CN115784950A - Preparation method of sitagliptin intermediate - Google Patents
Preparation method of sitagliptin intermediate Download PDFInfo
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- CN115784950A CN115784950A CN202211571885.1A CN202211571885A CN115784950A CN 115784950 A CN115784950 A CN 115784950A CN 202211571885 A CN202211571885 A CN 202211571885A CN 115784950 A CN115784950 A CN 115784950A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 63
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 87
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- 229940125898 compound 5 Drugs 0.000 claims abstract description 45
- 229940125904 compound 1 Drugs 0.000 claims abstract description 36
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002738 chelating agent Substances 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 73
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 62
- 239000000243 solution Substances 0.000 claims description 60
- 238000003756 stirring Methods 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 238000001914 filtration Methods 0.000 claims description 34
- 229940125782 compound 2 Drugs 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 29
- 238000007792 addition Methods 0.000 claims description 28
- 238000005406 washing Methods 0.000 claims description 28
- 229940126214 compound 3 Drugs 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 13
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 13
- 229960004034 sitagliptin Drugs 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000010949 copper Substances 0.000 abstract description 17
- 239000003446 ligand Substances 0.000 abstract description 17
- 229910052802 copper Inorganic materials 0.000 abstract description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 14
- 239000012535 impurity Substances 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract description 2
- 230000020477 pH reduction Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 146
- 239000007787 solid Substances 0.000 description 28
- 239000012071 phase Substances 0.000 description 24
- 238000011084 recovery Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 206010013774 Dry eye Diseases 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- -1 o-methylthiobenzyl Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- OHHLQFCWNFSQEY-UHFFFAOYSA-N O.O.O.O.[Na].[Na].[Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O Chemical group O.O.O.O.[Na].[Na].[Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O OHHLQFCWNFSQEY-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 238000010979 pH adjustment Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000208445 Sarcodes Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003163 gonadal steroid hormone Substances 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- ZAWGLAXBGYSUHN-UHFFFAOYSA-M sodium;2-[bis(carboxymethyl)amino]acetate Chemical compound [Na+].OC(=O)CN(CC(O)=O)CC([O-])=O ZAWGLAXBGYSUHN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- 206010052143 Ocular discomfort Diseases 0.000 description 1
- 208000023715 Ocular surface disease Diseases 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229940127284 new molecular entity Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QLVDOWBJYVLGIP-UHFFFAOYSA-M sodium;methyl sulfite Chemical group [Na+].COS([O-])=O QLVDOWBJYVLGIP-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 229940023106 xiidra Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparation method of a sitagliptin intermediate compound 1, which comprises the steps of adopting a specific copper ligand compound, reacting an organic solvent and sodium hydroxide to obtain a compound 4, acidifying the compound 4 in the specific organic solvent, adding a chelating agent, then alkalifying to obtain a compound 5, recovering a catalyst compound 6 after acidification, and reacting the compound 5 with Boc anhydride to obtain a target compound 1. The method has high reaction stereoselectivity and low content of isomers and disubstituted impurities, does not need purification, and can be directly used for the subsequent synthesis reaction of the sitaxel.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a preparation method of a sitaxetil intermediate.
Background
Dry Eye Disease (DED), also known as keratoconjunctivitis sicca, is a multifactorial tear and ocular surface disease that can lead to symptoms such as ocular discomfort, visual disturbances, and instability of the tear film, with accompanying increased tear film permeability and ocular surface inflammation. DED is more prevalent in women and the elderly, and can have a greater impact on the quality of life of the patient, and can be severely blinding. The cause of DED is complex, the pathogenesis is not clear, wherein inflammation is the most important factor causing DED, and apoptosis, sex hormone level change and the like are also important factors. At present, the conventional treatment scheme of the DED mainly adopts artificial tear wetting, and in addition, schemes of inflammation inhibition and sex hormone therapy and the like also exist, and medicaments for relieving DED symptoms comprise carbomer eye drops, sodium carboxymethylcellulose eye drops, artificial tear preparations, cyclosporin A, androgen preparations and the like. Only 0.05% cyclosporin a ophthalmic emulsion was previously approved by the FDA in the united states as a prescribed drug for DED clinical treatment, but this drug has side effects causing burning sensation after use, and many patients have stopped using it.
Ritatest (lifitegrant) is a new molecular entity designed and developed by SARcode Bioscience, usa for treating dry eye, SARcode Bioscience was purchased by irish pharmaceutical grand arison (fire) in 2013 at $ 1.6 million, and was entitled to develop and sell ritatest under its flag. The ritastol eye drops developed by shengrui corporation were approved by the FDA for the treatment of dry eye symptoms and signs in 2016, 7/11, under the trade name Xiidra, the first FDA-approved drug for the treatment of lymphocyte function-related antigen (LFA-1) in dry eye, and are the only prescription eye drops in the us market.
The structural formula of sitagliptin is as follows:
wherein L-Boc-m-methanesulfonylalanine (Compound No.)Thing 1)
Is a key intermediate for synthesizing the sitagliptin, and the preparation methods which are published and reported are as follows.
The preparation methods reported in patents WO2014/18748A1 and WO2009/102876A1 take L-m-bromophenyl alanine as a starting material, and obtain the L-Boc-m-methylsulfonyl alanine by Boc protection and sodium methylsulfite substitution. Although the method is short, a large amount of copper salt is used when the methanesulfonyl is introduced, so that pollution is caused, and the starting material L-m-bromophenyl alanine is expensive and is not easy to prepare. The L-m-bromophenyl alanine can be obtained through multi-step reaction of m-bromobenzaldehyde, wherein one step is asymmetric hydrogenation with noble metal, special hydrogenation equipment is needed, and the method is not suitable for industrial production.
Chinese patent zl201410826534.X at 2015.05.06 discloses a synthesis method for preparing OMLT01, OMLT02 and OMLT03, which uses S-glycine schiff base Ni (II) complex [ Ni- (S) -BPB-Gly ] as a starting material to synthesize the target chiral amino acid, but the method still has the influence of isomer impurities and disubstituted impurities.
Smith, daniel J, et al 2011 published "Enhanced stereoselectivity of aCu (II) Complex Chiral in The Synthesis of Fmoc-L-gamma-carboxyglutamic Acid" (The Journal of Organic Chemistry,76 (6), 1513-1520) and reported a series of copper (Cu) or nickel (Ni) Complex Chiral aids for The selective Synthesis of Fmoc-L-gamma-carboxyglutamic Acid, but this reaction was directed to addition on The olefinic bond, and it was difficult to achieve simultaneous improvement in yield and Chiral selectivity.
The requirement of the sitagliptin on impurities is far higher than that of a common preparation as an eye drop for treating the xerophthalmia, and the defects of long route, complex reaction, low yield, low catalyst recovery rate and the like exist in the existing synthesis process of the sitagliptin intermediate, so that the development of the preparation process of the sitagliptin intermediate, which is simple to operate, economic and environment-friendly and has high yield and purity, is a technical problem which is to be solved in the field. According to the scheme, the specific copper ligand compound is added in the technical process, and the high-purity high-chirality sitagliptin intermediate can be obtained through specific reaction steps, can be directly used for synthesis of the sitagliptin, does not need purification, and is high in catalyst recovery rate, economic and environment-friendly.
Disclosure of Invention
The invention aims to provide a novel hand-type center construction method of a sitagliptin intermediate compound 1, which has the advantages of simple operation, high yield and purity, high catalyst recovery rate, economy and environmental protection, and the obtained sitagliptin intermediate can be used subsequently without purification.
Specifically, according to the preparation method of the intermediate compound 1 of the sitaxel, a specific copper ligand compound is adopted to react with an organic solvent and sodium hydroxide to obtain a compound 4, the compound 4 is acidified under the specific organic solvent, a chelating agent is added to the acidified compound and then alkalized to obtain a compound 5, a catalyst compound 6 is recovered after the acidification, and the compound 5 is reacted with Boc anhydride to obtain a target compound 1.
The beneficial effects of the invention are realized by the following technical scheme.
A preparation method of a sitaxetil intermediate compound 1 comprises the following three steps:
A. adding the compound 2 into an organic solvent, mixing with a sodium hydroxide solution, cooling, dropwise adding a solution of the compound 3 for reaction, adding ice water after the reaction is finished, preserving heat, filtering and drying to obtain a compound 4;
B. dissolving a compound 4 in an organic solvent I, adding hydrochloric acid, heating for reaction, adding a chelating agent after the reaction is finished, concentrating under reduced pressure, adding water and an organic solvent II, adding a sodium hydroxide solution, separating liquid and washing to obtain a compound 5 water solution, combining the organic phases, dropwise adding hydrochloric acid at room temperature, stirring at room temperature after dropwise adding is finished, filtering, and drying to obtain a compound 6;
C. reacting the compound 5 water solution with Boc anhydride, adding hydrochloric acid after the reaction is finished, stirring, filtering and drying to obtain a compound 1;
in the present invention, the copper ligand compound in step a is one of the important keys to achieve the technical effect. The inventors have found that when the substituent on the pyrrolyl N atom in the copper ligand compound is o-methylthiobenzyl, the yield of compound 4 is low, whereas when the substituent on the pyrrolyl N atom in the copper ligand compound is benzyl, compound 4 is produced by the reaction while a small amount of dimer impurity is produced. In the above case, when the substituent on the pyrrolyl N atom is o-methylthiobenzyl, the steric hindrance of the reaction is large, which is not favorable for the substitution reaction of the compound 3, and when the substituent on the pyrrolyl N atom is benzyl, the steric hindrance of the reaction is small, which is likely to cause the di-substitution or multi-substitution reaction. Therefore, only with the specific copper ligand compound of the present invention, sufficient reaction with the compound 3 can be achieved while avoiding the occurrence of di-or poly-substitution reaction.
In the present invention, the kind of the organic solvent, the mass/volume ratio (g/ml) of the compound 2 to the organic solvent, and the molar ratio of the compound 2 to the compound 3 in the step a are one of the important keys to achieve the technical effect. Specifically, when the organic solvent is acetonitrile or acetone, and the mass-to-volume ratio of the compound 2 to the solution is 1. More specifically, in the present invention, the organic solvent in step a is acetone, the mass-to-volume ratio of compound 2 to the solution is 1.
In the present invention, the selection of the substituent X in compound 3 in step a is one of the keys to achieve the technical effect. Specifically, when X is F, cl or Br, the leaving of halogen ions and the occurrence of substitution reaction are facilitated. More specifically, in the present invention, the preparation method of compound 1, step a, X is Cl.
In the invention, the reaction pH condition, temperature and time in the step A are one of the keys for realizing the technical effect. The proper pH condition and temperature can further shorten the reaction time and improve the reaction efficiency while ensuring the yield and the purity, and when the concentration of the sodium hydroxide is 40-60 percent, the pH is adjusted to 6.5-8.5, the temperature is 0-10 ℃, and the reaction is carried out for 2-4 hours, so that the yield and the purity of the reaction are better. Specifically, when the concentration of sodium hydroxide is 50%, the pH is adjusted to 7.0-8.0, the temperature is 0-5 ℃, the reaction is carried out for 3 hours, and the yield and the purity of the reaction can be optimal.
In the present invention, the selection of the hydrolysis reaction conditions in step B is one of the keys to achieve the technical effect. The hydrolysis reaction can be more sufficient by proper solvents and proportion, and pH conditions and temperature, the reaction time is shortened, when the organic solvent I is methanol, ethanol, acetonitrile and tetrahydrofuran, and the mass volume ratio of the compound 4 to the organic solvent I is 1-2 to 5, the pH is slowly adjusted to 1.5-3.0 by using concentrated hydrochloric acid, the temperature is raised to 60-70 ℃, the hydrolysis reaction is sufficiently performed when the reaction is carried out for 2-4h, the yield and the purity of the compound 5 are ensured, and the recovery rate of the removed compound 6 is improved. Specifically, when the organic solvent I is acetonitrile, the mass-to-volume ratio of the compound 4 to the organic solvent I is 1.
In the present invention, the selection of the reaction conditions for recovering the compound 6 in the step B is one of the keys to achieve the technical effect. Proper chelating agent, organic solvent and pH condition ensure the yield of compound 5 and raise the recovery rate of compound 6. When the chelating agent is sodium ethylene diamine tetracetate or sodium aminotriacetate and the organic solvent is dichloromethane or chloroform, the compound 5, the compound 6 and the chelating agent are preferably dissolved, when the concentration of sodium hydroxide is 40-60% and the pH value is adjusted to 9.0-10.0, the compound 5 can be fully dissolved in the water phase, the residue of the compound 6 in the water phase is reduced, after the water phase is extracted by dichloromethane or chloroform, dichloromethane or chloroform is combined, and the pH value is adjusted to 1.5-2.5 by concentrated hydrochloric acid, so that the solid of the compound 6 can be gradually precipitated. Specifically, when the chelating agent is ethylenediaminetetraacetic acid tetrasodium tetrahydrate and the organic solvent is dichloromethane, the compound 5, the compound 6 and the chelating agent are preferably dissolved, when the concentration of sodium hydroxide is 50% and the pH is adjusted to 9.0-10.0, the compound 5 is more fully dissolved in the water phase, the residue of the compound 6 in the water phase is reduced, the use of water in a reaction system is reduced, the water phase is extracted by the dichloromethane, the dichloromethane is combined, the pH is adjusted to 1.5-2.5 by concentrated hydrochloric acid, the solid of the compound 6 can be analyzed, and the yield of the compound 6 is improved.
In the present invention, the molar ratio of the chelating agent to the compound 4 has a certain influence on the reaction of the compound 6, and it is known to those skilled in the art that the reaction is complete when the amount of the substance of the chelating agent is equal to or greater than the amount of the substance of the compound 4, and therefore, the molar ratio of the ethylenediaminetetraacetic acid tetrasodium tetrahydrate to the compound 4 is 1.
In the present invention, in step C, after obtaining an aqueous solution containing compound 5, boc anhydride is added dropwise to the aqueous solution containing compound 5 at room temperature, and after completion of the dropwise addition, the reaction is carried out for 8 to 12 hours, preferably 10 hours, whereby Compound 1, which is the target product, can be obtained. The mole ratio of Boc anhydride to compound 4 was 1.7. After the reaction is finished, dichloromethane is added, liquid is extracted and separated, the water phase is washed by dichloromethane again, the temperature of the water phase is controlled to be 10-20 ℃, 12% hydrochloric acid is used for adjusting the pH to be =3-5, stirring is carried out for 1-2 hours, the compound 1 can be gradually separated out, and the purity of the obtained compound 1 can be further improved after washing and drying by isopropyl ether.
The preparation method of the compound 1 comprises the following three steps:
A. adding a compound 2 into acetone, mixing with 50-percent-wt sodium hydroxide solution until the pH is 7.0-8.0, the mass-to-volume ratio of the compound 2 to the acetone is 1;
B. adding a compound 4 into acetonitrile, wherein the mass-to-volume ratio of the compound 4 to the acetonitrile is 1;
C. after obtaining an aqueous solution containing the compound 5, c. adding Boc anhydride dropwise to the aqueous solution containing the compound 5 at room temperature, wherein the molar ratio of the Boc anhydride to the compound 4 is 1.7, reacting for 10h after the dropwise addition, adding dichloromethane after the reaction is finished, extracting and separating liquid, washing the aqueous phase with dichloromethane again, controlling the temperature of the aqueous phase to 10-20 ℃, adjusting the pH =3-5 with 12% hydrochloric acid, stirring for 1-2 hours, filtering, washing the filter cake with isopropyl ether, and drying to obtain the compound 1.
The invention also provides application of the compound 1 prepared by the preparation method in preparation of the sitagliptin, and the compound 1 can be directly used in the subsequent synthesis reaction of the sitagliptin without purification.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. the copper ligand compound is used for synthesizing the key intermediate of the sitagliptin for the first time, the reaction stereoselectivity is high, the contents of isomers and disubstituted impurities are low, the purification is not needed, and the copper ligand compound can be directly used for the subsequent synthesis reaction of the sitagliptin.
2. The copper ligand compound can be recovered after reaction, the recovery rate is high, the resource loss is reduced, and the cost is further reduced.
3. The reaction conditions are simple and easy to implement, and the method is suitable for industrial scale-up production.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein, and Compound 2 can be prepared according to the methods of Enhanced stereoselectioty of Cu (II) Complex Automation in the Synthesis of Fmoc-L-gamma-carboxglutamic Acid.
In the present invention, boc represents t-butyloxycarbonyl, EDTA-4 Na4H 2 O represents ethylenediaminetetraacetic acid tetrasodium tetrahydrate, bnOH represents benzyl alcoholEDCI for 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, DCM for dichloromethane, DMAP for 4-dimethylaminopyridine, dioxane for Dioxane, IPAc for isopropyl acetate, SOCl 2 Represents thionyl chloride, DMF represents N, N-dimethylformamide, and THF represents tetrahydrofuran.
Example 1
Preparation of Compound 4
Adding 40mL of acetone and 10g of compound 2 into a 100mL three-neck flask at room temperature, stirring, adding 50 percent by weight of aqueous sodium hydroxide solution, adjusting the pH to 7.0-8.0, cooling to 0-5 ℃ after the addition is finished, slowly dropwise adding 10mL of acetone solution of compound 3 (chlorine substituted, 4.26 g), continuing to react for 3 hours after the dropwise adding is finished, dropwise adding 100mL of ice water after the reaction is finished, keeping the temperature at 0-5 ℃ for 1 hour, filtering and drying to obtain compound 4.9g, the yield is about 98.0 percent, and the purity is 99.2 percent.
Preparation of compound B5
At room temperature, 12.9g of compound 4 and 38.7mL of acetonitrile are added into a 100mL single-neck flask, concentrated hydrochloric acid is added, the pH is adjusted to 2.5, the temperature is raised to 65 ℃, after 3 hours of reaction, HPLC detection is finished, the temperature is lowered to room temperature, 8.5g of EDTA 4Na 4H is added 2 O, concentrating under reduced pressure to remove acetonitrile, adding 10mL of water and 25mL of dichloromethane, adjusting pH to 9-10 with 50% by weight of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with dichloromethane (25mL. Multidot.2) again to obtain an aqueous solution of Compound 5 for use in the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring at room temperature overnight after dropwise addition, filtering, and drying to obtain white solid compound 6.22g with yield of 95.0% and purity of 99.9%.
Preparation of Compound 1C
Slowly dropwise adding 6.87g of Boc anhydride into a flask filled with compound 5 water solution at room temperature, stirring for 10h after dropwise adding, adding 25mL of dichloromethane after reaction, stirring, separating, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating out a solid, stirring for 1-2 h, filtering, washing a filter cake with isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain 1.29g of a white solid compound, wherein the yield is 98.9%, and the purity is 99.5%.
Example 2
A. Preparation of Compound 4
Adding 20mL of acetonitrile and 10g of compound 2 into a 100mL three-neck flask at room temperature, stirring, adding 40 wt% of sodium hydroxide aqueous solution, adjusting the pH to 6.5-7.0, cooling to 0-5 ℃ after the addition is finished, slowly dropwise adding 10mL of acetonitrile solution of compound 3 (fluorine substituted, 3.74 g), continuing to react for 2 hours after the dropwise adding is finished, dropwise adding 100mL of ice water after the reaction is finished, keeping the temperature at 0-5 ℃ for 1 hour, filtering and drying to obtain 4.5 g of compound, wherein the yield is about 95.0%, and the purity is 99.0%.
B. Preparation of Compound 5
Adding 12.5g of compound 4 and 25.0mL of methanol into a 100mL single-neck flask at room temperature, adding concentrated hydrochloric acid, adjusting the pH to 1.5, heating to 60 ℃, reacting for 2 hours, cooling to room temperature after HPLC detection, adding 4.7g of sodium aminotriacetate, concentrating under reduced pressure to remove methanol, adding 10mL of water and 25mL of chloroform, adjusting the pH value to 9-10 by 40% by weight of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with chloroform (25mL. X.2) again to obtain an aqueous solution of compound 5 for the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring at room temperature overnight after dropwise addition, filtering, and drying to obtain white solid compound 6.82g with yield of about 92.5% and purity of 99.8%.
C. Preparation of Compound 1
Slowly dropwise adding 6.66g of Boc anhydride into a flask filled with compound 5 water solution at room temperature, stirring for 8h after dropwise adding, adding 25mL of dichloromethane after reaction, stirring, separating, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating out a solid, stirring for 1-2 h, filtering, washing a filter cake with isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain 1.99g of a white solid compound, wherein the yield is 97.2%, and the purity is 99.3%.
Example 3
A. Preparation of Compound 4
Adding 30mL of acetone and 10g of compound 2 into a 100mL three-neck flask at room temperature, stirring, adding 60 wt% of aqueous sodium hydroxide solution, adjusting the pH to 8.0-8.5, cooling to 5-10 ℃ after the addition is finished, slowly adding 10mL of acetone solution of compound 3 (bromine substituted, 5.70 g) dropwise, continuing the reaction for 4 hours after the dropwise addition is finished, adding 100mL of ice water dropwise after the reaction is finished, keeping the temperature at 0-5 ℃ for 1 hour, filtering and drying to obtain compound 4.8 g, wherein the yield is about 97.5%, and the purity is 98.7%.
B. Preparation of Compound 5
At room temperature, 12.8g of compound 4 and 64.2mL of tetrahydrofuran are added into a 100mL single-neck flask, concentrated hydrochloric acid is added, the pH is adjusted to 3.0, the temperature is raised to 70 ℃, after 4 hours of reaction, HPLC detection is finished, the temperature is lowered to room temperature, and 8.4g of EDTA 4Na 4H is added 2 O, concentrating under reduced pressure to remove tetrahydrofuran, adding 10mL of water and 25mL of dichloromethane, adjusting pH to 9-10 with 60 wt% of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with dichloromethane (25mL. Times.2) again to obtain aqueous solution of compound 5 for the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dropwise addition, filtering, and drying to obtain white solid compound 6.10 g, with yield of about 93.8% and purity of 99.9%.
C. Preparation of Compound 1
Slowly dropwise adding 6.84g of Boc anhydride into a flask filled with compound 5 water solution at room temperature, stirring for 12h after dropwise adding, adding 25mL of dichloromethane after reaction, stirring, separating, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating out a solid, stirring for 1-2 h, filtering, washing a filter cake with isopropyl ether, and drying in vacuum at 50-60 ℃ to obtain 1.19g of a white solid compound, wherein the yield is 97.8%, and the purity is 99.3%.
Example 4
A. Preparation of Compound 4
Adding 40mL of acetone and 10g of Compound 2 to a 100mL three-necked flask at room temperature, stirring, adding 45% by weight of an aqueous sodium hydroxide solution, adjusting the pH to 6.5 to 7.0, after the completion of the addition, cooling to 0 to 5 ℃, slowly adding 10mL of an acetone solution of Compound 3 (chloro-substituted, 4.14 g) dropwise, after the completion of the dropwise addition, continuing the reaction for 3 hours, after the completion of the reaction, adding 100mL of ice water dropwise, incubating at 0 to 5 ℃ for 1 hour, filtering, and drying to obtain Compound 4.8g, with a yield of about 97.0% and a purity of 99.1%.
B. Preparation of Compound 5
At room temperature, 12.8g of compound 4 and 51.1mL of ethanol are added into a 100mL single-neck flask, concentrated hydrochloric acid is added, the pH is adjusted to 2.0, the temperature is raised to 65 ℃, after 3 hours of reaction, HPLC detection is finished, the temperature is lowered to room temperature, and 8.4g of EDTA 4Na 4H is added 2 O, concentrating under reduced pressure to remove ethanol, adding 10mL of water and 25mL of dichloromethane, adjusting the pH to 9-10% by weight with 45% by weight of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with dichloromethane (25ml × 2) again to obtain an aqueous solution of compound 5 for the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dropwise addition, filtering, and drying to obtain white solid compound 6.10 g, with yield of about 94.3% and purity of 99.8%.
C. Preparation of Compound 1
Slowly dropwise adding 6.80g of Boc anhydride into a flask filled with compound 5 water solution at room temperature, stirring for 9h after dropwise adding, adding 25mL of dichloromethane after reaction, stirring, separating, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to be 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating out a solid, stirring for 1-2 h, filtering, washing a filter cake with isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain 1.18g of a white solid compound, wherein the yield is 98.1%, and the purity is 99.5%.
Example 5
A. Preparation of Compound 4
Adding 40mL of acetone and 10g of Compound 2 to a 100mL three-necked flask at room temperature, stirring, adding 55 wt% of aqueous sodium hydroxide solution, adjusting pH to 8.0-8.5, cooling to 5-10 ℃ after the addition is completed, slowly adding 10mL of an acetone solution of Compound 3 (chloro-substituted, 4.22 g) dropwise, continuing the reaction for 3 hours after the dropwise addition is completed, adding 100mL of ice water dropwise after the reaction is completed, keeping the temperature at 0-5 ℃ for 1 hour, filtering, and drying to obtain Compound 4.7g, with a yield of about 96.5% and a purity of 99.0%.
B. Preparation of Compound 5
At room temperature, 12.7g of compound 4 and 38.2mL of acetonitrile are added into a 100mL single-neck flask, concentrated hydrochloric acid is added, the pH is adjusted to 2.5, the temperature is raised to 70 ℃, after 3 hours of reaction, HPLC detection is finished, the temperature is lowered to room temperature, and 8.3g of EDTA 4Na 4H is added 2 O, concentrating under reduced pressure to remove acetonitrile, adding 10mL of water and 25mL of dichloromethane, adjusting pH to 9-10 with 55 wt% of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with dichloromethane (25mL. Times.2) again to obtain aqueous compound 5 solution for the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dropwise adding, filtering, and drying to obtain off-white solid compound 6.08g, with yield of about 94.6% and purity of 99.9%.
C. Preparation of Compound 1
Slowly dripping 6.77g of Boc anhydride into a flask filled with a compound 5 water solution at room temperature, stirring for 11h after dripping is finished, adding 25mL of dichloromethane after reaction is finished, stirring, separating liquid, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to be 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating solid, stirring for 1-2 h, filtering, washing a filter cake by using isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain 1.15g of a white solid compound, wherein the yield is 98.2% and the purity is 99.3%.
Comparative examples 1 to 6
Preparation of Compound 4
Referring to the procedure of example 1, in comparative examples 1 to 6, compound 2 was replaced with the same type of copper ligand or nickel ligand compound, and the compound 2 was represented by the same type of analogue, yield and purity as shown in table 1, and the compound 2 was represented by the analogue, isomer and disubstituted structure as shown in table 2.
TABLE 1 Compound 2 analogs, yield, purity table
TABLE 2 Compound 2 analogs, isomers and disubstituted structural tables
As can be seen from the data in table 2, the purity and yield of compound 4 were high in the preparation method described in example 1, using the copper ligand catalyst of the present invention, whereas the yield of compound 4 was relatively high in the preparation method of comparative example 2, in which the R substituent was H and steric hindrance was small, and therefore, the content of isomer and disubstituted impurity compounds was relatively high, and the yield of compound was relatively low in the preparation methods of comparative examples 5 and 6, in which the R substituent was SMe and steric hindrance was large, although stereoselectivity was good. Meanwhile, under the same conditions, the copper ligand compound has certain advantages in purity and yield compared with the nickel ligand compound in the reaction of the invention.
Comparative example 7
A. Preparation of Compound 4
Adding 70mL of acetone and 10g of compound 2 into a 100mL three-neck flask at room temperature, stirring, adding 50 percent by weight of aqueous sodium hydroxide solution, adjusting the pH to 9.0-9.5, cooling to 0-5 ℃ after the addition is finished, slowly dropwise adding 10mL of acetone solution of compound 3 (chloro-substituted, 5.03 g), continuing the reaction for 3 hours after the dropwise adding is finished, dropwise adding 100mL of ice water after the reaction is finished, keeping the temperature at 0-5 ℃ for 1 hour, filtering and drying to obtain 4.1 g of compound, wherein the yield is about 92.0 percent and the purity is 97.5 percent.
B. Preparation of Compound 5
At room temperature, 12.1g of compound 4 and 72.7mL of dichloromethane are added into a 100mL single-neck flask, concentrated hydrochloric acid is added, the pH is adjusted to 1.0, the temperature is raised to 75 ℃, after 3 hours of reaction, HPLC detection is finished, the temperature is lowered to room temperature, 7.9g of EDTA 4Na 4H is added 2 O, concentrating under reduced pressure to remove dichloromethane, adding 10mL of water and 25mL of dichloromethane, adjusting pH to 11-12 with 50% by weight of aqueous sodium hydroxide solutionThe layers were separated and the aqueous phase was washed again with dichloromethane (25ml x 2) to give compound 5 as an aqueous solution for further reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 3.0-3.5, stirring at room temperature overnight after dropwise addition, filtering, and drying to obtain white solid compound 6.78g with yield of about 81.0% and purity of 96.7%.
C. Preparation of Compound 1
Slowly dripping 6.45g of Boc anhydride into a flask filled with a compound 5 water solution at room temperature, stirring for 13h after dripping is finished, adding 25mL of dichloromethane after reaction is finished, stirring, separating liquid, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to be 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating solid, stirring for 1-2 h, filtering, washing a filter cake with isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain 1.15g of a white solid compound, wherein the yield is 86.2% and the purity is 97.5%.
Comparative example 8
A. Preparation of Compound 4
Adding 10mL of acetone and 10g of Compound 2 into a 100mL three-necked flask at room temperature, stirring, adding 30 wt% of an aqueous sodium hydroxide solution, adjusting the pH to 7.0 to 8.0, cooling to 5 to 10 ℃ after the completion of the addition, slowly adding 10mL of an acetone solution of Compound 3 (chloro-substituted, 3.87 g) dropwise, continuing the reaction for 3 hours after the completion of the dropwise addition, adding 100mL of ice water dropwise after the completion of the reaction, incubating at 0 to 5 ℃ for 1 hour, filtering, and drying to obtain 9.9g of Compound 4.2% in a yield of about 75.2% and a purity of 99.1%.
B. Preparation of Compound 5
Adding 9.9g of compound 4 and 14.9mL of acetonitrile into a 100mL single-neck flask at room temperature, adding concentrated hydrochloric acid, adjusting the pH to 3.5, heating to 55 ℃, reacting for 5 hours, reducing the temperature to room temperature after HPLC detection is finished, adding 6.5g of EDTA 4Na 4H 2 O, concentrating under reduced pressure to remove acetonitrile, adding 10mL of water and 25mL of dichloromethane, adjusting the pH to 8-9 with 30% by weight of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with dichloromethane (25ml. Times.2) again to obtain an aqueous solution of compound 5 for the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring at room temperature overnight after dropwise addition, filtering, and drying to obtain white solid compound 6.49g with yield of about 77.0% and purity of 95.2%.
C. Preparation of Compound 1
Slowly dripping 5.27g of Boc anhydride into a flask filled with a compound 5 water solution at room temperature, stirring for 14h after dripping is finished, adding 25mL of dichloromethane after reaction is finished, stirring, separating liquid, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to be 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating solid, stirring for 1-2 h, filtering, washing a filter cake with isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain a white solid compound 1.39g, wherein the yield is 69.4% and the purity is 92.5%.
Comparative example 9
A. Preparation of Compound 4
Adding 40mL of N, N-dimethylformamide and 10g of the compound 2 into a 100mL three-neck flask at room temperature, stirring, adding 50 wt% of an aqueous solution of sodium hydroxide, adjusting the pH to 7.0-8.0, after the addition is finished, cooling to 0-5 ℃, slowly adding 10mL of an N, N-dimethylformamide solution of the compound 3 (chloro-substituted, 4.26 g) dropwise, after the dropwise addition is finished, continuing the reaction for 3 hours, after the reaction is finished, adding 100mL of ice water dropwise, keeping the temperature at 0-5 ℃ for 1 hour, filtering and drying to obtain 4.5 g of the compound, wherein the yield is about 95.0%, and the purity is 98.6%.
B. Preparation of Compound 5
At room temperature, 12.5g of compound 4 and 37.5mL of acetonitrile are added into a 100mL single-neck flask, concentrated hydrochloric acid is added, the pH is adjusted to 2.5, the temperature is raised to 65 ℃, after 3 hours of reaction, HPLC detection is finished, the temperature is lowered to room temperature, 8.2g of EDTA 4Na 4H is added 2 O, concentrating under reduced pressure to remove acetonitrile, adding 10mL of water and 25mL of dichloromethane, adjusting pH to 9-10 with 50% by weight of aqueous sodium hydroxide solution, separating, and washing the aqueous phase with dichloromethane (25mL. Multidot.2) again to obtain an aqueous solution of Compound 5 for use in the next reaction.
Recovery of compound 6:
mixing the above organic phases, slowly adding concentrated hydrochloric acid dropwise at room temperature, adjusting pH to 1.5-2.5, stirring overnight at room temperature after dropwise addition, filtering, and drying to obtain white solid compound 6.97g with yield of about 94.5% and purity of 99.8%.
C. Preparation of Compound 1
Slowly dripping 6.66g of Boc anhydride into a flask filled with a compound 5 water solution at room temperature, stirring for 10h after dripping is finished, adding 25mL of dichloromethane after reaction is finished, stirring, separating liquid, washing the water phase with 25mL of dichloromethane again, controlling the temperature of the water phase to be 10-20 ℃, adjusting the pH to be 3-5 by using 12% hydrochloric acid, separating solid, stirring for 1-2 h, filtering, washing a filter cake by using isopropyl ether, and performing vacuum drying at 50-60 ℃ to obtain a white solid compound 1.68g, wherein the yield is 92.2% and the purity is 99.2%.
As can be seen from examples 1 to 5 and comparative examples 7 to 9, the selection of the reaction conditions has a large influence on the purity and yield of compound 1 and the recovery of compound 6. In comparative example 7, the solvent addition in step a was excessive, the compound 3 addition was excessive, and the pH was adjusted to be too basic, resulting in the compound 4 containing a part of the compound 3 impurity, and the purity was decreased, and the yield was decreased, in step B, methylene chloride was used as the reaction solvent, and the solvent addition was excessive, and the pH was adjusted to be too acidic, which was not favorable for the hydrolysis reaction, and the subsequent pH adjustment of more than 10, which was not favorable for the purity of the compound 5, whereas the pH in the organic phase was adjusted to 3.0 to 3.5, which was not favorable for the precipitation of the compound 6, resulting in the decrease in the recovery of the compound 6. In comparative example 8, the amount of solvent added in step a was too small, the amount of compound 3 added was too small, the reaction did not proceed sufficiently, and the yield of compound 4 decreased, in step B, the amount of reaction solvent added was insufficient, the degree of acidity for pH adjustment was insufficient, which was also unfavorable for the hydrolysis reaction, the subsequent pH adjustment was less than 9, compound 5 was not sufficiently dissolved in the aqueous phase, the yield of subsequent compound 1 decreased, and a part of compound 6 remained in the aqueous phase, which was unfavorable for the precipitation of compound 6, resulting in a decrease in the recovery rate of compound 6. In comparative example 9, the nucleophilic substitution reaction was performed using an amide solution in step A, but the stereoselectivity was still not as good as that of acetone and acetonitrile for this reaction. And all parameters of the embodiments 1 to 5 fall within the scope of the invention, and the proper metal ligand compound, reaction solvent and reaction conditions are selected, so that the yield and purity of the intermediate compound 1 of the sitaxel are ensured, the recovery rate of the compound 6 is high, the purity is high, the loss is reduced, and the economic benefit is increased. In particular, the technical parameters of example 1, the yield and purity of compound 1 and the recovery of compound 6 are optimized at the same time.
Example 6 preparation of sitaxetil
A. Preparation of Compound 3-1
To a flask containing 10.0g of Compound 1 prepared in example 1, 100mL of dichloromethane, 4.7g of benzyl alcohol and 0.36g of DMAP were added, the temperature was lowered to 0-5 ℃, and the mixture was stirred for 30 minutes, 5.56g of EDCI was added, and after the completion of the TLC detection reaction, 50mL of sodium bicarbonate solution was added to quench, and the mixture was separated, and the organic phase was washed successively with 50mL of citric acid solution and 50mL of saturated saline solution to obtain an organic phase of Compound 2-1, which was used directly in the next reaction. Controlling the temperature of the organic phase to be 10-15 ℃, adding 10mL of 4M HCl dioxane solution, concentrating after the reaction is finished, and recrystallizing by a dimethylformamide/dichloromethane system to obtain 3-1.5 g of the compound, wherein the yield is 97.4%, and the purity is 99.2%.
B. Preparation of Compound 6-1
Adding 100mL of isopropyl acetate and 5.2g of thionyl chloride into a flask containing 14.2g of compound 4-1, controlling the temperature to be not more than 20 ℃, stirring for 2 hours, concentrating, adding 100mL of tetrahydrofuran and 10.5g of compound 3-1, dropwise adding 6g of diisopropylethylamine, adding water for separating liquid after reaction is finished, drying an organic phase by anhydrous sodium sulfate, concentrating the organic phase, adding 30mL of dioxane solution of 4M HCl, stirring overnight at room temperature, filtering, and drying in vacuum to obtain 6-1.3 g of compound, wherein the yield is 96.0 percent and the purity is 99.3 percent.
C. Preparation of Compound 8-1
100mL of tetrahydrofuran, 5.2g of thionyl chloride and a catalytic amount of DMF (0.3 mL) were added to a flask containing 4.7g of Compound 7-1, stirred overnight, concentrated, 100mL of dichloromethane and 16.3g of Compound 6-1 were added, 6.0g of diisopropylethylamine was added dropwise, and after completion of the reaction at 0-5 ℃, water was added to separate the solution, and the mixture was concentrated to give 8-118.2g of Compound, 94.6% yield and 98.5% purity.
D. Preparation of sitagliptin
100mL of methanol, 10mL of tetrahydrofuran, 10mL of formic acid and 2.0g of 10% palladium-carbon were added to a flask containing 18.2g of the compound 8-1, stirred overnight under nitrogen protection, filtered, concentrated, slurried with butanone, filtered and dried to obtain 15.1g of sitaxel, yield 95.1% and purity 99.6%.
EXAMPLE 7 preparation of Compound 2
2.73g of Compound 6 recovered by the preparation of example 1 was dissolved in 30mL of methanol at room temperature, and 2.50g of glycine and 3.32g of copper sulfate pentahydrate were added. After 2.61g of potassium hydroxide was dissolved in 10mL of methanol, it was added to the above mixture. The mixture system was stirred at room temperature for 1h, 30mL of 10% citric acid solution was added, extraction was performed with dichloromethane (3 x 50ml), liquid separation concentration was performed, dichloromethane-acetone was used for gradient elution in an automatic flash chromatography system on silica gel to obtain a solid, which was then rinsed with acetone solution and dried to obtain 2.1g of solid compound with a yield of 60.1%.
From examples 6 and 7, it can be seen that the intermediate compound 1 of sitagliptin prepared by the invention can be directly used for the subsequent preparation of the sitagliptin, and the prepared sitagliptin has better yield and purity and is beneficial to the preparation of the subsequent preparation. The obtained compound 6 is recovered, and the copper ligand compound can be prepared again, so that the method is economic and environment-friendly.
The foregoing is a further detailed description of the invention in connection with specific preferred embodiments and it is not intended to limit the invention to the specific embodiments described. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (10)
1. A preparation method of a sitagliptin intermediate compound 1 is characterized by comprising the following three steps:
A. adding the compound 2 into an organic solvent, mixing with a sodium hydroxide solution, cooling, adding the compound 3 for reaction, adding ice water after the reaction is finished, preserving heat, filtering and drying to obtain a compound 4;
B. dissolving a compound 4 in an organic solvent I, adding hydrochloric acid, heating for reaction, adding a chelating agent after the reaction is finished, concentrating under reduced pressure, adding water and an organic solvent II, adding a sodium hydroxide solution, separating liquid and washing to obtain a compound 5 water solution, combining the organic phases, adding hydrochloric acid at room temperature, stirring at room temperature after the addition is finished, filtering, and drying to obtain a compound 6;
C. reacting the compound 5 water solution with Boc anhydride, adding hydrochloric acid after the reaction is finished, stirring, filtering and drying to obtain a compound 1;
and X is F, cl or Br.
2. The process for preparing a sitagliptin intermediate compound 1 according to claim 1, characterized in that in step a, X is Cl.
3. The preparation method of a sitagliptin intermediate compound 1 according to claim 1, wherein in the step A, the solution of the compound 3 is acetonitrile solution or acetone solution, the mass-to-volume ratio of the compound 2 to the solution is 1 to 3, the molar ratio of the compound 2 to the compound 3 is 1.05 to 1.20, and sodium hydroxide aqueous solution with the mass concentration of 40 to 60 percent is added to adjust the pH value to 6.5 to 8.5.
4. The preparation method of a sitaxel intermediate compound 1 according to claim 3, wherein in the step A, the solution of the compound 3 is an acetone solution, the mass volume ratio of the compound 2 to the solution is 1.
5. The preparation method of the sitagliptin intermediate compound 1 according to claim 1, characterized in that in the step A, the temperature is reduced to 0-10 ℃, preferably 0-5 ℃, and the solution of the compound 3 is dripped for reaction for 2-4h, preferably 3h.
6. The preparation method of the sitagliptin intermediate compound 1 as claimed in claim 1, wherein in the step B, the used organic solvent I is one or more of methanol, ethanol, acetonitrile and tetrahydrofuran, the mass volume ratio of the compound 4 to the organic solvent I is 1.
7. The preparation method of a sitagliptin intermediate compound 1 according to claim 6, wherein in the step B, the organic solvent I is acetonitrile, the mass volume ratio of the compound 2 to the organic solvent is 1.
8. The preparation method of a sitagliptin intermediate compound 1 according to claim 1, characterized in that in step C, the reaction time is 8-12h, preferably 10h.
9. A preparation method of a sitaxetil intermediate compound 1 comprises the following three steps:
A. adding the compound 2 into acetone, mixing with 50-wt% of sodium hydroxide solution until the pH is 7.0-8.0, the mass-to-volume ratio of the compound 2 to the acetone is 1.5, the molar ratio of the compound 2 to the compound 3 is 1.1, cooling to 0-5 ℃, dropwise adding the solution of the compound 3 for reaction, continuing the reaction for 3 hours after the dropwise addition is finished, adding ice water after the reaction is finished, preserving the heat at 0-5 ℃, filtering and drying to obtain a compound 4;
B. adding a compound 4 into acetonitrile, wherein the mass-volume ratio of the compound 4 to the acetonitrile is 1; mixing the organic phases, dropwise adding concentrated hydrochloric acid at room temperature until the pH value is 1.5-2.5, stirring at room temperature after dropwise adding, filtering, and drying to obtain compound 6;
C. after obtaining an aqueous solution containing a compound 5, dropwise adding Boc anhydride into the aqueous solution containing the compound 5 at room temperature, wherein the molar ratio of the Boc anhydride to the compound 4 is 1.7;
10. use of compound 1 obtained by the process according to any one of claims 1 to 9 for the preparation of sitagliptin.
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