阅读说明：本技术 一种hiv蛋白酶抑制剂中间体化合物的合成方法 (Synthetic method of HIV protease inhibitor intermediate compound ) 是由 稂琪伟 丁小兵 高爽 于 2019-08-30 设计创作，主要内容包括：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：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。(The invention is applicable to the technical field of drug synthesis, and provides a method for synthesizing an HIV protease inhibitor intermediate compound, which comprises the following steps: under the protection of argon, adding a catalyst and a hydrogen source mixture into a reaction solvent to carry out asymmetric transfer hydrogenation reaction to obtain HIV protease inhibitor intermediate compounds 2a and 2 a', wherein the synthetic route is as follows:)

1. A method of synthesizing an HIV protease inhibitor intermediate compound, comprising:

adding a catalyst and a hydrogen source mixture into a reaction solvent to carry out asymmetric transfer hydrogenation reaction on the compound 1a to obtain HIV protease inhibitor intermediate compounds 2a and 2 a', wherein the synthetic route is as follows:

the group R is one of tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, acetyl and benzoyl.

2. The method for synthesizing the intermediate compound of HIV protease inhibitor according to claim 1, wherein the catalyst is one or more of the following 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:

3. the method of synthesizing an intermediate compound of an HIV protease inhibitor according to claim 1, wherein the hydrogen source is one or both of triethylamine formate and sodium formate.

4. The method of synthesizing an intermediate compound of an HIV protease inhibitor according to claim 1, wherein the reaction solvent is one or more of methanol, tetrahydrofuran, isopropanol, o-dichloroethane, dichloromethane, toluene, water, N-dimethylformamide.

5. The method for synthesizing an intermediate compound of an HIV protease inhibitor according to claim 4, wherein the reaction solvent is one of 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 mixture of N, N-dimethylformamide and water in a volume ratio of 1: 1.

6. The method of synthesizing an HIV protease inhibitor intermediate compound as claimed in claim 1, wherein the asymmetric transfer hydrogenation reaction is performed under an argon or nitrogen atmosphere.

7. The method for synthesizing the intermediate compound of the HIV protease inhibitor according to claim 1, wherein the molar ratio of the catalyst to the compound 1a is 1: 1000-5000.

8. The method of synthesizing an intermediate compound for an HIV protease inhibitor according to claim 1, wherein the concentration of the compound 1a in the reaction system is 0.1M to 0.5M.

9. The method for synthesizing an HIV protease inhibitor intermediate compound according to claim 1, wherein the reaction time of the asymmetric transfer hydrogenation reaction is 2 to 48 hours.

10. The method of synthesizing an HIV protease inhibitor intermediate compound as claimed in claim 1, wherein the reaction temperature of the asymmetric transfer hydrogenation reaction is 25 ℃.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of an HIV protease inhibitor intermediate compound.

Background

AIDS is one of the most difficult diseases to cure in the world. In the past decades, significant progress has been made in the treatment of aids, HIV protease inhibitors are currently the most promising therapeutic technologies, but the high drug price makes many aids patients abandon treatment, so it is crucial to develop a synthetic method of HIV protease inhibitor intermediates with high efficiency and low price, and the structures of the currently common HIV protease inhibitors and intermediates thereof are shown as follows:

in the prior art, the intermediate is mainly synthesized by adopting an enzyme catalysis and asymmetric hydrogenation method, wherein chiral amino aldehyde is adopted as a raw material, the intermediate is synthesized by a chemical method, and a large amount of chemical reagent NaBH is needed₄Reducing to obtain a product with poor stereoselectivity control, and obtaining a product with a single configuration by recrystallization; in 2001, the group b.moon Kim reported that the intermediate was synthesized by a multi-step complex process using a natural chiral source as a starting material; in 2013, Ioannis N.Houpis synthesizes the intermediate by using asymmetric hydrogenation and enzyme catalysis methods respectively, although the stereoselectivity is better, the catalytic activity is poor, the conversion can not be complete under most conditions, the raw material loss is large, and the enzyme dosage is also large.

Therefore, the existing method for synthesizing the HIV protease inhibitor intermediate has the problems of poor stereoselectivity control, low reaction activity, large raw material loss and complex synthesis process.

Disclosure of Invention

The embodiment of the invention provides a method for synthesizing an HIV protease inhibitor intermediate compound, aiming at solving the problems of poor stereoselectivity control, low reaction activity, large raw material loss and complex synthesis process existing in the conventional method for synthesizing the HIV protease inhibitor intermediate.

The embodiment of the invention is realized by a method for synthesizing an HIV protease inhibitor intermediate compound, which comprises the following steps:

adding a catalyst and a hydrogen source mixture into a reaction solvent to carry out asymmetric transfer hydrogenation reaction on the compound 1a to obtain HIV protease inhibitor intermediate compounds 2a and 2 a', wherein the synthetic route is as follows:

the group R is one of tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, acetyl and benzoyl.

According to the synthesis method of the HIV protease inhibitor intermediate compound provided by the embodiment of the invention, by using an asymmetric transfer hydrogenation technology, compared with the existing similar intermediate, the stereoselectivity and yield of the synthesized HIV protease inhibitor intermediate compound can be greatly improved, and the diastereoselectivity ratio of the product reaches 94: 6; in addition, the catalyst has the advantages of small using amount, high catalytic efficiency, improved reaction activity, less raw material loss, quick and simple whole process and greatly reduced cost.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

According to the synthesis method of the HIV protease inhibitor intermediate compound provided by the embodiment of the invention, under the protection of argon, the compound 1a is added into a reaction solvent, a catalyst and a hydrogen source mixture are added for an asymmetric transfer hydrogenation reaction, and the HIV protease inhibitor intermediate compounds 2a and 2 a' are obtained, wherein the synthesis route is as follows:

nomenclature of compound 1 a:

tert-butyl(S)-(4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate。

nomenclature of HIV protease inhibitor intermediate compounds:

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。

in the embodiment of the invention, the group R is one of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz), p-toluenesulfonyl (Ts), acetyl (Ac) and benzoyl (Bz).

In the examples of the present invention, the structure of the catalyst used in the transfer hydrogenation process is shown below:

in the embodiment of the invention, 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 to 0.5M.

In the embodiment of the invention, the asymmetric transfer hydrogenation reaction is carried out under the protection of argon or nitrogen.

In the embodiment of the invention, the reaction solvent is one or more of methanol, tetrahydrofuran, isopropanol, o-dichloroethane, dichloromethane, toluene, water and N, N-dimethylformamide.

In the embodiment of the present invention, the reaction solvent may be one of a mixed solution of tetrahydrofuran and water in a volume ratio of 1:1, a mixed solution of isopropanol and water in a volume ratio of 1:1, and a mixed solution of N, N-dimethylformamide and water in a volume ratio of 1: 1.

In the embodiment of the invention, the hydrogen source is one or two of triethylamine formate (5:2) azeotropic mixture and sodium formate.

In the embodiment of the invention, the reaction time of the asymmetric transfer hydrogenation reaction is 2-16 h, wherein the reaction time of the system is different under the condition of different reaction solvents or different hydrogen sources, and when the hydrogen source is triethylamine formate, and the reaction solvents are tetrahydrofuran, isopropanol, o-dichloroethane, dichloromethane and toluene, the corresponding reaction time is preferably 2 h; when the hydrogen source is triethylamine formate and the reaction solvent is methanol, the corresponding reaction time is preferably 12 h; when the hydrogen source is sodium formate and the reaction solvents are water, a mixed solution of tetrahydrofuran and water, a mixed solution of isopropanol and water and a mixed solution of N, N-dimethylformamide and water, the corresponding reaction time is 16 h.

In the embodiment of the invention, the reaction temperature of the asymmetric transfer hydrogenation reaction is 25 ℃; when the reaction temperature is higher than 30 ℃, the heating system becomes complicated, so that the examples of the present invention are all carried out at 25 ℃.

According to the synthesis method of the HIV protease inhibitor intermediate compound provided by the embodiment of the invention, by using an asymmetric transfer catalysis technology, compared with the existing similar intermediate, the stereoselectivity and yield of the synthesized HIV protease inhibitor intermediate compound can be greatly improved, and the diastereoselectivity ratio of the product reaches 94: 6; in addition, the catalyst has the advantages of small using amount, high catalytic efficiency, improved reaction activity, less raw material loss, quick and simple whole process and greatly reduced cost.

The technical effects of the method for synthesizing the intermediate compound of the HIV protease inhibitor of the present invention will be further described below by way of specific examples.

Example 1

The compound 1a (0.2mmol) is added into methanol (2mL) at the temperature of 25 ℃ under the protection of argon, a mixture of a catalyst cat.1 and triethylamine formate (5:2) (40uL) is added (100 uL is used for taking 0.002M methanol solution as the catalyst), and the asymmetric transfer hydrogenation reaction is carried out for 16h, so as to obtain HIV protease inhibitor intermediate compounds 2a and 2 a', wherein the synthetic route is shown as follows:

examples 2 to 18

In order to examine the influence of the type of the catalyst used in the asymmetric transfer hydrogenation reaction on the conversion rate (conv.) and the diastereomer ratio (dr) of the HIV protease inhibitor intermediate compound, the catalyst cat.1 is replaced by 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, and (S, S) -cat.13, cat.14, cat.15, cat.16 and cat.17 in sequence on the basis of example 1.

The results of the effect of the different catalysts of examples 1-18 on the conversion and dr values of the intermediate compounds of the HIV protease inhibitor are shown in table 1 below; where the conversion is determined by LC (reversed phase C18 column) and the dr value is determined by LC and NMR hydrogen and carbon spectra.

TABLE 1

From the above, it is clear from table 1 that the kind of catalyst determines the stereoselectivity of the entire reaction. Examples 1-18 respectively used different catalysts, the diastereoselectivity of the reaction was very large, and the difference in activity was also large, and the difference in activity relative to the optimal catalyst cat.13 may be that other catalyst structures are relatively dispersed and are easily captured by small molecules in the catalytic cycle to be inactivated, and the reason for the poor selectivity may be that the dispersed chiral catalyst cannot provide a relatively excellent chiral pocket for such substrates, and the chain structure of cat.13 can provide.

Further, it was found through studies that the catalysts showed different performances in different solvent environments, and to examine the influence of the kind of reaction solvent used in asymmetric transfer hydrogenation reaction on the conversion rate of the HIV protease inhibitor intermediate compound and the ratio of diastereoisomers, on the basis of example 13, the reaction time was 3 hours, S/C was 1000, and the reaction solvents methanol was sequentially replaced with Tetrahydrofuran (THF), Isopropanol (IPA), o-Dichloroethane (DCE), Dichloromethane (DCM), toluene (tolumene), methanol (MeOH), other components, contents, and process conditions were all unchanged, and examples 19 to 24 were performed; and on the basis of example 14, the synthetic route is as follows:

the results of the effect of different reaction solvent types on the conversion and dr values of the intermediate compounds of the HIV protease inhibitor are shown in table 2 below.

TABLE 2

	Kind of reaction solvent	conv.(％)	dr(2a:2a’)
				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

As can be seen from table 2, in example 13, when the reaction time was 2 hours and S/C was 1000, and the reaction solvents methanol were sequentially replaced with Tetrahydrofuran (THF), Isopropanol (IPA), o-Dichloroethane (DCE), Dichloromethane (DCM), toluene (tolumene), and methanol (MeOH), the conversion of the HIV protease inhibitor intermediate compound was less affected, and the dr value was more affected; wherein the conversion rates of the HIV protease inhibitor intermediate compounds of examples 19-24 were all above 99%, and the ratio of diastereoisomers in the HIV protease inhibitor intermediate compound obtained in example 24 was 94:6, namely, the three-dimensional control capability of the reaction is improved compared with the prior art.

Further, to obtain an intermediate compound of an HIV protease inhibitor having a higher diastereomer ratio, triethylamine hydrogen formate was replaced with sodium formate HCOONa (6eq.) for 16 hours, S/C was 1000, and the reaction solvent was sequentially replaced with water and a mixture H of tetrahydrofuran and water at a volume ratio of 1:1 in example 13₂O/THF (1:1), mixed solution H of isopropanol and water in a volume ratio of 1:1₂The results of the effects of O/IPA (1:1), conducted in examples 25-27 below, on the conversion and dr values of the HIV protease inhibitor intermediate compounds are shown in Table 3 below.

TABLE 3

	Hydrogen source	Reaction solvent	conv.(％)	dr(2a:2a’)
					Example 25	HCOONa(6eq.)	H2O	20	83:17
Example 26	HCOONa(6eq.)	H2O/THF(1:1)	90	92:8
					Example 27	HCOONa(6eq.)	H2O/IPA(1:1)	＞99	89:11

As can be seen from table 3, when sodium formate is used as the hydrogen source, the selection of the reaction solvent has a significant effect on the conversion rate of the HIV protease inhibitor intermediate compound and the ratio of the diastereoisomers, wherein the conversion rate and the stereocontrol are poor when the reaction solvent is water, which means that the conversion rate and the ratio of the diastereoisomers of the HIV protease inhibitor intermediate compounds obtained in examples 25 to 27 are inferior to those of the example in which triethylamine formate is used as the hydrogen source when S/C is 1000.

Further, to examine the effect of different R groups on the conversion rate of HIV protease inhibitor intermediate compounds and the ratio of diastereoisomers in asymmetric transfer hydrogenation reactions, on the basis of examples 13-14, S/C ═ 1000, the reaction solvent is DCM, the substrate was changed, and the R groups of substrate compound I were sequentially changed into Boc, Bz, Ac, Ts, CBz groups, and the synthetic route is as follows:

the results of the effect on the conversion of the intermediate compounds of the HIV protease inhibitor and the dr value are shown in table 4 below.

TABLE 4

In summary, it can be seen from table 4 that the chiral configuration of the catalyst determines the chiral configuration of the product, i.e. the substrate R to SS configuration of the catalyst in S, S configuration, the substrate to S, R configuration of the catalyst in R configuration; the catalyst has good compatibility with substrates of different N protective groups and excellent diastereoselectivity, wherein the optimal diastereoselectivity can be obtained when the protective group on nitrogen is benzoyl and is more than 99:1 dr. In addition, when the protecting group on nitrogen is tert-butoxycarbonyl or benzyloxycarbonyl, the catalyst of S, S configuration has slightly higher diastereoselectivity than the catalyst of R, R configuration. This may be the substrate itself in the S configuration, with a higher degree of chiral pocket matching when reacted with the SS catalyst. .

Further, the R group in the substrate is benzoyl, the optimal catalyst cat.13 is used as a catalyst, DCM is used as a reaction solvent, triethylamine formate (5:2) is used as a hydrogen source, the hydrogen source dosage, the reaction time, the concentration of the substrate in the reaction system and the like are respectively changed, and the synthetic route is as follows:

the results of the effect on the conversion of the intermediate compounds of the HIV protease inhibitor and the dr value are shown in table 5 below.

TABLE 5

From table 5, it can be seen that the change in the amount of triethylamine formate from 1eq to 100eq does not greatly affect the conversion of the reaction at S/C5000, but the dr value of the product is slightly decreased by a large excess of hydrogen source. In addition, in the 0.1M to 0.5M concentration range, the reaction system substrate concentration on the reaction is relatively small, so in a small amount of reaction time with 0.1M concentration, amplification of the reaction time with 0.5M concentration.

In summary, the synthesis method of the intermediate compound of the HIV protease inhibitor provided by the embodiment of the present invention utilizes the asymmetric transfer hydrogenation technology, and compared with the existing similar intermediate, the stereoselectivity and yield of the synthesized intermediate compound of the HIV protease inhibitor can be greatly improved, and the diastereoselectivity ratio of the product reaches 94: 6; in addition, the catalyst has the advantages of small using amount, high catalytic efficiency, improved reaction activity, less raw material loss, quick and simple whole process and greatly reduced cost.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.