WO2021036256A1 - 一种hiv蛋白酶抑制剂中间体化合物的合成方法 - Google Patents

一种hiv蛋白酶抑制剂中间体化合物的合成方法 Download PDF

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WO2021036256A1
WO2021036256A1 PCT/CN2020/082630 CN2020082630W WO2021036256A1 WO 2021036256 A1 WO2021036256 A1 WO 2021036256A1 CN 2020082630 W CN2020082630 W CN 2020082630W WO 2021036256 A1 WO2021036256 A1 WO 2021036256A1
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protease inhibitor
hiv protease
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稂琪伟
丁小兵
高爽
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凯特立斯（深圳）科技有限公司
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Definitions

  • the invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing an HIV protease inhibitor intermediate compound.
  • HIV protease inhibitors are currently the most promising treatment technology.
  • the high drug prices have caused many AIDS patients to give up treatment, so the development of an efficient and cheap
  • the synthesis method of HIV protease inhibitor intermediates is very important.
  • the structures of common HIV protease inhibitors and their intermediates are as follows:
  • the prior art mainly adopts enzymatic catalysis and asymmetric hydrogenation methods to synthesize this intermediate.
  • chiral aminoaldehyde is used as a raw material to synthesize this intermediate chemically, and a large amount of chemical reagent NaBH 4 is required for reduction, and the resulting product is stereoselective
  • the control is poor, and a product with a single configuration must be obtained through recrystallization; in 2001, the B. Moon Kim group reported a natural chiral source as a starting material to synthesize this intermediate through a multi-step complex process; in 2013, Ioannis N. Houpis synthesized the intermediate by asymmetric hydrogenation and enzymatic catalysis. Although it has relatively good stereocontrol, its catalytic activity is poor, and the conversion cannot be completed in most cases, and the loss of raw materials is large. The amount of enzyme is also large.
  • the existing methods for synthesizing HIV protease inhibitor intermediates have the problems of poor stereoselectivity control, low reaction activity, large loss of raw materials and complex synthesis process.
  • the embodiment of the present invention provides a method for synthesizing an HIV protease inhibitor intermediate compound, which aims to solve the existing methods for synthesizing HIV protease inhibitor intermediates, which have poor stereoselectivity control, low reactivity, large loss of raw materials, and synthesis technology. The process is complicated.
  • a method for synthesizing an intermediate compound of an HIV protease inhibitor includes:
  • Compound 1a is added to a reaction solvent, a mixture of catalyst and hydrogen source is added to carry out asymmetric transfer hydrogenation reaction to obtain HIV protease inhibitor intermediate compounds 2a, 2a', and the synthetic route is shown as follows:
  • the group R is one of tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, acetyl and benzoyl.
  • the method for synthesizing HIV protease inhibitor intermediate compounds uses asymmetric transfer hydrogenation technology. Compared with existing similar intermediates, the synthesized HIV protease inhibitor intermediate compounds have stereoselectivity and yield. The rate can be greatly improved, and the diastereoselectivity ratio of the product reaches 94:6; in addition, the amount of catalyst is small, the catalytic efficiency is high, the reaction activity is improved, the loss of raw materials is small, the overall process is fast and simple, and the cost is greatly reduced.
  • the group R is one of tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), p-toluenesulfonyl (Ts), acetyl (Ac), and benzoyl (Bz).
  • Boc tert-butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Ts p-toluenesulfonyl
  • Ac acetyl
  • benzoyl Bz
  • the structure of the catalyst used in the transfer hydrogenation process is as follows:
  • the molar ratio of the catalyst to the compound 1a is 1:100 ⁇ 5000; the concentration of the compound 1a in the reaction system is 0.1M ⁇ 0.5M.
  • the asymmetric transfer hydrogenation reaction is carried out under the protection of argon or nitrogen.
  • the reaction solvent used is one or more of methanol, tetrahydrofuran, isopropanol, o-dichloroethane, dichloromethane, toluene, water, and N,N-dimethylformamide .
  • the reaction solvent may also be a mixture of tetrahydrofuran and water in a volume ratio of 1:1, a mixture of isopropanol and water in a volume ratio of 1:1, and a volume ratio of N, One of the mixed liquids of N-dimethylformamide and water.
  • the hydrogen source is one or two of triethylamine formate (5:2) azeotropic mixture and sodium formate.
  • the reaction time of the asymmetric transfer hydrogenation reaction is 2 ⁇ 16h.
  • the reaction time used in the system is different in the case of different reaction solvents or different hydrogen sources.
  • the hydrogen source used is triethyl formic acid
  • the reaction solvent is tetrahydrofuran, isopropanol, o-dichloroethane, dichloromethane, toluene
  • the corresponding reaction time is preferably 2h
  • the hydrogen source is triethylamine formate and the reaction solvent is methanol
  • the corresponding reaction time is preferably 12h
  • the hydrogen source used is sodium formate
  • the reaction solvent is water, a mixture of tetrahydrofuran and water, a mixture of isopropanol and water, and a mixture of N,N-dimethylformamide and water.
  • the reaction time is 16h.
  • the reaction temperature of the asymmetric transfer hydrogenation reaction is 25°C; when the reaction temperature is higher than 30°C, the heating system will become complicated, so the embodiments of the present invention are performed at 25°C.
  • the method for synthesizing HIV protease inhibitor intermediate compounds provided in the embodiments of the present invention utilizes asymmetric transfer catalysis technology. Compared with existing similar intermediates, the synthesized HIV protease inhibitor intermediate compounds have stereoselectivity and yield. The rate can be greatly improved, and the diastereoselectivity ratio of the product reaches 94:6; in addition, the amount of catalyst is small, the catalytic efficiency is high, the reaction activity is improved, the loss of raw materials is small, the overall process is fast and simple, and the cost is greatly reduced.
  • the present invention is to investigate the influence of the type of catalyst used in the asymmetric transfer hydrogenation reaction on the conversion rate (conv.) of the HIV protease inhibitor intermediate compound and the ratio of diastereomers (dr), based on Example 1. , Replace the catalyst cat.1 with cat.2, cat.3, cat.4, cat.5, cat.6, cat.7, cat.8, cat.9, cat.10, cat.11, cat in turn .12, ( R,R )-cat.13 and ( S,S )-cat.13, cat.14, cat.15, cat.16, cat.17.
  • the type of catalyst determines the overall stereoselectivity of the reaction.
  • Examples 1-18 used different catalysts.
  • the diastereoselectivity of the reaction was very large, and the difference in activity was also relatively large.
  • the difference in activity relative to the optimal catalyst cat.13 may be that the structure of other catalysts is relatively dispersed and easy to In the catalytic cycle, small molecules are trapped and deactivated.
  • the reason for the poor selectivity may be that the dispersed chiral catalyst cannot provide an excellent chiral pocket for this type of substrate, while the chain structure of cat.13 can.
  • Example 19 THF >99 90:10
  • Example 20 IPA >99 91:9
  • Example 21 DCE >99 93:7
  • Example 22 DCM >99 91:9
  • Example 23 toluene >99 91:9
  • Example 24 MeOH >99 94:6
  • the hydrogen source triethylamine formate was replaced with sodium formate HCOONa (6 eq.), and the reaction time was 16 hours.
  • S/C 1000
  • the reaction solvent is replaced with water, a mixture of tetrahydrofuran and water H 2 O/THF (1:1) with a volume ratio of 1:1, and a mixture of isopropanol and water with a volume ratio of 1:1.
  • Liquid H 2 O/IPA (1:1), the following Examples 25-27 were performed, and the results of the effect on the conversion rate and dr value of the HIV protease inhibitor intermediate compound are shown in Table 4 below.
  • the chiral configuration of the catalyst determines the chiral configuration of the product, that is, from the S, S configuration of the catalyst to the SS configuration of the substrate R, R configuration of the catalyst to S, R-configuration substrate; the catalyst has good compatibility with substrates of different N protecting groups, and has very excellent diastereoselectivity, which can be obtained when the protecting group on the nitrogen is benzoyl The best diastereoselectivity, >99:1 dr.
  • the protective group on the nitrogen is tert-butoxycarbonyl or benzyloxycarbonyl
  • the S, S configuration catalyst has a slightly higher diastereoselectivity than the R, R configuration catalyst. This may be because the substrate itself is in the S configuration, and the chiral pocket matching degree is higher when reacting with the SS catalyst. .
  • the R group in the substrate is a benzoyl group
  • the best catalyst cat.13 is used as the catalyst
  • DCM is used as the reaction solvent
  • triethylamine formate (5:2) is used as the hydrogen source.
  • the amount of hydrogen source and the reaction are changed respectively. Time, substrate concentration in the reaction system, etc., the synthesis route is as follows:
  • the method for synthesizing HIV protease inhibitor intermediate compounds utilizes asymmetric transfer hydrogenation technology.
  • the synthesized HIV protease inhibitor intermediate compounds are stereoselective.
  • the performance and yield can be greatly improved, and the diastereoselectivity ratio of the product reaches 94:6; in addition, the amount of catalyst is small, the catalytic efficiency is high, the reaction activity is improved, the loss of raw materials is small, the overall process is fast and simple, and the cost is greatly reduced.

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Abstract

本发明适用于药物合成技术领域，提供了一种HIV蛋白酶抑制剂中间体化合物的合成方法，包括：在氩气保护下，将化合物1a在反应溶剂中，加入催化剂和氢源混合物进行不对称转移氢化反应，得到HIV蛋白酶抑制剂中间体化合物2a、2a'，其合成路线如下所示：(I)；所述基团R为叔丁氧羰基、苄氧羰基、对甲苯磺酰基、乙酰基、苯甲酰基中的一种。本发明利用不对称转移氢化技术，所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比，其立体选择性和收率能够大幅提高，产物的非对映选择性比例达到94:6；另外，催化剂用量少且催化效率高，改善了反应活性，原料损耗少，整体工艺快速简便、成本大幅下降。

Description

一种HIV蛋白酶抑制剂中间体化合物的合成方法 技术领域
本发明属于药物合成技术领域，尤其涉及一种HIV蛋白酶抑制剂中间体化合物的合成方法。
 背景技术
艾滋病是世界上最难治愈的疾病之一。在过去的几十年里，艾滋病的治疗已经取得了重大的进步，HIV蛋白酶抑制剂是目前最有前景的治疗技术，但是高昂的药物价格使得很多艾滋病人放弃治疗，所以发展一种高效廉价的HIV蛋白酶抑制剂中间体的合成方法至关重要，目前常见的HIV蛋白酶抑制剂及其中间体的结构如下所示：
Figure 544640dest_path_image001
现有技术中主要采用酶催化以及不对称氢化方法合成该中间体，其中，采用手性氨基醛为原料采用化学方法合成该中间体，需要大量化学试剂NaBH 4进行还原，得到的产物立体选择性控制较差，必须通过重结晶得到单一构型的产物；2001年，B. Moon Kim小组报道了一种以天然手性源为起始原料，经过多步复杂过程合成该中间体； 2013年，Ioannis N. Houpis分别用不对称氢化和酶催化的方法合成了该中间体，虽然有比较好的立体控制性，但是催化的活性较差，大多数情况下不能够转化完全，原料损耗较大，酶的用量也很大。
技术问题
现有合成HIV蛋白酶抑制剂中间体的方法存在立体选择性控制较差、反应活性低、原料损耗大以及合成工艺过程复杂的问题。
 技术解决方案
本发明实施例提供一种HIV蛋白酶抑制剂中间体化合物的合成方法，旨在解决现有合成HIV蛋白酶抑制剂中间体的方法存在立体选择性控制较差、反应活性低、原料损耗大以及合成工艺过程复杂的问题。
本发明实施例是这样实现的，一种HIV蛋白酶抑制剂中间体化合物的合成方法，包括：
将化合物1a在反应溶剂中，加入催化剂和氢源混合物进行不对称转移氢化反应，得到HIV蛋白酶抑制剂中间体化合物2a、2a’，其合成路线如下所示：
Figure 564548dest_path_image002
；
所述基团R为叔丁氧羰基、苄氧羰基、对甲苯磺酰基、乙酰基、苯甲酰基中的一种。
 有益效果
本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法，利用不对称转移氢化技术，所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比，其立体选择性和收率能够大幅提高，产物的非对映选择性比例达到94:6；另外，催化剂用量少且催化效率高，改善了反应活性，原料损耗少，整体工艺快速简便、成本大幅下降。
 本发明的实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法，在氩气保护下，将化合物1a在反应溶剂中，加入催化剂和氢源混合物进行不对称转移氢化反应，得到HIV蛋白酶抑制剂中间体化合物2a、2a’，其合成路线如下所示：
Figure 504822dest_path_image003
；
化合物1a的命名：
tert-butyl (S)-(4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate。
HIV蛋白酶抑制剂中间体化合物的命名：
2a：tert-butyl ((2S,3R)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate；
2a’：tert-butyl ((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate。
在本发明实施例中，所述基团R为叔丁氧羰基（Boc）、苄氧羰基（CBz）、对甲苯磺酰基（Ts）、乙酰基（Ac）、苯甲酰基（Bz）中的一种。
在本发明实施例中，所用催化剂在转移氢化过程中的结构如下所示：
Figure 293787dest_path_image004
 
在本发明实施例中，催化剂与化合物1a的摩尔比为1:100~5000；化合物1a在反应体系的浓度为0.1M~0.5M。
在本发明实施例中，不对称转移氢化反应是在氩气或氮气保护下进行。
在本发明实施例中，所用的反应溶剂为甲醇、四氢呋喃、异丙醇、邻二氯乙烷、二氯甲烷、甲苯、水、N,N-二甲基甲酰胺中的一种或几种。
在本发明实施例中，所述反应溶剂还可以为体积比1:1 的四氢呋喃与水的混合液、体积比1:1的异丙醇与水的混合液、体积比1:1的N,N-二甲基甲酰胺与水的混合液中的一种。
在本发明实施例中，氢源为甲酸三乙胺（5:2）共沸混合物、甲酸钠中的一种或两种。
在本发明实施例中，所述不对称转移氢化反应的反应时间为2~16h，其中，体系在不同反应溶剂或不同氢源的情况下，所用反应时间不同，当所用氢源为甲酸三乙胺，反应溶剂分别为四氢呋喃、异丙醇、邻二氯乙烷、二氯甲烷、甲苯时对应的反应时间优选为2h；当所用氢源为甲酸三乙胺，反应溶剂为甲醇时对应的反应时间优选为12h；当所用氢源为甲酸钠，反应溶剂分别为水、四氢呋喃与水的混合液、异丙醇与水的混合液、N,N-二甲基甲酰胺与水的混合液时对应的反应时间为16h。
在本发明实施例中，不对称转移氢化反应的反应温度为25℃；当反应温度高于30℃，加热体系会变得复杂，故本发明实施例都是在25℃下进行。
本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法，利用不对称转移催化技术，所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比，其立体选择性和收率能够大幅提高，产物的非对映选择性比例达到94:6；另外，催化剂用量少且催化效率高，改善了反应活性，原料损耗少，整体工艺快速简便、成本大幅下降。
以下通过具体实施例对本发明的HIV蛋白酶抑制剂中间体化合物的合成方法的技术效果做进一步的说明。
实施例1
在温度为25℃下，在氩气保护下，将化合物1a（0.2mmol）在甲醇（2mL）中，加入催化剂cat.1和甲酸三乙胺（5:2）（40uL）混合物（催化剂是0.002M的甲醇溶液取用100uL），进行不对称转移氢化反应16h，，得到HIV蛋白酶抑制剂中间体化合物2a、2a’，其合成路线如下所示：
Figure 723631dest_path_image005
 
实施例2-18
本发明为考察不对称转移氢化反应所用催化剂的种类对HIV蛋白酶抑制剂中间体化合物的转化率 (conv.)以及非对映异构体的比例(dr)的影响，在实施例1的基础上，将催化剂cat.1依次替换为cat.2、cat.3、cat.4、cat.5、cat.6、cat.7、cat.8、cat.9、cat.10、cat.11、cat.12、( R,R)-cat.13和( S,S)-cat.13、cat.14、cat.15、cat.16、cat.17。
实施例1-18中不同催化剂对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表1所示；其中，转化率由LC测得（反相C18柱），dr值由LC和核磁共振氢谱及碳谱所确定。
表1
  催化剂种类 conv.(%) dr (2a:2a’)
实施例1 cat.1 14 87:13
实施例2 cat.2 4 87:13
实施例3 cat.3 13 80:20
实施例4 cat.4 19 73:27
实施例5 cat.5 21 54:46
实施例6 cat.6 23 87:13
实施例7 cat.7 45 82:18
实施例8 cat.8 29 79:21
实施例9 cat.9 8 78:22
实施例10 cat.10 9 80:20
实施例11 cat.11 8 77:23
实施例12 cat.12 11 73:27
实施例13 ( R,R)-cat.13 ＞99 94.2:5.8
实施例14 ( S,S)-cat.13 ＞99 4:96
实施例15 cat.14 ＞99 93.7:6.3
实施例16 cat.15 ＞99 93.5:6.5
实施例17 cat.16 ＞99 92.4:7.6
实施例18 cat.17 ＞99 93.5:6.5
 
综上，从表1中可知，催化剂的种类决定了反应整体的立体选择性。实施例1-18分别使用了不同催化剂，反应的非对映选择性很大，同时活性的差别也比较大，相对于最优催化剂cat.13活性的差别可能是其他催化剂结构比较分散，容易在催化循环中被小分子捕获而失活，选择性差的原因可能是分散的手性催化剂对该类底物不能够提供一个比较优秀的手性口袋，而cat.13的链式结构可以提供。
进一步，经研究发现催化剂在不同的溶剂环境中的表现不一，为考察不对称转移氢化反应所用反应溶剂的种类对HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例的影响，在实施例13的基础上，反应时间为3h，S/C=1000，并依次将反应溶剂甲醇替换为四氢呋喃（THF）、异丙醇（IPA）、邻二氯乙烷（DCE）、二氯甲烷（DCM）、甲苯（toluene）、甲醇（MeOH），其他组分、含量，工艺条件均不变，进行实施例19-24；以及在实施例14的基础上， 其合成路线如下所示：
Figure 168519dest_path_image006
 
不同反应溶剂种类对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表2所示。
                       表2
  反应溶剂种类 conv.(%) dr (2a:2a’)
实施例19 THF ＞99 90:10
实施例20 IPA ＞99 91:9
实施例21 DCE ＞99 93:7
实施例22 DCM ＞99 91:9
实施例23 toluene ＞99 91:9
实施例24 MeOH ＞99 94:6
 
综上，从表2可知，在实施例13的基础上，反应时间为2h，S/C=1000，并依次将反应溶剂甲醇替换为四氢呋喃（THF）、异丙醇（IPA）、邻二氯乙烷（DCE）、二氯甲烷（DCM）、甲苯（toluene）、甲醇（MeOH），对HIV蛋白酶抑制剂中间体化合物的转化率影响较小，对dr值影响较大；其中，实施例19-24中HIV蛋白酶抑制剂中间体化合物的转化率均高于99%，实施例24所得HIV蛋白酶抑制剂中间体化合物中非对映异构体的比例为94：6，即相对现有技术提高了反应的立体控制能力。
进一步，为获得非对映异构体比例更高的HIV蛋白酶抑制剂中间体化合物，在实施例13的基础上，将氢源甲酸三乙胺替换为甲酸钠HCOONa (6 eq.)，反应时间16h，S/C = 1000，反应溶剂依次替换为水、体积比1:1 的四氢呋喃与水的混合液H 2O/THF (1:1)、体积比1:1的异丙醇与水的混合液H 2O/IPA (1:1)，进行以下实施例25-27，对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表4所示。
表4
  氢源 反应溶剂 conv.(%) dr (2a:2a’)
实施例25 HCOONa (6 eq.) H 2O 20 83:17
实施例26 HCOONa (6 eq.) H 2O/THF(1:1) 90 92:8
实施例27 HCOONa (6 eq.) H 2O/IPA(1:1) ＞99 89:11
 
综上，从表4可知，当氢源选用甲酸钠时，反应溶剂种类的选择对HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例影响显著，其中，反应溶剂为水时，转化率与立体控制性均较差，说明在S/C=1000时，实施例25-27所得HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例均不如氢源选用甲酸三乙胺的实施例。
进一步，为考察不对称转移氢化反应中不同R基团对HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例的影响，在实施例13-14的基础上，S/C=1000，反应溶剂为DCM，改变底物，将底物化合物I的R基团依次变为Boc、Bz、Ac、Ts、CBz基团，其合成路线如下所示：
Figure 709222dest_path_image007
对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表5所示。
表5
R cat. conv.(%) (S,R)-2/(S,S)-2’(yield%)
Boc ( R,R)-cat.13 ＞99 94/6(92)
Boc ( S, S)-cat.13 ＞99 4/96(93)
Bz ( R, R)-cat.13 ＞99 ＞99/1(98)
Bz ( S, S)-cat.13 ＞99 <1/99 (99)
Ac ( R, R)-cat.13 ＞99 98/2(96)
Ac ( S, S)-cat.13 ＞99 2/98(97)
Ts ( R, R)-cat.13 ＞99 98/2(97)
Ts ( S, S)-cat.13 ＞99 2/98(97)
CBz ( R, R)-cat.13 ＞99 94/6(92)
CBz ( S, S)-cat.13 ＞99 3/97(92)
 
综上，从表5可知，催化剂的手性构型决定了产物的手性构型，即S,S构型的催化剂的到SS构型的底物R,R构型的催化剂的到S,R构型的底物；催化剂对不同N保护基团的底物有很好的兼容性，有非常优异的非对映选择性，其中当氮上的保护基团是苯甲酰基的时候可以得到最佳的非对映选择性，>99:1 dr。另外，当氮上的保护基团是叔丁氧羰或者苄氧羰基的时候，S,S构型的催化剂比R,R构型催化剂的非对映选择性略高一点。这可能是底物本身是S构型，在与SS催化剂进行反应的时候，手性口袋匹配度更高一些。。
进一步，底物中R基团为苯甲酰基，以最佳催化剂cat.13作为催化剂、以DCM作为反应溶剂，以甲酸三乙胺（5:2）作为氢源，分别改变氢源用量、反应时间、底物在反应体系中浓度等，合成路线如下所示：
Figure 555955dest_path_image008
 
对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表6所示。
表6
Figure 156701dest_path_image009
 
综上，从表6中可知，在S/C=5000 的时候，甲酸三乙胺的量从1eq~100eq的改变对反应的转化率的影响不大，但是大大过量的氢源会使产物的dr值略微降低。另外，在0.1M~0.5M的浓度范围，反应体系中底物的浓度对反应的影响比较小，所以在小量反应的时候用0.1M的浓度，放大反应的时候采用0.5M的浓度。
综上，本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法，利用不对称转移氢化技术，所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比，其立体选择性和收率能够大幅提高，产物的非对映选择性比例达到94:6；另外，催化剂用量少且催化效率高，改善了反应活性，原料损耗少，整体工艺快速简便、成本大幅下降。
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作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，包括：
    将化合物1a在反应溶剂中，加入催化剂和氢源混合物进行不对称转移氢化反应，得到HIV蛋白酶抑制剂中间体化合物2a、2a’，其合成路线如下所示：
    Figure 810354dest_path_image001
    ；
    所述基团R为叔丁氧羰基、苄氧羰基、对甲苯磺酰基、乙酰基、苯甲酰基中的一种。
  2. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述催化剂为以下cat.1、cat.2、cat.3、cat.4、cat.5、cat.6、cat.7、cat.8、cat.9、cat.10、cat.11、cat.12、( R,R)-cat.13、( S,S)-cat.13、cat.14、cat.15、cat.16、cat.17中的一种或几种：
    Figure 511593dest_path_image002
    。
  3. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述氢源为甲酸三乙胺、甲酸钠中的一种或两种。
  4. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述反应溶剂为甲醇、四氢呋喃、异丙醇、邻二氯乙烷、二氯甲烷、甲苯、水、N,N-二甲基甲酰胺中的一种或几种。
  5. 如权利要求4所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述反应溶剂为体积比1:1的四氢呋喃与水的混合液、体积比1:1的异丙醇与水的混合液、体积比1:1的N,N-二甲基甲酰胺与水的混合液中的一种。
  6. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述不对称转移氢化反应在氩气或者氮气氛围下进行。
  7. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述催化剂与化合物1a的摩尔比为1:1000~5000。
  8. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述化合物1a在反应体系的浓度为0.1M~0.5M。
  9. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述不对称转移氢化反应的反应时间为2~48h。
  10. 如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法，其特征在于，所述不对称转移氢化反应的反应温度为25℃。
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