WO2022222473A1 - 阿哌沙班的中间体及制备方法 - Google Patents
阿哌沙班的中间体及制备方法 Download PDFInfo
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- WO2022222473A1 WO2022222473A1 PCT/CN2021/133634 CN2021133634W WO2022222473A1 WO 2022222473 A1 WO2022222473 A1 WO 2022222473A1 CN 2021133634 W CN2021133634 W CN 2021133634W WO 2022222473 A1 WO2022222473 A1 WO 2022222473A1
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- Prior art keywords
- formula
- compound
- reaction
- apixaban
- preparation
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- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 229960003886 apixaban Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 238000006243 chemical reaction Methods 0.000 claims abstract description 132
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 33
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 230000015572 biosynthetic process Effects 0.000 claims description 34
- 238000003786 synthesis reaction Methods 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- HJEZRYIJNHAIGY-UHFFFAOYSA-N tert-butyl 4-bromobutanoate Chemical compound CC(C)(C)OC(=O)CCCBr HJEZRYIJNHAIGY-UHFFFAOYSA-N 0.000 claims description 11
- 238000005917 acylation reaction Methods 0.000 claims description 8
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000007098 aminolysis reaction Methods 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 238000005815 base catalysis Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- 244000025254 Cannabis sativa Species 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000047 product Substances 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 238000003756 stirring Methods 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000000543 intermediate Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 239000010410 layer Substances 0.000 description 23
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
- 239000012141 concentrate Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- YETADMJLYUOUID-UHFFFAOYSA-N 2-o-tert-butyl 1-o-phenyl oxalate Chemical compound CC(C)(C)OC(=O)C(=O)OC1=CC=CC=C1 YETADMJLYUOUID-UHFFFAOYSA-N 0.000 description 4
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 4
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 4
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 4
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- SVNNWKWHLOJLOK-UHFFFAOYSA-N 5-chloropentanoyl chloride Chemical compound ClCCCCC(Cl)=O SVNNWKWHLOJLOK-UHFFFAOYSA-N 0.000 description 3
- SCVWQFDPLBFZAP-UHFFFAOYSA-N 5-morpholin-4-yl-1-[4-(2-oxopiperidin-1-yl)phenyl]-2,3-dihydropyridin-6-one Chemical compound O=C1CCCCN1C1=CC=C(N2C(C(N3CCOCC3)=CCC2)=O)C=C1 SCVWQFDPLBFZAP-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 150000005224 alkoxybenzenes Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 3
- 150000005171 halobenzenes Chemical class 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 3
- BOTNYLSAWDQNEX-UHFFFAOYSA-N phenoxymethylbenzene Chemical compound C=1C=CC=CC=1COC1=CC=CC=C1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- SCCCFNJTCDSLCY-UHFFFAOYSA-N 1-iodo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(I)C=C1 SCCCFNJTCDSLCY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- KMLWZVZIOMCHRL-UHFFFAOYSA-N COC(C(CCN(C(C=C1)=CC=C1N(CCCC1)C1=O)C1=O)C1=O)=O Chemical compound COC(C(CCN(C(C=C1)=CC=C1N(CCCC1)C1=O)C1=O)C1=O)=O KMLWZVZIOMCHRL-UHFFFAOYSA-N 0.000 description 2
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940047562 eliquis Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- QAWFLJGZSZIZHO-UHFFFAOYSA-N methyl 4-bromobutanoate Chemical compound COC(=O)CCCBr QAWFLJGZSZIZHO-UHFFFAOYSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical group O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- UJBSLJVGDLGXPS-UHFFFAOYSA-N C(OC(=O)C1C(=O)C(=O)N(CC1)C1=CC=C(N2CCCCC2=O)C=C1)C Chemical compound C(OC(=O)C1C(=O)C(=O)N(CC1)C1=CC=C(N2CCCCC2=O)C=C1)C UJBSLJVGDLGXPS-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- -1 amino compound Chemical class 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 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 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
- C07C15/02—Monocyclic hydrocarbons
- C07C15/107—Monocyclic hydrocarbons having saturated side-chain containing at least six carbon atoms, e.g. detergent alkylates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
- C07C69/36—Oxalic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the invention relates to the field of medicine and chemical industry, in particular to a new intermediate for preparing apixaban and a preparation method thereof.
- Apixaban is a new generation of oral antithrombotic drugs. Among many coagulation factor Xa inhibitors, it shows high selectivity, good bioavailability and efficient therapeutic effect. It is mainly used for hip or knee joints. Prevention of venous thromboembolic events (VTE) in adult patients undergoing elective joint replacement surgery. Apixaban was first discovered by Bristol-Myers Squibb in 2003, and jointly developed the drug with Pfizer in 2007. Since its launch in 2011, its sales have increased year by year. For BMS & Pfizer, Eliquis (Apixaban) Class) total sales for the first three quarters of 2019 were $9.016 billion, up 25% year-over-year. Eliquis is projected to have sales of $12 billion in 2025.
- the present invention provides a new intermediate for synthesizing apixaban and a preparation method thereof.
- the method has the advantages of simplicity and practicability, and the yield of each step reaction is high, and the synthesis route is green and environmentally friendly at the same time. The cost is reduced and the industrialized production is facilitated.
- the present invention provides the following technical solutions:
- the invention provides a kind of intermediate for preparing apixaban formula (1-a), and the structural formula is as follows:
- the present invention provides a preparation method for preparing apixaban whose intermediate formula is (1-a): in an organic solvent, under organic base catalysis conditions, tert-butanol and oxalyl chloride undergo an acylation reaction and then It is obtained from acylation reaction with phenol.
- the compound represented by the formula (1-a) in the present invention has good selectivity when the compound represented by the formula (2) is prepared by the aminolysis reaction.
- the fifth aspect provides a kind of intermediate for preparing apixaban formula (3-1), the structural formula is as follows:
- the sixth aspect provides a kind of intermediate for preparing apixaban formula (4), the structural formula is as follows:
- R1, R2 are independently C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl;
- substituted phenyl in the present invention includes benzyl, benzene, halobenzene, nitrobenzene, alkoxybenzene and benzyloxybenzene.
- R 1 and R 2 are each independently C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl; X is halogen, OSO 2 Ph-p-Me, OSO 2 Me or OSO 2 Ph.
- substituted phenyl in the present invention includes benzyl, benzene, halobenzene, nitrobenzene, alkoxybenzene and benzyloxybenzene.
- the present invention provides a method for preparing an apixaban intermediate of formula (4): the compound of formula (3) is subjected to a substitution reaction to prepare a compound of formula (4i), and then a compound of formula (4i) is obtained through a cyclization reaction. 4) Or directly obtain formula (4) by cyclization reaction from the compound of formula (4i), and the reaction formula is as follows:
- the invention provides a kind of intermediate for preparing apixaban formula (4-1), and the structural formula is as follows:
- the compound of formula (4i-1) may or may not be isolated.
- the synthesis step of the (4-1) is preferably, in an organic solvent, under the catalysis condition of an inorganic base, 3 and tert-butyl 4-bromobutyrate undergo a substitution reaction at a temperature of 50 to 70 ° C to prepare the formula (4i-1) ) compound, and then heated to 70 ⁇ 80 °C to carry out cyclization reaction to generate formula (4-1);
- the inorganic base is selected from one or more combinations of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate, and calcium carbonate.
- the preferred method includes two reactions but can be completed in one step, which greatly simplifies the reaction time and cost, and also ensures the yield and facilitates mass production.
- the present invention provides a preparation method in which the intermediate formula of apixaban is (4-1): the compound of formula (3) is reacted to obtain formula (4-1), and the reaction formula is as follows:
- a thirteenth aspect, the invention provides a kind of intermediate for preparing apixaban formula (5-1), the structural formula is as follows:
- the present invention provides a preparation method of apixaban whose intermediate formula is (5): the compound of formula (4) is prepared by cyclization reaction to obtain the compound of formula (5), and the reaction formula is as follows:
- R1 and R2 are each independently a C1-C6 aliphatic hydrocarbon, a phenyl group or a substituted phenyl group.
- the present invention provides a preparation method of apixaban whose intermediate formula is (5-1): the compound of formula (4-1) is prepared by cyclization reaction to obtain the compound of formula (5-1),
- the reaction formula is as follows:
- the invention provides a kind of intermediate for preparing apixaban formula (6), the structural formula is as follows:
- the present invention provides a preparation method of apixaban whose intermediate formula is (6): the compound of formula (5-1) is prepared by cyclization reaction to obtain the compound of formula (6), and the reaction formula is as follows:
- the eighteenth aspect, the invention provides a kind of intermediate for preparing apixaban formula (6i), the structural formula is as follows:
- the present invention provides a method for preparing an apixaban intermediate with the formula (7): the compound of the formula (6) is prepared by a condensation reaction to obtain the compound of the formula (7) or the compound of the formula (6) is prepared from the compound of the formula (6).
- the compound of formula (6i) is obtained through decarboxylation reaction, and then the compound of formula (7) is obtained through condensation reaction, and the reaction formula is as follows:
- a twentieth aspect, the present invention provides a preparation method of apixaban intermediate formula 7: it comprises the following steps:
- the compound of formula (2) is prepared by performing an aminolysis reaction between p-phenylenediamine and the compound of formula (1-a),
- the compound of formula (2) is subjected to substitution reaction to prepare the compound of formula (3),
- the compound of formula (4-1) is prepared by cyclization reaction to obtain the compound of formula (5-1),
- the compound of formula (6) is prepared by condensation reaction to obtain the compound of formula (7), or the compound of formula (6) is firstly decarboxylated to obtain the compound of formula (6i), and then the compound of formula (7) is obtained by condensation reaction.
- the present invention provides a preparation method of apixaban intermediate formula 7: it comprises the following steps:
- the compound of formula (2) is prepared by performing an aminolysis reaction between p-phenylenediamine and the compound of formula (1-a),
- the compound of formula (2) is subjected to substitution reaction to prepare the compound of formula (3),
- the compound of formula (3) is subjected to a substitution reaction to prepare a compound of formula (4i), and then a cyclization reaction is performed to obtain formula (4), or the compound of formula (3) is directly reacted to obtain formula (4),
- the compound of formula (4) is prepared by cyclization reaction to obtain the compound of formula (5),
- the compound of formula (5) is prepared by hydrolysis reaction to obtain the compound of formula (6),
- the compound of formula (6) is prepared by reaction to obtain the compound of formula (7), or the compound of formula (6) is first subjected to decarboxylation to obtain the compound of formula (6i), and then the compound of formula (7) is obtained by condensation reaction.
- the initial raw material with tert-butyl ester in each raw material of the synthetic route adopted in the present invention possesses the advantage of easy preparation, and the stability of each step product is greatly increased, and the transportation stability during factory production, The storage stability and use stability have been greatly increased, which makes the quality control of each intermediate in the reaction more convenient and reduces the requirements for equipment.
- there is no complicated reaction in the synthesis route which makes the entire synthesis route at the same time. It is simple and easy to operate;
- each raw material and reaction of the synthetic route of the present invention do not use precious catalysts or auxiliary reagents, and also avoid the use of expensive iodine-containing compounds, ensuring that the three wastes generated by each step process are less polluted and easy to handle. It makes the reaction both green and environmentally friendly, and also greatly reduces the cost;
- the yield is high: in the novel intermediate of apixaban of the present invention and the preparation method thereof, the yield of each step reaction can be more than 85%, and the post-processing is simple and convenient, which is more conducive to mass production control.
- Example 1 The preparation method of the apixaban precursor compound adopts the following specific process steps.
- Embodiment 2 Different from Embodiment 1, the preparation method of the apixaban precursor compound in this embodiment adopts the following specific process steps.
- Valeryl chloride (6.69g, 0.043mol), after dripping, was kept at 20°C for 0.5h, when HPLC and TLC showed that the reaction was complete, 40g of water was added to stir, suction filtration, and 40g of water was added to the filter cake to stir, and then suction filtration, filtration The cake was rinsed with water, dried to obtain the product, mixed two filtrate layers, recrystallized from the dichloromethane layer, dried to obtain the product, mixed twice, (14.2 g, theoretical value 15.0 g, yield 94.6%).
- Example 3 Different from Example 1, the preparation method of the apixaban precursor compound in this example adopts the following specific process steps.
- Embodiment 4 Different from Embodiment 1, the preparation method of the apixaban precursor compound in this embodiment adopts the following specific process steps.
- Morpholine (4.5g, 0.052mol) was added to the reaction flask, acetic acid (3.1g, 0.052mol) was added and stirred for 0.5h, acetonitrile (100ml) was added, compound 6i (10.0g, 0.035mol) was added, and the mixture was kept stirring at 80°C The reaction was carried out for 4 hours. When HPLC and TLC showed that the reaction was completed, the reaction system was cooled to 0°C-5°C for crystallization, filtered, and the filter cake was dried to obtain the product (10.7g, theoretical value 12.4g, yield 86.3%).
- the process route for preparing 6 in the present invention can also be prepared by the following examples.
- Example 5 The preparation method of preparation 6 in the present invention adopts the following specific process steps.
- Embodiment 6 The preparation method of preparation 6 in the present invention adopts the following specific process steps.
- Embodiment 7 The preparation method of preparation 6 in the present invention adopts the following specific process steps. (1) Synthesis of compound 4-(2-tert-butoxy-2-oxo-N-(4-(2-oxopiperidin-1-yl)-phenyl)acetamide)butyric acid ethyl ester:
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Abstract
本发明涉及一种合成阿哌沙班的新的中间体及其制备方法。该方法具体包含如下步骤：对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，式(2)化合物进行取代反应制备得到式(3)化合物，式(3)化合物进行取代反应制备得到式(4i)化合物，再经环合反应得到式(4)或者直接由式(3)化合物进行反应制备得到式(4)，式(4)化合物经环合反应制备得到式(5)化合物，式(5)化合物经水解反应制备得到式(6)化合物，式(6)化合物经反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i)化合物再经缩合反应得到式(7)，反应式如下：
Description
本发明涉及医药化工领域，具体涉及一种制备阿哌沙班的新的中间体及其制备方法。
阿哌沙班是一种新一代的口服抗血栓药物，在众多凝血因子Xa抑制剂中，表现出高度的选择性、良好的生物利用度和高效的治疗效果，其主要用于髋关节或膝关节择期置换术的成年患者，预防静脉血栓栓塞事件(VTE)。阿哌沙班2003年最初由百时美施贵宝公司发现，2007年与辉瑞共同研发该药，从2011年上市到现在，销售额逐年增加，BMS&辉瑞方面，艾乐妥(Eliquis)(阿哌沙班)2019年前3季度总销售额为90.16亿美元，同比增长25％。Eliquis预计在2025年的销售额达120亿美元。
目前市场中，对于阿哌沙班的合成工艺不少，但是绝大部分工艺路线都是通过其关键中间体5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮进行合成的，因此，对于该阿哌沙班中间体的合成研究至关重要，该关键中间体结构式如下所示：
以下现有技术报道了制备该中间体的方法：
1.Bristol-Myers Squibb公司于2003年公开的世界专利W02003049681中提出的一条路线：以对碘苯胺为原料，经过酰胺化-环合、二氯化、吗啡啉取代得到化合物4，再与2-哌啶酮在催化剂Cu(PPh
3)
3Br和碳酸铯存在下发生偶联反应得到化合物I。该路线使用对硝基碘苯1为起始原料，从而引入哌啶酮基团，对硝基碘苯价格昂贵，辅助试剂三苯基磷溴化亚铜用量 大且价格昂贵，限制了该路线的应用。
2.华东理工大学于2011年公开的中国专利CN101967145中提供了另一条工艺路线：以对硝基苯胺和5-氯戊酰氯为原料，经过酰胺化-环合、二氯化、消除、缩合反应得到化合物2，化合物2经硫化钠还原为相应的氨基化合物4，化合物4再和5-氯戊酰氯经酰胺化-环合得到化合物I。该路线中，通过引入对硝基苯胺来环合形成哌啶酮基团，对硝基苯胺原料成本低，但对硝基苯胺由于硝基强吸电子作用，会影响酰化反应的顺利进行，同时采用碱性硫化物对硝基的还原不够彻底，对酰胺键有破坏作用，故有较多副产物生成，从而限制了该路线的实际应用。
3.上海医药工业研究所针对以上两种制备方法进行了改进，并于2012年申请中国专利CN103626689A，提供了如下工艺路线：以苯胺作为起始原料，经过酰胺化-环合、硝化、二氯化、吗啡啉取代反应得到化合物4，化合物4经硫化钠还原为相应的氨基化合物3，化合物3再和5-氯戊酰氯经酰胺化-环合得到化合物。该路线中的起始原料价格低廉，但该路线中的硝化反应急剧放热，反应过程危险且会引入较多杂质，后处理困难，不适合工业化。
4、专利文献CN101967145等公开了一种方法，以对硝基苯胺为起始原料，经过酰胺化环合后，五氯化磷氯代消除，硫化钠还原后再次酰化环合，最终得到5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮，此方法由于硝基的钝化原因，使得整体收率偏低。
5、专利CN110143914以对氯苯胺为起始原料，经过酰化环合，氯代后，与吗啉反应并消除氯化氢，在2-哌啶酮偶联得到5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮。
6、专利CN104030972以对二苯胺为原料，经过双边酰化环合后，五氯化磷单边氯代，再与吗啉反应消除后得到5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮，此方法氯代的选择性是个关键的问题，导致收率不稳定。
综上所述，现阶段制备阿哌沙班中间体5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮的合成方法大致相同，这些类似工艺都存在许多相同的问题和缺陷：反应重复性差；后处理工艺比较繁琐；工艺对于设备的要求高；起始物料贵，成本高等。
鉴于已有的路线存在的一些缺陷，有必要进一步开发对环境友好，适用于商业化生产的阿哌沙班关键中间体路线。
本发明提供了本发明提供了一种合成阿哌沙班的新的中间体及其制备方法，该方法具有简单易行的优点且各步反应的收率较高，合成路线在绿色环保的同时降低了成本，方便实施工业化生产。
为了实现本发明的目的，本发明提供了如下技术方案：
第一方面，本发明提供了一种制备阿哌沙班式为(1-a)的中间体，结构式如下：
第二方面，本发明提供了一种制备阿哌沙班中间体式为(1-a)的制备方法：在有机溶剂中，有机碱催化条件下，叔丁醇与草酰氯发生酰基化反应后再与苯酚酰基化反应所得。
本发明中的式(1-a)所示化合物在氨解反应制备式(2)所示化合物时，具有良好的选择性。
所述一种制备阿哌沙班中间体式为(1-a)的制备方法优选为：有机碱为三乙胺，三乙胺与叔丁醇以摩尔比1:1混合滴入草酰氯的有机溶剂中；控制三乙胺与叔丁醇以相同当量滴加进入，一方面保证了草酰氯的稳定性，另一方面进一步减少反应产生双取代产物。
第三方面，一种制备阿哌沙班式为(2)的中间体，结构式如下：
第四方面，本发明提供了一种阿哌沙班中间体式为(2)的制备方法：其由对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，反应式如下：
第五方面，本发明提供了一种制备阿哌沙班式为(3-1)的中间体，结构式如下：
第六方面，本发明提供了一种制备阿哌沙班式为(4)的中间体，结构式如下：
其中，R1、R2各自独立地为C1-C6的脂肪烃、苯基或取代苯基；
其中在本发明中的“取代苯基”包括苄基、苯、卤代苯、硝基苯、烷氧基苯以及苄氧基苯。
第七方面，本发明提供了一种制备阿哌沙班式为(4i)的中间体，结构式如下：
其中，R
1、R
2各自独立地为C1-C6的脂肪烃、苯基或取代苯基；X为卤素、OSO
2Ph-p-Me、OSO
2Me或OSO
2Ph。
其中在本发明中的“取代苯基”包括苄基、苯、卤代苯、硝基苯、烷氧基苯以及苄氧基苯。
第八方面，本发明提供了一种阿哌沙班中间体式为(4)的制备方法：其由式(3)化合物进行取代反应制备得到式(4i)化合物，再经环合反应得到式(4)或者直接由式(4i)化合物经环合反应得到式(4)，反应式如下：
或者
其中，R
1、R
2各自独立地为C1-C6的脂肪烃、苯基或取代苯基；X为卤素、OSO
2Ph-p-Me、OSO
2Me或OSO
2Ph。
其中在本发明中的“取代苯基”包括苄基、苯、卤代苯、硝基苯、烷氧基苯以及苄氧基苯。其中式(4i)化合物可经分离或者不分离。
第九方面，本发明提供了一种制备阿哌沙班式为(4i-1)的中间体，结构式如下：
第十方面，本发明提供了一种制备阿哌沙班式为(4-1)的中间体，结构式如下：
第十一方面，本发明提供了一种阿哌沙班中间体式为(4-1)的制备方法：其由4-溴丁酸叔丁酯与式(3)化合物进行取代反应制备得到式(4i-1)化合物，再经环合反应得到式(4-1)或者直接由式(4i-1)制备得到式(4-1)，反应式如下：
或者
其中，式(4i-1)化合物可经分离或者不分离。
所述(4-1)的合成步骤优选为，在有机溶剂中，无机碱催化条件下，3与4-溴丁酸叔丁酯于温度50～70℃发生取代反应制备得到式(4i-1)化合物，再升温至70～80℃进行环合反应生成式(4-1)；
所述无机碱选自碳酸钾、碳酸铯、碳酸钠、碳酸锂、碳酸镁、碳酸钙中的一种或一种以上的组合。
该优选方法包含两个反应但能一步完成，在大大简化了反应时间和成本的同时，还保证了收率，方便了大批量的生产。
进一步，所述无机碱优选为碳酸钾或碳酸铯。此两种无机碱催化的反应能使得反应向目标方向进行，且反应选择性高。
4-1引入4-溴丁酸叔丁酯，是为了在5合环之后还有叔丁酯基团，叔丁酯基团能保证脱羧到的6的收率高。
第十二方面，本发明提供了一种阿哌沙班中间体式为(4-1)的制备方法：其由式(3)化合物经反应得到式(4-1)，反应式如下：
第十三方面，本发明提供了一种制备阿哌沙班式为(5-1)的中间体，结构式如下：
第十四方面，本发明提供了一种阿哌沙班中间体式为(5)的制备方法：其由式(4)化合物经环合反应制备得到式(5)化合物，反应式如下：
其中，R1、R2各自独立地为C1-C6的脂肪烃、苯基或取代苯基。
第十五方面，本发明提供了一种阿哌沙班中间体式为(5-1)的制备方法：其由式(4-1)化合物经环合反应制备得到式(5-1)化合物，反应式如下：
第十六方面，本发明提供了一种制备阿哌沙班式为(6)的中间体，结构式如下：
第十七方面，本发明提供了一种阿哌沙班中间体式为(6)的制备方法：其由式(5-1)化合物经环合反应制备得到式(6)化合物，反应式如下：
第十八方面，本发明提供了一种制备阿哌沙班式为(6i)的中间体，结构式如下：
第十九方面，本发明提供了一种阿哌沙班中间体式为(7)的制备方法：其由式(6)化合物经缩合反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i)化合物 再经缩合反应得到式(7)，反应式如下：
或者
第二十方面，本发明提供了一种阿哌沙班中间体式7的制备方法：其包括以下步骤：
对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，
式(2)化合物进行取代反应制备得到式(3)化合物，
4-溴丁酸叔丁酯与式(3-1)化合物进行取代反应制备得到式(4i-1)化合物，再经环合反应得到式(4-1)或者直接由式(3-1)化合物进行反应制备得到式(4-1)，
式(4-1)化合物经环合反应制备得到式(5-1)化合物，
式(5-1)化合物经水解反应制备得到式(6)化合物，
式(6)化合物经缩合反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i)化合物再经缩合反应得到式(7)。
其反应式如下：
第二十一方面，本发明提供了一种阿哌沙班中间体式7的制备方法：其包括以下步骤：
对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，
式(2)化合物进行取代反应制备得到式(3)化合物，
式(3)化合物进行取代反应制备得到式(4i)化合物，再经环合反应得到式(4)或者直接由式(3)化合物进行反应制备得到式(4)，
式(4)化合物经环合反应制备得到式(5)化合物，
式(5)化合物经水解反应制备得到式(6)化合物，
式(6)化合物经反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i)化合物再经缩合反应得到式(7)。
其反应式如下：
与现有技术相比，本发明的一种合成阿哌沙班的新的中间体及其制备方法具有如下显著的进步：
(1)简单易行：本发明所采用合成路线的各个原料中带有叔丁酯的初始原料具备易制备的优点，且各步产物的稳定性大大增加，在工厂生产时的运输稳定性、储存稳定性、使用稳定性都得到大幅增加，这使得反应中各个中间体的质量控制更加方便且降低了对设备的要求，加上在合成路线中的无复杂反应，这得整个合成路线在兼具简单的同时还具有易操作的优点；
(2)成本低：本发明合成路线的各个原料及反应中都没有使用贵重的催化剂或辅助试剂，也避免使用昂贵的含碘化合物，保证了各步工艺产生的三废污染少且易于处理，能使得反应在兼具绿色环保的同时也大大降低了成本；
(3)收率高：采用本发明阿哌沙班的新的中间体及其制备方法中，每步反应的收率都可在85％以上，且后处理简单方便，更利于大批量生产时的调控。
在以下实例中进一步定义本发明。应理解，这些实例虽然指示本发明的优选实施例，但是仅以说明方式给出，并不限制本发明的权利要求。
实施例1：本阿哌沙班前体化合物的制备方法采用下述具体工艺步骤。
(1)化合物1-a的合成：
于反应瓶中加入二氯甲烷(70ml)，加入草酰氯(10.0g，0.079mol)，于-10℃保温搅拌0.5h，滴加叔丁醇(5.85g，0.079mol)：二氯甲烷(10ml)：三乙胺(7.97g，0.079mol)混合溶液，滴加完毕后于-10℃保温搅拌0.5h，，然后滴加苯酚(7.43g，0.079mol)：二氯甲烷(10ml)：三乙胺(7.97g，0.079mol)混合溶液，滴加完毕后于-10℃保温搅拌0.5h，当HPLC和TLC显示反应完成时；过滤，滤液减压浓缩得到产品(11.6g，理论值12.9g，收率90.2％)，LCMS m/z 223(M
++H,C
12H
14O
4)。
(2)化合物2的合成：
于反应瓶中加入乙酸乙酯(100ml)，加入对苯二胺(10.0g，0.093mol)，加入草酸叔丁酯苯酯(21.1g，0.095mol)，于18℃保温搅拌3.5h，当HPLC和TLC显示反应完成时，加入50g水和浓盐酸(6.94ml，0.083mol)萃取分层，乙酸乙酯层加入100g水和浓盐酸(0.77ml，0.009mol)萃取分层；合并水层，水层加入碳酸钠调PH至7，抽滤，滤饼用水淋洗后烘干得到产品(19.7g，理论值21.8g，收率90.3％)，LCMS m/z 236(M
++H,C
12H
16N
2O
3)。
(3)化合物3的合成：
于反应瓶中加入二氯甲烷(100ml)，加入化合物2(10.0g，0.042mol)，加入三乙胺(4.5g，0.044mol)，降温至15℃保温搅拌，边搅拌边滴加5-氯戊酰氯(6.9g，0.044mol)，滴毕，于15℃保温0.5h，当HPLC和TLC显示反应完成时，加入40g水搅拌，抽滤，滤饼再 加入40g水搅拌，再抽滤，滤饼用水淋洗后烘干得到产品，混合两次滤液分层，二氯甲烷层重结晶，干燥得到产品，混合两次产品(14.3g，理论值15.0g，收率95.3％)，LCMS m/z 355(M
++H,C
17H
23ClN
2O
4)。
(4)化合物4-1的合成：
于反应瓶中加入化合物3(10.0g，0.028mol)，加入碳酸钾(38.8g，0.282mol)，加入DMF(100ml)，加入4-溴丁酸叔丁酯(7.55g，0.034mol)，于55℃保温搅拌12h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减压浓缩得到产品(11.6g，理论值12.9g，收率89.9％)，LCMS m/z 461(M
++H,C
25H
36N
2O
6)。
(5)化合物5的合成：
于反应瓶中加入叔丁醇钠(2.71g，0.028mol)，加入四氢呋喃(90ml),于65℃保温搅拌，加入化合物4-1(10.0g，0.022mol)的四氢呋喃(30ml)溶液保温反应1h，当HPLC和TLC显示反应完成时，减压浓缩，5℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至2，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(6.9g，理论值7.9g，收率87.3％)，LCMS m/z 387(M
++H,C
21H
26N
2O
5)。
(6)化合物6的合成：
于反应瓶中加入二氯甲烷(70ml)，加入四氢呋喃(30ml),加入化合物5(10.0g，0.026mol)，于20℃保温搅拌，通入氯化氢气体保温反应2.5h，当HPLC和TLC显示反应完成时，减压浓缩，于20℃加入庚烷(50ml)保温搅拌0.5h，抽滤，滤饼用庚烷淋洗后烘干 得到产品(7.7g，理论值8.5g，收率90.5％)，LCMS m/z 331(M
++H,C
17H
18N
2O
5)。
(7)化合物7的合成：
于反应瓶中加入化合物6(10.0g，0.033mol)，加入乙腈(100ml)，加入吗啉(4.5g，0.052mol),加入乙酸(3.1g，0.052mol),于80℃保温搅拌反应4h，当HPLC和TLC显示反应完成时，将反应体系降温至0℃-5℃析晶，过滤，滤饼烘干得到产品(9.7g，理论值10.7g，收率90.7％)，LCMS m/z 356(M
++H,C
20H
25N
3O
3)。
实施例2：与实施例1不同的是，本实施例中阿哌沙班前体化合物的制备方法采用下述具体工艺步骤。
(1)化合物1-a的合成：
于反应瓶中加入二氯甲烷(80ml)，加入草酰氯(10.0g，0.079mol)，于-5℃保温搅拌0.5h，滴加叔丁醇(5.85g，0.079mol)：二氯甲烷(10ml)：三乙胺(8.10g，0.080mol)混合溶液，滴加完毕后于-10℃保温搅拌0.5h，当HPLC反应完成时，滴加苯酚(7.43g，0.079mol)：二氯甲烷(10ml)：三乙胺(8.10g，0.080mol)混合溶液，滴加完毕后于-5℃保温搅拌0.5h，当HPLC和TLC显示反应完成时；过滤，滤液减压浓缩得到产品(11.5g，理论值12.9g，收率90.2％)，LCMS m/z 223(M
++H,C
12H
14O
4)。
(2)化合物2的合成：
于反应瓶中加入乙酸乙酯(100ml)，加入对苯二胺(10.0g，0.093mol)，加入草酸叔丁酯苯酯(20.6g，0.093mol)，于15℃保温搅拌4h，当HPLC和TLC显示反应完成时，加入40g水和浓盐酸(6.94ml，0.083mol)萃取分层，乙酸乙酯层加入90g水和浓盐酸(0.77ml，0.009mol)萃取分层；合并水层，水层加入Na
2CO
3调PH至8，抽滤，滤饼用水淋洗后烘干得到产品(19.3g，理论值21.8g，收率88.5％)。
(3)化合物3的合成：
于反应瓶中加入二氯甲烷(100ml)，加入化合物2(10.0g，0.042mol)，加入三乙胺(4.4g，0.043mol)，降温至20℃保温搅拌，边搅拌边滴加5-氯戊酰氯(6.69g，0.043mol)，滴毕，于20℃保温0.5h，当HPLC和TLC显示反应完成时，加入40g水搅拌，抽滤，滤饼再加入40g水搅拌，再抽滤，滤饼用水淋洗后烘干得到产品，混合两次滤液分层，二氯甲烷层 重结晶，干燥得到产品，混合两次产品，(14.2g，理论值15.0g，收率94.6％)。
(4)化合物4-1的合成：
于反应瓶中加入化合物3(10.0g，0.028mol)，加入碳酸钾(38.8g，0.282mol)，加入DMF(90ml)，加入4-溴丁酸叔丁酯(7.3g，0.033mol)，于50℃保温搅拌11h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减压浓缩得到产品(11.3g，理论值12.9g，收率87.5％)。
(5)化合物5的合成：
于反应瓶中加入叔丁醇钠(2.71g，0.028mol)，加入四氢呋喃(80ml),于60℃保温搅拌，加入化合物4-1(10.0g，0.022mol)的四氢呋喃(20ml)溶液保温反应0.5h，当HPLC和TLC显示反应完成时，减压浓缩，0℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至3，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(6.8g，理论值7.9g，收率86.1％)。
(6)化合物6的合成：
于反应瓶中加入二氯甲烷(80ml)，加入四氢呋喃(20ml),加入化合物5(10.0g，0.026mol)，于15℃保温搅拌，通入氯化氢气体保温反应2h，当HPLC和TLC显示反应完成时，减压浓缩，于15℃加入庚烷(45ml)保温搅拌0.5h，抽滤，滤饼用庚烷淋洗后烘干得到产品(7.5g，理论值8.5g，收率88.2％)。
(7)化合物7的合成：
于反应瓶中加入化合物6(10.0g，0.033mol)，加入乙腈(90ml)，加入吗啉(4.4g，0.050mol),加入乙酸(3.0g，0.050mol),于60℃保温搅拌反应3h，当HPLC和TLC显示反应完成时，将反应体系降温至0℃-5℃析晶，过滤，滤饼烘干得到产品(9.3g，理论值10.7g，收率86.9％)。
实施例3：与实施例1不同的是，本实施例中阿哌沙班前体化合物的制备方法采用下述具体工艺步骤。
(1)化合物1-a的合成：
于反应瓶中加入二氯甲烷(70ml)，加入草酰氯(10.0g，0.079mol)，于0℃保温搅拌0.5h，滴加叔丁醇(5.92g，0.08mol)：二氯甲烷(10ml)：三乙胺(7.97g，0.079mol)混合溶液，滴加完毕后于-10℃保温搅拌0.5h，当HPLC反应完成时，滴加苯酚(7.53g，0.08mol)：二氯甲烷(10ml)：三乙胺(7.97g，0.079mol)混合溶液，滴加完毕后于0℃保温搅拌0.5h，当HPLC和TLC显示反应完成时；过滤，滤液减压浓缩得到产品(11.3g，理 论值12.9g，收率87.5％)，LCMS m/z 223(M
++H,C
12H
14O
4)。
(2)化合物2的合成：
于反应瓶中加入乙酸乙酯(110ml)，加入对苯二胺(10.0g，0.093mol)，加入草酸叔丁酯苯酯(21.6g，0.097mol)，于20℃保温搅拌4h，当HPLC和TLC显示反应完成时，加入45g水和浓盐酸(7.5ml，0.09mol)萃取分层，乙酸乙酯层加入95g水和浓盐酸(0.83ml，0.01mol)萃取分层；合并水层，水层加入Na
2CO
3调PH至7，抽滤，滤饼用水淋洗后烘干得到产品(19.5g，理论值21.8g，收率89.4％)。
(3)化合物3的合成：
于反应瓶中加入二氯甲烷(100ml)，加入化合物2(10.0g，0.042mol)，加入三乙胺(4.6g，0.045mol)，降温至15℃保温搅拌，边搅拌边滴加5-氯戊酰氯(6.98g，0.045mol)，滴毕，于15℃保温0.5h，当HPLC和TLC显示反应完成时，加入50g水搅拌，抽滤，滤饼再加入50g水搅拌，再抽滤，滤饼用水淋洗后烘干得到产品，混合两次滤液分层，二氯甲烷层重结晶，干燥得到产品，混合两次产品(14.3g，理论值15.0g，收率95.3％)。
(4)化合物4的合成：
于反应瓶中加入化合物3(10.0g，0.028mol)，加入碳酸钾(42.8g，0.310mol)，加入DMF(110ml)，加入4-溴丁酸叔丁酯(7.7g，0.035mol)，于70℃保温搅拌11h，升温至70℃保温4h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减压浓缩得到产品，(11.3g，理论值12.9g，收率87.5％)。
(5)化合物5的合成：
于反应瓶中加入叔丁醇钠(2.71g，0.031mol)，加入四氢呋喃(100ml),于75℃保温搅拌，加入化合物4-1(10.0g，0.022mol)的四氢呋喃(20ml)溶液保温反应1h，当HPLC和TLC显示反应完成时，减压浓缩，0℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至2，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(6.8g，理论值7.9g，收率86.1％)。
(6)化合物6的合成：
于反应瓶中加入二氯甲烷(60ml)，加入四氢呋喃(40ml),加入化合物5(10.0g，0.026mol)，于15℃保温搅拌，通入氯化氢气体保温反应3h，当HPLC和TLC显示反应完成时，减压浓缩，于18℃加入庚烷(55ml)保温搅拌0.5h，抽滤，滤饼用庚烷淋洗后烘干得到产品(7.8g，理论值8.5g，收率91.7％)。
(7)化合物7的合成：
于反应瓶中加入化合物6(10.0g，0.033mol)，加入乙腈(90ml)，加入吗啉(4.6g，0.054mol),加入乙酸(3.2g，0.054mol),于80℃保温搅拌反应3h，当HPLC和TLC显示反应完成时，将反应体系降温至0℃-5℃析晶，过滤，滤饼烘干得到产品(9.4g，理论值10.7g，收率87.9％)。
实施例4：与实施例1不同的是，本实施例中阿哌沙班前体化合物的制备方法采用下述具体工艺步骤。
(1)化合物1-a的合成，除下述不同之处，其余同实施例1：有机溶剂选用乙腈，保温温度于-8℃，得到产品(11.4g，理论值12.9g，收率88.3％)，LCMS m/z 223(M
++H,C
12H
14O
4)。
(2)化合物2的合成，除下述不同之处，其余同实施例1：有机溶剂选用乙腈，草酸叔丁酯苯酯(20.8g，0.094mol)，浓盐酸(7.16ml，0.086mol)，得到产品(19.1g，理论值21.8g，收率87.6％)。
(3)化合物3的合成，除下述不同之处，其余同实施例1：有机溶剂选用乙腈，化合物2:5-氯戊酰氯:三乙胺＝1.0:1.1:1.1(摩尔)，得到产品(14.0g，理论值15.0g，收率93.3％)。
(4)化合物4i-1的合成：
于反应瓶中加入化合物3(10.0g，0.028mol)，加入碳酸钾(38.8g，0.282mol)，加入DMF(100ml)，加入4-溴丁酸叔丁酯(7.55g，0.034mol)，于50℃保温搅拌12h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减压浓缩得到产品(12.6g，理论值14.0g，收率90.0％)，LCMS m/z 497(M
++H,C
25H
37ClN
2O
6)。
(5)化合物5的合成：
于反应瓶中加入叔丁醇钠(4.42g，0.046mol)，加入四氢呋喃(90ml),于65℃保温搅拌，加入化合物4i-1(10.0g，0.020mol)的四氢呋喃(30ml)溶液保温反应1h，当HPLC和TLC显示反应完成时，减压浓缩，5℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至2，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(6.7g，理论值7.8g，收率85.8％)，LCMS m/z 387(M
++H,C
21H
26N
2O
5)。
(6)化合物6的合成：于反应瓶中加入四氢呋喃(100ml),加入化合物5(10.0g，0.026mol)，于20℃保温搅拌，通入氯化氢气体保温反应2.5h，当HPLC和TLC显示反应完成时，减压浓缩，加乙酸乙酯50ml，过滤，于20℃加入庚烷(50ml)保温搅拌0.5h，抽滤，滤饼用庚烷淋洗后烘干得到产品(7.4g，理论值8.5g，收率87.1％)。
(7)化合物6i的合成：
于反应瓶中加入乙腈(100ml),加入化合物6(10.0g，0.026mol)，于80℃保温搅拌反应5h，当HPLC和TLC显示反应完成时，减压浓缩得到产品(8.4g，理论值8.6g，收率97.7％)，LCMS m/z 287(M
++H,C
16H
18N
2O
3)。
(8)化合物7的合成：
于反应瓶中加入吗啉(4.5g，0.052mol),加入乙酸(3.1g，0.052mol)搅拌0.5h，加入乙腈(100ml)，加入化合物6i(10.0g，0.035mol)，于80℃保温搅拌反应4h，当HPLC和TLC显示反应完成时，将反应体系降温至0℃-5℃析晶，过滤，滤饼烘干得到产品(10.7g，理论值12.4g，收率86.3％)。
本发明中制备6的工艺路线还可由以下实施例制备。
实施例5：本发明中制备6的制备方法采用下述具体工艺步骤。
(1)化合物4-(2-乙氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸乙酯的合成：
于反应瓶中加入2-((4-(5-氯戊酰胺)苯基)氨基)-2-氧代乙酰氨基乙酯(10.0g，0.031mol)，加入碳酸钾(42.2g，0.306mol)，加入DMF(100ml)，加入4-溴丁酸乙酯(6.52g，0.034mol)，于50℃保温搅拌12h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减4压浓缩得到产品(11.1g，理论值12.4g，收率89.5％)，LCMS m/z 405(M
++H,C
21H
28N
2O
6)。
(2)化合物4-(2-乙氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸乙酯的合成：
于反应瓶中加入2-((4-(5-溴戊酰胺)苯基)氨基)-2-氧代乙酰氨基乙酯(10.0g，0.027mol)，加入碳酸钾(37.3g，0.270mol)，加入DMF(100ml)，加入4-溴丁酸乙酯(6.52g，0.034mol)，于50℃保温搅拌12h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减4压浓缩得到产品(11.2g，理论值12.4g，收率90.3％)，LCMS m/z 405(M
++H,C
21H
28N
2O
6)。
(3)化合物1-(4-(2-氧代哌啶-1-基)-苯基)哌啶-2,3-二酮-4-羧酸乙酯的合成：
于反应瓶中加入叔丁醇钠(3.17g，0.033mol)，加入四氢呋喃(90ml),于65℃保温搅拌，加入化合物4-(2-乙氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸乙酯(10.0g，0.025mol)的四氢呋喃(30ml)溶液保温反应1h，当HPLC和TLC显示反应完成时，减压浓缩，5℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至2，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(7.8g，理论值8.9g，收率87.6％)，LCMS m/z 359(M
++H,C
19H
22N
2O
5)。
(4)化合物6的合成：
于反应瓶中加入二氯甲烷(70ml)，加入四氢呋喃(30ml),加入化合物1-(4-(2-氧代哌啶-1基)苯基)哌啶-2,3-二酮-4-羧酸乙酯(10.0g，0.028mol)，于20℃保温搅拌，通入氯化氢气体保温反应2.5h，当HPLC和TLC显示反应完成时，减压浓缩，于20℃加入庚烷(50ml)保温搅拌0.5h，抽滤，滤饼用庚烷淋洗后烘干得到产品(0.7g，理论值9.21g，收率7.6％)，LCMS m/z 331(M
++H,C
17H
18N
2O
5)。
实施例6：本发明中制备6的制备方法采用下述具体工艺步骤。
(1)化合物4-(2-甲氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸甲酯的合成：
于反应瓶中加入2-((4-(5-氯戊酰胺)苯基)氨基)-2-氧代乙酰氨基甲酯(10.0g，0.032mol)，加入碳酸钾(44.2g，0.320mol)，加入DMF(100ml)，加入4-溴丁酸甲酯(6.84g，0.038mol)，于50℃保温搅拌12h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减压浓缩得到产品(9.8g，理论值11.3g，收率86.7％)，LCMS m/z 377(M
++H,C
19H
24N
2O
6)。
(2)化合物4-(2-甲氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸甲酯的合成：
于反应瓶中加入2-((4-(5-磺酸苯酯戊酰胺)苯基)氨基)-2-氧代乙酰氨基甲酯(10.0g，0.023mol)，加入碳酸钾(31.7g，0.230mol)，加入DMF(100ml)，加入4-溴丁酸甲酯(6.84g，0.038mol)，于50℃保温搅拌12h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减压浓缩得到产品(7.6g，理论值8.7g，收率87.3％)，LCMS m/z 377(M
++H,C
19H
24N
2O
6)。
(3)化合物1-(4-(2-氧代哌啶-1-基)-苯基)哌啶-2,3-二酮-4-羧酸甲酯的合成：
于反应瓶中加入叔丁醇钠(3.11g，0.032mol)，加入四氢呋喃(90ml),于65℃保温搅拌，加入化合物4-(2-甲氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸甲酯(10.0g，0.027mol)的四氢呋喃(30ml)溶液保温反应1h，当HPLC和TLC显示反应完成时，减压浓缩，5℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至2，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(8.2g，理论值9.2g，收率89.1％)，LCMS m/z 345(M
++H,C
19H
22N
2O
5)。
(4)化合物6的合成：
于反应瓶中加入二氯甲烷(70ml)，加入四氢呋喃(30ml),加入化合物1-(4-(2-氧代哌啶-1基)苯基)哌啶-2,3-二酮-4-羧酸甲酯(10.0g，0.029mol)，于20℃保温搅拌，通入氯化氢气体保温反应2.5h，当HPLC和TLC显示反应完成时，减压浓缩，于20℃加入庚烷(50ml)保温搅拌0.5h，抽滤，滤饼用庚烷淋洗后烘干得到产品(0.9g，理论值9.6g，收率9.3％)，LCMS m/z 331(M
++H,C
17H
18N
2O
5)。
实施例7：本发明中制备6的制备方法采用下述具体工艺步骤。(1)化合物4-(2-叔丁氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸乙酯的合成：
于反应瓶中加入化合物3(10.0g，0.028mol)，加入碳酸钾(38.8g，0.282mol)，加入DMF(100ml)，加入4-溴丁酸乙酯(6.56g，0.034mol)，于50℃保温搅拌12h，升温至80℃保温3h，当HPLC和TLC显示反应完成时，抽滤，减压浓缩，浓缩液用二氯甲烷和水萃取分液，有机层用无水硫酸钠干燥，减4压浓缩得到产品(10.8g，理论值12.2g，收率88.5％)，LCMS m/z 433(M
++H,C
21H
28N
2O
6)。
(2)化合物1-(4-(2-氧代哌啶-1-基)-苯基)哌啶-2,3-二酮-4-羧酸甲酯的合成：
于反应瓶中加入叔丁醇钠(2.88g，0.030mol)，加入四氢呋喃(90ml),于65℃保温搅拌，加入化合物4-(2-叔丁氧基-2-氧代-N-(4-(2-氧代哌啶-1-基)-苯基)乙酰胺)丁酸甲酯(10.0g，0.023mol)的四氢呋喃(30ml)溶液保温反应1h，当HPLC和TLC显示反应完成时，减压浓缩，5℃加水(100ml)和乙酸乙酯(100ml)，加入盐酸调PH至2，分相，乙酸乙酯层用无水硫酸钠干燥，减压浓缩得到产品(7.0g，理论值8.0g，收率87.5％)，LCMS m/z 345(M
++H,C
19H
22N
2O
5)。
(3)化合物6的合成，同实施例5。
上述对本申请中涉及的发明的一般性描述和对其具体实施例的描述不应理解为是对该发明技术方案构成的限制。本领域所属技术人员根据本申请的公开，可以在不违背所涉及的发明构成要素的前提下，对上述一般性描述或/和实施例中的公开技术特征进行增加、减少或组合，形成属于本申请保护范围之内的其它的技术方案。
Claims (24)
- 一种制备阿哌沙班式为(1-a)的中间体，其特征在于，其结构式如下：
- 一种阿哌沙班中间体式为(1-a)的制备方法，其特征在于，所述(1-a)的合成步骤包括，在有机溶剂中，有机碱催化条件下，叔丁醇与草酰氯发生酰基化反应后再与苯酚酰基化反应所得。
- 根据权利要求2所述的(1-a)的制备方法，其特征在于，所述有机碱为三乙胺，三乙胺与叔丁醇以摩尔比1:1混合滴入草酰氯的有机溶剂中。
- 一种制备阿哌沙班式为(2)的中间体，其特征在于，其结构式如下：
- 一种阿哌沙班中间体式为(2)的制备方法，其特征在于，对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，反应式如下：
- 一种制备阿哌沙班式为(3-1)的中间体，其特征在于，其结构式如下：
- 一种制备阿哌沙班式为(4)的中间体，其特征在于，其结构式如下：
其中，R 1、R 2各自独立地为C1-C6的脂肪烃、苯基或取代苯基。 - 一种制备阿哌沙班式为(4i)的中间体，其特征在于，其结构式如下：
其中，R 1、R 2各自独立地为C1-C6的脂肪烃、苯基或取代苯基；X为卤素、OSO 2Ph-p-Me、OSO 2Me或OSO 2Ph。 - 一种阿哌沙班中间体式为(4)的制备方法，其特征在于，式(3)化合物进行取代反应制 备得到式(4i)化合物，再经环合反应得到式(4)或者直接由式(4i)化合物，经环合反应得到式(4)，反应式如下：
其中，R 1、R 2各自独立地为C1-C6的脂肪烃、苯基或取代苯基；X为卤素、OSO 2Ph-p-Me、OSO 2Me或OSO 2Ph。 - 一种制备阿哌沙班式为(4i-1)的中间体，其特征在于，其结构式如下：
- 一种制备阿哌沙班式为(4-1)的中间体，其特征在于，其结构式如下：
- 一种阿哌沙班中间体式为(4-1)的制备方法，其特征在于，4-溴丁酸叔丁酯与式(3-1)化合物进行取代反应制备得到式(4i-1)化合物，再经环合反应得到式(4-1)或者直接由式(4i-1)制备得到式(4-1)，反应式如下：
- 根据权利要求12所述的一种阿哌沙班中间体式为(4-1)的制备方法，其特征在于：所述(4)的合成步骤包括，在有机溶剂中，无机碱催化条件下，式(3-1)与4-溴丁酸叔丁酯于温度50～70℃发生取代反应，再升温至70～80℃进行环合反应生成式(4-1)。
- 根据权利要求13所述的一种阿哌沙班中间体式为(4-1)的制备方法，其特征在于：所述无机碱选自碳酸钾、碳酸铯、碳酸钠、碳酸锂、碳酸镁、碳酸钙中的一种或一种以上的组合。
- 一种阿哌沙班中间体式为(4-1)的制备方法，其特征在于，式(3-1)化合物经环合反应 得到式(4-1)，反应式如下：
- 一种制备阿哌沙班式为(5-1)的中间体，其特征在于，其结构式如下：
- 一种阿哌沙班中间体式为(5)的制备方法，其特征在于，式(4)化合物经环合反应制备得到式(5)化合物，反应式如下：
其中，R 1、R 2各自独立地为C1-C6的脂肪烃、苯基或取代苯基。 - 一种阿哌沙班中间体式为(5-1)的制备方法，其特征在于，式(4-1)化合物经环合反应制备得到式(5-1)化合物，反应式如下：
- 一种制备阿哌沙班式为(6)的中间体，其特征在于，其结构式如下：
- 一种阿哌沙班中间体式为(6)的制备方法，其特征在于，式(5-1)化合物经环合反应制备得到式(6)化合物，反应式如下：
- 一种制备阿哌沙班式为(6i)的中间体，其特征在于，其结构式如下：
- 一种阿哌沙班中间体式为(7)的制备方法，其特征在于，式(6)化合物经反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i)化合物再经缩合反应得到式(7)，反应式如下：
- 一种阿哌沙班中间体式(7)的制备方法，其特征在于，包括以下步骤：对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，式(2)化合物进行取代反应制备得到式(3)化合物，式(3)化合物进行取代反应制备得到式(4i)化合物，再经环合反应得到式(4)或者直接 由式(3)化合物进行反应制备得到式(4)，式(4)化合物经环合反应制备得到式(5)化合物，式(5)化合物经水解反应制备得到式(6)化合物，式(6)化合物经反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i)化合物再经缩合反应得到式(7)；其反应式如下：
- 一种阿哌沙班中间体式(7)的制备方法，其特征在于，包括以下步骤：对苯二胺与式(1-a)化合物进行氨解反应制备得到式(2)化合物，式(2)化合物进行取代反应制备得到式(3)化合物，4-溴丁酸叔丁酯与式(3-1)化合物进行取代反应制备得到式(4i-1)化合物，再经环合反应得到式(4-1)或者直接由式(3-1)化合物进行反应制备得到式(4-1)，式(4-1)化合物经环合反应制备得到式(5-1)化合物，式(5-1)化合物经水解反应制备得到式(6)化合物，式(6)化合物经反应制备得到式(7)化合物或者由式(6)化合物先经脱羧反应得到式(6i) 化合物再经缩合反应得到式(7)；反应式如下：
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| CN104030972A (zh) * | 2014-06-17 | 2014-09-10 | 河北序能生物技术有限公司 | 一种吡啶酮的合成方法 |
| US20180099963A1 (en) * | 2014-09-05 | 2018-04-12 | Unichem Laboratories Limited | Process for the preparation of apixaban and intermediates thereof |
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| WO2014108919A2 (en) * | 2013-01-09 | 2014-07-17 | Msn Laboratories Limited | NOVEL INTERMEDIATE AND POLYMORPHS OF 1-(4-METHOXYPHENYL)-7-OXO-6-[4-(2-OXOPIPERIDIN-1-YL)PHENYL]-4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[3,4-c] PYRIDINE-3-CARBOXAMIDE AND PROCESS THEREOF |
| CN104030972A (zh) * | 2014-06-17 | 2014-09-10 | 河北序能生物技术有限公司 | 一种吡啶酮的合成方法 |
| US20180099963A1 (en) * | 2014-09-05 | 2018-04-12 | Unichem Laboratories Limited | Process for the preparation of apixaban and intermediates thereof |
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