WO2016055015A1 - 一种不对称还原法制备西他列汀中间体的方法 - Google Patents

一种不对称还原法制备西他列汀中间体的方法 Download PDF

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WO2016055015A1
WO2016055015A1 PCT/CN2015/091539 CN2015091539W WO2016055015A1 WO 2016055015 A1 WO2016055015 A1 WO 2016055015A1 CN 2015091539 W CN2015091539 W CN 2015091539W WO 2016055015 A1 WO2016055015 A1 WO 2016055015A1
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compound
hydrogen
ammonium
formula
acid
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PCT/CN2015/091539
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French (fr)
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洪健
王育盛
汪博宇
黄鲁宁
顾虹
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浙江华海药业股份有限公司
上海科胜药物研发有限公司
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Priority to US15/319,370 priority Critical patent/US10189760B2/en
Priority to CN201580024946.4A priority patent/CN106458853B/zh
Priority to ES15848178T priority patent/ES2817909T3/es
Priority to EP15848178.8A priority patent/EP3156391B1/en
Publication of WO2016055015A1 publication Critical patent/WO2016055015A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/15—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively
    • C07C29/151—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively with hydrogen or hydrogen-containing gases
    • C07C29/153—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively with hydrogen or hydrogen-containing gases characterised by the catalyst used
    • 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
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/14—Phosphorus; Compounds thereof
    • B01J27/16—Phosphorus; Compounds thereof containing oxygen, i.e. acids, anhydrides and their derivates with N, S, B or halogens without carriers or on carriers based on C, Si, Al or Zr; also salts of Si, Al and Zr
    • B01J27/18—Phosphorus; Compounds thereof containing oxygen, i.e. acids, anhydrides and their derivates with N, S, B or halogens without carriers or on carriers based on C, Si, Al or Zr; also salts of Si, Al and Zr with metals other than Al or Zr
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/02—Monocyclic aromatic halogenated hydrocarbons
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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    • C07—ORGANIC CHEMISTRY
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/15—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively
    • C07C29/151—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively with hydrogen or hydrogen-containing gases
    • C07C29/1512—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively with hydrogen or hydrogen-containing gases characterised by reaction conditions
    • C07C29/1514—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of oxides of carbon exclusively with hydrogen or hydrogen-containing gases characterised by reaction conditions the solvents being characteristic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/001—General concepts, e.g. reviews, relating to catalyst systems and methods of making them, the concept being defined by a common material or method/theory
    • B01J2531/002—Materials
    • B01J2531/004—Ligands

Definitions

  • the present invention relates to a process for the preparation of sitagliptin intermediates by asymmetric reduction.
  • Sitagliptin phosphate chemical name 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6 , 7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazole[4,3-a]piperazine phosphate, a commercially available pharmaceutical form of monohydrate, its chemistry
  • the structure is as shown in the following formula III:
  • Sitagliptin phosphate is the first commercially available orally effective selective DPP-IV inhibitor to be administered orally once a day for type 2 diabetes. Since its listing in 2006, sitagliptin phosphate has entered 60 countries and more than 15 million prescription drugs worldwide. Sistatin is undergoing a phase III clinical trial for the treatment of type 1 diabetes. The tradename of sitagliptin phosphate produced by Merck is called Janoglipin Phosphate.
  • the core step in the synthesis of compounds of formula IV is to construct a chiral center that is linked to the amino group C3.
  • the methods reported in the literature basically use trifluorophenylacetic acid as a starting material to prepare a suitable substrate to construct a chiral center.
  • the reaction can be carried out after the borohydride is catalyzed by sulfuric acid to form borane, but the use of sulfuric acid increases the discharge of the three wastes.
  • borane gas is highly toxic and presents a safety hazard.
  • Patent PCT International Publications WO2010122578, WO2004087650, and WO2009045507 respectively report a method for asymmetric reduction of a ketone intermediate to obtain a chiral alcohol by a chiral reducing agent (a chiral boron reagent, a chiral guanidine reagent, and an enzyme, respectively)
  • a chiral reducing agent a chiral boron reagent, a chiral guanidine reagent, and an enzyme, respectively
  • the chiral alcohol intermediate can be further subjected to a Mitsunobu reaction or the like to obtain a compound IV.
  • the specific route is as follows:
  • the isomer has low purity and the yield is only 41%. Although 24% of the raw materials can be recovered in the mother liquor, the cost and energy consumption are large, which is not suitable for industrial production.
  • the main problem with this method is that the enamine formed in the second step reaction requires an amino group to be protected before asymmetric reduction, and the yield of the enamine protection step is reported to be low.
  • the intermediate of sitagliptin, the reaction formula is:
  • R 1 and R 2 are each independently selected from hydrogen, C 1 -C 12 straight or branched alkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkyne a C 7 -C 12 arylalkyl group; preferably, R 1 and R 2 are each independently selected from: hydrogen, C 1 -C 4 straight or branched alkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 7 -C 12 arylalkyl; R 1 and R 2 are each independently preferably: hydrogen, C 1 -C 4 straight chain or branch Alkenyl and C 7 -C 12 arylalkyl; further preferably, R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
  • the ammonium salt may be selected from the group consisting of ammonium salts of inorganic acids such as ammonium chloride and ammonium sulfate; ammonium salts of organic acids such as ammonium acetate, ammonium formate, ammonium salicylate and ammonium benzoate. .
  • the chiral phosphine-coordinated transition metal catalyst is a transition metal catalyst coordinated to (R)-dm-Segphos, preferably ruthenium coordinated to (R)-dm-Segphos
  • the catalyst is more preferably a metal catalyst coordinated with (R)-dm-Segphos such as Ru(OAc) 2 ((R)-dm-Segphos) or Ru(Cl) 2 ((R)-dm-Segphos).
  • the acidic additive may be an organic acid, preferably selected from the group consisting of organic acids such as salicylic acid, benzoic acid, p-toluenesulfonate and tartaric acid.
  • organic acids such as salicylic acid, benzoic acid, p-toluenesulfonate and tartaric acid.
  • the organic solvent used may be an alcohol solvent, acetonitrile, toluene, N,N-dimethylformamide, 1,2-dichloroethane, ethyl acetate, two Oxyhexane, etc.
  • the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol and the like, preferably methanol, ethanol or the like.
  • the hydrogen pressure in the asymmetric reductive amination reaction is preferably from 2 to 10 MPa.
  • the temperature of the asymmetric reductive amination reaction is preferably from 50 to 100 °C.
  • the molar percentage of catalyst relative to the compound of formula II is from 0.1 to 10.0 mol%, preferably from 1 to 3 mol%.
  • the compound VI and an ammonium or ammonium salt (ammonium acetate) are added with an acidic additive (salicylic acid) in the presence of Ru(OAc) 2 ((R)-dm-Segphos) and hydrogen in a suitable organic solvent ( Asymmetric reductive amination in methanol) gives compound V, and compound V is selectively hydrolyzed by Boc to give compound IV.
  • an acidic additive salicylic acid
  • Ru(OAc) 2 ((R)-dm-Segphos)
  • a suitable organic solvent Asymmetric reductive amination in methanol
  • the method for preparing the sitagliptin intermediate by the asymmetric reduction method provided by the present invention can directly reduce the compound II or the coordination with the ammonia or ammonium salt in the chiral phosphine without resolution and amino protection.
  • the transition metal catalyst for example, Ru(OAc) 2 ((R)-dm-Segphos)
  • the transition metal catalyst can be reductively aminated to obtain compound I (ee% ⁇ 94%), and the compound I is selectively protected by Boc and hydrolyzed.
  • Compound IV (ee% ⁇ 99%) can be prepared.
  • a one-step asymmetric reduction yields the sitagliptin compound, and if other substituents or heterocycles are selectively subjected to amino-protection followed by hydrolysis or direct hydrolysis to obtain the desired intermediate of sitagliptin Body compound.
  • the invention provides the asymmetric reduction reaction which belongs to green synthesis, has high atomic utilization rate, short steps, high yield and ee% value, simple operation, convenient purification, low production cost, environmental friendliness and suitable for industrial production.
  • the temperature was lowered to 0 to 5 ° C, and pivaloyl chloride (76 mL, 1.17 mol) was added dropwise to the system, and the temperature was controlled to 30 ° C or less when added dropwise, and the temperature was raised to 40 to 45 ° C. After 3 to 5 hours, the reaction was completed and the temperature was lowered to 25 to 30 °C. After filtration, the filter cake was washed twice with 200 mL of methyl tertiary ether, and the solvent ( ⁇ 30 ° C) was distilled off under reduced pressure to 3 volumes (visually viscous).
  • Example number R 2 group in compound I Ee% Yield 19 Ethyl 99.2% 82.3% 20 Benzyl 99.6% 84.1% twenty one Tert-butyl 99.5% 82.7%

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Abstract

本发明涉及一种合成西他列汀中间体的方法。该方法包括将式II化合物与氨或铵盐在手性膦配位的过渡金属催化剂以及氢气存在下，在加入酸性添加剂的条件下，在合适的有机溶剂中不对称还原氨化反应以得到式I化合物，其中立构中心的R-或S-构型用*表示，R构型的式I化合物可用于制备西他列汀，反应式如下：其中R1和R2各自独立地选自氢、C1-C12直链或支链烷基、C3-C12环烷基、C2-C12链烯基、C2-C12链炔基、C7-C12芳基烷基。该方法的收率及ee％值高、反应条件温和、操作简单、便于纯化、生产成本低廉、对环境友好、适合工业化生产。

Description

一种不对称还原法制备西他列汀中间体的方法
本申请要求于2014年10月11日提交中国专利局、申请号为201410532331.X发明名称为“一种合成西他列汀中间体的方法”的中国专利申请的优先权，其全部内容通过引用并入本申请中。
技术领域
本发明涉及一种不对称还原法制备西他列汀中间体的方法。
背景技术
磷酸西他列汀(Sitagliptin phosphate)，化学名称为7-[(3R)-3-氨基-1-氧代-4-(2，4，5-三氟苯基)丁基]-5，6，7，8-四氢-3-(三氟甲基)-1，2，4-三唑[4，3-a]哌嗪磷酸盐，市售的药用形式为一水合物，其化学结构如下式III所示：
Figure PCTCN2015091539-appb-000001
磷酸西他列汀是第一个上市的口服有效的选择性DPP-IV抑制剂，每天口服一次治疗II型糖尿病。自2006年上市以来，磷酸西他列汀已进入60个国家，全球超过1500万处方配药。正在对西他列汀进行治疗I型糖尿病的III期临床试验。默沙东生产的磷酸西他列汀片商品名为捷诺维JANUVIA(Sitagliptin Phosphate)。
(R)-3-叔丁氧羰基氨基-4-(2，4，5-三氟苯基)丁酸是合成西他列汀的重要中间体之一，其化学结构如下式IV所示：
Figure PCTCN2015091539-appb-000002
通过全面的文献调研，发明人发现合成式IV化合物的核心步骤在于构建与氨基相连C3的手性中心。目前，文献报道的方法基本都是以三氟苯乙酸为起始原料，制备适当的底物，构建手性中心。主要有以下3种方法：1)外消旋体拆分；2)用Ru-BINAP催化前手性酮得到手性仲醇，叠氮化后还原；3)制备酰基保护的烯胺，不对称催化氢化。
方法1：PCT国际公开WO2010009630公开了对外消旋体β-氨基酸中间体F进行拆分然后再进行相关转化得到化合物IV的方法。具体路线如下：
Figure PCTCN2015091539-appb-000003
该方法的主要问题在于：
1)在第四步还原反应中，在用硫酸催化硼氢化钠生成硼烷后反应才能进行，但是硫酸的使用会增加三废的排放。此外，硼烷气体毒性较大，存在安全隐患。
2)在第五步反应中，需要进行拆分才能得到G，收率约为31％，收率较低，经济性较差，生产成本大幅提高。
方法2：专利PCT国际公开WO2010122578、WO2004087650及WO2009045507分别报道了用手性还原剂(分别为手性硼试剂、手性钌试剂及酶)对酮中间体进行不对称还原以得到手性醇的方法，该手性醇中间体再通过Mitsunobu反应等过程可得到化合物IV。具体路线如下：
Figure PCTCN2015091539-appb-000004
该方法的主要问题在于：
1)在第三步的还原反应中，所用的(R)-Me-CBS催化剂价格昂贵，硼烷试剂毒性较大；酶较难购得。
2)在第四步反应中，需要使用叠氮物，在放大生产中存在较大的安全隐患。
3)制备化合物IV需要7步反应，路线较长。
方法3：PCT国际公开WO2009064476及WO2010078440中分别报道了不对称催化氢化带保护基的烯胺的方法，得到的中间体经过合适的反应可制备化合物IV。具体路线如下：
Figure PCTCN2015091539-appb-000005
该方法异构体纯度低，收率仅为41％，尽管母液中可以回收24％的原料，但成本和能耗较大，不适合工业化生产。
PCT国际公开WO2010078440中描述的反应路线如下：
Figure PCTCN2015091539-appb-000006
该方法的主要问题在于：第二步反应生成的烯胺需要氨基被保护后才能进行不对称还原，而据报道烯胺保护步骤的收率较低。
发明内容
本发明的目的是提供了一种合成西他列汀重要中间体化合物的新方法。
本发明采用不对称还原氨化的方法制备中间体化合物I的技术方案如下：
将式II化合物与氨或铵盐在手性膦配位的过渡金属催化剂及氢气的存在下，在加入酸性添加剂的条件下，在合适的有机溶剂中不对称还原氨化反应以得到式I所示的西他列汀中间体，反应式为：
Figure PCTCN2015091539-appb-000007
其中，立构中心的R-或S-构型用*表示；
R1和R2各自独立地选自氢、C1-C12直链或支链烷基、C3-C12环烷基、C2-C12链烯基、C2-C12链炔基、C7-C12芳基烷基；优选地，R1和R2各自独立地选自：氢、C1-C4直链或支链烷基、C3-C6环烷基、C2-C4链烯基、C2-C4链炔基、C7-C12芳基烷基；R1和R2各自独立地优选为：氢、C1-C4直链或支链烷基及C7-C12 芳基烷基；进一步优选地，R1和R2各自独立地选自氢、甲基、乙基及苄基。
在根据本发明方法的一个实施方案中，铵盐可选自：氯化铵、硫酸铵等无机酸的铵盐；乙酸铵、甲酸铵、水杨酸铵、苯甲酸铵等有机酸的铵盐。
在根据本发明方法的一个实施方案中，手性膦配位的过渡金属催化剂为与(R)-dm-Segphos配位的过渡金属催化剂、优选为与(R)-dm-Segphos配位的钌催化剂，更优选：Ru(OAc)2((R)-dm-Segphos)、Ru(Cl)2((R)-dm-Segphos)等与(R)-dm-Segphos配位的金属催化剂。
在根据本发明方法的一个实施方案中，酸性添加剂可以为有机酸，优选选自：水杨酸、苯甲酸、对甲苯磺酸盐及酒石酸等有机酸。应该注意的是，向反应体系中添加酸性添加剂的目的是获得酸性环境，因此酸性添加剂的种类并不限于此。本领域技术人员知道，只要能够实现本发明的目的且不会负面地影响本发明的反应进行的酸性添加剂均在本发明的范围内。
在根据本发明方法的一个实施方案中，所使用的有机溶剂可以是醇类溶剂、乙腈、甲苯、N，N-二甲基甲酰胺、1，2-二氯乙烷、乙酸乙酯、二氧六环等。在根据本发明方法的一个实施方案中，醇类溶剂选自甲醇、乙醇、异丙醇、正丁醇、叔丁醇、苄醇等，优选甲醇、乙醇等。
在根据本发明方法的一个实施方案中，不对称还原氨化反应中氢气压力优选为2～10MPa。
在根据本发明方法的一个实施方案中，不对称还原氨化反应的温度优选为50～100℃。
在根据本发明方法的一个实施方案中，催化剂相对于式II化合物的摩尔百分比为0.1～10.0摩尔％，优选1～3摩尔％。
本发明较优选的技术方案如下：
Figure PCTCN2015091539-appb-000008
本发明中，化合物VI与氨或铵盐(乙酸铵)在Ru(OAc)2((R)-dm-Segphos)和氢气存在下，加入酸性添加剂(水杨酸)，在合适的有机溶剂(甲醇)中不对称还原氨化反应得到化合物V，化合物V选择性地经Boc保护后水解即可制得化合物IV。
本发明有益的技术效果：本发明提供的不对称还原法制备西他列汀中间体的方法，无需拆分及氨基保护直接经不对称还原化合物II或与氨或铵盐在手性膦配位的过渡金属催化剂(例如Ru(OAc)2((R)-dm-Segphos))存在下一步即可还原氨化得到化合物I(ee％≥94％)，选择性地化合物I经过Boc保护、水解即可制备化合物IV(ee％≥99％)。其中如果反应物为化合物VII时，则一步不对称还原得到西他列汀化合物，若其它取代基或杂环则可选择性地进行氨基保护后水解或直接水解得到所需要的西他列汀中间体化合物。本发明提供不对称还原反应属于绿色合成，原子利用率高、步骤短、收率及ee％值高、操作简单、便于纯化、生产成本低廉、对环境友好、适合工业化生产。
具体实施方式
以下将结合实施例对本发明的技术方案及其所产生的技术效果作进一步说明，以充分地了解本发明的目的、技术特征和效果。
实施例1：化合物C的制备
Figure PCTCN2015091539-appb-000009
氮气保护下，依次向1000mL三口瓶中加入化合物A(100g，0.524mol)，化合物B(84g，0.583mol)，4-二甲氨基吡啶(DMAP，5.2g，0.042mol)，乙腈(250mL)，降温至0～5℃。控温0～30℃，向体系滴加三乙胺(150mL，1.079mol)。降温至0～5℃，向体系中滴加特戊酰氯(76mL，1.17mol)，滴加时控温30℃以下，加毕，升温至40～45℃。3～5小时后，反应结束，降温至25～30℃。过滤，滤饼用甲叔醚200mL洗涤2次，减压蒸出溶剂(＜30℃)至3倍体积(呈 黏稠状)。加入600mL二氯甲烷，搅拌5分钟(25～30℃)，15分钟内滴加约300mL 1.5M的盐酸，调节pH＝2～3。二氯甲烷(DCM)相加入100mL饱和食盐水洗涤，有机相减压蒸出溶剂(＜15℃)2倍体积，加入正庚烷200mL，减压蒸出溶剂(＜15℃)3倍体积，加入50mL乙酸乙酯，正庚烷300mL打浆2小时。抽滤，100ml(正庚烷∶乙酸乙酯＝10∶1)洗涤滤饼，干燥得产物134.23g，收率80.7％。ESI：m/z：317[M+H]+.
实施例2：化合物VI的制备
Figure PCTCN2015091539-appb-000010
氮气保护下，依次向250mL三口瓶中加入乙腈(284mL)，化合物C(56.7g，0.179mol)及苄醇(19.4g，0.179mol)，搅拌。升温至回流(内温80～84℃为正常沸点)约24小时。降温至30℃以下，浓缩，加入3倍体积量甲醇，0～5℃析晶12h，抽滤得产物47.2g，收率81.6％。1H NMR(400MHz，CDCl3)δ：7.37-7.35(m，5H)，6.99-6.89(m，2H)，5.19(s，2H)，3.81(s，2H)，3.57(s，2H)；ESI：m/z：323[M+H]+.
实施例3：化合物V的制备
Figure PCTCN2015091539-appb-000011
将化合物VI(100g，0.310mol)，水杨酸(214g，0.898mol)，乙酸铵(119g，1.544mol)，手性催化剂Ru(OAc)2((R)-dm-Segphos)(2.93g，0.003mol)及甲醇(400mL)加入到1000mL氢化釜中。氮气置换5次，氢气置换3次，加氢至2.5MPa，升温至40～50℃，压力升至2.7MPa，加氢至3.6MPa，继续升温至70～80℃，压力为3.6MPa，保温反应。TLC跟踪，约20h反应完全，停止 加热，降至室温，放出氢气，氮气置换3次，反应液抽滤。滤液浓缩，加200mL碳酸钠水溶液，乙酸乙酯萃取2次(300mL×2)，浓缩有机相得产物72.96g，收率95.2％，ee％＝94.2％。1H NMR(400MHz，CDCl3)δ：7.26-7.09(m，1H)，6.94-6.89(m，1H)，3.71(s，3H)，3.59-3.49(m，1H)，2.84-2.83(m，3H)，2.61-2.45(m，3H)；ESI：m/z：248[M+H]+.
实施例4：化合物V的制备
Figure PCTCN2015091539-appb-000012
将VI(100g，0.310mol)，水杨酸(214g，0.898mol)，乙酸铵(119g，1.544mol)，手性催化剂Ru(OAc)2((R)-dm-Segphos)(2.93g，0.003mol)及甲醇(400mL)加入到1000mL氢化釜中。氮气置换5次，氢气置换3次，加氢至2.0MPa，升温至90～100℃，保温反应。TLC跟踪，约20h反应完全，停止加热，降至室温，放出氢气，氮气置换3次，反应液抽滤。滤液浓缩，加200mL碳酸钠水溶液，乙酸乙酯萃取2次(300mL×2)，浓缩有机相得产物67.85g，收率88.5％。ESI：m/z：248[M+H]+.
实施例5：化合物V的制备
Figure PCTCN2015091539-appb-000013
将化合物VI(100g，0.310mol)，水杨酸(214g，0.898mol)，乙酸铵(119g，1.544mol)，手性催化剂Ru(OAc)2((R)-dm-Segphos)(2.93g，1mol％)及甲醇(400mL)加入到1000mL氢化釜中。氮气置换5次，氢气置换3次，加氢至9～10MPa，升温至40～50℃，保温反应。TLC跟踪，约12h反应完全，停止加热，降至室温，放出氢气，氮气置换3次，反应液抽滤。滤液浓缩，加200mL碳 酸钠水溶液，乙酸乙酯萃取2次(300mL×2)，浓缩有机相得产物73.82g，收率96.3％。ESI：m/z：248[M+H]+.
实施例6：化合物IV的制备
Figure PCTCN2015091539-appb-000014
将化合物V(32.0g，0.129mol)，二碳酸二叔丁酯((Boc)2O 29.5g，0.135mol)及三乙胺(21.2g，0.210mol)溶于乙酸乙酯(150mL)中，控温20～30℃反应。TLC监测，7h反应完全，加入10mL水洗涤，浓缩有机相，得粗品。将粗品溶于乙醇中，加入10％氢氧化钠水溶液，控温20～30℃反应2h。TLC检测，反应完全，加入水30mL，3M盐酸调pH＝1～2，析出大量固体，抽滤，干燥得产物36.8g，收率85.5％，ee％＝99.3％。[a]＝+32.3(c 1.0，CHCl3)；1H NMR(400MHz，CDCl3)δ：7.26-7.03(m，1H)，6.94-6.88(m，1H)，5.08(d，J＝9.6Hz，1H)，4.15(br，1H)，2.89(d，J＝7.2Hz，1H)，2.63(d，J＝5.2Hz，1H)，1.38(s，9H)；ESI：m/z：233[M-Boc]+，356[M+Na]+.
实施例7-10：
以与实施例2类似的方式制备化合物II，结果如下表1所示：
表1
实施例编号 反应物1 反应物2 化合物II中的R1基团 收率
7 化合物C 甲醇 甲基 83.1％
8 化合物C 乙醇 乙基 80.3％
9 化合物C 异丙醇 异丙基 82.4％
10 化合物C 叔丁醇 叔丁基 79.7％
实施例11-18：
以与实施例3-5类似的方式制备化合物I，结果如下表2所示：
Figure PCTCN2015091539-appb-000015
实施例19-21：
以与实施例6类似的方式，分别将实施例11-18中制得的化合物I水解得到化合物IV，结果如下表3所示：
表3
实施例编号 化合物I中的R2基团 ee％ 收率
19 乙基 99.2％ 82.3％
20 苄基 99.6％ 84.1％
21 叔丁基 99.5％ 82.7％
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (11)

  1. 一种不对称还原法制备西他列汀中间体的方法，其特征在于，包括如下步骤：将式II化合物与氨或铵盐在手性膦配位的过渡金属催化剂及氢气存在下，在加入酸性添加剂的条件下，在合适的有机溶剂中不对称还原氨化反应以得到式I所示的西他列汀中间体，反应式为：
    Figure PCTCN2015091539-appb-100001
    其中，立构中心的R-或S-构型用*表示；
    R1和R2各自独立地选自氢、C1-C12直链或支链烷基、C3-C12环烷基、C2-C12链烯基、C2-C12链炔基、C7-C12芳基烷基。
  2. 根据权利要求1所述的方法，其特征在于，R1和R2各自独立地选自：氢、C1-C4直链或支链烷基、C3-C6环烷基、C2-C4链烯基、C2-C4链炔基、C7-C12芳基烷基；R1和R2各自独立地优选为：氢、C1-C4直链或支链烷基及C7-C12芳基烷基；R1和R2各自进一步独立地优选氢、甲基、乙基及苄基。
  3. 根据权利要求1或2所述的方法，其特征在于，所述手性膦配位的过渡金属催化剂为与(R)-dm-Segphos配位的过渡金属催化剂、优选为与(R)-dm-Segphos配位的钌催化剂，更优选选自：Ru(OAc)2((R)-dm-Segphos)和/或Ru(Cl)2((R)-dm-Segphos)。
  4. 根据权利要求1至3中任一项所述的方法，其特征在于，所述铵盐选自无机酸的铵盐或有机酸的铵盐。
  5. 根据权利要求4所述的方法，其特征在于，所述无机酸的铵盐选自氯化铵或硫酸铵或其组合；所述有机酸的铵盐选自乙酸铵、甲酸铵、水杨酸铵或苯甲酸铵或其组合。
  6. 根据权利要求1至5中任一项所述的方法，其特征在于，所述有机溶剂选 自醇类溶剂、乙腈、甲苯、N，N-二甲基甲酰胺或1，2-二氯乙烷或其组合。
  7. 根据权利要求1至6中任一项所述的方法，其特征在于，所述有机溶剂选自醇类溶剂，所述醇类溶剂选自甲醇、乙醇、异丙醇、正丁醇、叔丁醇或苄醇或其组合，优选甲醇或乙醇或其组合。
  8. 根据权利要求1至7中任一项所述的方法，其特征在于，所述催化剂相对于式II化合物的摩尔百分比为0.1～10.0摩尔％，优选1～3摩尔％。
  9. 根据权利要求1至8中任一项所述的方法，其特征在于，不对称还原氨化反应中氢气压力条件为2～10MPa。
  10. 根据权利要求1至9中任一项所述的方法，其特征在于，不对称还原氨化反应的温度为50～100℃。
  11. 根据权利要求1至10中任一项所述的方法，其特征在于，所述酸性添加剂为有机酸，优选选自：水杨酸、苯甲酸、酒石酸、对甲苯磺酸或其组合。
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