CN115594613A - 依度沙班中间体及其制备方法 - Google Patents
依度沙班中间体及其制备方法 Download PDFInfo
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- CN115594613A CN115594613A CN202211343010.6A CN202211343010A CN115594613A CN 115594613 A CN115594613 A CN 115594613A CN 202211343010 A CN202211343010 A CN 202211343010A CN 115594613 A CN115594613 A CN 115594613A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 title claims abstract description 17
- 229960000622 edoxaban Drugs 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 25
- 102000003929 Transaminases Human genes 0.000 claims abstract description 16
- 108090000340 Transaminases Proteins 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 108090000790 Enzymes Proteins 0.000 claims abstract description 13
- 102000004190 Enzymes Human genes 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 7
- 239000005515 coenzyme Substances 0.000 claims abstract description 5
- 238000001212 derivatisation Methods 0.000 claims abstract description 5
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000007800 oxidant agent Substances 0.000 claims abstract description 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000005909 Kieselgur Substances 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 4
- 238000006911 enzymatic reaction Methods 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000008363 phosphate buffer Substances 0.000 claims 1
- 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 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000001590 oxidative effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- -1 amino alcohol compound Chemical class 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- ZSEPOKOVRBPMOH-XLPZGREQSA-N ethyl (1s,3r,4r)-3-azido-4-hydroxycyclohexane-1-carboxylate Chemical compound CCOC(=O)[C@H]1CC[C@@H](O)[C@H](N=[N+]=[N-])C1 ZSEPOKOVRBPMOH-XLPZGREQSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 239000005708 Sodium hypochlorite Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- HIEDNXSBEYNHJB-ZLUOBGJFSA-N (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one Chemical compound Br[C@H]1CC[C@@H]2C(=O)O[C@H]1C2 HIEDNXSBEYNHJB-ZLUOBGJFSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- ZLFZITWZOYXXAW-QXXZOGQOSA-N edoxaban tosylate Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 ZLFZITWZOYXXAW-QXXZOGQOSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- OXKRFEWMSWPKKV-GHTZIAJQSA-N n-[(2s,3r)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzofuran-2-carboxamide Chemical compound C([C@@H]1N2CCC(CC2)[C@H]1NC(=O)C=1OC2=CC=CC=C2C=1)C1=CC=CN=C1 OXKRFEWMSWPKKV-GHTZIAJQSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- VUSWCWPCANWBFG-UHFFFAOYSA-N cyclohex-3-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=CC1 VUSWCWPCANWBFG-UHFFFAOYSA-N 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960005378 edoxaban tosylate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical class O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
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- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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Abstract
Description
技术领域
本发明属于生物催化技术领域,具体涉及一种依度沙班关键中间体及其酶催化制备方法。
背景技术
一水合对甲苯磺酸依度沙班(Edoxaban)是由第一三共株式会社研发的,是一种小分子药物,是一种凝血因子Xa抑制剂。目前该药物最高研发阶段为批准上市,用于治疗肺栓塞,静脉血栓栓塞,中风,静脉血栓形成和栓塞。2011年04月22日,甲苯磺酸依度沙班获得日本医药品与医疗器械局PMDA批准,由第一三共株式会社销售。2015年01月08日,甲苯磺酸依度沙班获得美国食品药品管理局FDA批准,由Daiichi Sankyo Inc销售,商品名为(NDA206316)2015年06月19日,甲苯磺酸依度沙班获得欧洲药品管理局EMA批准,由Daiichi Sankyo Europe Gmbh销售,商品名为(EMEA/H/C/002629)2018年12月25日,甲苯磺酸依度沙班获得中国国家药品监督管理局NMPA批准,由Daiichi SankyoEurope Gmbh销售,商品名为
依度沙班具有三个手性中心共有8种异构体,但是只有一种构型具有较好的活性,依度沙班的结构如下:
日本第一三共株式会社研发,在WO2008156159A1公布其合成路线如下所示。外消旋S-1在手性胺S-2的存在下进行拆分,随后在亲电溴代试剂的作用下,接受分子内亲核进攻得到桥环化合物S-4。S-4经过胺解,再在NH4OH作用下经过环氧丙烷中间体S-6,开环得到氨基醇化合物S-7。S-7随后经过Boc保护氨基,Ms保护醇羟基,NaN3进攻引入N3基团,得到化合物S-10。随后通过氢化还原得到氨基,再和S-13缩合,得到化合物S-14。化合物S-14在酸性条件下脱除Boc保护基,随后和羧酸S-16进行缩合,得到最终化合物S-17,成TsOH盐即可得到依度沙班。该工艺的合成路线如下:
该化合物合成的难点在于化合物S-10一类手性底物的制备。
日本第一三共株式会社在专利CN101263110中公布的合成路线:该路线中叠氮化钠取代甲磺酸酯会出现超过10%的消旋体。该工艺的合成路线如下:
第一三共株式会社在CN105008325A;DOI:10.1021/acs.oprd.8b00413中发表了优化该工艺路线,使用了Burgess试剂,避免了第一代路线中的消旋问题,收率有20%幅度提升;但是该试剂使用过程中放热剧烈,放大过程中放大效应明显。该工艺的合成路线如下:
CN106866452中发表了一种化学法构建胺基手性中心的方法,该方法较难重现,该工艺的合成路线如下:
发明内容
本发明所要解决的技术问题是:提供一种酶催化法制备依度沙班关键中间体的方法。
为了解决上述问题,本发明采取以下技术方案:
一种依度沙班中间体,其结构通式如式Ⅰ或式Ⅱ所示:
其中,R1为OH、烷氧基或N,N-二烷基类基团,R2为氢、烷氧基羰基或其它氨基保护基。
优选地,所述结构通式中,R1为N,N-二甲基或乙氧基,R2为氢、叔丁氧羰基、苄基氧羰基、乙氧基羰基、苄基或苯甲酰基。
本发明还提供了上述依度沙班中间体的制备方法,包括以下步骤:
步骤1):将式Ⅲ化合物通过氧化反应得到式Ⅱ化合物;
步骤1)的工艺路线如下:
步骤2):将式Ⅱ化合物、转氨酶、转氨酶辅酶及磷酸盐缓冲溶液混合进行酶催化反应或进一步经过胺基衍生化反应后,得到式Ⅰ化合物。
步骤2)的工艺路线如下:
优选地,所述步骤1)中的氧化剂为John’s试剂、PCC试剂或TEMPO试剂,优选TEMPO试剂。
优选地,所述步骤2)中的转氨酶选自尚科生物(上海)有限公司的转氨酶酶库。
优选地,所述步骤2)体系中,底物的浓度为10~100g/L;所述转氨酶为湿菌体、液体酶一种或多种形式的结合参与反应;当转氨酶以液体酶的形式加入时,液体酶质量占比为1~20%,反应温度为0~30℃,反应pH值为6.5-7.0,反应时间为12-30h。
优选地,所述步骤2)中,式Ⅱ化合物的浓度为10~100g/L,转氨酶的浓度为5~20g/L,转氨酶辅酶的浓度为1~10mg/L,磷酸盐缓冲液的浓度为10~100mM。
优选地,所述步骤2)中的胺基衍生化反应,得到胺基物后,胺基官能团保护基的特征反应为,直接向酶酶催化反应的反应液中加入保护基试剂后经过反应得到。
优选地,还包括后处理步骤:在步骤2)反应结束的反应液中加入助滤剂,经过滤、萃取、过滤、浓缩、结晶,得到式Ⅰ化合物。
更优选地,所述的助滤剂为硅藻土。
本发明的工艺路线如下:
进一步地,式Ⅲ化合物的制备可以由如下方法得到:
与现有技术相比,本发明的有益效果在于:
本发明提供的酶催化制备式Ⅰ化合物的方法,可以达到较高收率及手性纯度。其中使用少量环境友好型有机溶剂,反应条件温和、工艺操作简单,适合工业化生产。
为了进一步确认本发明所述的关键步骤,即通过转氨酶构建的胺基手性中心的手性构型,本发明将所得的式Ⅰ-2化合物,通过如下衍生后,得到式Ⅴ化合物,并通过实验得到式Ⅴ化合物的单晶X衍射图谱,进一步确认本发明所得的关键中间体的绝对构型正确的。
附图说明
图1为式Ⅴ化合物((1R,2S,5S)-2-(((苄氧基)羰基)氨基)-5-(二甲基氨基甲酰基)环己基)-l4-氮甲酸叔丁酯的HPLC谱图;
图2为式Ⅴ化合物((1R,2S,5S)-2-(((苄氧基)羰基)氨基)-5-(二甲基氨基甲酰基)环己基)-l4-氮甲酸叔丁酯及其手性异构体的HPLC谱图;
图3为式Ⅴ化合物((1R,2S,5S)-2-(((苄氧基)羰基)氨基)-5-(二甲基氨基甲酰基)环己基)-l4-氮甲酸叔丁酯的单晶X衍射谱图。
具体实施方式
为使本发明更明显易懂,兹以优选实施例,并配合附图作详细说明如下。
实施例1(1S,4S,5S)-4-溴-6-氧杂双环[3.2.1]辛烷-7-酮(Ⅳ)的制备
向反应瓶中,依次加入(S)-3-环己烯甲酸(126.2g,1.0mol),200mL水和氢氧化钾(41g,1.05mol);反应体系搅拌下降温至-10℃左右,缓慢加入NBS(196g,1.1mol),加毕,保持反应体系的温度在-5~5℃左右继续搅拌反应1小时;TLC监控反应安全后,加入亚硫酸钠(25.2g,0.2mol)搅拌反应0.5小时后过滤得到化合物Ⅲ,198.8g,收率97%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,Chloroform-d)δ4.79(d,J=5.1Hz,1H),4.39(d,J=4.7Hz,1H),2.65(d,J=12.3Hz,2H),2.46-2.35(m,1H),2.35-2.27(m,1H),2.13(dd,J=16.4,5.4Hz,1H),1.93(dt,J=12.9,5.5,2.2Hz,1H),1.84(dt,J=12.1,11.0,4.9,3.1Hz,1H)。
一锅法制备系列化合物Ⅲ的方法,以R为OCH2CH3和N(CH3)2为代表。
实施例2(1S,3R,4R)-3-叠氮-4-羟基环己烷-1-羧酸乙酯(Ⅲ-1)制备
向100mL三口瓶中分别加入化合物Ⅳ(20.5g,0.1mol)和20mL乙醇,冷却至0~5℃,缓慢向上述反应体系中加入乙醇钠(10.2g,0.15mol),保温0~5℃搅拌反应1~2小时;加入向上述反应体系中30mL水和叠氮化钠(9.7g,0.15mol),升至15~20℃搅拌反应3小时,加入50mL二氯甲烷分液,二氯甲烷层减压浓缩除去二氯甲烷,得到化合物Ⅲ-1(18.7g),收率88.4%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ4.16(dd,J=7.2,1.2Hz,2H),3.52(dt,J=24.7,8.5,4.0Hz,2H),2.72(d,J=4.8Hz,1H),2.59-2.48(m,1H),2.36(dt,J=14.0,4.4Hz,1H),2.14-2.05(m,1H),1.95-1.85(m,1H),1.63-1.46(m,3H),1.26(dt,J=8.9,5.1,1.4Hz,3H)。
实施例3(1S,3R,4R)-3-叠氮-4-羟基-N,N-二甲基环己烷-1-甲酰胺(Ⅲ-2)的制备
化合物Ⅳ(20.5g,0.1mol)和20mL乙腈加入250mL三口瓶中,冷却至0~5℃,加入40%二甲胺水溶液(16.8g,0.15mol),保温0~5℃搅拌反应10~11小时;减压蒸出二甲胺和乙腈,加入30mL水和氢氧化钠(6g,0.15mol)0~10℃下搅拌反应5~6小时;称取叠氮化钠(9.7g,0.15mol)加至体系中,升至15~20℃搅拌反应3~4小时,加入50mL二氯甲烷分液,二氯甲烷层减压浓缩除去二氯甲烷,得到化合物Ⅲ-1(19.1g),收率90.1%。所得产物的核磁共振氢谱数据如下:
1HNMR(400MHz,CDCl3)δ3.98(dd,J=10.0,6.0Hz,1H),3.64(s,1H),3.43(s,1H),3.03(s,3H),2.91(s,3H),2.88(d,J=3.9Hz,1H),2.23-2.09(m,1H),1.95-1.77(m,2H),1.76-1.65(m,1H),1.54(dt,J=16.4,5.8Hz,2H);13C NMR(101MHz,CDCl3)δ174.93,69.31,62.25,37.34,35.70,34.58,29.01,28.11,23.48。
实施例4(1S,3R)-3-叠氮-4-氧代环己烷-1-羧酸乙酯(Ⅱ-1)的制备
化合物Ⅲ-1(2.1g,0.01mol)、碳酸氢钠(1.9g,0.02mol),溴化钠(0.1g,0.001mol)和TEMPO(0.08g,4%,w/w)加至100mL三口瓶中,加入二氯甲烷15mL搅拌溶解,并降温至-5~0℃,称取次氯酸钠水溶液(15.8g,0.015mol)缓慢滴加至反应体系中,保持温度不超过0℃;滴加完毕后继续搅拌0.5~1.0小时,静置分液,二氯甲烷层减压浓缩去除溶剂后得到化合物Ⅱ-1(1.9g),收率90.5%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ4.16(dd,J=7.2,1.2Hz,2H),3.9(d,J=4.8Hz,1H),2.72(d,J=4.8Hz,1H),2.36(dd,J=14.0,4.4Hz,1H),2.14-2.05(m,1H),1.95-1.85(m,1H),1.63-1.46(m,3H),1.26(dd,J=8.9,5.1,1.4Hz,3H);13C NMR(125MHz,CDCl3)δ209.75,174.15,60.85,59.37,39.24,36.44,34.75,27.08,14.26。
实施例5(1S,3R)-3-叠氮-N,N-二甲基-4-氧环己烷-1-甲酰胺(Ⅱ-2)的制备
化合物Ⅲ-2(2.1g,0.01mol)、碳酸氢钠(1.9g,0.02mol),溴化钠(0.1g,0.001mol)和TEMPO(0.08g,4%,w/w)加至100mL三口瓶中,加入二氯甲烷15mL搅拌溶解,并降温至-5~0℃,称取次氯酸钠水溶液(15.8g,0.015mol)缓慢滴加至反应体系中,保持温度不超过0℃;滴加完毕后继续搅拌0.5~1.0小时,静置分液,二氯甲烷层减压浓缩去除溶剂后得到化合物Ⅱ-2(1.8g),收率86.5%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ4.68-4.56(m,1H),3.17(dd,J=11.2,6.7Hz,1H),3.07(s,3H),2.95(s,3H),2.76-2.63(m,1H),2.49(dd,J=11.7,4.9Hz,1H),2.32(dd,J=13.4,5.5Hz,1H),2.14-2.02(m,1H),2.02-1.91(m,1H),1.91-1.79(m,1H);13CNMR(101MHz,CDCl3)d 205.55,173.40,63.68,37.21,37.06,35.27,34.27,33.94,27.86。
实施例6(1S,3R,4S)-4-氨基-3-叠氮杂环己烷-1-羧酸乙酯(Ⅰ-1)的制备
Ⅱ-1(5g),PBS缓冲液(pH 7.0,1M,50mL)、水(350mL)、PLP(2.6mg,5.3mg/L)、异丙胺(100mL,50g/L)和ATA101(5.0g),加至500mL反应瓶中,25~30℃机械搅拌反应25~30小时;反应完毕后硅藻土过滤,母液用二氯甲烷萃取得到化合物Ⅰ-1(4.3g),收率86.5%。
实施例7(1S,3R,4S)-4-氨基-3-叠氮-N,N-二甲基环己烷-1-甲酰胺(Ⅰ-2)的制备
Ⅱ-2(5g),PBS缓冲液(pH 7.0,1M,50mL)、水(350mL)、PLP(2.6mg,5.3mg/L)、异丙胺(50mL,100g/L)和ATA101(5.0g),加至500mL反应瓶中,25~30℃机械搅拌反应25~30小时;反应完毕后硅藻土过滤,母液用二氯甲烷萃取得到化合物Ⅰ-2。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ3.82(d,J=2.3Hz,1H),2.99(s,3H),2.85(s,3H),2.79-2.63(m,2H),1.92(dd,J=14.3,2.7Hz,1H),1.87-1.72(m,1H),1.72-1.56(m,2H),1.54-1.18(m,4H)。13C NMR(101MHz,CDCl3)δ174.62,64.49,52.00,37.08,35.53,33.66,32.15,30.05,27.55。
实施例8(1S,3R,4S)-3-叠氮-4-(叔丁氧羰基)氨基)环己烷-1-羧酸乙酯的制备
Ⅰ-1(2.1g,10mmol)、Boc2O(2.6g,12mmol)、碳酸钾(2.1g,15mmol)和50mL水一次性加入至100mL三口瓶中,升温至40~50℃,搅拌反应3~4小时,白色固体析出,减压抽滤得到化合物Ⅰ-3 2.8g,收率90%。
实施例9((1S,2R,4S)-2-叠氮-4-(二甲基氨基甲酰基)环己基)氨基甲酸叔丁酯的制备
Ⅰ-2(2.1g,10mmol)、Boc2O(2.6g,12mmol)、碳酸钾(2.1g,15mmol)和50mL水一次性加入至100mL三口瓶中,升温至40~50℃,搅拌反应3~4小时,白色固体析出,减压抽滤得到化合物Ⅰ-3 2.9g,收率94%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ4.87(d,J=7.2Hz,1H),4.03(s,1H),3.54(s,1H),2.95(s,3H),2.82(s,3H),2.70(t,J=11.1Hz,1H),1.85(dd,J=31.3,13.5Hz,2H),1.66(t,J=13.1Hz,2H),1.57–1.40(m,2H),1.33(s,9H)。13C NMR(101MHz,CDCl3)δ174.20,154.89,79.42,61.16,50.94,37.00,35.48,33.51,31.83,28.24,27.41,26.40。
实施例10((1S,2R,4S)-2-叠氮-4-(二甲基氨基甲酰基)环己基)氨基甲酸甲酯的制备
Ⅰ-2(2.0g),向其中加入2-甲基四氢呋喃(80mL),加入碳酸氢钠(1.6g,2.0eq),室温搅拌下向体系中加入氯甲酸甲酯(1.2g,1.3eq),保温搅拌2~3小时,TLC检测原料转化完毕,滤去不溶物,2-甲基四氢呋喃洗涤滤饼,滤液进行分液,浓缩有机相,PE/EA重结晶得白色固体Ⅰ-5,收率84%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ4.87(d,J=8.5Hz,1H),4.13(d,J=4.2Hz,1H),3.69(s,4H),3.08(s,3H),2.96(s,3H),2.83(d,J=11.7,3.6Hz,1H),2.09-1.92(m,2H),1.84-1.75(m,2H),1.67-1.45(m,2H)。
实施例11((1S,2R,4S)-2-叠氮-4-(二甲基氨基甲酰基)环己基)氨基甲酸苄酯的制备
Ⅰ-2(2.0g),向其中加入2-甲基四氢呋喃(80mL),加入碳酸氢钠(1.6g,2.0eq),室温搅拌下向体系中加入氯甲酸苄酯(2.1g,1.3eq),保温搅拌2~3小时,TLC检测原料转化完毕,滤去不溶物,2-甲基四氢呋喃洗涤滤饼,滤液进行分液,浓缩有机相,PE/EA重结晶得白色固体Ⅰ-6,收率86%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,CDCl3)δ7.41-7.30(m,5H),5.12(s,2H),4.95(d,J=8.5Hz,1H),4.14(s,1H),3.83-3.69(m,1H),3.08(s,3H),2.96(s,3H),2.90-2.75(m,1H),2.10-1.91(m,2H),1.81(d,J=12.6Hz,2H),1.69(s,1H),1.58-1.46(m,1H)。
实施例12((1R,2S,5S)-2-(((苄氧基)羰基)氨基)-5-(二甲基氨基甲酰基)环己基)-l4-氮甲酸叔丁酯的制备
Ⅰ-6(1.05g),向其中加入三苯基膦(2.4g,3.0eq),四氢呋喃(30mL),去离子水(7mL),反应完毕后向其中加入1N HCl,调节pH=2-3,浓缩去除四氢呋喃,二氯甲烷萃取水相,保留水相,通过加入氢氧化钠调节水相pH=8~9,加入Boc酸酐(1.0g,1.5eq)搅拌过夜,抽滤水洗得白色固体Ⅴ,收率85%。所得产物的核磁共振氢谱数据如下:
1H NMR(400MHz,cdcl3)δ7.38–7.26(m,5H),5.22(s,1H),5.09(t,J=10.3Hz,2H),4.12(s,1H),3.70(s,1H),3.02(s,3H),2.92(s,3H),2.62(s,1H),1.99(d,J=37.6Hz,2H),1.72(d,J=18.7Hz,5H),1.43(s,9H).
Claims (10)
2.如权利要求1所述的依度沙班中间体,其特征在于,所述结构通式中,R1为N,N-二甲基或乙氧基,R2为氢、叔丁氧羰基、苄基氧羰基、乙氧基羰基、苄基或苯甲酰基。
4.如权利要求3所述的依度沙班中间体的制备方法,其特征在于,所述步骤1)中的氧化剂为John’s试剂、PCC试剂或TEMPO试剂。
5.如权利要求3所述的制备方法,其特征在于,所述步骤2)中的转氨酶选自尚科生物(上海)有限公司的转氨酶酶库。
6.如权利要求3所述的制备方法,其特征在于,所述步骤2)体系中,底物的浓度为10~100g/L;所述转氨酶为湿菌体、液体酶一种或多种形式的结合参与反应;当转氨酶以液体酶的形式加入时,液体酶质量占比为1~20%,反应温度为0~30℃,反应pH值为6.5-7.0,反应时间为12-30h。
7.如权利要求3所述的制备方法,其特征在于,所述步骤2)中,式Ⅱ化合物的浓度为10~100g/L,转氨酶的浓度为5~20g/L,转氨酶辅酶的浓度为1~10mg/L,磷酸盐缓冲液的浓度为10~100mM。
8.如权利要求3所述的制备方法,其特征在于,所述步骤2)中的胺基衍生化反应,得到胺基物后,胺基官能团保护基的特征反应为,直接向酶酶催化反应的反应液中加入保护基试剂后经过反应得到。
9.如权利要求3所述的制备方法,其特征在于,还包括后处理步骤:在步骤2)反应结束的反应液中加入助滤剂,经过滤、萃取、过滤、浓缩、结晶,得到式Ⅰ化合物。
10.如权利要求9所述的制备方法,其特征在于,所述的助滤剂为硅藻土。
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