CN115894496A - Preparation method of ticagrelor and intermediate thereof - Google Patents
Preparation method of ticagrelor and intermediate thereof Download PDFInfo
- Publication number
- CN115894496A CN115894496A CN202111165401.9A CN202111165401A CN115894496A CN 115894496 A CN115894496 A CN 115894496A CN 202111165401 A CN202111165401 A CN 202111165401A CN 115894496 A CN115894496 A CN 115894496A
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- Prior art keywords
- formula
- compound
- reaction
- compound shown
- difluorophenyl
- Prior art date
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- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 28
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 189
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- -1 3,4-difluorophenyl Chemical group 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 60
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 42
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 38
- 239000002994 raw material Substances 0.000 claims abstract description 24
- 230000007062 hydrolysis Effects 0.000 claims abstract description 20
- 102000004190 Enzymes Human genes 0.000 claims abstract description 19
- 108090000790 Enzymes Proteins 0.000 claims abstract description 19
- 230000006103 sulfonylation Effects 0.000 claims abstract description 10
- 108090001060 Lipase Proteins 0.000 claims description 47
- 102000004882 Lipase Human genes 0.000 claims description 47
- 239000004367 Lipase Substances 0.000 claims description 47
- 235000019421 lipase Nutrition 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 108090000371 Esterases Proteins 0.000 claims description 24
- 230000003301 hydrolyzing effect Effects 0.000 claims description 23
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims description 22
- 238000005917 acylation reaction Methods 0.000 claims description 20
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 20
- 230000008569 process Effects 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 229940088598 enzyme Drugs 0.000 claims description 18
- 102000004157 Hydrolases Human genes 0.000 claims description 16
- 108090000604 Hydrolases Proteins 0.000 claims description 16
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 13
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000006722 reduction reaction Methods 0.000 claims description 12
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 11
- 241001661345 Moesziomyces antarcticus Species 0.000 claims description 11
- 239000004365 Protease Substances 0.000 claims description 11
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical group [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 241000588724 Escherichia coli Species 0.000 claims description 8
- 108091005804 Peptidases Proteins 0.000 claims description 8
- 230000010933 acylation Effects 0.000 claims description 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 8
- 239000000194 fatty acid Substances 0.000 claims description 8
- 229930195729 fatty acid Natural products 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- 230000009466 transformation Effects 0.000 claims description 8
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 7
- 150000001263 acyl chlorides Chemical class 0.000 claims description 7
- 235000019419 proteases Nutrition 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 6
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 235000002732 Allium cepa var. cepa Nutrition 0.000 claims description 4
- 240000006439 Aspergillus oryzae Species 0.000 claims description 4
- 235000002247 Aspergillus oryzae Nutrition 0.000 claims description 4
- 102000005600 Cathepsins Human genes 0.000 claims description 4
- 108010084457 Cathepsins Proteins 0.000 claims description 4
- 108090000317 Chymotrypsin Proteins 0.000 claims description 4
- 108090000526 Papain Proteins 0.000 claims description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000004280 Sodium formate Substances 0.000 claims description 4
- 108090000787 Subtilisin Proteins 0.000 claims description 4
- 241000179532 [Candida] cylindracea Species 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229960002376 chymotrypsin Drugs 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000003541 multi-stage reaction Methods 0.000 claims description 4
- 235000019834 papain Nutrition 0.000 claims description 4
- 229940055729 papain Drugs 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 claims description 4
- 239000004331 potassium propionate Substances 0.000 claims description 4
- 235000010332 potassium propionate Nutrition 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 4
- 235000019254 sodium formate Nutrition 0.000 claims description 4
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 4
- 239000004324 sodium propionate Substances 0.000 claims description 4
- 235000010334 sodium propionate Nutrition 0.000 claims description 4
- 229960003212 sodium propionate Drugs 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 244000291564 Allium cepa Species 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 55
- 239000000243 solution Substances 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000012074 organic phase Substances 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 230000002255 enzymatic effect Effects 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 23
- 239000007788 liquid Substances 0.000 description 23
- 239000008346 aqueous phase Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 238000000605 extraction Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 238000005406 washing Methods 0.000 description 17
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- QVUBIQNXHRPJKK-IMTBSYHQSA-N (1r,2s)-2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound N[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-IMTBSYHQSA-N 0.000 description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- RYOLLNVCYSUXCP-MRVPVSSYSA-N (1s)-2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClC[C@@H](O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-MRVPVSSYSA-N 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- IIPKDNLHLXDNRT-VIFPVBQESA-N (1s)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol Chemical compound [O-][N+](=O)CC[C@H](O)C1=CC=C(F)C(F)=C1 IIPKDNLHLXDNRT-VIFPVBQESA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- VMEDAWUIKFAFJQ-UHFFFAOYSA-N 2-chloro-1-(3,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C=C1F VMEDAWUIKFAFJQ-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- RYOLLNVCYSUXCP-UHFFFAOYSA-N 2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClCC(O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 5
- CSLVZAGSOJLXCT-NKWVEPMBSA-N (1r,2r)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 CSLVZAGSOJLXCT-NKWVEPMBSA-N 0.000 description 4
- LQBABPIBBJIGEJ-JTQLQIEISA-N (4s)-4-(3,4-difluorophenyl)-4-hydroxybutanenitrile Chemical compound N#CCC[C@H](O)C1=CC=C(F)C(F)=C1 LQBABPIBBJIGEJ-JTQLQIEISA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- IIPKDNLHLXDNRT-SECBINFHSA-N (1r)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol Chemical compound [O-][N+](=O)CC[C@@H](O)C1=CC=C(F)C(F)=C1 IIPKDNLHLXDNRT-SECBINFHSA-N 0.000 description 3
- RYOLLNVCYSUXCP-QMMMGPOBSA-N (1r)-2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClC[C@H](O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-QMMMGPOBSA-N 0.000 description 3
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 description 3
- LQBABPIBBJIGEJ-UHFFFAOYSA-N 4-(3,4-difluorophenyl)-4-hydroxybutanenitrile Chemical compound N#CCCC(O)C1=CC=C(F)C(F)=C1 LQBABPIBBJIGEJ-UHFFFAOYSA-N 0.000 description 3
- RXLXNXOGJOBDAP-UHFFFAOYSA-N 4-(3,4-difluorophenyl)-4-oxobutanenitrile Chemical compound FC1=CC=C(C(=O)CCC#N)C=C1F RXLXNXOGJOBDAP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000234282 Allium Species 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- SCDFAHSIYYBVTF-UHFFFAOYSA-N (3,4-difluorophenyl) acetate Chemical compound CC(=O)OC1=CC=C(F)C(F)=C1 SCDFAHSIYYBVTF-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- VYHQBUSVVNQXPV-IMTBSYHQSA-N 1,2-difluoro-4-[(1s,2r)-2-nitrocyclopropyl]benzene Chemical compound [O-][N+](=O)[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 VYHQBUSVVNQXPV-IMTBSYHQSA-N 0.000 description 2
- IIPKDNLHLXDNRT-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-3-nitropropan-1-ol Chemical compound [O-][N+](=O)CCC(O)C1=CC=C(F)C(F)=C1 IIPKDNLHLXDNRT-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- NDQKGYXNMLOECO-UHFFFAOYSA-N acetic acid;potassium Chemical compound [K].CC(O)=O NDQKGYXNMLOECO-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 2
- 235000017454 sodium diacetate Nutrition 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 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
- 239000002699 waste material Substances 0.000 description 2
- HLVDWMSYSIMRNI-DUXPYHPUSA-N (e)-3-(3,4-difluorophenyl)prop-2-enoyl chloride Chemical compound FC1=CC=C(\C=C\C(Cl)=O)C=C1F HLVDWMSYSIMRNI-DUXPYHPUSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- QVUBIQNXHRPJKK-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound NC1CC1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 102000005751 Alcohol Oxidoreductases Human genes 0.000 description 1
- 108010031132 Alcohol Oxidoreductases Proteins 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000005257 alkyl acyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- KRCSBYPKUJAPSQ-UHFFFAOYSA-N benzene formyl chloride Chemical compound C(=O)Cl.C1=CC=CC=C1 KRCSBYPKUJAPSQ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- AWQVKAURKXXOCG-UHFFFAOYSA-N n-cyclopropylformamide Chemical compound O=CNC1CC1 AWQVKAURKXXOCG-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- 229960001553 phloroglucinol Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a brand new synthesis method of ticagrelor and a key intermediate (S) -1- (3,4-difluorophenyl) -alpha-alcohol thereof. The method takes 1- (3,4-difluorophenyl) -alpha-alcohol ester as a raw material to prepare (S) -1- (3,4-difluorophenyl) -alpha-alcohol through enzyme resolution (hydrolysis); the resulting compound of another configuration can be used to prepare (S) -1- (3,4-difluorophenyl) -alpha-alcohol by (hydrolysis), sulfonylation, waldenstein conversion and hydrolysis. The method has the advantages of simple operation, cheap and easily obtained raw materials and reagents, mild reaction conditions, high yield and environmental friendliness, thereby realizing industrial production.
Description
Technical Field
The invention belongs to the field of medicine and fine chemical engineering. In particular, the invention relates to a synthesis method of a key intermediate of ticagrelor.
Background
Ticagrelor (ticagrelor) is a novel small molecule anticoagulant with selective effect, and is approved to be sold on the market by the european union and the U.S. Food and Drug Administration (FDA) in 12 months 2010 and 7 months 2011, respectively. The medicine can reversibly act on ADP P2Y12 receptors, has obvious inhibition effect on platelet aggregation caused by ADP, has quick oral administration effect, and is clinically used for reducing the incidence rate of thrombotic cardiovascular events of patients with acute coronary syndrome.
The (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine is a key intermediate for synthesizing ticagrelor, and the synthesis methods in the prior art comprise two methods: one is to synthesize racemic 2- (3,4-difluorophenyl) cyclopropylamine, then obtain (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine by resolution; this results in a loss of half of the raw material, resulting in considerable waste and a low efficiency of synthesis. Secondly, (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine is synthesized by synthesizing chiral (S) - (3,4-difluorophenyl) -alpha-alcohol intermediate or S- (3,4-difluorophenyl) ethylene oxide which is used as a raw material.
In the method in WO 2008018822A1, o-difluorobenzene is used as a raw material to prepare 2-chloro-1- (3,4-difluorophenyl) ethanone through Friedel-crafts reaction, and then 2-chloro-1-S- (3,4-difluorophenyl) ethanol is prepared through chiral reduction; the disadvantages of this process are the use of expensive chiral oxazaborolidine catalysts and toxic borane dimethylsulfide complex, and the use of the explosive material sodium hydride. The specific process route is as follows:
WO2011017108a discloses a method for synthesizing E-3- (3,4-difluorophenyl) acryloyl chloride from E-3- (3,4-difluorophenyl) allyl acid, followed by reaction with chiral oxazaborolidine and subsequent conversion to chiral compounds by catalytic reaction. The disadvantage of this process is the use of expensive chiral oxazaborolidines and palladium catalysts. The specific synthetic route is as follows:
WO2013124280 discloses a method for preparing 2-chloro-1- (3,4-difluorophenyl) ethanone by Friedel-crafts reaction by using o-difluorobenzene as a raw material, and then reducing the prepared product by expensive ligands to produce (S) -4- (3,4-difluorophenyl) -4-hydroxybutyronitrile. The method has the defects that expensive ligand is used in chiral reduction, the ligand cannot be recycled, the overall yield is low, the environmental pollution is large, the cost is high, and the method is not suitable for industrial production.
In the method disclosed in WO2011132083, o-difluorobenzene is used as a raw material to prepare 3-chloro-1- (3,4-difluorobenzene) acetone through Friedel-crafts reaction, sodium nitrite and sodium iodide are used for nitration reaction, and then a CBS catalyst is used for asymmetric reduction to prepare (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol; the route uses expensive chiral reducing agent and expensive and highly toxic sodium iodide, and is not suitable for industrial production.
CN102775314A discloses a method which adopts condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxy-benzo-triazole, dicyclohexylcarbodiimide and the like and a 4-dimethylaminopyridine catalyst to carry out kinetic resolution. The method has high cost, pollutes the environment and wastes 50 percent of raw materials.
In the method disclosed in CN106906249a, o-difluorobenzene is used as a raw material to prepare 3-chloro-1- (3,4-difluorophenyl) acetone, and carbonyl reductase is used for reduction to prepare 2-chloro-1-S- (3,4-difluorophenyl) ethanol; the method has the disadvantages of low biological activity of enzyme and large using amount. The specific process route is as follows:
although the prior art has many researches on the preparation of (S) -1- (3,4-difluorophenyl) -alpha-alcohol, the disclosed synthetic method has many disadvantages, such as low yield, difficult separation and purification, large use of expensive chiral reagents, heavy pollution, high cost and the like. These disadvantages limit the industrial production.
Therefore, there is an urgent need in the art for other methods for preparing (S) -1- (3,4-difluorophenyl) - α -ol intermediates, so as to reduce the synthesis cost thereof and further reduce the preparation cost of ticagrelor.
Disclosure of Invention
The invention aims to provide a brand new preparation method of an (S) -1- (3,4-difluorophenyl) -alpha-alcohol intermediate, which has the advantages of simple process, low cost and environmental friendliness, so that the production cost of ticagrelor can be reduced, and the method is suitable for industrial production.
In a first aspect, the present invention provides a process for the preparation of ticagrelor, said process comprising the steps of:
(1-1) taking 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially carrying out Friedel-crafts reaction and reduction reaction to obtain a compound shown as a formula I, and then carrying out hydroxyl acylation to obtain a compound shown as a formula II;
(1-2 a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;
in the formula, R 1 Selected from halogens (preferably F, cl or Br);
R 2 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(1-3) preparing ticagrelor by utilizing the compound shown in the formula III through multi-step reaction;
alternatively, the method comprises the steps of:
(2-1) taking 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially carrying out Friedel-crafts reaction, substitution reaction and reduction reaction to obtain a compound shown in a formula i, and carrying out hydroxyl acylation to obtain a compound shown in a formula ii;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(2-2) enzymatically resolving the compound of formula ii obtained in step (2-1) to obtain a compound of formula iii and a compound of formula iv;
(2-3 a) hydrolyzing the compound represented by the formula iv obtained in the step (2-2) to obtain a compound represented by the formula v;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(2-4) preparing ticagrelor by utilizing the compound shown in the formula v through multi-step reaction.
In a preferred embodiment, in the step (1-1), the compound shown as the formula I is utilized to perform hydroxylation reaction to form an ester so as to obtain a compound shown as the formula II;
the compound of formula i is hydroxyacylated to an ester in step (2-1) to give a compound of formula ii.
In a preferred embodiment, the solvent utilized in the acylation reaction of step (1-1) or (2-1) is acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran, or a combination thereof, preferably dichloromethane;
the base used in the acylation reaction is triethylamine, N-dimethylethylamine, N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine;
the acyl chloride utilized in the acylation reaction is C 1-6 Alkyl acyl chloride, allyl chloride, benzeneFormyl chloride or phenylacetyl chloride, preferably acetyl chloride;
the compound shown in the formula I or the compound shown in the formula i in the acylation reaction has the molar ratio of 1 (1-2) to 1-1.2, preferably 1;
the temperature of the acylation reaction is 10-30 ℃, preferably 10-20 ℃;
the time of the acylation reaction is 1 to 5 hours, preferably 2 hours.
In particular embodiments, the enzyme utilized in step (1-2 a) or (2-2) is a hydrolase, including but not limited to a lipase, a protease, or an esterase;
preferably, the lipase is candida antarctica lipase, candida cylindracea lipase, candida onion lipase PS, lipase TL, distillers yeast lipase, lipase AS1 and the like;
the protease is chymotrypsin, cathepsin, papain, subtilisin and the like;
the esterase is porcine liver esterase PL, esterase RO, an Aspergillus oryzae TL recombinant, an Escherichia coli esterase BS1 recombinant, an Escherichia coli esterase BS2 recombinant and the like;
more preferably, the hydrolase is a lipase PS from candida cepacia or a lipase from candida antarctica.
In a preferred embodiment, the concentration of the compound of formula II in step (1-2 a) is from 5 to 20%, preferably about 10%; the weight ratio of the compound shown in the formula II to the hydrolase is 1-20, preferably 10; or
The concentration of the compound of formula ii in step (2-2) is from 5 to 20%, preferably about 10%; the weight ratio of the compound represented by formula ii to the hydrolase is 1 to 20, preferably 10.
In a preferred embodiment, in step (1-2 a) or (2-2), the temperature of the enzyme resolution reaction is in the range of 15 to 40 ℃, preferably 25 to 30 ℃.
In a preferred embodiment, in step (1-2 a) or (2-2), the pH of the enzyme resolution reaction is between 6 and 9, preferably between 7 and 7.5.
In a preferred embodiment, in step (1-2 a) or (2-2), the enzyme resolution reaction time is about 12 to 30 hours, preferably about 18 hours.
In a specific embodiment, the method further comprises the step of preparing the compound shown in the formula III by using the compound shown in the formula IV obtained in the step (1-2 a) through hydrolysis reaction, sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (1-2 a); or
And (3) preparing the compound shown in the formula v by using the compound shown in the formula iii obtained in the step (2-2) through sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (2-3 a).
In a specific embodiment, the method further comprises the following steps after the step (1-2 a):
(1-2 b) hydrolyzing the compound represented by the formula IV obtained in the step (1-2 a) to obtain a compound represented by the formula V;
(1-2 c) carrying out a sulfonylation reaction on the compound shown in the formula V obtained in the step (1-2 b) so as to obtain a compound shown in a formula VI;
(1-2 d) subjecting the compound represented by the formula VI obtained in the step (1-2 c) to a Walton configuration transformation to obtain a compound represented by the formula VII;
(1-2 e) hydrolyzing the compound represented by the formula VII obtained in the step (1-2 d) to obtain a compound represented by the formula III;
in the formula, R 1 As described above; r is 5 Selected from: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Is H, C 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )；
Or, the following steps are also included after the step (2-3 a):
(2-3 b) carrying out a sulfonylation reaction on the compound shown in the formula iii obtained in the step (2-2) to obtain a compound shown in the formula vi;
(2-3 c) carrying out Waldenstein configuration conversion on the compound shown in the formula vi obtained in the step (2-3 b) to obtain a compound shown in the formula vii;
(2-3 d) hydrolyzing the compound of formula vii obtained in step (2-3 c) to obtain a compound of formula v;
wherein R is 3 As described above; r is 5 Selected from: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Selected from: H. c 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )。
In a preferred embodiment, the solvent utilized in the hydrolysis reaction of step (1-2 b), (1-2 e) or step (2-3 a), (2-3 d) is water, methanol, ethanol, isopropanol, or a combination thereof, preferably methanol;
the utilized hydrolysis reagent is concentrated hydrochloric acid, aqueous hydrogen bromide solution, sodium carbonate or potassium bicarbonate;
the temperature of the hydrolysis reaction is 40-80 ℃, preferably 45-50 ℃;
the time for the hydrolysis reaction is 3 to 10 hours, preferably about 5 hours.
In a preferred embodiment, the solvent utilized in the sulfonylation reaction of step (1-2 c) or (2-3 b) is acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran, or a combination thereof, preferably dichloromethane;
the base utilized in the sulfonylation reaction is triethylamine, N-dimethylethylamine, N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine;
the sulfonyl chloride utilized in the sulfonylation reaction is C 1-6 Alkylsulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, preferably methanesulfonyl chloride;
the molar ratio of the compound shown in the formula V or the formula iii to the base in the sulfonylation reaction is 1 (1-2) to (1-1.2), preferably 1;
the temperature of the sulfonylation reaction is 0-20 ℃, preferably 0-5 ℃;
the time for the sulfonylation reaction is 1 to 5 hours, preferably 2 hours.
In a specific embodiment, C utilized in the Waldenstein configuration conversion reaction of step (1-2 d) or (2-3C) 1-6 The fatty acid salt is preferably cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, most preferably cesium acetate;
the solvent used in the Valden configuration transformation reaction is DMF, DMSO or acetonitrile, preferably DMF;
the molar ratio of the compound shown in the formula VI or the compound shown in the formula vi in the conversion of the Waldensen configuration to the fatty acid salt is 1:1-4, and 1.5 is preferred;
the temperature of the Valden configuration conversion reaction is 20-50 ℃, and preferably 22-26 ℃;
the time for the conversion of the Valden configuration is 10 to 30 hours, preferably 12 hours.
In a second aspect, the present invention provides a process for the preparation of (S) -1- (3,4-difluorophenyl) - α -alcohol, said (S) -1- (3,4-difluorophenyl) - α -alcohol being a compound of formula III, said process comprising the steps of:
(1-1) taking 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially carrying out Friedel-crafts reaction and reduction reaction to obtain a compound shown as a formula I, and then carrying out hydroxyl acylation to obtain a compound shown as a formula II;
(1-2 a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;
in the formula, R 1 Selected from halogens (preferably F, cl or Br);
R 2 selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
Alternatively, the (S) -1- (3,4-difluorophenyl) - α -alcohol is a compound of formula v, comprising the steps of:
(2-1) taking 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially carrying out Friedel-crafts reaction, substitution reaction and reduction reaction to obtain a compound shown in a formula i, and carrying out hydroxyl acylation to obtain a compound shown in a formula ii;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(2-2) enzymatically resolving the compound of formula ii obtained in step (2-1) to obtain a compound of formula iii and a compound of formula iv;
(2-3 a) hydrolyzing the compound shown in the formula iv obtained in the step (2-2) to obtain a compound shown in a formula v;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 。
In a specific embodiment, the method further comprises the step of preparing the compound shown in the formula III by using the compound shown in the formula IV obtained in the step (1-2 a) through hydrolysis reaction, sulfonylation reaction, waldensein configuration conversion reaction and hydrolysis reaction after the step (1-2 a); or alternatively
And (3) preparing the compound shown in the formula v by using the compound shown in the formula iii obtained in the step (2-2) through sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (2-3 a).
In a specific embodiment, the method further comprises the following steps after the step (1-2 a):
(1-2 b) hydrolyzing the compound represented by the formula IV obtained in the step (1-2 a) to obtain a compound represented by the formula V;
(1-2 c) carrying out a sulfonylation reaction on the compound shown in the formula V obtained in the step (1-2 b) so as to obtain a compound shown in a formula VI;
(1-2 d) subjecting the compound represented by the formula VI obtained in the step (1-2 c) to a Waldenstein configuration conversion to obtain a compound represented by the formula VII;
(1-2 e) hydrolyzing the compound represented by the formula VII obtained in the step (1-2 d) to obtain a compound represented by the formula III;
in the formula, R 1 As claimed in claim 1; r 5 Selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ； R 6 Is H, C 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )；
Or, the following steps are also included after the step (2-3 a):
(2-3 b) carrying out a sulfonylation reaction on the compound shown in the formula iii obtained in the step (2-2) to obtain a compound shown in the formula vi;
(2-3 c) carrying out Waldenstein configuration conversion on the compound shown in the formula vi obtained in the step (2-3 b) to obtain a compound shown in the formula vii;
(2-3 d) hydrolyzing the compound of formula vii obtained in step (2-3 c) to obtain a compound of formula v;
wherein R is 3 As claimed in claim 1; r 5 Selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ； R 6 Selected from the group consisting of: H. c 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )。
In a third aspect, the present invention provides a compound of formula II
In the formula, R 1 Selected from halogens (preferably F, cl or Br);
R 2 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 (ii) a Or
A compound of formula ii
In the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 。
In a fourth aspect, the present invention provides the use of a compound of formula II or a compound of formula II for the preparation of ticagrelor.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have conducted extensive and intensive studies and have unexpectedly found that, starting from a specific starting compound, (S) -1- (3,4-difluorophenyl) - α -ol intermediate can be directly obtained by enzymatic resolution, and subsequent configuration transformation of the enzymatic resolution by-product can further convert the by-product into the desired (S) -1- (3,4-difluorophenyl) - α -ol intermediate, thereby enabling simple and low-cost production of (S) -1- (3,4-difluorophenyl) - α -ol intermediate and finally ticagrelor. The present invention has been completed based on this finding.
On the basis of researching a plurality of synthesis routes and reaction conditions of (S) -1- (3,4-difluorophenyl) -alpha-alcohols as key medicine intermediates of ticagrelor and considering industrial production, the inventor creatively selects a process route which is simple to operate and easy for industrial production, namely (S) -1- (3,4-difluorophenyl) -alpha-alcohol ester is used as a raw material to prepare (S) -1- (3,4-difluorophenyl) -alpha-alcohols through enzymatic resolution; (S) -1- (3,4-difluorophenyl) -alpha-alcohol can be prepared by hydrolysis, sulfonylation, waldenstein conversion and hydrolysis on the resulting compound of another configuration.
The invention relates to application of an enzyme resolution and configuration conversion technology in preparation of a ticagrelor intermediate, in particular to preparation of a ticagrelor intermediate (S) -1- (3,4-difluorophenyl) -alpha-alcohol by enzymatic resolution and hydrolysis of 1- (3,4-difluorophenyl) -alpha-alcohol ester; and preparing ticagrelor intermediate (S) -1- (3,4-difluorophenyl) -alpha-alcohol by resolving by-products through (hydrolysis), sulfonylation, configuration inversion and hydrolysis.
In a specific embodiment, the method comprises the following steps:
(1) The key intermediate (S) -2-chloro-1- (3,4-difluorophenyl) ethanol of ticagrelor was prepared by enzymatic resolution of ethyl 2-chloro-1- (3,4-difluorophenyl) acetate; in addition, the other compound obtained by the enzymatic resolution, namely the ethyl 2-chloro-1R- (3,4-difluorophenyl) acetate, is hydrolyzed, sulfonylated, converted into a Waldenstrom configuration and hydrolyzed to prepare the (S) -2-chloro-1- (3,4-difluorophenyl) ethanol.
(2) The key intermediate (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol of ticagrelor was prepared by enzymatic resolution of 1- (3,4-difluorophenyl) -3-nitro-propyl acetate and hydrolysis reaction; in addition, (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol was prepared by sulfonylation, conversion to the Waldenstein configuration and hydrolysis of another compound (R) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol obtained by enzymatic resolution.
(3) The key intermediate (S) -1- (3,4-difluorophenyl) -4-hydroxybutyronitrile of ticagrelor was prepared by enzymatic resolution of 1- (3,4-difluorophenyl) -3-cyano-propyl acetate and hydrolysis reaction, and in addition (S) -1- (3,4-difluorophenyl) -4-hydroxybutyronitrile was prepared by sulfonylation, conversion in the walden configuration and hydrolysis of another compound (R) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate obtained by enzymatic resolution.
Through a large number of experiments, reaction conditions of each step of reaction in the synthesis process are discussed, so that the synthesis yield and quality are improved, the synthesis period is shortened, the synthesis cost is reduced, and more reasonable process conditions are finally determined. The whole reaction route is simple, the used raw materials and reagents are cheap and easy to obtain, the reaction condition is mild, the yield is high, and the method is environment-friendly, so that the industrial production can be realized.
The method for synthesizing (S) -1- (3,4-difluorophenyl) -alpha-alcohol and ticagrelor comprises the following steps:
1. in the step (1-1), the compound shown in the formula I is used as a raw material, and the compound shown in the formula II is obtained through a hydroxyacylation esterification reaction. The specific chemical reaction equation of the method is as follows,
in the formula, R 1 Selected from halogens (preferably F, cl or Br); r is 2 Selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
Specifically, in the acylation reaction, the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base is triethylamine, N-dimethylethylamine, N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the molar ratio of the compound of formula I, alkali and acyl chloride is 1 (1-2) to 1-1.2, preferably 1; the temperature of the acylation reaction is 10-30 ℃, preferably 10-20 ℃; the time of the acylation reaction is 1 to 5 hours, preferably 2 hours.
2. In the step (1-2 a), the compound shown in the formula II is subjected to enzyme resolution to obtain a compound shown in an S-type III and a compound shown in an R-type IV. The specific chemical reaction equation of the method is as follows,
in the formula, R 1 Selected from halogens (preferably F, cl or Br); r is 2 Selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
Specifically, the method comprises the following steps: mixing hydrolase, a buffering agent and an optional alkali, adding a compound shown as a formula II, and maintaining the pH = 6-9 with the optional alkali at the temperature of 15-40 ℃ for 12-30 hours to obtain a compound shown as an S type III and a compound shown as an R type IV.
The enzymes utilized in the process are hydrolases, including but not limited to lipases, proteinases, or esterases;
preferably, the lipase is candida antarctica lipase, candida cylindracea lipase, candida onion lipase PS, lipase TL, distillers yeast lipase, lipase AS1 and the like. Preferably, the protease is chymotrypsin, cathepsin, papain, subtilisin and the like. Preferably, the esterase is porcine liver esterase PL, esterase RO, aspergillus oryzae TL recombinant, escherichia coli esterase BS1 recombinant, escherichia coli esterase BS2 recombinant, and the like. More preferably, the hydrolase is a lipase PS from candida cepacia or a lipase from candida antarctica.
The concentration of the compound of the formula II is usually 5 to 20%, preferably about 10%. The weight ratio of the compound shown in the formula II to the hydrolase is 1-20, and the weight ratio is preferably 10. The hydrolase can be reused for 5-15 times, preferably 8 times, without affecting the resolution result, and is suitable for industrial scale application.
The activity of the enzyme is usually temperature dependent. In a particular embodiment, the temperature of the enzymatic resolution reaction is controlled between 15 and 40 ℃, preferably between 25 and 30 ℃.
The time for the enzymatic resolution reaction is generally about 12 to 30 hours, preferably about 18 hours.
The enzyme is typically used in combination with a buffer to provide a pH suitable for the enzyme activity. In a particular embodiment, the buffer pH =6 to 9, preferably pH =7 to 7.5; the solvent used for enzyme resolution is water, the molar concentration of the buffer is 0.001-0.2 mol/L, and the preferred molar concentration is 0.01mol/L; the buffer salt is sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen acetate, potassium hydrogen acetate or their combination, preferably disodium hydrogen phosphate.
The pH control of the enzymatic resolution reaction is generally aided by the addition of a base, which may be an alkali metal hydroxide, carbonate or bicarbonate, preferably sodium hydroxide or potassium hydroxide.
After the enzymatic resolution reaction is finished, solvent extraction is usually required, and the extraction solvent is ethyl acetate, dichloromethane, toluene or dichloroethane, preferably dichloromethane.
The effect of pH on the enzymatic resolution reaction is given in the following table:
in a specific embodiment, 2-chloro-1- (3,4-difluorophenyl) ethyl acetate is used as a substrate, lipase PS of Candida cepacia is used, and the reaction is carried out for 18 hours at the temperature of between 25 and 30 ℃.
3. A process for the enzymatic resolution of by-product R, formula iv to produce S, formula iii, said process comprising:
(1-2 b) taking a compound shown in the R type IV as a raw material, and performing hydrolysis reaction to obtain a compound shown in the R type V;
(1-2 c) carrying out sulfonylation reaction on the compound shown in the R type V obtained in the step (1-2 b) to obtain a compound shown in the R type VI;
(1-2 d) converting the compound shown in the R formula VI obtained in the step (1-2 c) through a Waldensenconfiguration to obtain a compound shown in the S formula VII;
(1-2 e) hydrolyzing the compound of S form VII obtained in step (1-2 d) to obtain a compound of S form III.
The specific synthetic route of the method is as follows,
in the formula, R 1 Selected from halogens (preferably F, cl or Br); r 5 Selected from: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Selected from the group consisting of: H. c 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )；
In the hydrolysis reaction of step (1-2 b) or step (1-2 e), the solvent used is usually water, methanol, ethanol, isopropanol or a combination thereof, preferably methanol; the hydrolysis agent is usually concentrated hydrochloric acid, aqueous hydrogen bromide, sodium carbonate or potassium bicarbonate; the hydrolysis reaction temperature is 40-80 ℃, and preferably 45-50 ℃; the hydrolysis reaction time is 3 to 10 hours, preferably about 5 hours.
In the sulfonylation reaction of step (1-2 c), the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base used is triethylamine, N-dimethylethylamine, N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the sulfonyl chloride used is methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, preferably methanesulfonyl chloride; the molar ratio of the compound in the general formula V to the alkali to the sulfonyl chloride is 1 (1-2) to 1-1.2, preferably 1; the temperature of the sulfonylation reaction is 0-20 ℃, and preferably 0-5 ℃; the time for the sulfonylation reaction is 1 to 5 hours, preferably 2 hours.
In the Waldenstein configuration conversion reaction of the step (1-2 d), the used fatty acid salt is cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, and preferably cesium acetate; the solvent used is DMF, DMSO or acetonitrile, preferably DMF; the molar ratio of the compound in the general formula VI to the fatty acid salt is 1:1-4, and the preferable ratio is 1.5; the temperature of the Valden configuration conversion reaction is 20-50 ℃, and preferably 22-26 ℃; the time for the vardend configuration conversion reaction is 10 to 30 hours, preferably 12 hours.
4. In the step (2-1), the compound shown in the formula i is used as a raw material, and the compound shown in the formula ii is obtained by the hydroxylation reaction into ester. The specific chemical reaction equation of the method is as follows,
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 。
Specifically, in the acylation reaction, the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base is triethylamine, N-dimethylethylamine, N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the molar ratio of the compound shown in the formula i, alkali and acyl chloride is 1 (1-2) to 1-1.2, preferably 1; the temperature of the acylation reaction is 10-30 ℃, preferably 10-20 ℃; the time of the acylation reaction is 1 to 5 hours, preferably 2 hours.
5. The compound represented by the formula ii in the step (2-2) is enzymatically resolved to produce a compound represented by the formula iv and a compound represented by the formula iii, and the reaction equations are as follows,
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 。
In a specific embodiment, the method comprises: mixing a hydrolase, a buffer and an optional alkali, adding a compound shown as a formula ii, and maintaining the pH = 6-9 with the optional alkali at the temperature of 15-40 ℃ for 12-30 hours to obtain a compound shown as an R type iii and a compound shown as an S type iv.
In a specific embodiment, the hydrolase used in the method is a lipase, a protease, or an esterase. Preferably, the lipase is candida antarctica lipase, candida cylindracea lipase, candida onion lipase PS, lipase TL, distillers yeast lipase, lipase AS1 and the like. Preferably, the protease is chymotrypsin, cathepsin, papain, subtilisin and the like. Preferably, the esterase is porcine liver esterase PL, esterase RO, aspergillus oryzae TL recombinant, escherichia coli esterase BS1 recombinant, escherichia coli esterase BS2 recombinant, and the like. More preferably, the hydrolase is a lipase PS from candida cepacia or a lipase from candida antarctica.
The concentration of the compound of formula ii is generally between 5 and 20%, preferably about 10%. The weight ratio of the compound represented by formula ii to the hydrolase is 1 to 20, preferably 10. The hydrolase can be reused for 5-15 times, preferably 8 times, without affecting the resolution result, and is suitable for industrial scale application.
The activity of the enzyme is generally temperature dependent, and in particular embodiments, the enzyme resolution reaction is controlled at a temperature between 15 ℃ and 40 ℃, preferably between 25 ℃ and 30 ℃.
The time for the enzymatic resolution reaction is generally about 12 to 30 hours, preferably about 18 hours.
The enzyme is typically used in combination with a buffer to provide a pH suitable for the enzyme activity. In particular embodiments, the buffer has a pH =6 to 9, preferably a pH =7 to 7.5; the solvent used is water, the molar concentration of the buffer is 0.001-0.2 mol/L, and preferably, the molar concentration is 0.01mol/L; the buffer salt is sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen acetate, potassium hydrogen acetate or their combination, preferably disodium hydrogen phosphate.
The pH control of the enzymatic resolution reaction is generally aided by the addition of a base, which may be an alkali metal hydroxide, carbonate or bicarbonate, preferably sodium hydroxide or potassium hydroxide.
Solvent extraction is generally required after the completion of the enzymatic resolution reaction, and the extraction solvent used is ethyl acetate, dichloromethane, toluene or dichloroethane, preferably dichloromethane.
In general, in the hydrolysis reaction of the compound of formula iv to the compound of formula v, the solvent is water, methanol, ethanol, isopropanol or a combination thereof, preferably the solvent is ethanol; the hydrolysis reagent is concentrated hydrochloric acid, aqueous hydrogen bromide, sodium carbonate or potassium bicarbonate, and preferably, the hydrolysis reagent is concentrated hydrochloric acid; the hydrolysis reaction temperature is 40-80 ℃, and preferably, the reaction temperature is 45-50 ℃; the reaction time is 3 to 10 hours, and preferably, the reaction time is about 5 hours.
6. A process for the preparation of a compound of formula v by hydrolysis of a compound of formula iv of formula S by enzymatic resolution and of a compound of formula iii of by-product R of formula iii of formula v of formula S, said process comprising:
(2-3 a) hydrolyzing the product S of the enzymatic resolution of step (2-2) to obtain a compound S of formula v.
(2-3 b) carrying out sulfonylation reaction by using the compound shown as the by-product R type iii of the enzyme resolution in the step (2-2) as a raw material to obtain a compound shown as the R type vi;
(2-3 c) converting the Waldenstein configuration of the compound shown in the R type vi obtained in the step (2-3 b) into a compound shown in the S type vii;
(2-3 d) hydrolysing the compound of formula vii obtained in step (2-3 c) to give the compound of formula v.
The specific synthetic route of the method is as follows,
wherein R is 3 Selected from: NO 2 Or CN; r 5 Selected from: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ； R 6 Selected from the group consisting of: H. c 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )；
In the sulfonylation reaction of step (2-3 b), the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base is triethylamine, N-dimethylethylamine, N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the sulfonyl chloride is methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, preferably methanesulfonyl chloride; the molar ratio of the compound shown in the R type iii, the alkali and the sulfonyl chloride is 1 (1-2) to (1-1.2), and the molar ratio is preferably 1; the temperature of the sulfonylation reaction is 0-20 ℃, and preferably 0-5 ℃; the time for the sulfonylation reaction is 1 to 5 hours, preferably 2 hours.
In the Waldenstein configuration conversion reaction of step (2-3 c), the fatty acid salt used is usually cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, preferably cesium acetate; the solvent used is DMF, DMSO or acetonitrile, preferably DMF; the molar ratio of the compound of the R type vi to the fatty acid salt is 1:1-4, and 1.5 is preferred; the temperature of the Waldenstein configuration conversion reaction is 20-50 ℃, and preferably 22-26 ℃; the conversion reaction of the Valden configuration is carried out for 10 to 30 hours, preferably 12 hours.
In the hydrolysis reaction of step (2-3 d), the solvent used is typically water, methanol, ethanol, isopropanol or a combination thereof, preferably ethanol; the hydrolytic reagent is concentrated hydrochloric acid, aqueous hydrogen bromide solution, sodium carbonate or potassium bicarbonate, preferably concentrated hydrochloric acid; the temperature of the hydrolysis reaction is 40-80 ℃, and preferably 45-50 ℃; the time for the hydrolysis reaction is 3 to 10 hours, preferably about 5 hours.
7. Ticagrelor can be synthesized using a compound of formula iii or a compound of formula v. The compound shown in the formula III is preferably (S) -2-chloro-1- (3,4-difluorophenyl) ethanol 1; compounds of formula v are preferably (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol 2 and (S) -4- (3,4-difluorophenyl) -4-hydroxybutyronitrile 3. The intermediate compound (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine 4 can be simply and conveniently synthesized through the intermediate compound 1, the intermediate compound 2 or the intermediate compound 3, and the specific synthetic route is as follows:
the intermediate compound (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine 4 can be continuously subjected to two-step reaction to synthesize ticagrelor, and the specific synthetic route is shown as follows:
the invention has the advantages that:
1. the invention provides a brand new preparation method of (S) -1- (3,4-difluorophenyl) -alpha-alcohol intermediate;
2. the preparation method of the (S) -1- (3,4-difluorophenyl) -alpha-alcohol intermediate has the advantages of simple process, easily obtained raw materials, low cost and environmental friendliness;
3. the intermediate has high chiral purity, the byproduct is effectively recovered, and the yield is high.
4. The (S) -1- (3,4-difluorophenyl) -alpha-alcohol intermediate prepared by the method can reduce the production cost of ticagrelor, and is very favorable for large-scale industrial production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1 preparation of 2-chloro-1- (3,4-difluorophenyl) ethanone 5
Under the protection of nitrogen, 100g of o-difluorobenzene, 120g of aluminum trichloride and 200mL of dichloromethane are put into a reaction bottle, stirred, cooled to 5-15 ℃, 99g of chloroacetyl chloride is dropwise added, the temperature is controlled not to exceed 40 ℃, and after the dropwise addition is finished, the reaction is carried out for 4-5 hours at the temperature of 30-40 ℃.
Cooling the reaction solution, controlling the temperature to be 20-40 ℃, dropwise adding the reaction solution into a mixed solution of 25mL concentrated hydrochloric acid and 500mL water, stirring until the solid is dissolved, separating and extracting, extracting an aqueous phase by 100mL dichloromethane x 2, combining organic phases, washing by 100mL water, washing by 200mL saturated sodium bicarbonate solution once, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2-chloro-1- (3,4-difluorophenyl) ethanone 5 (164 g, yield is about 98%). 1 H-NMR(400MHz,CDCl 3 ):δ5.2(2H, s),7.6(1H,dd),7.8(1H,m),8.0(1H,dd)。
EXAMPLE 2 preparation of 2-chloro-1- (3,4-difluorophenyl) ethanol 6
100g of 2-chloro-1- (3,4-difluorophenyl) ethanone 5 and 400mL of absolute ethyl alcohol are put into a reaction bottle, the temperature is controlled to be 10-20 ℃, 6g of sodium borohydride is added in batches, and after the addition is finished, the temperature is increased to be 25-30 ℃ and the stirring is carried out for 2 hours. The reaction mixture was concentrated under reduced pressure in ethanol, 200mL of water was added, 200ml × 2 dichloromethane was used to extract the aqueous phase, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 2-chloro-1- (3,4-difluorophenyl) ethanol 6 (100 g, 99% yield).
EXAMPLE 3 preparation of ethyl 2-chloro-1- (3,4-difluorophenyl) acetate 7
100g of 2-chloro-1- (3,4-difluorophenyl) ethanol 6, 500mL of dichloromethane and 58g of triethylamine are put into a reaction bottle, the temperature is controlled to be 10-20 ℃ under the protection of nitrogen, 40.8g of acetyl chloride solution is dropwise added, and stirring is continued for 2 hours after the dropwise addition is finished.
After the reaction, 200mL of a 5% diluted hydrochloric acid solution was added, followed by liquid-phase extraction, aqueous phase extraction with 100mL of dichloromethane, and organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 2-chloro-1- (3,4-difluorophenyl) acetate 7 (120 g, yield 98.5%). 1 H-NMR(400MHz,CDCl 3 ):δ2.15(3H,s),3.70-3.72(1H, m),3.75-3.77(1H,m),5.45-5.47(1H,m),7.02-7.25(3H,m)。MS(ESI):m/z ＝235[M+H] + 。
EXAMPLE 4 preparation of (S) -2-chloro-1- (3,4-difluorophenyl) ethanol 1 by enzymatic resolution
(1) 440mL of a 0.01M disodium hydrogenphosphate solution was prepared, and the pH was adjusted to 7.0 to 7.5 with dilute hydrochloric acid. 44g of ethyl 2-chloro-1- (3,4-difluorophenyl) acetate 7, 4.4g of lipase PS from Candida cepacia and a disodium hydrogen phosphate buffer are put into a reaction flask, the temperature is raised to 25 to 30 ℃ for reaction, the pH =7 to 7.5 is maintained by a 10% sodium hydroxide solution, the pH does not change greatly after about 18 hours of reaction, the filtration is carried out, 200mL of dichloromethane is used for washing a filter cake, liquid separation extraction is carried out, 100mL of dichloromethane is used for extracting an aqueous phase, organic phases are combined, anhydrous sodium sulfate is dried, an oily liquid crude product is obtained after decompression and concentration, and silica gel column chromatography purification is carried out to obtain (S) -2-chloro-1- (3,4-difluorophenyl) ethanol 1 (17.33g, ee value 99.6%, yield is 48.5%). 1 H-NMR(400MHz,CDCl 3 ):δ2.774(1H,s),3.56-3.64(1H,m),3.72-3.76 (1H,m),4.90-4.92(1H,m),7.27-7.42(3H,m)。MS(ESI):m/z＝174.9[M-OH] +
Purification by silica gel column chromatography gave ethyl 2-chloro-1R- (3,4-difluorophenyl) acetate 8 (22g, 99% ee, 50% yield). 1 H-NMR(400MHz,CDCl 3 ):δ2.15(3H,s),3.70-3.72(1H,m),3.75-3.77(1H,m), 5.45-5.47(1H,m),7.02-7.25(3H,m)。MS(ESI):m/z＝235[M+H] + 。
(2) 440mL of a 0.01M disodium hydrogenphosphate solution was prepared, and the pH was adjusted to 7.0 to 7.5 with dilute hydrochloric acid. Putting 44g of ethyl 2-chloro-1- (3,4-difluorophenyl) acetate 7, 4.4g of candida antarctica lipase and disodium hydrogen phosphate buffer solution into a reaction flask, heating to 25-30 ℃ for reaction, maintaining the pH = 7-7.5 with 10% sodium hydroxide solution, reacting for about 18 hours without a large change in pH, filtering, washing the filter cake with 200mL of dichloromethane (), liquid separation and extraction, extracting the aqueous phase with 100mL of dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain an oily crude liquid, and performing column chromatography on silica gel to purify to obtain (S) -ethyl 2-chloro-1- (3,4-difluorophenyl) ethanol 1 (17.1g, ee value 99.4%, yield 48%), and obtaining ethyl 2-chloro-1R- (3,4-difluorophenyl) acetate 8 (22g, ee value 99%, yield 50%).
EXAMPLE 5 hydrolytic preparation of (R) -2-chloro-1- (3,4-difluorophenyl) ethanol 9
Putting 10g of 2-chloro-1R- (3,4-difluorophenyl) ethyl acetate 8, 15mL of concentrated hydrochloric acid and 50mL of ethanol into a reaction flask, heating to t = 45-50 ℃, reacting for 5-6 hours, concentrating under reduced pressure, adding 30mL of water, extracting with 40mL of dichloromethane x 2, combining organic phases, drying by anhydrous sodium sulfate, and filtering to obtain a dichloromethane solution of (R) -2-chloro-1- (3,4-difluorophenyl) ethanol 9.
EXAMPLE 6 sulfonylation preparation of ethyl 2-chloro-1R- (3,4-difluorophenyl) methanesulfonate 10
Adding a dichloromethane solution (80 mL) of (R) -2-chloro-1- (3,4-difluorophenyl) ethanol 9 prepared in the previous step and 5.2g triethylamine into a reaction flask, cooling to t = 0-5 ℃, dropwise adding 4.9g methanesulfonyl chloride, reacting at t = 0-5 ℃ for 2 hours after dropwise adding, after TLC detection reaction is finished, adding 40mL water, separating an organic phase, extracting an aqueous phase with 40mL dichloromethane, combining the organic phases, washing with 30mL saturated saline solution for 1 time, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain oily oilLiquid ethyl 2-chloro-1R- (3,4-difluorophenyl) methanesulfonate 10 (11.3 g, 98% yield). 1 H-NMR (400MHz,CDCl 3 ):δ3.15(3H,s),3.70-3.72(1H,m),3.75-3.77(1H,m),5.89-6.01(1H, m),7.02-7.25(3H,m)。MS(ESI):m/z＝175.2[M-OMs] + 。
EXAMPLE 7 preparation of ethyl (S) -2-chloro-1 (3,4-difluorophenyl) acetate 11 by Waldenstein inversion
10g of ethyl 2-chloro-1R- (3,4-difluorophenyl) methanesulfonate 10, 10.7g of cesium acetate and 50mlDMF were added to a three-necked flask and reacted at 22 to 26 ℃ for about 12 hours, TLC detection was performed after the reaction was completed, a small amount of salt was removed by filtration, DMF was removed by distillation under reduced pressure, 50mL of dichloromethane was added, the mixture was washed once with 30mL of saturated saline, anhydrous sodium sulfate was added, and concentration under reduced pressure was performed to obtain ethyl (S) -2-chloro-1 (3,4-difluorophenyl) acetate 11 as an oily liquid (8.24 g, yield 95%). 1 H-NMR(400MHz,CDCl 3 ):δ2.15(3H,s),3.70-3.72(1H,m),3.75-3.77(1H,m), 5.45-5.47(1H,m),7.02-7.25(3H,m)。MS(ESI):m/z＝235[M+H] + 。
EXAMPLE 8 preparation of (S) -2-chloro-1- (3,4-difluorophenyl) ethanol 1 by hydrolysis
10g of ethyl 2-chloro-1S- (3,4-difluorophenyl) acetate 11, 15mL of concentrated hydrochloric acid and 50mL of ethanol were put into a reaction flask, heated to t =45 to 50 ℃ to react for 5 to 6 hours, concentrated under reduced pressure, added with 30mL of water, extracted with 40mL of dichloromethane × 2 for the aqueous phase, combined with the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S) -2-chloro-1- (3,4-difluorophenyl) ethanol 1 as an oily liquid (8.2g, ee value 99%, yield 98%). 1 H-NMR(400MHz, CDCl 3 ):δ2.774(1H,s),3.56-3.64(1H,m),3.72-3.76(1H,m),4.90-4.92(1H,m), 7.27-7.42(3H,m)。MS(ESI):m/z＝174.9[M-OH] + 。
Example 9 preparation of 3-chloro-1- (3,4-difluorophenyl) propanone 12
Under the protection of nitrogen, 100g of o-difluorobenzene, 120g of aluminum trichloride and 200mL of dichloromethane are put into a reaction bottle, stirred, cooled to 5-15 ℃, 111g of chloropropionyl chloride is dripped, the temperature is controlled not to exceed 40 ℃, and after the dripping is finished, the temperature is kept at 30-40 ℃ for reaction for 4-5 hours.
The reaction solution was cooled. And (3) dropwise adding the mixture into a mixed solution of 25mL of concentrated hydrochloric acid and 500mL of water at the temperature of 20-40 ℃, stirring until the solid is clear, performing liquid separation extraction, extracting an aqueous phase by 100mL of dichloromethane x 2, combining organic phases, washing once by 100mL of water, washing once by 200mL of saturated sodium bicarbonate solution, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3-chloro-1- (3,4-difluorophenyl) acetone 12 (176 g, the yield is about 98%).
EXAMPLE 10 preparation of 1- (3,4-difluorophenyl) -3-nitroacetone 13
25g of 3-chloro-1- (3,4-difluorophenyl) acetone 12, 50mL of N, N-dimethylformamide, 5.5g of phloroglucinol and 0.25g of sodium iodide are put into a reaction flask, the temperature is controlled to be 5-10 ℃,16.8g of sodium nitrite is added into the mixed solution in batches, after stirring is carried out at 5-10 ℃ for 30min, the reaction solution is heated to 25-30 ℃ and stirring is continued for 3-4h. Then quenching the reaction liquid into 280mL of water in batches at 0-5 ℃, stirring for 30min, filtering, washing a filter cake with ice water, drying the crude product at 30-35 ℃ under reduced pressure, dissolving the crude product in 75mL of isopropanol at 50-60 ℃, cooling to 10-15 ℃, stirring for 2h, cooling to 0-5 ℃, stirring for 2h, filtering, washing the filter cake with 25mL of isopropanol precooled at 0-5 ℃, washing the filter cake with 25mL of cyclohexane, and drying at 30-35 ℃ under reduced pressure to obtain 1- (3,4-difluorophenyl) -3-nitropropane-1-ol 13 (19.7 g, yield 75.2%). 1 H-NMR(400MHz,CDCl 3 ):δ3.61(2H,m),4.82(2H,m),7.29(1H,m),7.82 (2H,m),7.80(1H,m)。MS(ESI):m/z＝216[M+H] + 。
EXAMPLE 11 preparation of 4- (3,4-difluorophenyl) -4-oxobutanenitrile 14
20g of 3-chloro-1- (3,4-difluorophenyl) acetone 12, 50mL of ethyl acetate and 9.6g of potassium tert-butoxide are put into a reaction bottle, the temperature is controlled to be 70 ℃, the mixture is heated for 30 minutes, then the mixture is cooled to 25-30 ℃, 9.6g of 50mL of aqueous solution of sodium cyanide is dropwise added, after the dropwise addition is finished, the stirring is continued for 30 minutes, and 30mL of ethanol is added for stirring for 3 hours. The aqueous phase was extracted with 25mL of ethyl acetate, the organic phase was washed with 50mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4- (3,4-difluorophenyl) -4-oxobutyronitrile 14 (18.5 g, yield 97%). 1 H-NMR(400MHz,CDCl 3 ): δ2.78-2.80(2H,m),3.34-3.36(2H,m),7.29(1H,m),7.74(1H,m),7.80(1H,m)。 MS(ESI):m/z＝196[M+H] + 。
Example 12 preparation of 1- (3,4-difluorophenyl) -3-nitropropane-1-ol 15
100g of 2-chloro-1- (3,4-difluorophenyl) ethanone 13 and 400mL of absolute ethyl alcohol are put into a reaction bottle, the temperature is controlled to be 10-20 ℃,5.5g of sodium borohydride is added in batches, and after the addition is finished, the temperature is increased to 25-30 ℃ and the stirring is carried out for 2 hours. The reaction mixture was concentrated under reduced pressure in ethanol, 200mL of water was added, 200mL of dichloromethane × 2 was extracted into the aqueous phase, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 2-chloro-1- (3,4-difluorophenyl) ethanol 15 (98 g, yield 97%). 1 H-NMR (400MHz,CDCl 3 ):δ2.24-2.27(3H,m),4.44-4.47(1H,m),4.61-4.65(1H,m), 4.82-4.85(1H,m),7.07-7.15(3H,m)。MS(ESI):m/z＝218[M+H] + 。
EXAMPLE 13 preparation of 1- (3,4-difluorophenyl) -3-nitro-propyl acetate 16
100g of 2-chloro-1- (3,4-difluorophenyl) ethanol 15, 500mL of dichloromethane and 51.2g of triethylamine are put into a reaction bottle, the temperature is controlled to be 10-20 ℃ under the protection of nitrogen, 36.2g of acetyl chloride solution is added dropwise, and stirring is continued for 2 hours after the dropwise addition is finished. After the reaction, 200mL of a 5% diluted hydrochloric acid solution was added, followed by liquid-separation extraction, aqueous phase extraction with 100mL of dichloromethane, and organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (3,4-difluorophenyl) -3-nitro-propyl acetate 16 (113.4 g, yield 95%). 1 H-NMR(400MHz,CDCl 3 ):δ2.15(3H,s),2.43-2.48 (2H,m),4.50-4.55(1H,m),4.75-4.77(1H,m),5.25-5.27(1H,m),7.02-7.25(3H,m)。 MS(ESI):m/z＝260[M+H] + 。
EXAMPLE 14 preparation of (S) -1- (3,4-difluorophenyl) -3-nitro-propyl acetate 17 by enzymatic resolution
(1) 400mL of a 0.01M disodium hydrogenphosphate solution was prepared, and the pH was adjusted to 7.0 to 7.5 with dilute hydrochloric acid. 40g of 1- (3,4-difluorophenyl) -3-nitro-propyl acetate 16, 4.0g of lipase PS from Candida cepacia and a disodium hydrogen phosphate buffer are put into a reaction flask, the temperature is raised to 25 to 30 ℃ for reaction, the pH =7 to 7.5 is maintained by 10% sodium hydroxide solution, the pH does not change greatly after about 18 hours of reaction, the filtration is carried out, 200mL of dichloromethane is used for washing a filter cake, liquid separation extraction is carried out, 100mL of dichloromethane is used for extracting an aqueous phase, an organic phase is combined, anhydrous sodium sulfate is dried, an oily liquid crude product is obtained after decompression and concentration, and silica gel column chromatography purification is carried out to obtain (S) -1- (3,4-difluorophenyl) -3-nitro-propyl acetate 17 (20g, ee value 99%, yield 50%). 1 H-NMR(400MHz,CDCl 3 ):δ2.15(3H,s),2.43-2.48(2H, m),4.50-4.55(1H,m),4.75-4.77(1H,m),5.25-5.27(1H,m),7.02-7.25(3H,m)。 MS(ESI):m/z＝260[M+H] + 。
Purifying by silica gel column chromatography to obtain (R) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol 18 (1lg, ee value 99.4%, yield 48%). 1 H-NMR(400MHz,CDCl 3 ):δ2.24-2.27(3H,m),4.44-4.47(1H,m), 4.61-4.65(1H,m),4.82-4.85(1H,m),7.07-7.15(3H,m)。MS(ESI):m/z＝218[M+H] + 。
(2) 400mL of a 0.01M disodium hydrogenphosphate solution was prepared, and the pH was adjusted to 7.0 to 7.5 with dilute hydrochloric acid. 40g of 1- (3,4-difluorophenyl) -3-nitro-propyl acetate 16, 4.0g of Candida antarctica lipase and disodium hydrogen phosphate buffer solution are put into a reaction flask, the temperature is raised to 25-30 ℃ for reaction, 10% sodium hydroxide solution is used for maintaining the pH = 7-7.5, the pH change is not large about 18 hours, the reaction is filtered, 200mL of dichloromethane is used for washing a filter cake, liquid separation and extraction are carried out, 100mL of dichloromethane is used for extracting an aqueous phase, an organic phase is combined, anhydrous sodium sulfate is used for drying, an oily liquid crude product is obtained after decompression and concentration, silica gel column chromatography purification is carried out to obtain (S) -1- (3,4-difluorophenyl) -3-nitro-propyl acetate 17 (20g, ee value 99%, yield is 50%), and obtain (R) -1- (3,4-difluorophenyl) -3-nitropropane-1-alcohol 18 (15.7g, ee value is 99.2%, yield is 47%).
EXAMPLE 15 hydrolytic preparation of (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol 2
10g of (S) -1- (3,4-difluorophenyl) -3-nitro-propyl acetate 17, 15mL of concentrated hydrochloric acid and 50mL of ethanol were put into a reaction flask, heated to t = 45-50 ℃ to react for 5-6 hours, concentrated under reduced pressure, added with 30mL of water, extracted with 40mL of dichloromethane 2 times, combined with organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol 2 (8g, ee value 99%, yield 95%). 1 H-NMR(400MHz, CDCl 3 ):δ2.24-2.27(3H,m),4.44-4.47(1H,m),4.61-4.65(1H,m),4.82-4.85(1H,m), 7.07-7.15(3H,m)。MS(ESI):m/z＝218[M+H] + 。
EXAMPLE 16 sulfonylation preparation of (R) -1- (3,4-difluorophenyl) -3-nitro-propyl methanesulfonate 19
10g of (R) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol 18, 80Putting mL of dichloromethane into a reaction flask, adding 5.6g of triethylamine, cooling to t = 0-5 ℃, dropwise adding 5.27g of methanesulfonyl chloride, reacting for 2 hours at t = 0-5 ℃ after dropwise adding, detecting the reaction by TLC, adding 30mL of water, separating and extracting, extracting an aqueous phase by 30mL of dichloromethane, combining organic phases, washing once by 30mL of saturated saline, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain (R) -1- (3,4-difluorophenyl) -3-nitro-propyl methanesulfonate 19 (13.2 g, yield 97%). 1 H-NMR (400MHz,CDCl 3 ):δ2.45-2.48(2H,m),3.2(3H,s),4.61-4.65(1H,m),4.72-4.74(1H, m),5.82-5.85(1H,m),7.17-7.25(3H,m)。MS(ESI):m/z＝200[M-OMs] + 。
EXAMPLE 17 preparation of (S) -1- (3,4-difluorophenyl) -3-nitro-propyl acetate 17 by Waldenstein inversion
10g of (R) -1- (3,4-difluorophenyl) -3-nitro-propyl methanesulfonate 19, 9.75g of cesium acetate and 50mL of DMF were put in a reaction flask, reacted at 22 to 26 ℃ for about 12 hours, after completion of the TLC detection reaction, a small amount of salt was removed by filtration, DMF was distilled off under reduced pressure, 50mL of dichloromethane was added, washing was carried out with 30mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (S) -1- (3,4-difluorophenyl) -3-nitro-propyl acetate 17 (8.3g, ee value 99.4%, yield 95%). 1 H-NMR(400MHz,CDCl 3 ):δ2.15(3H,s),2.43-2.48(2H,m), 4.50-4.55(1H,m),4.75-4.77(1H,m),5.25-5.27(1H,m),7.02-7.25(3H,m)。 MS(ESI):m/z＝260[M+H] + 。
EXAMPLE 18 preparation of 4- (3,4-difluorophenyl) -4-hydroxybutyronitrile 20
100g of 4- (3,4-difluorophenyl) -4-oxobutyronitrile 14 and 400mL of absolute ethyl alcohol are put into a reaction bottle, the temperature is controlled to be 10-20 ℃, 5.9g of sodium borohydride is added in batches, and after the addition is finished, the temperature is increased to 25-30 ℃ and the stirring is carried out for 2 hours. Concentrating the reaction solution under reduced pressureEthanol, 200mL of water, 200mL of dichloromethane x 2, extraction of the aqueous phase, combination of the organic phases and drying over anhydrous sodium sulfate. Concentration under reduced pressure gave 4- (3,4-difluorophenyl) -4-hydroxybutyronitrile 20 (98 g, yield 97%). 1 H-NMR (400MHz,CDCl 3 ):δ1.96-2.01(2H,m),2.37-2.39(2H,m),2.54-2.57(1H,m),4.72-4.75 (1H,m),7.07-7.15(3H,m)。MS(ESI):m/z＝198[M+H] + 。
EXAMPLE 19 preparation of 1- (3,4-difluorophenyl) -3-cyano-propyl acetate 21
100g of 4- (3,4-difluorophenyl) -4-hydroxybutyronitrile 20, 500mL of dichloromethane and 56.5g of triethylamine are put into a reaction bottle, the temperature is controlled to be 10-20 ℃ under the protection of nitrogen, 39.8g of acetyl chloride solution is dropwise added, and stirring is continued for 2 hours after the dropwise addition is finished. After the reaction was completed, 200mL of 5% diluted hydrochloric acid solution was added to conduct liquid-separation extraction, the aqueous phase was extracted with 100mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1- (3,4-difluorophenyl) -3-cyano-propyl acetate 21 (115.2 g, yield 95%). 1 H-NMR(400MHz，CDCl 3 ):δ1.96-2.01(2H,m),2.15 (3H,s),2.33-2.35(1H,m),2.44-2.46(1H,m),5.05-5.07(1H,m),7.02-7.25(3H,m)。 MS(ESI):m/z＝240[M+H] + 。
EXAMPLE 20 preparation of (S) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate 22 by enzymatic resolution
(1) 400mL of a 0.01M disodium hydrogenphosphate solution was prepared, and the pH was adjusted to 7.0 to 7.5 with dilute hydrochloric acid. 40g of 1- (3,4-difluorophenyl) -3-cyano-propyl acetate 21, 4.0g of lipase PS from Candida cepacia and disodium hydrogen phosphate buffer were put into a reaction flask, heated to 25 to 30 ℃ for reaction, kept at pH =7 to 7.5 with 10% sodium hydroxide solution, and reacted for about 18 hours without a large change in pH, filtered, washed with 200mL of dichloromethane, subjected to liquid-phase extraction, and extracted with 100mL of dichloromethane aqueous phaseThe organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude oily liquid, which was purified by silica gel column chromatography to give (S) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate 22 (20 g, ee 99%, yield 50%). 1 H-NMR(400MHz，CDCl 3 ):δ1.96-2.01(2H,m),2.15(3H,s), 2.33-2.35(1H,m),2.44-2.46(1H,m),5.05-5.07(1H,m),7.02-7.25(3H,m)。 MS(ESI):m/z＝240[M+H] + 。
Purification by silica gel column chromatography gave (R) -1- (3,4-difluorophenyl) -3-cyanopropan-1-ol 23 (1lg, ee 99.4, 48% yield). 1 H-NMR(400MHz,CDCl 3 ):δ1.96-2.01(2H,m),2.37-2.39(2H,m), 2.54-2.57(1H,m),4.72-4.75(1H,m),7.07-7.15(3H,m)。MS(ESI):m/z＝198[M+H] + 。
(2) 400mL of a 0.01M disodium hydrogenphosphate solution was prepared, and the pH was adjusted to 7.0 to 7.5 with dilute hydrochloric acid. 40g of 1- (3,4-difluorophenyl) -3-cyano-propyl acetate 21, 4.0g of candida antarctica lipase and disodium hydrogen phosphate buffer were put in a reaction flask, heated to 25 to 30 ℃ for reaction, kept at pH =7 to 7.5 with 10% sodium hydroxide solution, reacted for about 18 hours without a large change in pH, filtered, the filter cake was washed with 200mL of dichloromethane, liquid-separation extracted, 100mL of dichloromethane-extracted aqueous phase was combined with organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude oily liquid, and purified by silica gel column chromatography to obtain (S) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate 22 (20g, ee value 99%, yield 50%) and (R) -1- (3,4-difluorophenyl) -3-cyanopropane-1-ol 23 (15.6g, ee value 99.4%, yield 47%).
EXAMPLE 21 hydrolytic preparation of (S) -1- (3,4-difluorophenyl) -3-cyanopropan-1-ol 3
Putting 10g (S) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate 22, 15mL concentrated hydrochloric acid and 50mL ethanol into a reaction flask, heating to t = 45-50 ℃, reacting for 5-6 hours, concentrating under reduced pressure, adding 30mL water, extracting with 40mL dichloromethane for 2 times, combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain oily liquid(S) -1- (3,4-difluorophenyl) -3-cyanopropan-1-ol 3 (7.8g, ee 99, yield 95%). 1 H-NMR (400MHz,CDCl 3 ):δ1.96-2.01(2H,m),2.37-2.39(2H,m),2.54-2.57(1H,m),4.72-4.75 (1H,m),7.07-7.15(3H,m)。MS(ESI):m/z＝198[M+H] + 。
EXAMPLE 22 sulfonylation preparation of (R) -1- (3,4-difluorophenyl) -3-cyano-propyl methanesulfonate 24
Adding 10g of (R) -1- (3,4-difluorophenyl) -3-cyanopropane-1-ol 23 and 80mL of dichloromethane into a reaction flask, adding 6.15g of triethylamine, cooling to t = 0-5 ℃, dropwise adding 5.8g of methanesulfonyl chloride, reacting for 2 hours at t = 0-5 ℃ after dropwise adding, adding 30mL of water after TLC detection reaction, performing liquid separation extraction, extracting an aqueous phase by 30mL of dichloromethane, combining organic phases, washing with 30mL of saturated saline once, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain (R) -1- (3,4-difluorophenyl) -3-cyano-propyl methanesulfonate 24 (13.2 g, yield 95%). 1 H-NMR (400MHz,CDCl 3 ):δ1.96-2.01(2H,m),2.37-2.39(1H,m),2.54-2.57(1H,m),3.2(3H, s),5.72-5.75(1H,m),7.07-7.15(3H,m)。MS(ESI):m/z＝180[M-OMs] + 。
EXAMPLE 23 preparation of (S) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate 22 by Waldenstein inversion
10g of (R) -1- (3,4-difluorophenyl) -3-cyano-propyl methanesulfonate 24, 10.45g of cesium acetate and 50mL of DMF were put in a reaction flask, reacted at 22 to 26 ℃ for about 12 hours, TLC checked for completion of the reaction, a small amount of salt was removed by filtration, DMF was distilled off under reduced pressure, 50mL of dichloromethane was added, washing was carried out with 30mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (S) -1- (3,4-difluorophenyl) -3-cyano-propyl acetate 22 (8.2 g, ee value 99.4%, yield 94%).
EXAMPLE 24 preparation of ethyl (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxylate 25
Suspending 17g of sodium tert-butoxide in 80mL of toluene, slowly adding 20.6g of triethyl phosphonoethyl under the protection of nitrogen, reacting and releasing heat, after the addition is finished, heating to 70-80 ℃, slowly dropwise adding 20mL of toluene solution of 13.6g of (S) -2-chloro-1- (3,4-difluorophenyl) ethanol 1, and after the dropwise addition is finished, continuing the reaction at the temperature for 3-4h. TLC confirmed the reaction was complete, and the reaction mixture was cooled to room temperature, 100mL of water was added, liquid-separation extraction was performed, the aqueous phase was extracted with 50mL of toluene, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxylate 25 as a tan oily liquid (15.6 g, yield 98%) with an HPLC purity of 86%. 1 H-NMR(400MHz,CDCl 3 ):δ1.23-1.27(1H,m), 1.28-1.32(3H,t),1.58-1.63(1H,m),1.84-1.88(1H,m),2.46-2.51(1H,m),4.16-4.22 (2H,m),6.84-6.93(2H,m),7.03-7.10(1H,m)。MS(ESI):m/z＝227[M+H] + 。
EXAMPLE 25 preparation of (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxamide 26
(1)
15.2g of (1R, 2R) -2- (3,4-difluorophenyl) ethyl cyclopropylcarboxylate 25, 20% (g/g) of ammonia methanol solution 62g,15g of methyl formate and 30mL of 30% sodium methoxide solution were put into a thick-walled pressure-resistant bottle and the bottle was sealed. Heating to 70 deg.C, and reacting for 10 hr under 0.2 MPa. The reaction was cooled to room temperature. The temperature is controlled to be 35-40 ℃,200mL of water is added dropwise under stirring, and about 1 hour of dripping is finished. Cooling to room temperature, standing and crystallizing. Filtration was carried out and the filter cake was washed with 100mL of 30% aqueous methanol, 100mL of isopropyl ether. Drying in a constant temperature oven at 45 ℃ gave (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxamide 26 as an off-white solid (10.5 g, yield 79%). 1 H-NMR(400MHz,CDCl 3 ):δ1.17-1.24(1H,m),1.57-1.68(2H,m), 2.44-2.51(1H,m),5.2-5.7(2H,d),6.81-6.88(2H,m),6.9-7.01(1H,m)。MS(ESI):m/z ＝198[M+H] + 。
(2)
16.6g of (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxylic acid 29 was dissolved in 160mL of toluene, 16.6g of thionyl chloride was added thereto, the mixture was refluxed for 2 hours, concentrated under reduced pressure, dissolved in 20mL of toluene, added dropwise to a mixed solution composed of 30% aqueous ammonia (20.25 g), 50mL of water and 115mL of ethyl acetate, the temperature was controlled at 15 to 30 ℃ for 30 minutes, stirred for 1 to 2 hours, subjected to liquid-separation extraction, extracted with 50mL of ethyl acetate to obtain an aqueous phase, combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an off-white solid (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxamide 26 (14.35 g, yield 87%).
EXAMPLE 26 preparation of (1R, 2S) -2- (3,4-difluorophenyl) -1-nitrocyclopropane 27
Putting 41.5g of triphenylphosphine and 100mL of toluene into a reaction bottle, controlling the temperature to be 5-10 ℃, dropwise adding 30.7g of diisopropyl azodicarboxylate 70mL of toluene solution, continuously stirring for 40min, then controlling the temperature to be 5-10 ℃, dropwise adding 27.5g of (S) -1- (3,4-difluorophenyl) -3-nitropropane-1-ol 2 70mL of toluene solution, and continuously stirring the reaction solution for 2h after about 1h of dropwise addition. After TLC confirmed that the reaction was complete, 2g of acetic acid was added dropwise, the mixture was stirred at 5-10 ℃ for 30min, the solid was separated by filtration, 30mL of precooled toluene was used to wash the filter cake, the toluene filtrate was combined, washed once with 100mL of 10% aqueous hydrochloric acid, once with 100mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude brown oily liquid, which was then purified by distillation under reduced pressure to give (1R, 2S) -2- (3,4-difluorophenyl) -1-nitrocyclopropane 27 (22.2 g, 88% yield). 1 H-NMR(400MHz,CDCl 3 ):δ1.6(1H,m),2.21(1H,m),3.1(1H,m),4.35(1H,m),6.89 (2H,m),7.10(1H,m)。MS(ESI):m/z＝200[M+H] + 。
EXAMPLE 27 preparation of (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarbonitrile 28
11.5g of (S) -1- (3,4-difluorophenyl) -3-cyanopropane-1-ol 3 and 16.3mL of triethylamine are dissolved in 200mL of tetrahydrofuran, the temperature is controlled between 0 ℃ and 5 ℃, 8.0g of methanesulfonyl chloride is added dropwise, and the temperature is controlled between 25 ℃ and 30 ℃ after the dropwise addition, and the mixture is stirred for 1 hour. Then controlling the temperature to be 0-5 ℃, adding 6.4g of potassium tert-butoxide in batches, controlling the temperature to be 25-30 ℃ and stirring for 1h after the addition is finished. 2M aqueous HCl (50 mL) was added and extracted with 50mL ethyl acetate 2, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude oil which was purified by column chromatography to give (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarbonitrile 28 (4.17 g, 40% yield). 1 H-NMR(400MHz, CDCl 3 ):δ1.41(1H,m),1.53(1H,m),1.64(1H,m),2.60(1H,d),6.87(1H,m),6.92 (1H,m),7.10(1H,m)。MS(ESI):m/z＝180[M+H] + 。
EXAMPLE 28 preparation of (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxylic acid 29
7.7g of (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarbonitrile 28 and 4M aqueous lithium hydroxide (280 mL) were charged to a reaction flask and heated under reflux for 3.5h. Cooling to 15-20 ℃, adjusting PH to 2-3 with concentrated hydrochloric acid, extracting with 50mL of dichloromethane × 3, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain (1r, 2r) -2- (3,4-difluorophenyl) cyclopropylcarboxylic acid 29 (8.12 g, yield 95%). 1 H-NMR(400MHz,CDCl 3 ):δ1.36(1H,m),1.68(1H,m), 1.87(1H,m),2.57(1H,m),6.87(1H,m),6.92(1H,m),7.10(1H,m)。
Example 29 preparation of (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine 4
(1)
30g of (1R, 2R) -2- (3,4-difluorophenyl) Adding 26 parts of cyclopropyl formamide and 200mL of 30% sodium hydroxide solution into a reaction bottle, controlling the temperature to be 20-30 ℃, adding 250g of 12% sodium hypochlorite solution, stirring the reaction solution until the solid is dissolved clearly, quickly heating to 65-70 ℃, reacting for 1h, cooling the reaction solution to 10-20 ℃, and dropwise adding concentrated hydrochloric acid to adjust the pH to be 8-9. 150mL of ethyl acetate 3 extracted the aqueous phase, combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine 4 as an oily liquid (20.8 g, 80% yield). 1 H-NMR(400MHz,CDCl 3 ):δ0.88(1H,m),1.03(1H, m),1.71(2H,s),1.79(1H,m),2.47(1H,m),6.92(2H,m),6.97(1H,m)。MS(ESI):m/z ＝170[M+H] + 。
(2)
10g (1R, 2R) -2- (3,4-difluorophenyl) cyclopropylcarboxylic acid 29 and 100mL of methanol were put into a hydrogenation reactor, 1g of 10% palladium on carbon was added, hydrogen was replaced, and hydrogenation was carried out at 50 to 55 ℃ under 0.2 to 0.4 MPa. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with 20mL of methanol, and the filtrates were combined and concentrated under reduced pressure to give (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine 4 as a pale yellow oily liquid (8.1 g, yield 95%)
EXAMPLE 30 preparation of Compound intermediate 31
16.9g (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine 4 and 19.5g potassium carbonate were dissolved in 150mL water, and 250mL of toluene solution of 43g compound 30 was added dropwise with stirring for 3h, controlling the temperature to 20-30 ℃. After the reaction, the solution was extracted by liquid separation, the aqueous phase was extracted with 100mL of toluene, the organic phases were combined and washed once with 20mL of saturated sodium chloride solution to obtain a toluene solution of Compound 31, which was used directly in the next reaction.
Example 31 preparation of ticagrelor
And cooling the toluene solution of the compound 31 obtained in the last step to 10-15 ℃, adding a mixed solution of 100mL of concentrated hydrochloric acid and 150mL of methanol in batches, and stirring the reaction mixture at 10-15 ℃ for reaction for 2h. After the reaction is finished, separating liquid, controlling the temperature to be 10-15 ℃, adjusting the pH of a methanol/water solution containing the product to be 7.0-7.3 by using a saturated sodium bicarbonate solution, extracting water by using 100mL of ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to obtain an oily liquid, adding 100mL of ethyl acetate into a concentrate, heating to 60 ℃ for dissolution, then cooling to about 50 ℃, adding 110mL of normal hexane, cooling to 0-5 ℃, crystallizing for 2h, filtering, washing a filter cake by using a mixed solution of 22mL of ethyl acetate and 25mL of normal hexane precooled to 0 ℃, and drying under reduced pressure at 40-45 ℃ to obtain ticagrelor (42 g, yield 80%) 1 H-NMR(400MHz,CDCl 3 ):δ0.83-0.86and 0.94-1.09(3H,m),1.38-1.59 and 1.67-1.75(4H,m),2.06-2.14and 2.28(2H,s),2.61-2.70(1H,m),2.83-2.98(2H,m), 3.18-3.2(1H,m),3.52-3.54(4H,m),3.77(1H,s),3.99(1H,s),4.58-4.88(2H,m),4.96- 5.04(1H,m),5.10-5.18(2H,m),7.10(1H,m),7.28-7.38(2H,m),8.97-8.99and 9.35 -9.37(1H,d),。MS(ESI):m/z＝523[M+H] + 。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for preparing ticagrelor, the process comprising the steps of:
(1-1) taking 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially carrying out Friedel-crafts reaction and reduction reaction to obtain a compound shown as a formula I, and then carrying out hydroxyl acylation to obtain a compound shown as a formula II;
(1-2 a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;
in the formula, R 1 Selected from halogens (preferably F, cl or Br);
R 2 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(1-3) preparing ticagrelor by utilizing the compound shown in the formula III through multi-step reaction;
alternatively, the method comprises the steps of:
(2-1) taking 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially carrying out Friedel-crafts reaction, substitution reaction and reduction reaction to obtain a compound shown in a formula i, and carrying out hydroxyl acylation to obtain a compound shown in a formula ii;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(2-2) enzymatically resolving the compound of formula ii obtained in step (2-1) to obtain a compound of formula iii and a compound of formula iv;
(2-3 a) hydrolyzing the compound shown in the formula iv obtained in the step (2-2) to obtain a compound shown in a formula v;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(2-4) preparing ticagrelor by utilizing the compound shown in the formula v through multi-step reaction.
2. The method of claim 1, wherein the enzyme utilized in step (1-2 a) or (2-2) is a hydrolase, including but not limited to a lipase, a protease, or an esterase;
preferably, the lipase is candida antarctica lipase, candida cylindracea lipase, candida onion lipase PS, lipase TL, distillers yeast lipase, lipase AS1 and the like;
the protease is chymotrypsin, cathepsin, papain, subtilisin and the like;
the esterase is porcine liver esterase PL, esterase RO, an Aspergillus oryzae TL recombinant, an Escherichia coli esterase BS1 recombinant, an Escherichia coli esterase BS2 recombinant and the like;
more preferably, the hydrolase is a lipase PS from candida cepacia or a lipase from candida antarctica.
3. The method of claim 1 or 2, wherein the step (1-2 a) is further followed by hydrolysis, sulfonylation, waldenstein configuration transformation, and hydrolysis of the compound of formula IV obtained in step (1-2 a) to obtain a compound of formula III; or alternatively
And (3) preparing the compound shown in the formula v by using the compound shown in the formula iii obtained in the step (2-2) through sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (2-3 a).
4. The method of claim 3, further comprising, after step (1-2 a), the steps of:
(1-2 b) hydrolyzing the compound represented by the formula IV obtained in the step (1-2 a) to obtain a compound represented by the formula V;
(1-2 c) carrying out a sulfonylation reaction on the compound shown in the formula V obtained in the step (1-2 b) so as to obtain a compound shown in a formula VI;
(1-2 d) subjecting the compound represented by the formula VI obtained in the step (1-2 c) to a Walton configuration transformation to obtain a compound represented by the formula VII;
(1-2 e) hydrolyzing the compound represented by the formula VII obtained in the step (1-2 d) to obtain a compound represented by the formula III;
in the formula, R 1 As described above; r is 5 Selected from: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Is H, C 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )；
Or, the following steps are also included after the step (2-3 a):
(2-3 b) subjecting the compound represented by the formula iii obtained in the step (2-2) to a sulfonylation reaction to obtain a compound represented by the formula vi;
(2-3 c) carrying out Waldenstein configuration conversion on the compound shown in the formula vi obtained in the step (2-3 b) to obtain a compound shown in the formula vii;
(2-3 d) hydrolysing the compound of formula vii obtained in step (2-3 c) to give a compound of formula v;
wherein R is 3 As described above; r 5 Selected from: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Selected from: H. c 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )。
5. The method of claim 4, wherein C used in the conversion of the Waldenstein configuration of step (1-2 d) or (2-3C) 1-6 The fatty acid salt is preferably cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, most preferably cesium acetate;
the solvent used in the Valden configuration transformation reaction is DMF, DMSO or acetonitrile, preferably DMF;
the molar ratio of the compound shown in the formula VI or the compound shown in the formula vi in the Valden configuration conversion to the fatty acid salt is 1:1-4, and 1.5 is preferred;
the temperature of the Waldenstein configuration conversion reaction is 20-50 ℃, and preferably 22-26 ℃;
the time for the conversion reaction of the Valden configuration is 10 to 30 hours, preferably 12 hours.
6. A method of preparing (S) -1- (3,4-difluorophenyl) - α -alcohol, said (S) -1- (3,4-difluorophenyl) - α -alcohol being a compound of formula III, said method comprising the steps of:
(1-1) taking 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially carrying out Friedel-crafts reaction and reduction reaction to obtain a compound shown as a formula I, and then carrying out hydroxyl acylation to obtain a compound shown as a formula II;
(1-2 a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;
in the formula, R 1 Selected from halogens (preferably F, cl or Br);
R 2 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
Alternatively, the (S) -1- (3,4-difluorophenyl) - α -alcohol is a compound of formula v, comprising the steps of:
(2-1) taking 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially carrying out Friedel-crafts reaction, substitution reaction and reduction reaction to obtain a compound shown in a formula i, and carrying out hydroxyl acylation to obtain a compound shown in a formula ii;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 ；
(2-2) enzymatically resolving the compound of formula ii obtained in step (2-1) to obtain a compound of formula iii and a compound of formula iv;
(2-3 a) hydrolyzing the compound shown in the formula iv obtained in the step (2-2) to obtain a compound shown in a formula v;
in the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 。
7. The method of claim 6, wherein the step (1-2 a) is further followed by hydrolysis, sulfonylation, waldenstein configuration transformation, and hydrolysis of the compound of formula IV obtained in step (1-2 a) to obtain a compound of formula III; or
And (3) preparing the compound shown in the formula v by using the compound shown in the formula iii obtained in the step (2-2) through sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (2-3 a).
8. The method of claim 7, further comprising, after step (1-2 a), the steps of:
(1-2 b) hydrolyzing the compound represented by the formula IV obtained in the step (1-2 a) to obtain a compound represented by the formula V;
(1-2 c) carrying out a sulfonylation reaction on the compound shown in the formula V obtained in the step (1-2 b) so as to obtain a compound shown in a formula VI;
(1-2 d) subjecting the compound represented by the formula VI obtained in the step (1-2 c) to a Walton configuration transformation to obtain a compound represented by the formula VII;
(1-2 e) hydrolyzing the compound represented by the formula VII obtained in the step (1-2 d) to obtain a compound represented by the formula III;
in the formula, R 1 As claimed in claim 1; r is 5 Selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Is H, C 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )；
Or, the following steps are also included after the step (2-3 a):
(2-3 b) carrying out a sulfonylation reaction on the compound shown in the formula iii obtained in the step (2-2) to obtain a compound shown in the formula vi;
(2-3 c) performing Waldenstein configuration conversion on the compound shown in the formula vi obtained in the step (2-3 b) to obtain a compound shown in the formula vii;
(2-3 d) hydrolyzing the compound of formula vii obtained in step (2-3 c) to obtain a compound of formula v;
wherein R is 3 As claimed in claim 1; r 5 Selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 )、C 6 H 5 Or p-CH 3 C 6 H 4 ；R 6 Selected from the group consisting of: H. c 1-6 Alkyl (preferably CH) 3 Or CH 2 CH 3 )。
9. A compound of formula II
In the formula, R 1 Selected from halogen (preferably F, cl or Br);
R 2 selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 (ii) a Or
A compound of formula ii
In the formula, R 3 Selected from NO 2 Or CN;
R 4 selected from the group consisting of: c 1-6 Alkyl (preferably CH) 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 )、CH＝CH 2 、C 6 H 5 Or CH 2 C 6 H 5 。
10. Use of a compound of formula II or a compound of formula II for the preparation of ticagrelor.
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| CN101495442A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | Chemical process for preparation of aromatic cyclopropane esters and amides |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN103073525A (en) * | 2013-02-04 | 2013-05-01 | 北京科技大学 | Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide |
| CN104411676A (en) * | 2012-02-20 | 2015-03-11 | 力奇制药公司 | Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid |
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| CN101495442A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | Chemical process for preparation of aromatic cyclopropane esters and amides |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN104411676A (en) * | 2012-02-20 | 2015-03-11 | 力奇制药公司 | Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid |
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