CN111511725B - 1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯、L-脯氨酸和水的1:1:1共晶体的合成 - Google Patents
1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯、L-脯氨酸和水的1:1:1共晶体的合成 Download PDFInfo
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960002429 proline Drugs 0.000 title claims abstract description 22
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 title claims abstract description 11
- 229930182821 L-proline Natural products 0.000 title claims abstract description 11
- -1 4-cyclopropyl-benzyl Chemical group 0.000 title claims description 29
- 238000003786 synthesis reaction Methods 0.000 title claims description 11
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 239000013078 crystal Substances 0.000 title description 6
- WELSVHHDAXZSJK-RMPHRYRLSA-N (2r,3r,4s,5s,6r)-6-(hydroxymethyl)-2-phenyloxane-2,3,4,5-tetrol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@]1(O)C1=CC=CC=C1 WELSVHHDAXZSJK-RMPHRYRLSA-N 0.000 title description 2
- 239000000543 intermediate Substances 0.000 claims abstract description 147
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 12
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 10
- 230000006196 deacetylation Effects 0.000 claims abstract description 7
- 238000003381 deacetylation reaction Methods 0.000 claims abstract description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 40
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical group FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 10
- 230000021736 acetylation Effects 0.000 claims description 10
- 238000006640 acetylation reaction Methods 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 6
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- 229910000077 silane Inorganic materials 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 5
- ZYUBLYYYBZEEOE-UHFFFAOYSA-N 2-[(4-bromophenyl)methyl]-4-iodobenzonitrile Chemical compound BrC1=CC=C(CC2=C(C#N)C=CC(=C2)I)C=C1 ZYUBLYYYBZEEOE-UHFFFAOYSA-N 0.000 claims description 4
- WHQVXHBSTRFRCE-UHFFFAOYSA-N 2-fluoro-4-iodobenzonitrile Chemical compound FC1=CC(I)=CC=C1C#N WHQVXHBSTRFRCE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- KWAHADSKPFGJQF-UHFFFAOYSA-N 2-iodoprop-1-ene Chemical compound CC(I)=C KWAHADSKPFGJQF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000000850 deacetylating effect Effects 0.000 claims description 3
- 150000002596 lactones Chemical class 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 229910052723 transition metal Inorganic materials 0.000 claims description 3
- 150000003624 transition metals Chemical class 0.000 claims description 3
- HGXWRDPQFZKOLZ-UHFFFAOYSA-N 4-bromo-2-fluorobenzonitrile Chemical compound FC1=CC(Br)=CC=C1C#N HGXWRDPQFZKOLZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 2
- 230000001035 methylating effect Effects 0.000 claims 2
- 125000001743 benzylic group Chemical group 0.000 claims 1
- 238000006114 decarboxylation reaction Methods 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 238000001465 metallisation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- PESZPPAQWQMZAM-XNBWIAOKSA-N 2-[(4-cyclopropylphenyl)methyl]-4-[(2r,3r,4s,5s,6r)-2,3,4,5-tetrahydroxy-6-(hydroxymethyl)oxan-2-yl]benzonitrile Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@]1(O)C1=CC=C(C#N)C(CC=2C=CC(=CC=2)C2CC2)=C1 PESZPPAQWQMZAM-XNBWIAOKSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 150000008359 benzonitriles Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- AHVVBCGSOVKEQJ-VKLFGAAUSA-N N1[C@@H](CCC1)C(=O)O.C(#N)C1=C(C=C(C=C1)[C@]1(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)CC1=CC=C(C=C1)C1CC1 Chemical compound N1[C@@H](CCC1)C(=O)O.C(#N)C1=C(C=C(C=C1)[C@]1(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)CC1=CC=C(C=C1)C1CC1 AHVVBCGSOVKEQJ-VKLFGAAUSA-N 0.000 description 1
- HNQDWNYMWSDRMD-GMYKVFRHSA-N O.N1[C@@H](CCC1)C(=O)O.C(#N)C1=C(C=C(C=C1)[C@]1(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)CC1=CC=C(C=C1)C1CC1 Chemical compound O.N1[C@@H](CCC1)C(=O)O.C(#N)C1=C(C=C(C=C1)[C@]1(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)CC1=CC=C(C=C1)C1CC1 HNQDWNYMWSDRMD-GMYKVFRHSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000005908 aromatic decarboxylation reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- JFDZBHWFFUWGJE-KWCOIAHCSA-N benzonitrile Chemical group N#[11C]C1=CC=CC=C1 JFDZBHWFFUWGJE-KWCOIAHCSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- ZFDCWHPNBWPPHG-UHFFFAOYSA-N ethyl 2-(4-bromophenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(Br)C=C1 ZFDCWHPNBWPPHG-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- ZHOVAWFVVBWEGQ-UHFFFAOYSA-N tripropylsilane Chemical compound CCC[SiH](CCC)CCC ZHOVAWFVVBWEGQ-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/614—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety of phenylacetic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明涉及用于制备根据式(I)的结晶化合物的方法,所述方法包括以下步骤:(a)使最终中间体(FI)脱乙酰,(b)通过将步骤(a)的脱乙酰的最终中间体与L‑脯氨酸和水反应并且分离最终反应产物来形成根据式(I)的结晶化合物;制备其中间体的方法;方法中间体及其在根据本发明的方法中的用途。
Description
技术领域
本发明涉及化学领域,特别是合成化学。特别地,本发明涉及合成结晶的1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物,更特别地涉及所有三种晶体成分1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯、L-脯氨酸和水的1:1:1共晶体。
背景技术
WO 2007/093610描述了吡喃葡萄糖基取代的苄腈衍生物、包含这种化合物的药物组合物、其医学用途以及其制备方法。许多其它化合物中,它还公开了1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯。
WO 2007/128749涉及吡喃葡萄糖基取代的苄腈衍生物、包含这种化合物的药物组合物、其医学用途以及其制备方法。许多其它化合物中,它还公开了1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯。
WO 2014/016381描述了1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯与天然氨基酸的结晶复合物、其制备方法以及其用于制备药物的用途。尽管WO公开描述了结晶的1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸,但其没有明确提及1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物。
另外的现有技术如下:
Li-Yuan Bao等人(Chem.Commun.2015,32:6884-6900),其综述了Turbo-Grignard试剂i-PrMgCl*LiCl的进展和开发。
现有技术的缺点如下:
-1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯作为粗制品是无定形油,其在不进一步处理/修饰的情况下不能在技术上和在商业规模上被处理。
-1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯通过众多中间体步骤的复杂合成。
-需要非商业可购的起始原料来合成用于最终合成1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯的前体。
因此,本发明的目的是提供克服上述现有技术问题的合成方法。
发明内容
一方面,本发明涉及用于制备根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物的方法,其包括以下步骤:
(a)使最终中间体(FI)脱乙酰;
(b)通过使步骤(a)的脱乙酰的最终中间体与L-脯氨酸和水反应以能够分离最终反应产物来形成根据式(I)的结晶化合物。
另一方面,本发明涉及用于制备最终中间体(FI)的方法,其包括以下步骤:
(a)将其中X为Br或I的中间体I1与至少一种金属化试剂、优选Turbo-Grignard(iPrMgCl*LiCl)反应,随后将这种金属化的反应产物加入到中间体I2中,以产生中间体I3,其中在中间体I2中,PG为保护基、优选三甲基甲硅烷基(TMS);
(b)用甲醇处理中间体I3以产生中间体I4;
(c)将中间体I4用还原剂、优选硅烷、更优选三乙基硅烷还原,以产生中间体I5;
(d)使中间体I5乙酰化以产生最终中间体FI;
其中中间体I3、I4和/或I5的优选至少一种、更优选全部不进行分离和/或纯化,然后进一步处理,即,分别进行步骤(b)、(c)和/或(d)。
在其它方面,本发明涉及用于制备最终中间体(FI)的方法,其包括以下步骤:
(a)将其中X为Br或I的中间体I1与至少一种金属化试剂、优选Turbo-Grignard(iPrMgCl*LiCl)反应,随后将这种金属化的反应产物加入到中间体I2中,以产生中间体I3,其中在中间体I2中,PG为保护基、优选三甲基甲硅烷基(TMS);
(b)用甲醇处理中间体I3以产生中间体I4;
(c)使中间体I4乙酰化以产生中间体I6;
(d)将中间体I6用还原剂、优选硅烷、更优选三乙基硅烷还原,以产生最终中间体FI;
其中中间体I3、I4和/或I6的优选至少一种、更优选全部不进行分离和/或纯化,然后进一步处理,即,分别进行步骤(b)、(c)和/或(d)。
还在另一方面,本发明涉及用于制备中间体I1的方法,其包括以下步骤:
(a)在碱、优选叔丁醇钾(KOtBu)的存在下,使中间体I7与中间体I8反应,以产生中间体I1,其中在中间体I8中,X为Br或I并且其中Hal为F或Cl;
(b)从步骤(a)的反应混合物中分离中间体I1,
还在另一方面,本发明涉及根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物
还在其它方面,本发明涉及中间体化合物,其选自中间体(1)至(13):
还在另一方面,本发明涉及选自本申请公开的中间体化合物(1)至(13)的中间体化合物,其可通过本申请公开的根据本发明的一种或多种方法得到。
还在其它方面,本发明涉及选自本申请公开的中间体化合物(1)至(13)的中间体化合物在本申请公开的根据本发明的一种或多种方法中的用途。
根据本发明的合成方法的优点如下:
-与游离化合物的油状物形式相比,可以在技术上处理1:1:1共晶体,即以商业规模进行结晶、分离、表征和进一步处理。
-“非显而易见的”化学:很难以开发出包含具有苄腈部分的分子的合成策略,对于合成非氰化葡萄糖苷来说采用有机镁或锂化合物可能是麻烦的,因为腈部分可干扰卤素-金属交换及随后的加成反应。
-由于从一开始就将氰基引入糖苷配基(aglycon)中,而不是随后在额外的合成步骤中从卤代、溴化或氯化的前体中引入氰基,因此合成路线更短/更有效/更经济。
-商购可得的起始原料或可容易地制备的起始原料。
具体实施方式
在进一步详细描述本发明的实施方案之前,应当注意,除非上下文明确指出,否则本申请和所附权利要求书所用的单数形式的“一个”、“一种”和“所述”包括复数指代物。
除非另有定义,否则本申请使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。除非另有说明或本领域技术人员另外已知,否则所有给定的范围和值都可以相差1%至5%,因此,通常从说明书和权利要求书中省略术语“约”。尽管类似于或等同于本申请描述的那些方法和物质的任何方法和物质都可以用于本发明的实践或测试中,但是现在描述优选的方法、装置和物质。本申请描述的所有出版物都通过引用并入本申请,以描述和公开可与本发明结合使用的出版物中报道的物质、赋形剂、载体和方法。本申请中的任何内容都不得解释为承认本发明无权借助于在先发明而早于这种公开内容进行公开。
在本发明的过程中,结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物由此理解为所有三种晶体成分1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯、L-脯氨酸和水的1:1:1共晶体,如式(I)所示的:
这种1:1:1共晶体在WO 2014/016381中进行物理化学表征。
在一个优选实施方案中,本发明提供用于制备根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物的方法,所述方法包括以下步骤:
(a)使最终中间体(FI)脱乙酰;
(b)通过使步骤(a)的脱乙酰的最终中间体与L-脯氨酸和水反应并且分离最终反应产物来形成根据式(I)的结晶化合物;
其中脱乙酰步骤(a)包括以下步骤:
(a1)在碱、优选NaOH和水的存在下,使溶解在至少一种有机溶剂、优选甲基四氢呋喃(MeTHF)中的最终中间体(FI)反应;
(a2)任选地,将步骤(a1)中产生的有机相的至少一种有机溶剂、优选甲基四氢呋喃(MeTHF)交换为至少一种不同的有机溶剂、优选2-丙醇,并且任选地加入水。
优选地,形成结晶化合物的步骤(b)进一步包括以下步骤:
(b1)将溶解在至少一种不同的有机溶剂、优选2-丙醇和水中的L-脯氨酸加入到步骤(a1)或任选的步骤(a2)中产生的水-有机相混合物、优选2-丙醇和水中,并且孵育这种反应混合物;
(b2)将根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物从步骤(b1)的反应混合物中分离。
在另一个优选的实施方案中,本发明提供用于制备最终中间体(FI)的方法,其包括以下步骤:
(a)将其中X为Br或I的中间体I1与至少一种金属化试剂、优选Turbo-Grignard(iPrMgCl*LiCl)反应,随后将这种金属化的反应产物加入到中间体I2中,以产生中间体I3,其中在中间体I2中,PG为保护基、优选三甲基甲硅烷基(TMS);
(b)用甲醇处理中间体I3以产生中间体I4;
(c)将中间体I4用还原剂、优选硅烷、更优选三乙基硅烷还原,以产生中间体I5;
(d)使中间体I5乙酰化以产生最终中间体FI;
其中中间体I3、I4和/或I5的优选至少一种、更优选全部不进行分离和/或纯化,然后进一步处理,即,分别进行步骤(b)、(c)和/或(d),其中X为I和/或PG为三甲基甲硅烷基(TMS),优选X为I和PG为三甲基甲硅烷基(TMS)。
在另一个优选的实施方案中,本发明提供用于制备最终中间体(FI)的方法,其包括以下步骤:
(a)将其中X为Br或I的中间体I1与至少一种金属化试剂、优选Turbo-Grignard(iPrMgCl*LiCl)反应,随后将这种金属化的反应产物加入到中间体I2中,以产生中间体I3,其中在中间体I2中,PG为保护基、优选三甲基甲硅烷基(TMS);
(b)用甲醇处理中间体I3以产生中间体I4;
(c)使中间体I4乙酰化以产生中间体I6;
(d)将中间体I6用还原剂、优选硅烷、更优选三乙基硅烷还原,以产生最终中间体FI;
其中中间体I3、I4和/或I6的优选至少一种、更优选全部不进行分离和/或纯化,然后进一步处理,即,分别进行步骤(b)、(c)和/或(d),其中X为I和/或PG为三甲基甲硅烷基(TMS),优选X为I和PG为三甲基甲硅烷基(TMS)。
原则上,可以使用本领域技术人员已知的任何适宜的保护基。根据本发明的示例性保护基(PG)为三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、三异丙基甲硅烷基(TIPS)、叔丁基二甲基甲硅烷基(TBS,TBDMS)、叔丁基二苯基甲硅烷基(TBDPS)、苄基(Bn)、4-甲氧基苄基(PMB)、2-萘基甲基(Nap)、2-甲氧基乙氧基甲基(MEM)、2,2,2-三氯乙基羰基(Troc)、甲基等。根据本发明的优选的保护基(PG)为三甲基甲硅烷基(TMS)。
关于还原剂,原则上可以使用本领域技术人员已知的任何适宜的还原剂。根据本发明的示例性还原剂为硅烷,例如三乙基硅烷、三丙基硅烷、三异丙基硅烷或二苯基硅烷、硼氢化钠、氰基硼氢化钠、硼氢化锌、硼烷、氢化铝锂、氢化二异丁基铝等。优选的还原剂为硅烷,更优选三乙基硅烷。
还在另一个优选的实施方案中,本发明提供用于制备中间体I1的方法,其包括以下步骤:
(a)在碱、优选叔丁醇钾(KOtBu)的存在下,使中间体I7与中间体I8反应,以产生中间体I1,其中在中间体I8中,X为Br或I并且其中Hal为F或Cl;
(b)从步骤(a)的反应混合物中分离中间体I1;
其中X为I和/或Hal为F,优选X为I和Hal为F。
还在另一个优选的实施方案中,本发明提供中间体化合物,其选自:
实施例
下面的实施例用来进一步说明本发明。但是,不应将其解释为对本申请公开的发明范围的限制。
实施例1–从最终中间体FI开始制备根据式(I)的1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物
将30g中间体FI溶解在130g 2-甲基四氢呋喃中。加入9.3g NaOH(30%,在水中),将所得溶液加热至50℃持续3小时,冷却至5℃,使用1M HCl水溶液将pH调节至9.3。分相,有机相用水洗涤。在室温将有机溶剂交换为2-丙醇,并加入3.3g水。在23℃在4h内加入6.3gL-脯氨酸在8.5g水和42g 2-丙醇中的溶液,并在加入期间接种。所得悬浮液冷却至5℃,搅拌1h,将产物过滤。用60g 2-丙醇和3.5g水的溶剂混合物洗涤后,在真空中干燥,所得结晶化合物的纯度为100%(通过HPLC分析)和总收率为87%。
实施例2–从中间体I1和I2开始制备最终中间体FI–变体A
在-100℃将溶解在8mL四氢呋喃(THF)中的628mg中间体I1(X=Br)在15分钟内与2.4mL叔丁基锂(1.7M,在戊烷中)反应。加入934mg溶解在5mL THF中的中间体I2(PG=三甲基甲硅烷基,TMS),将反应混合物保持在-80℃。1小时后,反应用14mL饱和氯化铵水溶液淬灭,然后用乙酸乙酯萃取,经硫酸镁干燥,浓缩溶液。残留物溶解在9.4mL溶剂混合物甲醇中,加入0.32mL甲磺酸,将混合物保持在55℃。16小时后,通过加入饱和碳酸氢钠溶液将pH调节至8,在真空中浓缩。将残留物在乙酸乙酯与饱和氯化钠溶液之间分配。有机相经硫酸镁干燥并且在真空中浓缩,得到中间体I4。
在22℃在4.5g二氯甲烷和5g乙腈的混合物中用1.17g三乙基硅烷和1.6g三氟化硼乙醚络合物还原1400mg包含中间体I4的残留物1小时。将反应混合物加入至12hg 2N氢氧化钠水溶液中,用TBME萃取。在真空中浓缩有机相,用7g MeOH处理三次,蒸发至1/5体积。然后将残留物溶解在8g THF中,并且通过用2.2g乙酸酐、2.5g N-甲基吗啉和催化量的4-(二甲基氨基)-吡啶乙酰化来得到中间体FI。从甲醇水溶液(1:1)中分离和结晶,得到纯度为98.4%和总收率为26%的中间体I1。
实施例3–从中间体I1和I2开始制备最终中间体FI–变体B
中间体I4如实施例2中所述得到。
将220mg中间体I4用0.24mL乙酸酐、390mg N,N-二异丙基乙胺和催化量的在5mL二氯甲烷中的4-(二甲基氨基)-吡啶乙酰化。在萃取液中进行处理后,经硫酸镁干燥,在真空中蒸发,用0.19mL三乙基硅烷、0.11mL三氟化硼乙醚络合物和1当量的水在4mL乙腈中还原320mg乙酰化的中间体I6。中间体FI的纯度>85%,收率为26%。
实施例4a–从中间体I7和I8开始制备中间体I1
在6.6g中间体I7中,将8g中间体I8(Hal=F,X=I)溶解在28.5g四氢呋喃和6.2g二甲基甲酰胺中,在-20℃将8g叔丁醇钾在59g四氢呋喃中的溶液加入混合物中,搅拌1h。将反应通过加入27.2g水和13.2g 30%的氢氧化钠水溶液来淬灭。然后在55℃将所得混合物搅拌16h,冷却至22℃。加入10g乙酸和25g水,分相,将67.5g乙酸异丙酯加入有机相中。有机相用67g 5%氯化钠水溶液洗涤,溶剂交换为2-丙醇。通过接种和冷却至15℃来使产物从2-丙醇中结晶。将产物过滤,用2-丙醇洗涤,以产生纯度为97%,收率为50%的中间体I1。
实施例4b–从中间体I7和I8开始制备中间体I1
使用中间体I8(Hal=F,X=Br)重复实施例4a。总收率为47%,中间体纯度为>90%。
实施例5–制备中间体I7
通过在50℃的温度在于四氢呋喃中的三苯基膦(0.06eq.)和乙酸钯(II)(0.05eq.)的存在下将环丙基溴化镁(1.0eq.)、氯化锌(1.3eq.)和2-(4-溴苯基)乙酸乙酯(1.0eq.)混合来制备中间体I7。使用乙酸乙酯和水的萃取处理得到粗产物,将其通过蒸馏纯化。收率70%。纯度>97.0%。
实施例6–替代合成路线
缩写:
iPrMgCl=异丙基氯化镁;I2=碘;THF=四氢呋喃;MeTHF=2-甲基四氢呋喃;tBuOK=叔丁醇钾;DMF=二甲基甲酰胺;NaOH=氢氧化钠;iPrMgCl.LiCl=异丙基氯化镁氯化锂;TMS=四甲基硅烷;MeSO3H=甲磺酸;MeOH=甲醇;Et3SiH=三乙基硅烷;BF3.OEt=三氟化硼乙醚络合物;Ac2O=乙酸酐;NMM=N-甲基吗啉;DMAP=4-二甲基氨基吡啶;Ac=乙酰基;PdOAc2=乙酸钯(II);PCy3=三环己基膦;PhMe=甲苯;iPrOH=异丙醇。
或者,可以通过在如上方案所示合成的后期阶段安置环丙基部分来合成最终中间体FI。替代使用化合物2,可以使用相应的芳基溴碘苄腈。芳基溴碘苄腈可通过2-氟-4-碘苄腈和4-溴苯乙酸乙酯之间的亲核芳族取代/脱羧偶联来制备。然后可使芳基溴碘苄腈进行卤素-金属交换/内酯加成/酸性甲醇/还原/乙酰化的相同化学顺序。然后需要通过与适当的环丙基物质例如环丙基硼酸进行过渡金属催化的反应来从该顺序中安置分离产物的环丙基部分,以得到最终中间体FI。
具体来说,将2-氟-4-溴苄腈与异丙基氯化镁和碘反应以产生2-氟-4-碘苄腈。然后,将这样产生的中间体化合物与4-溴苯乙酸乙酯偶联,然后脱羧,以产生2-(4-溴苄基)-4-碘-苄腈。2-(4-溴苄基)-4-碘-苄腈然后与中间体“I2”[PG=三甲基甲硅烷基(TMS)]反应并且以类似于本申请所述和要求保护的用于制备最终中间体(FI)的方法、步骤(b)和步骤(c)的卤素-金属交换/内酯加成/酸性还原/乙酰化的化学合成顺序进行还原和乙酰化,其中涉及的中间体I3、I4和I5在远端的苄基部分携带溴取代基而不是显示的环丙基取代基。在该化学合成顺序的最后,通过与适当环丙基物质例如环丙基硼酸进行过渡金属催化的反应而将环丙基部分安置在最终中间体(FI)的相应溴类似物中,以得到最终中间体(FI)。然后使最终中间体(FI)进行本申请所述和要求保护的用于制备根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物的方法。
参考
(1)WO 2007/093610
(2)WO 2007/128749
(3)WO 2014/016381
(4)Li-Yuan Bao等人,Chem.Commun.2015,32:6884-6900
Claims (19)
1.用于制备最终中间体(FI)的方法,其包括以下步骤:
(a)将其中X为I的中间体I1与至少一种金属化试剂反应,随后将这种金属化的反应产物加入到中间体I2中,以产生中间体I3,其中在中间体I2中,PG为保护基,其中所述至少一种金属化试剂包含iPrMgCl*LiCl;
(b)在去除所有保护基团PG的同时,使中间体I3甲基化以产生中间体I4;
(c)将中间体I4用还原剂还原,以产生中间体I5;
(d)使中间体I5乙酰化以产生最终中间体FI;
其中中间体I3、I4和I5的全部不进行分离和/或纯化,然后进一步处理,即分别进行步骤(b)、(c)和/或(d),
2.用于制备最终中间体(FI)的方法,其包括以下步骤:
(a)将其中X为I的中间体I1与至少一种金属化试剂反应,随后将这种金属化的反应产物加入到中间体I2中,以产生中间体I3,其中在中间体I2中,PG为保护基,其中所述至少一种金属化试剂包含iPrMgCl*LiCl;
(b)在去除所有保护基团PG的同时,使中间体I3甲基化以产生中间体I4;
(c)使中间体I4乙酰化以产生中间体I6;
(d)将中间体I6用还原剂还原,以产生最终中间体FI;
其中中间体I3、I4和I6的全部不进行分离和/或纯化,然后进一步处理,即分别进行步骤(b)、(c)和/或(d),
3.根据权利要求1或2所述的方法,其中PG为三甲基甲硅烷基(TMS)。
4.根据权利要求1或2所述的方法,其中所述还原剂为硅烷。
5.根据权利要求4所述的方法,其中所述还原剂为三乙基硅烷。
6.中间体化合物,其为:
(2)
7.根据权利要求6所述的中间体化合物在根据权利要求1至5中任一项所述的方法中的用途。
8.用于制备根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物的方法,
其包括以下步骤:
(a)使2-氟-4-溴苄腈与异丙基氯化镁和碘反应以产生2-氟-4-碘苄腈;
(b)然后使2-氟-4-碘苄腈与4-溴苯乙酸乙酯偶联,然后脱羧,以产生2-(4-溴苄基)-4-碘-苄腈;
(c)然后使2-(4-溴苄基)-4-碘-苄腈与中间体I2反应并且以根据权利要求1的步骤(b)和步骤(c)的卤素-金属交换/内酯加成/酸性还原/乙酰化的化学合成顺序进行还原和乙酰化,其中涉及的中间体I3、I4和I5在远端的苄基部分携带溴取代基而不是显示的环丙基取代基,其中I2为I3为/>I4为/>以及I5为/>其中TMS=四甲基甲硅烷基;
(d)然后通过与适当环丙基物质进行过渡金属催化的反应而将环丙基部分安置在最终中间体(FI)的相应溴类似物中,以得到最终中间体(FI);
(e)然后使最终中间体(FI)进行用于制备根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物的方法,其包括以下步骤:
(A)使最终中间体(FI)脱乙酰;
(B)通过使步骤(A)的脱乙酰的最终中间体与L-脯氨酸和水反应并分离最终反应产物来形成根据式(I)的结晶化合物,
9.根据权利要求8所述的方法,其中所述环丙基物质为环丙基硼酸。
10.根据权利要求8所述的方法,其中脱乙酰步骤(A)包括以下步骤:
(A1)在碱和水的存在下,使溶解在至少一种有机溶剂中的最终中间体(FI)反应。
11.根据权利要求10所述的方法,进一步包括以下步骤:
(A2)将步骤(A1)中产生的有机相的至少一种有机溶剂交换为至少一种不同的有机溶剂。
12.根据权利要求11所述的方法,其中步骤(A2)进一步包括加入水。
13.根据权利要求10至12中任一项所述的方法,其中步骤(A1)中的至少一种有机溶剂包括甲基四氢呋喃(MeTHF)。
14.根据权利要求10所述的方法,其中步骤(A1)中的碱为NaOH。
15.根据权利要求11或12所述的方法,其中步骤(A2)中的至少一种不同的有机溶剂为2-丙醇。
16.根据权利要求8至11中任一项所述的方法,其中形成结晶化合物的步骤(B)进一步包括以下步骤:
(B1)将溶解在至少一种不同的有机溶剂和水中的L-脯氨酸加入到步骤(A1)或任选的步骤(A2)中产生的水-有机相混合物中,并且孵育这种反应混合物;
(B2)将根据式(I)的结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物从步骤(B1)的反应混合物中分离。
17.根据权利要求16所述的方法,其中步骤(B1)中的至少一种不同的有机溶剂为2-丙醇,以及所述水-有机相混合物为2-丙醇和水。
18.一种制备结晶化合物1-氰基-2-(4-环丙基-苄基)-4-(β-D-吡喃葡萄糖-1-基)-苯L-脯氨酸一水合物的方法,包括根据以下合成路线的步骤:
其中上述缩写具有以下含义:
iPrMgCl=异丙基氯化镁;I2=碘;THF=四氢呋喃;MeTHF=2-甲基四氢呋喃;tBuOK=叔丁醇钾;DMF=二甲基甲酰胺;NaOH=氢氧化钠;iPrMgCl.LiCl=异丙基氯化镁氯化锂;TMS=四甲基甲硅烷基;MeSO3H=甲磺酸;MeOH=甲醇;Et3SiH=三乙基硅烷;BF3.OEt=三氟化硼乙醚络合物;Ac2O=乙酸酐;NMM=N-甲基吗啉;DMAP=4-二甲基氨基吡啶;Ac=乙酰基;PdOAc2=乙酸钯(II);PCy3=三环己基膦;PhMe=甲苯;iPrOH=异丙醇。
19.根据权利要求18所述的方法,其由根据以下合成路线的步骤组成:
,
其中上述缩写具有以下含义:
iPrMgCl=异丙基氯化镁;I2=碘;THF=四氢呋喃;MeTHF=2-甲基四氢呋喃;tBuOK=叔丁醇钾;DMF=二甲基甲酰胺;NaOH=氢氧化钠;iPrMgCl.LiCl=异丙基氯化镁氯化锂;TMS=四甲基甲硅烷基;MeSO3H=甲磺酸;MeOH=甲醇;Et3SiH=三乙基硅烷;BF3.OEt=三氟化硼乙醚络合物;Ac2O=乙酸酐;NMM=N-甲基吗啉;DMAP=4-二甲基氨基吡啶;Ac=乙酰基;PdOAc2=乙酸钯(II);PCy3=三环己基膦;PhMe=甲苯;iPrOH=异丙醇。
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KR20200101421A (ko) | 2020-08-27 |
US11629161B2 (en) | 2023-04-18 |
JP2023166398A (ja) | 2023-11-21 |
EP3668846A1 (en) | 2020-06-24 |
AU2018387110B2 (en) | 2023-02-23 |
CA3085671A1 (en) | 2019-06-27 |
US20210139520A1 (en) | 2021-05-13 |
JP2021193102A (ja) | 2021-12-23 |
EA202091466A1 (ru) | 2020-10-23 |
CN111511725A (zh) | 2020-08-07 |
US11225500B2 (en) | 2022-01-18 |
AU2018387110A1 (en) | 2020-07-16 |
JP2021506962A (ja) | 2021-02-22 |
WO2019121509A1 (en) | 2019-06-27 |
US20220081461A1 (en) | 2022-03-17 |
MX2023004791A (es) | 2023-12-07 |
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