CN106478429B - 一种合成手性反式茚胺醇的方法 - Google Patents
一种合成手性反式茚胺醇的方法 Download PDFInfo
- Publication number
- CN106478429B CN106478429B CN201610886608.8A CN201610886608A CN106478429B CN 106478429 B CN106478429 B CN 106478429B CN 201610886608 A CN201610886608 A CN 201610886608A CN 106478429 B CN106478429 B CN 106478429B
- Authority
- CN
- China
- Prior art keywords
- trans
- indenes
- synthesis
- amine alcohol
- chiral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000002469 indenes Chemical class 0.000 title claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 150000001412 amines Chemical class 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 18
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 18
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 amine alcohols Chemical class 0.000 claims abstract description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000005194 fractionation Methods 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical group [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 claims description 2
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 claims description 2
- VWKWTYFNIQRCMT-UHFFFAOYSA-M [Cl-].C(C1=CC=CC=C1)[NH3+].C(CCCCCCCCCCCCCCC)[N+](CC1=CC=CC=C1)(C)C.[Cl-] Chemical compound [Cl-].C(C1=CC=CC=C1)[NH3+].C(CCCCCCCCCCCCCCC)[N+](CC1=CC=CC=C1)(C)C.[Cl-] VWKWTYFNIQRCMT-UHFFFAOYSA-M 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 229940011051 isopropyl acetate Drugs 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 abstract description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- 229960002510 mandelic acid Drugs 0.000 abstract description 2
- 239000004593 Epoxy Substances 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006735 epoxidation reaction Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- CBSOFSBFHDQRLV-UHFFFAOYSA-N N-methylbenzylamine hydrochloride Chemical compound [Cl-].C[NH2+]CC1=CC=CC=C1 CBSOFSBFHDQRLV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- 238000005360 mashing Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- MVODTGURFNTEKX-UHFFFAOYSA-N 2-bromo-n-(2-bromoethyl)-n-(thiophen-2-ylmethyl)ethanamine;hydrobromide Chemical compound Br.BrCCN(CCBr)CC1=CC=CS1 MVODTGURFNTEKX-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 240000005809 Prunus persica Species 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- RGSUDMCOVHKEHB-UHFFFAOYSA-N butan-1-amine;oxalic acid Chemical class CCCCN.OC(=O)C(O)=O RGSUDMCOVHKEHB-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- SXPWTBGAZSPLHA-UHFFFAOYSA-M cetalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SXPWTBGAZSPLHA-UHFFFAOYSA-M 0.000 description 1
- 229960000228 cetalkonium chloride Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical class C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- 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
-
- 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
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种合成手性反式茚胺醇的方法。以茚为原料,采用钨酸钠/相转移催化剂/双氧水体系反应环氧化,接着再与苄胺反应,经过扁桃酸拆分,氢化后得到≥98%ee反式茚胺醇。该方法使用原料简单易得,操作方便,相对以往的拆分方法,更容易实现放大生产。
Description
技术领域
本发明涉及一种合成手性反式茚胺醇的方法,属于药物中间体有机合成领域。
背景技术
茚胺醇包括顺式和反式两种非对映体结构,每种非对映体又各自包括两种对映异构体,作为重要的医药原料中间体,可以用来作为叔丁基亚磺酰胺的手性配体(顺式)或是用来合成毒蕈碱受体激动剂、支气管扩张药和降压药、钾离子通道调节剂或多药耐受性蛋白抑制剂等(反式)。目前的合成方法多集中在对于手性顺式茚胺醇的合成上,手性反式茚胺醇的合成研究相对较少。已有的合成方法主要包括:从茚出发,先进行环氧化,随后氨水开环(或叠氮化钠开环,随后还原),最后经过拆分得到手性的反式茚胺醇。
其中,环氧化步骤主要有两大类:第一种,直接环氧化,都是以茚为起始原料:采用铁催化剂,在新制备的四丁胺草酸盐存在下环氧化,参考Catalysis Communications,2011, 12, 761-765;采用Mn络合物为催化剂,在二乙酰氧碘苯条件下环氧化,参考European Journal of Inorganic Chemistry, 2013, 2657-2664;或是采用市售的羰基咪唑,在水性溶剂中,温和的酸性或碱性条件下,采用双氧水为氧化剂环氧化,参考Journalof Organic Chemistry, 1998, 63, 2564-2573。第二种,采用茚为原料,先经过NBS生成非对映异构体反式羟基溴,然后碱性条件下分子内关环得到环氧化合物。以上方法都存在原料不易获得,反应条件复杂,步骤多,或是所用试剂价格较贵的缺点。
尽管最直接的方法就是采用反式茚胺醇消旋体进行直接拆分后得到,但经过尝试,常见的拆分试剂酒石酸、DBTA、樟脑磺酸、扁桃酸与之1:1成盐时等都不能有效地取得良好的对映选择性,从而进一步获得对映醇的反式茚胺醇。其中效果最好的为DBTA成盐拆分,可以达到35%收率和78%ee但不能够通过重结晶再次提高Ee值(参考:Advanced Synthesisand Catalysis, 2005, 347, 255–265),使得该方法不具备实用性。
发明内容
为了克服上述缺陷,本发明公开了一种合成手性反式茚胺醇的方法,以茚和苄胺为原料,采用钨酸钠/相转移催化剂/双氧水体系反应生成反式苄基氨基醇,采用半当量扁桃酸(简称MA)拆分,氢化后得到≥98%ee反式茚胺醇。
一种手性反式茚胺醇的合成方法,其特征在于包括以下步骤:
第一步、将茚和苄胺混合后,再加入相转移催化剂和钨酸钠,升温至50-80℃,滴加20-25%双氧水,随后升温至80-100℃继续反应,得到反式苄基氨基醇;
第二步、将0.45-0.50当量扁桃酸与溶剂混合,滴加入第一步得到的反式苄基氨基醇与溶剂中,进行成盐拆分,游离后得到≥98%ee反式苄基氨基醇;
第三步、将第二步得到的≥98%ee反式苄基氨基醇加入钯碳和溶剂,升温至60-80℃通氢气加压反应得到≥98%ee反式茚胺醇。
进一步地,在上述技术方案中,第一步中,相转移催化剂选自十二烷基二甲基苄基氯化铵、十四烷基二甲基苄基氯化铵或十六烷基二甲基苄基氯化铵。
进一步地,在上述技术方案中,第一步中,茚、苄胺、相转移催化剂、钨酸钠和双氧水摩尔比为1-1.1:1:0.01-0.02:0.01-0.02: 1-1.2。
进一步地,在上述技术方案中,第二步中,拆分溶剂选自乙酸甲酯、乙酸乙酯或乙酸异丙酯。
进一步地,在上述技术方案中,第三步中,反应溶剂为甲醇、乙醇或乙酸乙酯,反应压力为0.6-0.8MPa;钯碳选自5%或10%,加入量为原料重量的2-5%。
发明的有益效果
本发明所采用技术方案中,原料易得,连续性强,克服了文献直接拆分法不能得到对映纯化合物的不足,提供了一种获得对映纯反式茚胺醇的补充方案。
具体实施方案
实施例1
将茚(116g,1.0mol)和苄胺(104g,0.97mol)混合后,向体系内再加入十四烷基二甲基苄基氯化铵(简称TDBAC,3.7g,0.01mol)和钨酸钠(2.9g,0.01mol),升温至50℃,滴加25%双氧水(1.1mol),滴加过程中控温在50-55℃,滴加结束后,接着升温至90-95℃搅拌反应1小时。降温至40℃,加入860mL乙酸乙酯两次萃取后,弃去水层,有机层外标折算含有产品190g,收率82%。
向上述有机层中,缓慢滴加(S)-MA(59.3g,0.39mol)溶解在220mL乙酸乙酯的溶液,滴加过程中逐渐有固体析出,滴加完毕,搅拌反应2小时。过滤得到固体,加入二氯甲烷450mL,控温不超过20℃,加入氢氧化钠调pH=10-11。分液,水层采用220mL二氯甲烷再萃取2次,合并有机层,无水硫酸镁干燥,过滤旋蒸后得到类白色固体34.5克,收率37%,98.2%ee。该固体加入250mL乙醇和5%钯碳1.70g,通氢气至0.8MPa,升温至60-65℃反应过夜,过滤掉钯碳,溶剂蒸干后,正庚烷打浆后得到20.0克(1R,2R)-茚胺醇,收率93%,98.4%ee,HNMR符合。
实施例2
将茚(116g,1.0mol)和苄胺(104g,0.97mol)混合后,向体系内再加入十四烷基二甲基苄基氯化铵(简称TDBAC,7.4g,0.02mol)和钨酸钠(5.8g,0.02mol),升温至50℃,滴加25%双氧水(1.1mol),滴加过程中控温在50-55℃,滴加结束后,接着升温至90-95℃搅拌反应1小时。降温至40℃,加入660mL乙酸异丙酯两次萃取后,弃去水层,有机层外标折算含有产品190g,收率82%。
向上述有机层中,缓慢滴加(S)-MA(59.3g,0.39mol)溶解在400mL乙酸异丙酯的溶液,滴加过程中逐渐有固体析出,滴加完毕,搅拌反应2小时。过滤得到固体,加入二氯甲烷450mL,控温不超过20℃,加入氢氧化钾调pH=10-11。分液,水层采用220mL二氯甲烷再萃取2次,合并有机层,无水硫酸镁干燥,过滤旋蒸后得到类白色固体32.7克,收率35%,98.7%ee。该固体加入450mL乙酸乙酯和10%钯碳0.65g,通氢气至0.6MPa,升温至60-65℃反应过夜,过滤掉钯碳,溶剂蒸干后,正庚烷打浆后得到19.3克(1R,2R)-茚胺醇,收率95%,98.7%ee,HNMR符合。
实施例3
将茚(116g,1.0mol)和苄胺(102g,0.95mol)混合后,向体系内再加入十二烷基二甲基苄基氯化铵(简称DDBAC,3.7g,0.01mol)和钨酸钠(2.9g,0.01mol),升温至60℃,滴加20%双氧水(1.0mol),滴加过程中控温在60-65℃,滴加结束后,接着升温至90-95℃搅拌反应1小时。降温至40℃,加入720mL乙酸乙酯两次萃取后,弃去水层,有机层外标折算含有产品175g,收率77%。
向上述有机层中,缓慢滴加(R)-MA(56.3g,0.37mol)溶解在220mL乙酸乙酯的溶液,滴加过程中逐渐有固体析出,滴加完毕,搅拌反应2小时。过滤得到固体,加入二氯甲烷420mL,控温不超过20℃,加入氢氧化钠调pH=10-11。分液,水层采用220mL二氯甲烷再萃取2次,合并有机层,无水硫酸镁干燥,过滤旋蒸后得到类白色固体33.6克,收率38%,98.0%ee。该固体加入250mL甲醇和5%钯碳1.20g,通氢气至0.8MPa,升温至60-65℃反应过夜,过滤掉钯碳,溶剂蒸干后,正庚烷打浆后得到19.5克(1S,2S)-茚胺醇,收率93%,98.0%ee,HNMR符合。
Claims (5)
1.一种合成手性反式茚胺醇的方法,其特征在于包括以下步骤:
第一步、将茚和苄胺混合后,再加入相转移催化剂和钨酸钠,升温至50-80℃,滴加20-25%双氧水,随后升温至80-100℃继续反应,得到反式N-苄基茚胺醇;
第二步、将0.45-0.50当量R-或S-扁桃酸与溶剂混合,滴加入第一步得到的反式N-苄基茚胺醇与溶剂中,进行成盐拆分,游离后得到≥98%ee反式N-苄基茚胺醇;
第三步、将第二步得到的≥98%ee反式N-苄基茚胺醇加入钯碳和溶剂,升温至60-80℃通氢气加压反应得到≥98%ee反式茚胺醇。
2.根据权利要求1所述一种合成手性反式茚胺醇的方法,其特征在于:第一步中,相转移催化剂选自十二烷基二甲基苄基氯化铵、十四烷基二甲基苄基氯化铵或十六烷基二甲基苄基氯化铵。
3.根据权利要求1所述一种合成手性反式茚胺醇的方法,其特征在于:第一步中,茚、苄胺、相转移催化剂、钨酸钠和双氧水摩尔比为1-1.1:1:0.01-0.02:0.01-0.02:1-1.2。
4.根据权利要求1所述一种合成手性反式茚胺醇的方法,其特征在于:第二步中,拆分溶剂选自乙酸甲酯、乙酸乙酯或乙酸异丙酯。
5.根据权利要求1所述一种合成手性反式茚胺醇的方法,其特征在于:第三步中,反应溶剂为甲醇、乙醇或乙酸乙酯,反应压力为0.6-0.8MPa;钯碳选自5%或10%,加入量为原料重量的2-5%。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610886608.8A CN106478429B (zh) | 2016-10-11 | 2016-10-11 | 一种合成手性反式茚胺醇的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610886608.8A CN106478429B (zh) | 2016-10-11 | 2016-10-11 | 一种合成手性反式茚胺醇的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106478429A CN106478429A (zh) | 2017-03-08 |
CN106478429B true CN106478429B (zh) | 2018-02-13 |
Family
ID=58270637
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610886608.8A Active CN106478429B (zh) | 2016-10-11 | 2016-10-11 | 一种合成手性反式茚胺醇的方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106478429B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1147243A (zh) * | 1994-03-11 | 1997-04-09 | 麦克公司 | 由环氧化物制备顺式-1-氨基-2-链烷醇的区域专一性方法 |
CN1147244A (zh) * | 1994-03-11 | 1997-04-09 | 麦克公司 | 由二醇或卤代醇制备顺式-1-氨基-2-链烷醇的区域专一性方法 |
CN1184464A (zh) * | 1995-05-12 | 1998-06-10 | 巴斯福股份公司 | 旋光活性氨基1,2-二氢化茚醇的合成 |
-
2016
- 2016-10-11 CN CN201610886608.8A patent/CN106478429B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1147243A (zh) * | 1994-03-11 | 1997-04-09 | 麦克公司 | 由环氧化物制备顺式-1-氨基-2-链烷醇的区域专一性方法 |
CN1147244A (zh) * | 1994-03-11 | 1997-04-09 | 麦克公司 | 由二醇或卤代醇制备顺式-1-氨基-2-链烷醇的区域专一性方法 |
CN1184464A (zh) * | 1995-05-12 | 1998-06-10 | 巴斯福股份公司 | 旋光活性氨基1,2-二氢化茚醇的合成 |
Also Published As
Publication number | Publication date |
---|---|
CN106478429A (zh) | 2017-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11884639B2 (en) | Preparation method for high optical indoxacarb intermediate | |
CN109705102A (zh) | 伏立康唑及其中间体的制备方法 | |
CN106478429B (zh) | 一种合成手性反式茚胺醇的方法 | |
CN107445921A (zh) | 一种高纯度丁香酚环氧的制备方法、产物及产物的应用 | |
CN106084197A (zh) | 一种窄分布聚醚的制备方法 | |
US9067965B2 (en) | Preparation method of rocuronium | |
CN103433050B (zh) | 一乙醇胺催化胺化一步法合成哌嗪催化剂的制备方法 | |
CN108147977A (zh) | N-对氨基苯甲酰-l-谷氨酸的制备方法 | |
CN111217756A (zh) | 一种盐酸右美托咪定的制备方法 | |
WO2016197320A1 (zh) | 一种西酞普兰二醇中间体的制备方法 | |
CN108017544A (zh) | 一种特比萘芬的合成方法 | |
CN105085513B (zh) | 一种制备(r)‑3‑奎宁环醇的方法 | |
CN108101860A (zh) | 顺式-2,6-二甲基吗啉的制备方法 | |
CN107262107A (zh) | 夹心型镍取代硅钨氧簇催化剂的制备方法 | |
CN109851547B (zh) | 一种醋酸巴多昔芬晶型d的制备方法及用途 | |
CN106748816A (zh) | 一种度鲁特韦关键中间体(r)‑3‑氨基丁醇的合成方法 | |
CN113549054A (zh) | 一种富马酸沃诺拉赞中间体及其制备方法 | |
CN107325102B (zh) | 自催化双亲混合溶剂中合成1,5,7-三氮杂双环[4.4.0]癸-5-烯的工艺方法 | |
CN107973752A (zh) | 一种1-甲基-2-乙基咪唑的制备方法 | |
CN111548302A (zh) | 一种呋罗曲坦合成方法 | |
CN108530401A (zh) | 一种3-羟甲基四氢呋喃的生产工艺 | |
CN107129437A (zh) | 4-[(2-氯乙基-2-羟乙基)氨基-]-l-苯丙氨酸盐酸盐的制备方法与应用 | |
CN108727445A (zh) | 一种阿奇霉素杂质f的合成方法 | |
CN108610341B (zh) | 一种米氮平合成及后处理方法 | |
CN102786511A (zh) | 一种制备盐酸氟哌噻吨中间体的改进方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Method for Synthesizing Chiral Transindenols Granted publication date: 20180213 Pledgee: The Bank of Shanghai branch Caohejing Limited by Share Ltd. Pledgor: SHANGHAI HANHONG TECHNOLOGY CO.,LTD. Registration number: Y2024980024446 |