwise to a THF (100ml) solution of compound 4(5.7g,15mmol,1.0eq), reacted at-50 ℃ for 6h, quenched with a saturated ammonium chloride solution (50ml), concentrated, ethyl acetate (100ml) and water (50ml) were added, the layers were allowed to stand, the aqueous phase was extracted with ethyl acetate (100ml × 2), washed with saturated brine (50ml), dried over anhydrous sodium sulfate, and concentrated to give compound 5a (6.60g, 83%).
(5) Synthesis of Compound 6a
To a solution of compound 5(5.1g,10mmol,1.0eq) in tetrahydrofuran (70ml) was added a solution of sodium borohydride (4M,7.5ml,3.0eq) under argon at-20 ℃ for 3h, the reaction was quenched with a saturated solution of ammonium chloride (50ml), concentrated, ethyl acetate (100ml) and water (50ml) were added, the layers were allowed to stand, the aqueous phase was extracted with ethyl acetate (100ml 2), washed with saturated brine (50ml), dried over anhydrous sodium sulfate and concentrated to give compound 6a (3.92g, 76%).
(6) Synthesis of Compound 7a
To a solution of compound 6(5.12g,10.0mmol) in ethylene glycol dimethyl ether (100ml) were added successively triphenyl phosphine bromovalerate (6.65,15.0mmol), sodium hexamethyldisilazide (30mmol,2.0eq), -78 ℃ for reaction for 7h, quenched with saturated ammonium chloride solution (20ml), concentrated, added ethyl acetate (50ml) and water (20ml), allowed to stand for stratification, the aqueous phase was extracted with ethyl acetate (50ml 2), washed with saturated brine (20ml), dried over anhydrous sodium sulfate, and concentrated to give compound 7a (4.78g, 80%).
(7) Synthesis of Compound 8
To a solution of compound 7a (2.99g,5.0mmol) in methanol (50ml) was added p-toluenesulfonic acid (10ml) under argon protection, reacted at room temperature for 8h, quenched with saturated ammonium chloride solution (20ml), allowed to stand for separation, the aqueous phase was extracted with dichloromethane (20ml × 2), the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, and concentrated to give compound 8a (1.80g, 93%).
Example 3 Synthesis of bimatoprost
(1) Synthesis of Compound 2b
Synthetic methods reference was made to the synthesis of 2a in example 1. (white solid)1H NMR(400MHz,CDCl3):δ4.25(brs,OH),4.13(dd,J＝9.2Hz,J＝2.3Hz,1H),3.56-3.33(m,3H),2.37-2.08(m,3H),1.80-1.83(m,2H),1.42(m,1H),0.95(t,J＝6.6Hz,9H),0.66(q,J＝6.6Hz,6H)ppm.MS(m/z):287(M++1)。
(2) Synthesis of Compound 3b
Synthetic methods reference was made to the synthesis of 3a in example 1.1H NMR(400MHz,CDCl3):δ9.71(s,1H),4.15(dd,J＝9.2Hz,J＝2.5Hz,1H),3.58(m,1H),2.37-2.12(m,4H),2.05-1.83(m,2H),0.96(t,J＝6.6Hz,9H),0.67(q,J＝6.6Hz,6H)ppm.MS(m/z):285(M++1)。
(3) Synthesis of Compound 4b
Synthetic methods reference was made to the synthesis of 4a in example 1.1H NMR(400MHz,CDCl3):δ7.29-7.16(m,5H),5.68-5.55(m,2H),3.25-3.17(m,2H),2.62(t,J＝6.8Hz,2H),2.11-1.75(m,8H),0.96(t,J＝6.6Hz,18H),0.66(q,J＝6.6Hz,6H)ppm.MS(m/z):415(M++1)。
(4) Synthesis of Compound 5b
Synthetic methods reference was made to the synthesis of 5a in example 1.1H NMR(400MHz,CDCl3):δ7.28-7.15(m,5H),5.66-5.53(m,3H),4.18(m,1H),3.23-3.16(m,2H),2.61(t,J＝6.8Hz,2H),2.09-1.72(m,8H),0.96(t,J＝6.6Hz,18H),0.66(q,J＝6.6Hz,12H)ppm.MS(m/z):531(M++1)。
(5) Synthesis of Compound 6b
Synthetic methods reference was made to the synthesis of 6a in example 1.1H NMR(400MHz,CDCl3):δ7.26-7.14(m,5H),5.65-5.52(m,3H),4.16(m,1H),3.22-3.14(m,2H),2.60(t,J＝6.8Hz,2H),2.08-1.71(m,8H),0.97(t,J＝6.6Hz,18H),0.67(q,J＝6.6Hz,12H)ppm.MS(m/z):533(M++1)。
(6) Synthesis of Compound 7b
Synthetic methods reference was made to the synthesis of 7a in example 1.1H NMR(400MHz,CDCl3):δ7.27-7.15(m,5H),5.66-5.41(m,3H),5.33(m,1H),4.14-4.06(m,2H),3.87(t,J＝8.5Hz,1H),3.20-3.12(m,2H),2.74-2.60(m,2H),2.41-1.56(m,13H),1.47(tt,J＝10.2,4.8Hz,1H),1.11(t,J＝7.3Hz,3H),0.97(t,J＝6.6Hz,18H),0.67(q,J＝6.6Hz,12H)ppm.MS(m/z):643(M++1)。
Example 4 Synthesis of bimatoprost
(1) Synthesis of Compound 2c
Synthetic methods reference was made to the synthesis of 2a in example 1.1H NMR(400MHz,CDCl3):δ4.23(brs,OH),4.11(dd,J＝9.2Hz,J＝2.3Hz,1H),3.54-3.31(m,3H),2.37-2.07(m,3H),1.80-1.78(m,2H),1.41(m,1H),0.20(s,9H)ppm.MS(m/z):246(M++1)。
(2) Synthesis of Compound 3c
Synthetic methods reference was made to the synthesis of 3a in example 1.1H NMR(400MHz,CDCl3):δ9.69(s,1H),4.11(dd,J＝9.0Hz,J＝2.4Hz,1H),3.55(m,1H),2.35-2.10(m,4H),2.03-1.80(m,2H),0.20(s,6H)ppm.MS(m/z):243(M++1)。
(3) Synthesis of Compound 4c
Synthetic methods reference was made to the synthesis of 4a in example 1.1H NMR(400MHz,CDCl3):δ7.27-7.16(m,5H),5.66-5.53(m,2H),3.24-3.15(m,2H),2.61(t,J＝6.8Hz,2H),2.10-1.74(m,8H),0.20(s,9H)ppm.MS(m/z):373(M++1)。
(4) Synthesis of Compound 5c
Synthetic methods reference was made to the synthesis of 5a in example 1.1H NMR(400MHz,CDCl3):δ7.26-7.14(m,5H),5.65-5.52(m,3H),4.16(m,1H),3.21-3.15(m,2H),2.60(t,J＝6.8Hz,2H),2.08-1.72(m,8H),0.20(s,18H)ppm.MS(m/z):447(M++1)。
(5) Synthesis of Compound 6c
Synthetic methods reference was made to the synthesis of 6a in example 1.1H NMR(400MHz,CDCl3):δ7.25-7.13(m,5H),5.64-5.52(m,3H),4.16(m,1H),3.21-3.13(m,2H),2.59(t,J＝6.8Hz,2H),2.07-1.71(m,8H),0.20(s,18H)ppm.MS(m/z):449(M++1)。
(6) Synthesis of Compound 7c
Synthetic methods reference was made to the synthesis of 7a in example 1.1H NMR(400MHz,CDCl3):δ7.26-7.14(m,5H),5.65-5.41(m,3H),5.32(m,1H),4.13-4.06(m,2H),3.86(t,J＝8.5Hz,1H),3.20-3.11(m,2H),2.73-2.59(m,2H),2.40-1.55(m,13H),1.46(tt,J＝10.2,4.8Hz,1H),1.11(t,J＝7.3Hz,3H),0.20(s,18H)ppm.MS(m/z):560(M++1)。
Example 5 Synthesis of bimatoprost
(1) Synthesis of Compound 2d
Synthetic methods reference was made to the synthesis of 2a in example 1.1H NMR(400MHz,CDCl3):δ7.60-7.36(m,10H),4.36(brs,OH),4.27(dd,J＝9.2Hz,J＝2.4Hz,1H),3.67(m,1H),3.63(m,1H),3.42(m,1H),2.39-2.22(m,3H),1.81-1.85(m,2H),1.47(m,1H),0.99(s,9H)ppm.MS(m/z):411(M++1)。
(2) Synthesis of Compound 3d
Synthetic methods reference was made to the synthesis of 3a in example 1.1H NMR(400MHz,CDCl3):δ9.75(s,1H),7.60-7.36(m,10H),4.29(dd,J＝9.6Hz,J＝2.6Hz,1H),3.69(m,1H),2.43-2.19(m,4H),2.06-1.85(m,2H),1.47(m,1H),0.99(s,9H)ppm.MS(m/z):409(M++1)。
(3) Synthesis of Compound 4d
Synthetic methods reference was made to the synthesis of 4a in example 1.1H NMR(400MHz,CDCl3):δ7.61-7.37(m,10H),7.29-7.16(m,5H),5.69-5.56(m,2H),3.26-3.18(m,2H),2.63(t,J＝6.8Hz,2H),2.11-1.75(m,8H),0.99(s,9H)ppm.MS(m/z):539(M++1)。
(4) Synthesis of Compound 5d
Synthetic methods reference was made to the synthesis of 5a in example 1.1H NMR(400MHz,CDCl3):δ7.60-7.36(m,10H),7.29-7.16(m,5H),5.69-5.55(m,2H),4.19(m,1H),3.27-3.17(m,2H),2.63(t,J＝6.8Hz,2H),2.12-1.75(m,8H),0.99(s,18H)ppm.MS(m/z):779(M++1)。
(5) Synthesis of Compound 6d
Synthetic methods reference was made to the synthesis of 6a in example 1.1H NMR(400MHz,CDCl3):δ7.61-7.38(m,10H),7.29-7.15(m,5H),5.66-5.53(m,3H),4.19(m,1H),3.24-3.16(m,2H),2.62(t,J＝6.8Hz,2H),2.09-1.72(m,8H),0.99(s,18H)ppm.MS(m/z):781(M++1)。
(6) Synthesis of Compound 7d
Synthetic methods reference was made to the synthesis of 7a in example 1.1H NMR(400MHz,CDCl3):δ7.61-7.38(m,10H),7.29-7.16(m,5H),5.67-5.42(m,3H),5.36(m,1H),4.15-4.07(m,2H),3.88(t,J＝8.5Hz,1H),3.21-3.15(m,2H),2.76-2.62(m,2H),2.43-1.59(m,13H),1.49(tt,J＝10.2,4.8Hz,1H),1.12(t,J＝7.3Hz,3H)0.99(s,18H)ppm.MS(m/z):892(M++1)。
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The synthesis method of bimatoprost is characterized by synthesizing according to the following route:
wherein: r1Is alkyl silicon base; x1、X2Is halogen;
step A: (A1) compounds 1 and R1X1Reacting under the action of a solvent A and an alkali A; (A2) performing suction filtration, and reacting the filtrate under the action of acid A;
and B: reacting the compound 2 under the action of a solvent B and an oxidant B;
and C: reacting the compound 3 with beta-carbonyl dimethoxy butyl phenyl phosphate under the action of a solvent C and a base C;
step D: compound 4 and R1X1Reacting under the action of a solvent D, a reducing agent D and a catalyst D; the reducing agent D is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, borane, lithium tri-sec-butylborohydride or (-) -diisopinocampheylchloroborane, the catalyst D is selected from p-toluenesulfonic acid and boron trifluoride diethyl ether, and the solvent D is selected from dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1, 2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, n-hexane or diethyl ether; in step D, the compound 4, a reducing agent D, catalysts D and R1X1The molar ratio of (a) to (b) is 1: 2-4: 0.05-0.2: 1-5; the temperature of the reaction is-78 to-30 ℃; the reaction time is 4-8 hours;
step E: the compound 5 reacts under the action of a solvent E and a reducing agent E;
step F: compound 6 and Ph3P(CH2)4CO2NHEtX2Reacting under the action of a solvent F and an alkali F; in step F, the compound 6 is reacted with Ph3P(CH2)4CO2NHEtX2And alkali F in a molar ratio of 1: 1-3: 1-3; the reaction temperature is-78-20 ℃; the reaction time is 5 to 8 hours;
step G: the compound 7 is reacted under the action of the solvent G and the acid G.
2. The method for synthesizing bimatoprost according to claim 1,
the R is1Selected from tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl or tert-butyldiphenylsilyl;
said X1、X2Each independently selected from chlorine, bromine or iodine.
3. The method for synthesizing bimatoprost according to claim 1,
in the step A, the base A is selected from imidazole, triethylamine, diethyl isopropylamine and piperidine; the acid A is selected from hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, hydrochloric acid methanol solution, and trifluoroacetic acid;
in the step B, the oxidant B is selected from Dess-Martin reagent, activated manganese dioxide, sodium hypochlorite, PCC or PDC;
in step C, the base C is selected from potassium carbonate, sodium hydride, potassium tert-butoxide, tert-butyllithium, imidazole, triethylamine, diisopropylethylamine, piperidine, lutidine, sodium hexamethyldisilazane, potassium hexamethyldisilazane, N-methylmorpholine, 1, 4-diazabicyclo [2.2.2] octane or pyridine;
in the step D, the reducing agent D is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, borane, lithium tri-sec-butylborohydride or (-) -diisopinocampheylchloroborane; the catalyst D is selected from p-toluenesulfonic acid and boron trifluoride diethyl etherate;
in the step E, the reducing agent E is selected from lithium borohydride, sodium borohydride, potassium borohydride, diisopropylaluminum hydride or lithium aluminum hydride;
in step F, the base F is selected from sodium hydride, potassium tert-butoxide, n-butyllithium, sodium hexamethyldisilazane or potassium hexamethyldisilazane;
in the step G, the acid G is selected from trifluoroacetic acid, aluminum trichloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoric acid, sulfuric acid or nitric acid.
4. The method for synthesizing bimatoprost according to claim 1, wherein the solvent A, B, C, D, E, F, G is selected from dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1, 2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, n-hexane and diethyl ether.
5. The method for synthesizing bimatoprost according to claim 1,
in step A1, the compound 1 and R1X1The molar ratio of (A) to (B) is 1: 1-10; the reaction temperature is 0-50 ℃, and the reaction time is 1-10 hours; in the step A2, the reaction temperature is 0-50 ℃, and the reaction time is 1-10 hours;
in the step B, the molar ratio of the compound 2 to the oxidant B is 1: 1-5; the reaction temperature is 0-50 ℃; the reaction time is 1-20 hours;
in the step C, the molar ratio of the compound 3, the beta-carbonyl dimethoxy butyl phenyl phosphate and the base C is 1: 1-5; the reaction temperature is 0-50 ℃; the reaction time is 1-10 hours;
in the step D, the reaction temperature is-50 ℃;
in the step E, the molar ratio of the compound 5 to the reducing agent E is 1: 1-5; the reaction temperature is-78-0 ℃; the reaction time is 1-10 hours;
in the step F, the reaction temperature is-78 ℃;
in the step G, the molar ratio of the compound 7 to the acid G is 1: 1-5; the reaction temperature is 0-40 ℃; the reaction time is 1 to 10 hours.
6. The method for synthesizing bemeprostane according to claim 5,
in step A1, the compound 1 and R1X1The molar ratio of (A) to (B) is 1: 1-5; the reaction temperature is 20-50 ℃, and the reaction time is 5-10 hours; in the step A2, the reaction temperature is 20-50 ℃, and the reaction time is 3-7 hours;
in the step B, the molar ratio of the compound 2 to the oxidant B is 1: 1-3; the reaction temperature is 20-40 ℃; the reaction time is 6-12 hours;
in the step C, the molar ratio of the compound 3 to the beta-carbonyl dimethoxy butyl phenyl phosphate and the base C is 1: 1-3: 2-5; the reaction temperature is 20-40 ℃; the reaction time is 1 to 3 hours;
in the step D, the reaction time is 6 hours;
in the step E, the molar ratio of the compound 5 to the reducing agent E is 1: 2-4; the temperature of the reaction is-40 to-10 ℃; the reaction time is 2-6 hours;
in the step F, the reaction time is 7 hours;
in the step G, the molar ratio of the compound 7 to the acid G is 1: 1-5; the reaction temperature is 20-40 ℃; the reaction time is 6 to 10 hours.
7. The method for synthesizing bimatoprost according to any one of claims 1 to 6, wherein the reactions of steps F and C are carried out under an inert gas atmosphere.
8. The method for synthesizing bimatoprost according to any one of claims 1 to 6, further comprising a separation and purification step after the completion of the reaction in step A, B, C, D, E, F, G.
9. The method for synthesizing bimatoprost according to claim 8,
the separation and purification steps are as follows: quenching the reaction with a quenching agent, adding an organic solvent and water, standing for layering, extracting the aqueous phase with the organic solvent, combining the organic phases, drying and concentrating.
10. The method for synthesizing bimatoprost according to claim 9, wherein the quenching agent is an aqueous ammonium chloride solution, and the organic solvent is ethyl acetate, chloroform, or dichloromethane.
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