CN115594591A - 一种催化不对称氢化制备哌仑他韦中间体的方法 - Google Patents
一种催化不对称氢化制备哌仑他韦中间体的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 16
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 6
- -1 transition metal salt Chemical class 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 12
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 6
- 238000011914 asymmetric synthesis Methods 0.000 claims abstract description 3
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 230000000536 complexating effect Effects 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- YLQBEKUKMJWXMC-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-ylphosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.P[c-]1cccc1 YLQBEKUKMJWXMC-UHFFFAOYSA-N 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000005394 methallyl group Chemical group 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 150000003624 transition metals Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- FSJSYDFBTIVUFD-XHTSQIMGSA-N (e)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C/C(C)=O.C\C(O)=C/C(C)=O FSJSYDFBTIVUFD-XHTSQIMGSA-N 0.000 claims description 2
- VNNDVNZCGCCIPA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;manganese Chemical compound [Mn].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O VNNDVNZCGCCIPA-FDGPNNRMSA-N 0.000 claims description 2
- SJBBXFLOLUTGCW-UHFFFAOYSA-N 1,3-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(C(F)(F)F)=C1 SJBBXFLOLUTGCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 2
- 229910018286 SbF 6 Inorganic materials 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 claims description 2
- 229930007927 cymene Natural products 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000010668 complexation reaction Methods 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 150000002009 diols Chemical class 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
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- VJYSBPDEJWLKKJ-NLIMODCCSA-N methyl n-[(2s,3r)-1-[(2s)-2-[6-[(2r,5r)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl]-5-[6-fluoro-2-[(2s)-1-[(2s,3r)-3-methoxy-2-(methoxycarbonylamino)butanoyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]pyrrolidin-2-yl]-5-fluoro-1h-benzimidazol-2 Chemical compound COC(=O)N[C@@H]([C@@H](C)OC)C(=O)N1CCC[C@H]1C1=NC2=CC(F)=C([C@@H]3N([C@H](CC3)C=3C(=CC=4N=C(NC=4C=3)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)F)C=3C=C(F)C(N4CCC(CC4)C=4C=CC(F)=CC=4)=C(F)C=3)C=C2N1 VJYSBPDEJWLKKJ-NLIMODCCSA-N 0.000 description 8
- 229950007513 pibrentasvir Drugs 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000004696 coordination complex Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 101800001014 Non-structural protein 5A Proteins 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- OGCGXUGBDJGFFY-INIZCTEOSA-N diphenyl-[(2s)-pyrrolidin-2-yl]methanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)[C@@H]1CCCN1 OGCGXUGBDJGFFY-INIZCTEOSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 229960003760 florfenicol Drugs 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl analogues
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- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
- B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/842—Iron
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明公开了一种催化不对称氢化制备哌仑他韦中间体的方法,具体为通过过渡金属盐/手性膦配体催化体系,经过不对称氢化反应,实现哌仑他韦手性二醇中间体的不对称合成。该方法步骤简单,操作简便,条件温和,反应迅速,污染小,效率高,为高效绿色不对称氢化合成哌仑他韦提供了新的方法,具有巨大的工业应用价值。
Description
技术领域
本发明属于医药化学合成领域,具体涉及一种催化不对称氢化制备哌仑他韦中间体的方法。
背景技术
哌仑他韦(Pibrentasvir/ABT-530),CAS:1353900-92-1,分子式:C57H65F5N10O8,分子量: 1113.18,化学名称:{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-二氟-4-[4-(4-氟苯基)哌啶-1- 基]苯基-5-(6-氟-2-(2S)-1-[N-(甲氧羰基)-O-甲基-L-苏氨酰基]吡咯烷-2-基}-1H-苯并咪唑-5-基)吡咯烷-2-基]6-氟-1H-苯并咪唑-2-基}吡咯烷-1-基]-3-甲氧基-1-氧代丁-2-基}氨基甲酸甲酯,结构式为:
哌仑他韦(Pibrentasvir/ABT-530)主要用于治疗无肝硬化或代偿性肝硬化的慢性HCV基因型感染,属于NS5A抑制剂,对来自基因型1至6含有NS5A的HCV复制子的EC50范围为1.4至5.0pM。HCV患者按疗程服用后,病毒学治愈率高达98%。哌仑他韦由美国艾伯维(AbbVie)公司研发,于2017年7月26日获欧洲药物管理局(EMA)批准上市,后于 2017年8月3日获美国食品药品管理局(FDA)批准上市,后又于2017年9月27日获得日本医药品医疗器械综合机构批准上市,又于2019年5月15日获得国家药品监督管理局 (NMPA)批准,商品名为2018及2019两年取得3,438 百万美元及2,893百万美元的销售额,是全球最为畅销的DAA药物(即直接抗病毒小分子药物)之一。据最新国际权威丙肝治疗指南,包括2018年EASL和2018年AASLD,该方案是目前泛基因型方案中唯一可实现初治、无肝硬化患者8周短疗程治愈的方案。
目前文献报道(J.Med.Chem.2018,61,4052-4066)的合成哌仑他韦手性醇中间体的方法需要使用17%的手性辅剂(R)-(+)-α,α-二苯基脯氨醇控制羰基还原后的手性(见下式),大量手性辅基的使用使哌仑他韦的生产成本居高不下。
另有使用Co催化剂进行不对称催化氢化反应,可能可以手性还原哌仑他韦二酮中间体的文献报道(Synthesis2004,No.9,1434–1438),但手性催化剂的用量至少也大于1.5mol%,且产率和手性控制效率不高。
当前如何绿色高效合成单一构型的手性二醇中间体是更加有效合成哌仑他韦的关键所在。
发明内容
本发明为哌仑他韦(Pibrentasvir/ABT-530)的合成提供了一种新的高效绿色的合成方法。
本发明是通过以下技术方案实行的。
本发明提出了合成哌仑他韦关键中间体手性二醇的制备的新方案。
在氢气氛围下,由手性膦配体与过渡金属盐络合得到的催化剂的存在下,加入哌仑他韦二酮中间体1,发生不对称氢化反应,该方法能够一步将两个羰基不对称氢化还原,形成两个手性中心,可以很好地控制反应产率及手性,从而高效绿色地实现哌仑他韦手性二醇中间体2的不对称合成。
所述手性膦配体包括但不限于下述的化合物f-amphox、f-ampha、f-amphol、f-amphamide、 O-SpiroPAP:
上述结构式中R表示甲基、异丙基、叔丁基、苯基、苄基或其它任意的C1-C6的直链或支链或环状取代基,优选为甲基,异丙基,进一步优选为异丙基;Ar表示苯基、4-甲基苯基、4-甲氧基苯基、3,5-二甲基苯基、3,5-二甲基-4-甲氧基苯基、3,4,5-三甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基-4-甲氧基、3,5-二叔丁基-4-甲基,优选为苯基,3,5-二甲基苯基,进一步优选为苯基。
不对称氢化反应的反应温度为20~120℃,优选后为20~70℃,进一步优选为20~50℃。氢气压力为10~60大气压,优选后为10~50大气压,进一步优选为20~40大气压。反应时间为2~120小时,优选后为6~24小时,进一步优选为8~18小时。
不对称氢化反应所用溶剂优选二氯甲烷,甲醇,乙醇,异丙醇,四氢呋喃,乙酸乙酯,甲基叔丁基醚等,进一步优选为异丙醇。
所述催化剂由手性二茂铁膦配体与过渡金属盐在iPrOH中络合得到;所述过渡金属盐与手性二茂铁膦配体的摩尔比为0.5:1.0~1.2,络合反应温度为室温,络合时间为1~3小时。
所述络合得到的催化剂不进行分离,直接用于催化不对称氢化反应。
所述的过渡金属盐包括:
(Rh(NBD)2)+BF4 -;[Rh(NBD)Cl]2;[Rh(COD)Cl]2;[Rh(COD)2]X;Rh(acac)(CO)2; Rh(ethylene)2(acac);(Rh(ethylene)2Cl)2;RhCl(PPh3)3;Rh(CO)2Cl2;RuHX(L)2(diphosphine);RuX2(L)2(diphosphine),Ru(arene)X2(diphosphine);Ru(arylgroup)X2;Ru(RCOO)2(diphosphine); Ru(methallyl)2(diphosphine);Ru(arylgroup)X2(PPh3)3;Ru(COD)(COT);Ru(COD)(COT)X; RuX2(cymene);Ru(COD)n;Ru(arylgroup)X2(diphosphine);RuCl2(COD);(Ru(COD)2)X; RuX2(diphosphine);RuCl2(=CHR)(PR'3)2;Ru(ArH)Cl2;Ru(COD)(methallyl)2;(Ir(NBD)2Cl)2; (Ir(NBD)2)X;(Ir(COD)Cl)2;Ir(COD))X;Ni(acac)2;NiX2;(Ni(allyl)X)2;Ni(COD)2;MoO2(acac)2; Ti(O-iPr)4;VO(acac)2;MeReO3;MnX2;Mn(acac)2。
在以上的过渡金属络合物中,R和R'可分别为烷基、烷氧基或取代烷基,aryl为芳基, Ar可为3,5-二三氟甲基苯或氟苯。X为平衡阴离子,如BF4 -,ClO4 -,SbF6 -,PF6 -,CF3SO3 -,RCOO-,B(C6H3(CF3)2)4 -,Cl-,Br-,I-。L为溶剂,如四氢呋喃等。
值得注意的是,氢化产物只需除去溶剂,即可直接进行后续的反应,再进行常规的后处理便可以高产率、高光学纯度得到哌仑他韦。
总之,上述技术方案具有操作简单、反应快速、成本低廉同时转化率和选择性都极高,以及原子经济性,环境友好的特点,具有极高的工业化价值。采用过渡金属盐/手性二茂铁膦配体的三齿配体催化剂体系,其高度的稳定性和反应活性,能够改善或克服因产物对催化剂金属中心配位导致的催化剂失活情况的发生。与目前的其他技术相比,工艺更为先进。另合成路线短,中间产物及废料产生明显减少,高效绿色,适宜工业化放大生产。
以下通过具体实施例对本发明的哌仑他韦二醇中间体化合物的合成方法的技术效果做进一步的说明。
具体实施方法
实施例:
催化剂金属络合物的合成:
在手套箱中,称取(R)-f-amphox(8.3mg,0.011mmol,2.2equiv),[Ir(COD)Cl]2(3.4mg,0.005 mmol,1equiv),加入1mL超干异丙醇,室温搅拌1小时,配制成浓度为0.01mol/L的催化剂金属络合物;
以底物和催化剂的摩尔比S/C=2000为例:
在手套箱中,称取底物433mg,1mmol),加入Cs2CO3(32.5mg,0.10mmol),10mL异丙醇(浓度0.1mol/L),室温搅拌1小时,使底物和碱充分溶解。在手套箱中,用微量注射器向底物溶液中加入上述催化剂金属络合物(50μL,5×10-4mmol),随后将该反应瓶转移到高压釜内,拧紧反应釜,将釜移出手套箱。用20atmH2置换釜体三次后向高压釜内充入60atmH2随即关紧进气阀,在室温搅拌12小时后,结束反应。在通风橱内,打开放气阀缓慢放尽釜体中的氢气。经过简单纯化即得到氟苯尼考中间体化合物产物433mg,收率99%,用液相色谱分析反应液,e.e.值>99%,d.r.值>100:1。
以上所述仅为本发明的优选而已,并不用于限制本发明,对于本领域的技术人员来说,本发明包括但不限于在反应温度、反应时间等具体实施条件上可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.催化不对称氢化制备哌仑他韦中间体的方法,其特征在于:
在氢气氛围下,在由手性膦配体与过渡金属盐在溶剂中络合得到的催化剂的作用下,哌仑他韦中间体1,通过不对称氢化反应,实现哌仑他韦手性醇中间体2的不对称合成;
所述手性膦配体包括但不限于下述的化合物f-amphox、f-ampha、f-amphol、f-amphamide、O-SpiroPAP:
上述结构式中R表示甲基、异丙基、叔丁基、苯基、苄基或其它任意的C1-C6的直链或支链或环状取代基;Ar表示苯基、4-甲基苯基、4-甲氧基苯基、3,5-二甲基苯基、3,5-二甲基-4-甲氧基苯基、3,4,5-三甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基-4-甲氧基、3,5-二叔丁基-4-甲基;
以及上式仅列举了膦配体的一种立体构型,包括且不限于该化合物的其他异构体也均应包含在本发明的保护范围之内。
2.根据权利要求1所述的方法,其特征在于,所述溶剂为甲醇、乙醇、异丙醇、二氯甲烷、四氢呋喃、甲苯、1,2-二氯乙烷中的一种或几种。
3.根据权利要求1所述的制备方法,其特征在于,所述不对称氢化反应的反应温度为20~120℃,氢气压力为10~60大气压,反应时间为1~120小时。
4.根据权利要求2所述的方法,其特征在于,所述催化剂由手性二茂铁膦配体与过渡金属盐在溶剂中络合得到;所述过渡金属盐与手性二茂铁膦配体的摩尔比为0.5:1.0~1.2,络合反应温度为室温,络合反应时间为1~3小时。
5.根据权利要求4所述的方法,其特征在于,络合得到的催化剂不进行分离,直接用于催化不对称氢化反应。
6.根据权利要求1至5任一所述的方法,其特征在于,所述的过渡金属包括:Ru,Ir,Fe,Co,Rh,Ti,V,Re和Mn;合适的过渡金属络合物包括:
(Rh(NBD)2)+BF4 -;[Rh(NBD)Cl]2;[Rh(COD)Cl]2;[Rh(COD)2]X;Rh(acac)(CO)2;Rh(ethylene)2(acac);(Rh(ethylene)2Cl)2;RhCl(PPh3)3;Rh(CO)2Cl2;RuHX(L)2(diphosphine);RuX2(L)2(diphosphine),Ru(arene)X2(diphosphine);Ru(arylgroup)X2;Ru(RCOO)2(diphosphine);Ru(methallyl)2(diphosphine);Ru(arylgroup)X2(PPh3)3;Ru(COD)(COT);Ru(COD)(COT)X;RuX2(cymene);Ru(COD)n;Ru(arylgroup)X2(diphosphine);RuCl2(COD);(Ru(COD)2)X;RuX2(diphosphine);RuCl2(=CHR)(PR'3)2;Ru(ArH)Cl2;Ru(COD)(methallyl)2;(Ir(NBD)2Cl)2;(Ir(NBD)2)X;(Ir(COD)Cl)2;Ir(COD))X;Ni(acac)2;NiX2;(Ni(allyl)X)2;Ni(COD)2;MoO2(acac)2;Ti(O-iPr)4;VO(acac)2;MeReO3;MnX2;Mn(acac)2;
在以上的过渡金属络合物中,R和R'可分别为烷基、烷氧基或取代烷基,aryl为芳基,Ar可为3,5-二三氟甲基苯或氟苯;X为平衡阴离子,如BF4 -,ClO4 -,SbF6 -,PF6 -,CF3SO3 -,RCOO-,B(C6H3(CF3)2)4 -,Cl-,Br-,I-;L为溶剂,如四氢呋喃等。
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