WO2017193913A1 - 一种福沙匹坦磷酸酯中间体及其制备方法 - Google Patents
一种福沙匹坦磷酸酯中间体及其制备方法 Download PDFInfo
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- WO2017193913A1 WO2017193913A1 PCT/CN2017/083630 CN2017083630W WO2017193913A1 WO 2017193913 A1 WO2017193913 A1 WO 2017193913A1 CN 2017083630 W CN2017083630 W CN 2017083630W WO 2017193913 A1 WO2017193913 A1 WO 2017193913A1
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- WIPO (PCT)
- Prior art keywords
- base
- group
- phosphate intermediate
- solvent
- preparation
- Prior art date
Links
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 39
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 39
- 239000010452 phosphate Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 229960002891 fosaprepitant Drugs 0.000 title abstract description 5
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 16
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 21
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 claims description 21
- 229960001372 aprepitant Drugs 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 16
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 229960004699 valsartan Drugs 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 10
- OKJPEAGHQZHRQV-UHFFFAOYSA-N iodoform Chemical compound IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 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
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- -1 halogenated methane compound Chemical class 0.000 claims description 3
- 238000006366 phosphorylation reaction Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004338 Dichlorodifluoromethane Substances 0.000 claims description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 2
- 235000019404 dichlorodifluoromethane Nutrition 0.000 claims description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 2
- 229940029284 trichlorofluoromethane Drugs 0.000 claims description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 claims 2
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 claims 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N lithium oxide Chemical compound [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 claims 1
- 229910001947 lithium oxide Inorganic materials 0.000 claims 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims 1
- YXJYBPXSEKMEEJ-UHFFFAOYSA-N phosphoric acid;sulfuric acid Chemical compound OP(O)(O)=O.OS(O)(=O)=O YXJYBPXSEKMEEJ-UHFFFAOYSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 229940044880 fosaprepitant dimeglumine Drugs 0.000 abstract 1
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- CUGDYSSBTWBKII-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(dimethylamino)hexane-1,2,3,4,5-pentol Chemical compound CN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO CUGDYSSBTWBKII-LXGUWJNJSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 206010047700 Vomiting Diseases 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 2
- XUVHCEGOKVEAGV-UHFFFAOYSA-N 2,3,4,8,9,10-hexahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCN=C21 XUVHCEGOKVEAGV-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@](c1cc(*)cc(C(F)(F)F)c1)O[C@@]1OCCN(CC(NC2=O)=NN2P(O*)(O*)=O)[C@]1c(cc1)ccc1F Chemical compound C[C@](c1cc(*)cc(C(F)(F)F)c1)O[C@@]1OCCN(CC(NC2=O)=NN2P(O*)(O*)=O)[C@]1c(cc1)ccc1F 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- UGJUJYSRBQWCEK-GGXTVIBHSA-N [5-[[(2r,3s)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-3-oxo-1h-1,2,4-triazol-2-yl]phosphonic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 UGJUJYSRBQWCEK-GGXTVIBHSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XNINJQATBBNSIK-UHFFFAOYSA-N benzyl methyl hydrogen phosphite Chemical compound COP(O)OCC1=CC=CC=C1 XNINJQATBBNSIK-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002351 wastewater 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
Definitions
- the invention belongs to the field of medicine, and particularly relates to a fusidaptan phosphate intermediate which is a key intermediate for treating and preventing chemotherapy-induced acute nausea and vomiting drug fushapitate dimethylglucamine, and a preparation method thereof, and a preparation method thereof Method for preparing fusidapride dimethylglucamine from such intermediates
- Aprepitant is developed by Merck as the first NK-1 receptor antagonist, which can significantly prevent acute nausea and vomiting caused by chemotherapy, and its outstanding advantage is that it can also be used to prevent vomiting in chemotherapy. Delayed vomiting, but aprepitant is difficult to dissolve in water, can only be taken orally, and sometimes oral administration of vomiting patients is difficult to achieve. Fushapitate is a prodrug of aprepitant, which is easily soluble in water and rapidly converted into aprepitant in the body. Its clinical efficacy and safety are comparable to those of aprepitant. Injectable dosage form, which can be replaced by rectal or intravenous administration during the treatment, so fosapride dimethylglucamine is a good supplement for oral aprepitant.
- valsartan dimethylglucamine 1-deoxy-1-(methylamino)-D-glucitol [3-[[(2R,3S)-2-[(1R)-1-[ 3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo -1H-1,2,4-triazol-1-yl]phosphonate, the structural formula is as follows:
- the method is to change the base and the reaction solvent, using DMF (N, N-dimethylformamide), sulfolane, DMSO (dimethyl sulfoxide) or NMP (N-methylpyrrolidone).
- the solvent is prepared by using lithium hydroxide, sodium hydroxide, potassium hydroxide, DBU or DBN as a base to prepare a fusididine phosphate intermediate.
- the condition utilizes a high boiling point solvent, and the post-treatment produces a large amount of waste water, and the whole process environment is poor in friendliness, and is not suitable for mass commercial production.
- the object of the present invention is to provide a preparation method of Fosaprepitant phosphate (IV), which has the advantages of easy raw materials, mild conditions, high yield, simple process and suitable for industrial production.
- the specific synthesis method is as follows:
- R 1 and R 2 are each independently selected from a C1-C7 alkyl group or a benzyl group; preferably a methyl group, an ethyl group, or a benzyl group.
- the invention relates to a method for preparing a fusipitan phosphate intermediate, characterized in that Aprepitant (I) and phosphite (II) undergo phosphorylation in a solvent under the action of a halogenated alkane and a base to obtain a fusidabant phosphate intermediate (IV) which is a key intermediate of fusidtan.
- the halogenated alkane is selected from the group consisting of a halogenated methane compound such as carbon tetrachloride, tetrabromomethane, trichlorofluoromethane, trichlorobromomethane, dichlorodifluoromethane or triiodomethane. More preferably, the halogenated alkane is selected from the group consisting of carbon tetrachloride, trichlorobromomethane and triiodomethane.
- a halogenated methane compound such as carbon tetrachloride, tetrabromomethane, trichlorofluoromethane, trichlorobromomethane, dichlorodifluoromethane or triiodomethane.
- the base is selected from the group consisting of common organic bases such as pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undecene- 7-ene (DBU), or a commonly used inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate; more preferably triethylamine, diisopropylethylamine, 4 - dimethylaminopyridine, sodium hydroxide, potassium hydroxide.
- common organic bases such as pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undecene- 7-ene (DBU), or a commonly used inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate
- the solvent is selected from the usual polar solvents such as dichloromethane, acetonitrile, chloroform, tetrahydrofuran, methyl tert-butyl ether.
- the phosphorylation reaction temperature is from -10 ° C to 30 ° C.
- the molar ratio of aprepitant to phosphite (II) in the reaction is 1 to 1 to 1 to 2; the molar ratio of aprepitant to halogenated alkane is 1 to 2 to 1 ratio 10; the molar ratio of aprepitant to base is 1 to 1 to 1 to 2.
- the present invention further provides a compound of formula IV-A or a pharmaceutically acceptable salt thereof, wherein R 1, R 2 independently selected from methyl, ethyl or benzyl, and R 1, R 2 are not simultaneously a benzyl group.
- R 1 and R 2 are both methyl or ethyl, as shown in formula IV-A1 or formula IV-A2.
- This type of compound is a compound of apreventan (I) and phosphite (II) which is phosphorylated in a solvent under the action of a halogenated alkane (III) and a base to give a key intermediate of valsartan. Phosphate intermediate (IV).
- the invention also relates to a process for the preparation of valsartan dimethyl glucamine using a compound of formula IV-A, It is characterized by:
- the fusididine phosphate intermediate (IV-A) is reacted in a mixture of a solvent and water under the action of a base, the pH is adjusted with an acid solution, and the crystals are filtered and crystallized to obtain valsartan.
- the volume ratio of the fushapitant phosphate intermediate (IV-A) to the solvent is 1: (5-20); the fushapitant phosphate intermediate (IV-A) and water
- the molar ratio is 1: (2.0-10.0); the molar ratio of the fushapitant phosphate intermediate (IV-A) to the base is 1: (2.0 to 4.0).
- the solvent is a lower alcohol
- the lower alcohol referred to in the present invention means an alcohol compound having 1 to 7 carbon atoms, such as methanol, ethanol or the like, preferably methanol.
- the base is selected from an organic base or an inorganic base
- the organic base comprises pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4 .0] one or more of undec-7-ene (DBU);
- the inorganic base comprising one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate Or more; preferably sodium hydroxide or potassium hydroxide.
- the acid solution is a 1N to 3N solution of hydrochloric acid in the solvent.
- the pH is adjusted to 1-2.
- the preparation method of the fusididine phosphate intermediate (IV) of the invention has the advantages of easy availability of raw materials, mild conditions, high yield, simple process, etc., which reduces the production cost and is beneficial to the production. Industrial production.
- aprepitant can be purchased in bulk.
- Example 2 Fosapate phosphate intermediate (IV, wherein R 1 and R 2 are methyl)
- Example 3 Fosapate phosphate intermediate (IV, wherein R 1 and R 2 are ethyl)
- Example 6 Fosapate phosphate intermediate (IV, wherein R 1 is benzyl and R 2 is methyl).
- Example 7 Preparation of valsartan dimethyl glucamine from a fusididine phosphate intermediate (IV, wherein R 1 , R 2 are methyl).
- the fushapitant phosphate intermediate (IV, wherein R 1 , R 2 is methyl) prepared according to Example 2 was dissolved in 120 mL of methanol, and 5.8 g of KOH and 1.2 g of water were added thereto, and the temperature was raised to 25-30. The reaction was carried out at ° C for 20 hours until the starting material was completely converted. After dropping to room temperature, the pH was gradually adjusted with a 2N hydrochloric acid methanol solution, and the precipitated solid was removed by filtration. After concentrating methanol to 38 mL of methyl tert-butyl ether, crystals were precipitated, and after filtration, a solid fushapittan was obtained.
- Example 8 Preparation of valsartan dimethyl glucamine from a fusididine phosphate intermediate (IV, wherein R 1 , R 2 is ethyl).
- the fushapitant phosphate intermediate (IV, wherein R 1 , R 2 is ethyl) prepared according to Example 3 was dissolved in 120 mL of methanol, added with 2.5 g of NaOH and 1.1 g of water, and heated to 25- The reaction was carried out at 30 ° C for 36 hours until the starting material was completely converted. After dropping to room temperature, the pH was gradually adjusted with a 2N hydrochloric acid methanol solution, and the precipitated solid was removed by filtration. After concentrating methanol to 30 mL of methyl tert-butyl ether, crystals were precipitated, and after filtration, a solid fushapittan was obtained.
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Abstract
提供一种福沙匹坦磷酸酯中间体(IV)的制备方法、福沙匹坦磷酸酯中间体(IV-A)以及使用中间体(IV-A)制备福沙匹坦二甲葡胺的方法（AA），IV：R 1、R 2独立地选自C1-C7烷基或苄基； IV-A：R 1、R 2独立地选自C1-C7烷基或苄基，并且R 1、R 2不同时为苄基。
Description
本发明属于医药领域，具体涉及一种用于治疗和预防化疗引起的急性恶心和呕吐药物福沙匹坦二甲葡胺的关键中间体福沙匹坦磷酸酯中间体及其制备方法，以及由该类中间体制备福沙匹坦二甲葡胺的方法
阿瑞匹坦是由默沙东公司开发的作为第一个NK-1受体拮抗，它可以明显有效的预防化疗引起的急性恶心和呕吐，而其突出优点是还可以用于预防化疗中的呕吐和延迟性呕吐,但是阿瑞匹坦难溶于水，只能口服，有时呕吐患者口服给药难以实现。福沙匹坦二甲葡胺是阿瑞吡坦的前体药物，易溶于水，在体内迅速转化成阿瑞匹坦，其临床疗效和安全性与阿瑞匹坦是相当的，且是注射剂型，在治疗过程中，其可以通过直肠或静脉给药的方式代替口服，所以福沙吡坦二甲葡胺对于口服阿瑞匹坦来说是个很好的补充。
福沙匹坦二甲葡胺的化学名为：1-脱氧-1-(甲基氨基)-D-葡萄糖醇[3-[[(2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)-4-吗啉基]甲基]-2,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]膦酸盐，其结构式如下：
而福沙匹坦磷酸酯作为制备福沙匹坦二甲葡胺的必备中间体的制备，是商业化中非常重要的一环，原研专利CN1075812C和WO2010018595均报道了同一种合成方法，如下式所示，即用阿瑞匹坦与焦亚磷酸四苄酯，在超低温条件下反应，以六甲基氨基钠为碱来制备福沙匹坦磷酸酯中间体。整个反应条件相对苛刻，需要利用强碱在低温下进行，工艺复杂，条件严苛，且工艺收率不
高。
专利WO201145817报道了另一种合成方法。如下式所示，该方法是将碱和反应溶剂进行了变化，采用DMF(N,N-二甲基甲酰胺)、环丁砜、DMSO(二甲亚砜)或NMP(N-甲基吡咯烷酮)为溶剂，采用氢氧化锂，氢氧化钠，氢氧化钾，DBU或者DBN为碱制备福沙匹坦磷酸酯中间体。该条件利用高沸点溶剂，后处理产生大量废水，整个工艺环境友好度差，不适合大量商业化生产。
鉴于目前福沙匹坦磷酸酯中间体的制备路线较少，且成本较高，故开发工艺简洁、条件温和、收率较高的合成路线是非常必要的。
发明内容
本发明的目的是提供一种福沙匹坦磷酸酯中间体(Fosaprepitant phosphate，IV)的制备方法，该制备方法原料易得、条件温和、收率高、工艺简洁、适合工业化生产。具体合成方法如下所示：
其中，R1、R2各自独立地选自C1-C7烷基或苄基；优选为甲基、乙基，苄基。
本发明涉及一种福沙匹坦磷酸酯中间体的制备方法，其特征在于，阿瑞匹
坦(Aprepitant，I)与亚磷酸酯(II)在卤代烷烃和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦关键中间体的福沙匹坦磷酸酯中间体(IV)。
优选地，所述卤代烷烃选自卤代甲烷类化合物，如：四氯化碳、四溴甲烷、三氯氟甲烷、三氯溴甲烷、二氯二氟甲烷、三碘甲烷。更优选地，所述的卤代烷烃选自四氯化碳、三氯溴甲烷和三碘甲烷。
优选地，所述碱选自常用有机碱，如吡啶、三乙胺、二异丙基乙胺、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)，或常用的无机碱，如氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸铯；更优选为三乙胺、二异丙基乙胺、4-二甲氨基吡啶、氢氧化钠、氢氧化钾。
优选地，所述溶剂选自常用极性溶剂，如二氯甲烷、乙腈、氯仿、四氢呋喃、甲基叔丁基醚。
优选地，所述磷酰化反应温度为-10℃～30℃。
优选地，所述反应中阿瑞吡坦的用量与亚磷酸酯(II)的摩尔比为1比1到1比2；阿瑞吡坦用量和卤代烷烃的摩尔比为1比2到1比10；阿瑞吡坦用量和碱的摩尔比为1比1到1比2。
本发明另外提供了一种式IV-A化合物或其可药用盐，其中R1、R2独立地选自甲基、乙基或苄基，并且R1、R2不同时为苄基。优选R1、R2同时为甲基或同时为乙基，如式IV-A1或式IV-A2所示。这类化合物是阿瑞匹坦(I)与亚磷酸酯(II)在卤代烷烃(III)和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦关键中间体的福沙匹坦磷酸酯中间体(IV)。
本发明还涉及一种使用式IV-A的化合物制备福沙匹坦二甲葡胺的方法，
其特征在于：
将福沙匹坦磷酸酯中间体(IV-A)于溶剂和水的混合液中在碱的作用下发生反应，以酸溶液调节pH，过滤析晶，得到福沙匹坦。
进一步地，将所得福沙匹坦与N-甲基-D-葡糖胺反应、析晶，得到福沙匹坦二甲葡胺。
优选地，所述福沙匹坦磷酸酯中间体(IV-A)与溶剂的体积比为1:(5～20)；所述福沙匹坦磷酸酯中间体(IV-A)与水的摩尔比为1:(2.0-10.0)；所述福沙匹坦磷酸酯中间体(IV-A)与碱的摩尔比为1:(2.0～4.0)。
优选地，所述溶剂为低级醇，本发明所称低级醇为指具有1～7个碳原子的醇类化合物，如甲醇、乙醇等，优选甲醇。
优选地，所述的碱选自有机碱或无机碱，所述有机碱包含吡啶、三乙胺、二异丙基乙胺、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)中的一种或多种；所述无机碱包含氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸铯中的一种或多种；优选为氢氧化钠或氢氧化钾。
优选地，所述的酸溶液为盐酸于所述溶剂中的1N～3N的溶液。
优选地，将pH调节为1～2。
与现有技术相比，本发明所述的福沙匹坦磷酸酯中间体(IV)的制备方法具有原料易得、条件温和、收率高、工艺简洁等优点，降低了生产成本，有利于工业生产。
为了进一步了解本发明，下面结合实施例对本发明具体实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。本发明使用的起始物料阿瑞吡坦可大宗采购。
实施例1：福沙匹坦磷酸酯中间体(IV，其中R1、R2为苄基)
在500mL反应瓶中加入二氯甲烷200mL和阿瑞匹坦(I)20g，25℃时
搅拌至溶清。再依次加入亚磷酸二苄酯9.8g，四氯化碳11.5g，将反应降温至0-5℃，滴加3.79g三乙胺，保持0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(IV)27.5g，收率92.4％。1H NMR(400MHz,CDCl3):δ1.15-1.25(m,2H),1.45(d,3H),2.48(td,1H),2.75(d,1H),2.86(d,2H),3.2(m,1H),3.46(m,2H),3.64(m,1H),4.19(td,1H),4.30(d,1H),4.87(q,1H),5.22(m,4H),7.07(d,2H),7.12(s,2H),7.28(m,4H),7.34(m,4H),7.63(s,1H),9.44(s,1H).Mass:795.2[M+H]+。
实施例2：福沙匹坦磷酸酯中间体(IV，其中R1、R2为甲基)
在500mL反应瓶中加入甲基叔丁基醚100mL和阿瑞匹坦(I)10g，25℃时搅拌至溶清。再依次加入亚磷酸二甲酯3.1g和三氯溴甲烷18.6g，将反应降温至0-5℃，滴加3.6g二异丙基乙胺，反应升至20-30℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入50mL水后用100mL*2次二氯甲烷萃取。合并二氯甲烷层以50mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(IV，其中R1、R2为甲基)10.9g，收率90.6％。1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.77(q,J＝1.8Hz,1H),7.64(t,J＝2.1Hz,1H),7.37(dt,J＝3.0,1.5Hz,1H),7.31(ddd,J＝7.1,5.8,1.1Hz,2H),7.18–7.10(m,2H),5.58(d,J＝7.0Hz,1H),4.68(qt,J＝6.8,1.0Hz,1H),4.17–4.00(m,3H),3.98(dt,J＝7.0,1.0Hz,1H),3.81(d,J＝12.5Hz,1H),3.39(d,J＝10.8Hz,6H),2.93(ddd,J＝12.5,11.2,3.5Hz,1H),2.44(dt,J＝12.6,1.8Hz,1H),1.49(d,J＝6.9Hz,3H).Mass:643.1[M+H]+。
实施例3：福沙匹坦磷酸酯中间体(IV，其中R1、R2为乙基)
在500mL反应瓶中加入氯仿133mL和阿瑞匹坦(I)13.3g，25℃时搅拌至溶清。再依次加入亚磷酸二乙酯6.87g和三碘甲烷98.0g，将反应降温至0-5℃，滴加6.1g的4-二甲氨基吡啶，反应升至10-20℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入130mL水后用270
mL*2次二氯甲烷萃取。合并二氯甲烷层以130mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(IV，其中R1、R2为乙基)15.1g，收率90.4％。1H NMR(400MHz,CDCl3)δ8.13(s,1H),7.77(q,J＝1.7Hz,1H),7.64(q,J＝2.5,2.0Hz,1H),7.37(t,J＝1.8Hz,1H),7.31(ddd,J＝7.0,5.8,1.1Hz,2H),7.14(dd,J＝8.9,7.5Hz,2H),5.59(d,J＝6.9Hz,1H),4.73–4.64(m,1H),4.18–4.02(m,5H),4.04–3.95(m,2H),3.92–3.78(m,2H),3.64(dp,J＝12.5,8.1Hz,1H),2.94(ddd,J＝12.5,11.1,3.5Hz,1H),2.43(dt,J＝12.7,1.9Hz,1H),1.49(d,J＝6.9Hz,3H),1.20(t,J＝8.0Hz,3H),1.12(t,J＝7.9Hz,3H).Mass:671.2[M+H]+。
实施例4：福沙匹坦磷酸酯中间体(IV，其中R1、R2为苄基)
在500mL反应瓶中加入乙腈200mL和阿瑞匹坦(Aprepitant，I)20g，25℃时搅拌至溶清。再依次加入亚磷酸二苄酯14.7g，四氯化碳28.9g，将反应降温至-10-0℃，滴加含有3.1g KOH的水溶液25mL，保持反应0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(IV)25.8g，收率88.4％。1H NMR(400MHz,CDCl3):δ1.15-1.25(m,2H),1.45(d,3H),2.48(td,1H),2.75(d,1H),2.86(d,2H),3.2(m,1H),3.46(m,2H),3.64(m,1H),4.19(td,1H),4.30(d,1H),4.87(q,1H),5.22(m,4H),7.07(d,2H),7.12(s,2H),7.28(m,4H),7.34(m,4H),7.63(s,1H),9.44(s,1H).Mass:795.2[M+H]+。
实施例5：福沙匹坦磷酸酯中间体(IV，其中R1、R2为苄基)
在500mL反应瓶中加入四氢呋喃200mL和阿瑞匹坦(I)20g，25℃时搅拌至溶清。再依次加入亚磷酸二苄酯12.8g，四氯化碳28.9g，将反应降温至-10-0℃，滴加含有2.5gNaOH的水溶液20mL，保持反应0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，以甲基叔丁基醚打浆，
得福沙匹坦磷酸酯中间体(IV)26.2g，收率89.8％。1H NMR(400MHz,CDCl3):δ1.15-1.25(m,2H),1.45(d,3H),2.48(td,1H),2.75(d,1H),2.86(d,2H),3.2(m,1H),3.46(m,2H),3.64(m,1H),4.19(td,1H),4.30(d,1H),4.87(q,1H),5.22(m,4H),7.07(d,2H),7.12(s,2H),7.28(m,4H),7.34(m,4H),7.63(s,1H),9.44(s,1H).Mass:795.2[M+H]+。
实施例6：福沙匹坦磷酸酯中间体(IV，其中R1为苄基、R2为甲基)。
在500mL反应瓶中加入二氯甲烷200mL和阿瑞匹坦(I)20g，25℃时搅拌至溶清。再依次加入亚磷酸一甲酯一苄酯9.8g，四氯化碳15.0g，将反应降温至0-5℃，加入3.8g三乙胺，保持0-10℃反应16-24小时直至TLC显示原料消失。向反应液中加入稀盐酸调节pH至中性，加入100mL水后用200mL*2次二氯甲烷萃取。合并二氯甲烷层以100mL*2次的5％NaCl溶液水洗。将二氯甲烷层以无水硫酸镁干燥后，将溶剂置换为以甲基叔丁基醚打浆，得福沙匹坦磷酸酯中间体(IV，R1为苄基、R2为甲基)21.7g，收率81.1％。1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.77(t,J＝1.8Hz,1H),7.65–7.61(m,1H),7.50(dq,J＝1.9,1.0Hz,1H),7.47–7.41(m,2H),7.41–7.29(m,5H),7.26–7.18(m,2H),5.51(d,J＝6.9Hz,1H),5.03(dd,J＝8.5,1.7Hz,2H),4.73(dd,J＝6.9,1.0Hz,1H),3.95(dd,J＝15.9,12.0Hz,2H),3.73(dt,J＝6.9,1.1Hz,1H),3.66(d,J＝12.2Hz,1H),3.39(d,J＝10.8Hz,3H),1.52(d,J＝6.8Hz,3H).Mass:719.2[M+H]+。
实施例7：由福沙匹坦磷酸酯中间体(IV，其中R1、R2为甲基)制备福沙匹坦二甲葡胺。
将根据实施例2制备的福沙匹坦磷酸酯中间体(IV，其中R1、R2为甲基)15.3g溶于120mL甲醇中，加入5.8g KOH和1.2g水，升温至25-30℃反应20小时至原料完全转化。降至室温后，以2N的盐酸甲醇溶液缓慢调节pH＝1后，将析出的固体过滤除去。将甲醇浓缩置换为38mL甲基叔丁基醚后析出结晶，过滤后得到固体福沙匹坦。将上述固体溶于44mL甲醇中，加入10.2g的N-甲基-D-葡糖胺，室温搅拌2-3小时后，将溶液缓慢滴入132mL异丙醇中，析晶得到福沙匹坦二甲葡胺19.1g，收率83.4％。Mass:615.4[M+H]+。
实施例8：由福沙匹坦磷酸酯中间体(IV，其中R1、R2为乙基)制备福沙匹坦二甲葡胺。
将根据实施例3制备的福沙匹坦磷酸酯中间体(IV，其中R1、R2为乙基)10.5g，溶于120mL甲醇中，加入2.5g NaOH和1.1g水，升温至25-30℃反应36小时至原料完全转化。降至室温后，以2N的盐酸甲醇溶液缓慢调节pH＝1后，将析出的固体过滤除去。将甲醇浓缩置换为30mL甲基叔丁基醚后析出结晶，过滤后得到固体福沙匹坦。将上述固体溶于29mL甲醇中，加入6.7g的N-甲基-D-葡糖胺，室温搅拌2-3小时后，将溶液缓慢滴入87mL异丙醇中，析晶得到福沙匹坦二甲葡胺12.9g，收率82.2％。Mass:615.4[M+H]+。
本发明提出的一种福沙匹坦磷酸酯中间体的制备方法已通过实施例进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的福沙匹坦磷酸酯中间体的制备方法进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明的精神、范围和内容中。
Claims (22)
- 一种福沙匹坦磷酸酯中间体(IV)的制备方法，其特征在于，阿瑞吡坦(I)与亚磷酸酯(II)在卤代烷烃和碱的作用下在溶剂中发生磷酰化反应得到福沙匹坦磷酸酯中间体(IV)，其中R1、R2独立地选自C1-C7的烷基或苄基：
- 根据权利要求1所述的制备方法，其特征在于，所述R1、R2独立地选自甲基、乙基或苄基。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述卤代烷烃选自卤代甲烷类化合物，如：四氯化碳、四溴甲烷、三氯氟甲烷、三氯溴甲烷、二氯二氟甲烷、三碘甲烷。
- 根据权利要求3所述的制备方法，其特征在于，所述卤代烷烃选自四氯化碳、三氯溴甲烷和三碘甲烷。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述碱为常用的有机碱，如：吡啶、三乙胺、二异丙基乙胺、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)，或常用的无机碱，如：氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸铯。
- 根据权利要求5所述的制备方法，其特征在于，所述碱选自三乙胺、二异丙基乙胺、4-二甲氨基吡啶、氢氧化钠和氢氧化钾。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述溶剂选自二氯甲烷、乙腈、氯仿、四氢呋喃和甲基叔丁基醚。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述磷酰化反应温度为-10℃～30℃。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述阿瑞吡坦用量与亚磷酸酯的摩尔比为1比1到1比2。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述阿瑞吡坦用量和卤代烷烃的摩尔比为1比2到1比10。
- 根据权利要求1～2任一项所述的制备方法，其特征在于，所述阿瑞吡坦用量和碱的摩尔比为1比1到1比2。
- 式IV-A化合物或其可药用盐：
其特征在于，R1、R2独立地选自C1-C7的烷基或苄基，并且R1、R2不同时为苄基。 - 根据权利要求12所述的式IV-A化合物或其可药用盐，其特征在于，所述R1、R2同时为甲基：
- 根据权利要求12所述的式IV-A化合物或其可药用盐，其特征在于，所述R1、R2同时为乙基：
- 一种由权利要求12～14中任一项所述的式IV-A的化合物制备福沙匹坦的方法，其特征在于：将式IV-A的化合物于溶剂和水的混合液中在碱的作用下反应，以酸溶液调节pH后过滤析晶，得到福沙匹坦。
- 根据权利要求15所述的方法，其特征在于，将福沙匹坦与N-甲基-D-葡糖胺反应、析晶，得到福沙匹坦二甲葡胺。
- 根据权利要求15～16任一项所述的方法，其特征在于，所述福沙匹坦磷酸酯中间体(IV-A)与溶剂的体积比为1:(5～20)；所述福沙匹坦磷酸酯中间体(IV-A)与水的摩尔比为1:(2.0-10.0)；所述福沙匹坦磷酸酯中间体(IV-A)与碱的摩尔比为1:(2.0～4.0)。
- 根据权利要求15～16任一项所述的方法，其特征在于，所述反应温度为20-35℃，所述反应时间为15-40h。
- 根据权利要求15～16任一项所述的方法，其特征在于，所述溶剂为低级醇，优选甲醇、乙醇等，更优选为甲醇。
- 根据权利要求15～16任一项所述的方法，其特征在于，所述的碱选自有机碱或无机碱，所述有机碱包含吡啶、三乙胺、二异丙基乙胺、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)中的一种或多种；所述无机碱包含氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸铯中的一种或多种；优选为氢氧化钠或氢氧化钾。
- 根据权利要求15～16任一项所述的方法，其特征在于，所述的酸溶液为盐酸于所述溶剂中的1N～3N的溶液。
- 根据权利要求15～16任一项所述的方法，其特征在于，将pH调节为1～2。
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| WO2011045817A2 (en) | 2009-10-15 | 2011-04-21 | Sandoz Private Limited | Process for the preparation of fosaprepitant, intermediate and pharmaceutical acceptable salt thereof |
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| WO2010018595A2 (en) | 2008-07-17 | 2010-02-18 | Glenmark Generics Limited | Fosaprepitant dimeglumine intermediate, neutral fosaprepitant, and amorphous fosaprepitant dimeglumine and processes for their preparations |
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