阅读说明：本技术 贝达喹啉及其中间体的制备方法 (Preparation method of bedaquiline and intermediate thereof ) 是由 郑国君 王亚平 郭立新 王志邦 王哲 陈小峰 裴冉冉 胡凯凯 高亮 高鹏鹏 张法 于 2020-07-07 设计创作，主要内容包括：本发明公开了一种贝达喹啉消旋体的制备方法及所使用的关键中间体化合物。本发明的制备贝达喹啉消旋体的方法改变了现有工艺的超低温反应,将原来工业上不容易实现的超低温反应在常规温度下进行,使大规模产业化成为可能。此外,本发明的方法大大提高了反应底物的转化率,提高了反应收率,使产品更容易结晶纯化,同时降低了生产成本。(The invention discloses a preparation method of a bedaquiline racemate and a key intermediate compound used in the preparation method. The method for preparing the bedaquiline racemate changes the ultralow temperature reaction of the prior art, and the ultralow temperature reaction which is not easy to realize in the original industry is carried out at the conventional temperature, so that the large-scale industrialization is possible. In addition, the method greatly improves the conversion rate of reaction substrates, improves the reaction yield, enables the product to be easier to crystallize and purify, and simultaneously reduces the production cost.)

1. A preparation method of a bedaquiline racemate shown as a formula X comprises the following steps:

step g): reacting the compound shown in the formula IX with copper bromide or cuprous bromide to obtain the bedaquiline racemate shown in the formula X,

2. the production method according to claim 1, wherein the reaction of step g) is carried out in the presence of nitroso-tert-butyl ester or isoamyl nitrite;

preferably, the molar ratio of the compound 1- (6-amino-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol represented by the formula IX to the nitroso-tert-butyl ester or the isoamyl nitrite to the cupric bromide or cuprous bromide is 1 (1-3) to (1-3), preferably 1:1.5: 2.

3. The production method according to claim 1 or 2, further comprising, before step g), step f): reacting the compound 1- (6- (N, N-dibenzylamino) -2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol represented by the formula VIII under the Pd/C catalytic hydrogenation condition to obtain a compound represented by the formula IX;

4. the method of claim 3, further comprising step e) prior to step f): reacting the compound 3-benzyl-6- (N, N-dibenzylamino) -2-methoxy-quinoline shown in the formula VI with the compound 3-dimethylamino-1- (naphthyl-5-yl) -1-acetone shown in the formula VII to obtain a compound shown in the formula VIII;

5. the method of claim 4, further comprising step d) prior to step e): reacting the compound 3-benzyl-6-amino-2-methoxy-quinoline shown in the formula V with benzyl halide to obtain a compound shown in a formula VI;

6. the method of claim 5, further comprising, prior to step d), step c): reacting a compound 2- (3-benzyl-2-methoxy-quinoline-6-yl) isoindole-1, 3-dione shown in a formula IV under the action of hydrazine hydrate or methylamine to obtain a compound shown in a formula V;

7. the method of claim 6, further comprising, prior to step c), step b): reacting the compound shown in the formula III with sodium methoxide to obtain a compound shown in a formula IV;

8. the method of claim 7, further comprising, prior to step b), step a): reacting a compound N- (4- (1, 3-diketoisoindol-2-yl) phenyl) -3-hydrocinnamamide shown as a formula II with DMF and POCl₃Reacting to obtain a compound shown in a formula III;

9. use of a compound of formula IX as an intermediate for the preparation of a bedaquiline racemate of formula X:

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of bedaquiline and an intermediate thereof.

Background

Bedaquiline was a drug developed by hadamard pharmaceutical limited and approved by the U.S. food and drug administration for the treatment of drug-resistant tuberculosis at 12/28 of 2012. The chemical name of the compound is (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, and the structure is shown as follows:

bedaquiline.

The bedaquiline prevents the mycobacterium tuberculosis from utilizing ATP to generate energy by inhibiting a proton transfer chain of ATP synthetase of the mycobacterium so as to play a role in resisting tuberculosis, and the bedaquiline is a brand-new action way for resisting the mycobacterium tuberculosis. Bedaquinoline is the first anti-tuberculosis drug with a new action mechanism approved for clinical use for more than 40 years, and is the only drug for treating multi-drug resistant tuberculosis at present.

Relatively few documents report synthetic routes to bedaquiline. European Journal of organic chemistry, (11),2057-2061, 2011 reports a process for preparing bedaquiline by chiral catalysis and asymmetric synthesis. The method has high yield, but has the problems of more steps, use of expensive reagents and catalysts and unsuitability for industrial production. The specific synthetic route is as follows:

patent documents US2005148581A and CN101180302A disclose a method for obtaining a racemate of bedaquiline by taking 4-bromoaniline and phenylpropionyl chloride as starting materials through multi-step reactions, and then obtaining a target product through chiral column chromatography purification or induced recrystallization by introducing a chiral reagent, wherein the specific synthetic route is as follows:

the process route has low material cost and simple operation, but the compound 1 and the compound 3 react at-78 ℃ under the action of LDA, the reaction time is long, the raw materials cannot be completely converted, the side reactions are more, the purity of the obtained bedaquiline is not high, the yield is very low, and the total yield is about 6%.

Patent document CN105085395A discloses a method in which compound 1 and compound 4 are reacted and then reduced to obtain a bedaquiline racemate. The specific synthetic route is as follows,

patent document CN105175329A discloses a method for obtaining a bedaquiline racemate by reacting a grignard reagent with naphthaldehyde, oxidizing the reaction product, and then reusing the grignard reagent. The specific synthetic route is as follows:

however, the above methods have some problems. For example, the first method is not suitable for industrial production because of long steps, expensive reagents and harsh reaction conditions. The second and third methods inevitably require reaction at ultralow temperature, and are not suitable for industrial production. The main reason for the above problems is that compound 1 has two reaction sites under the action of LDA, the first is benzyl of quinoline ring, which is the desired reaction site and relatively active, and the second is bromine on quinoline ring can react under the action of LDA to generate debrominated byproduct. In order to allow the reaction to proceed at the desired site, good selectivity can be obtained only under ultra-low temperature conditions. In addition, the reaction can generate two chiral centers, four chiral isomers and four chiral isomers of the debrominated product, and the target configuration can be obtained almost impossible by crystallization purification, so the reaction must be carried out under the condition that the reaction temperature is strictly controlled below-70 ℃. In addition, two substrates, compound 1 and compound 3, have large reaction steric hindrance, and have the advantages of low required reaction temperature, long reaction time and huge energy consumption. At present, many domestic medicine enterprises do not have large-scale ultralow temperature reaction kettles, the low reaction temperature is easy to realize in a laboratory or a reaction kettle of 100L-200L, but the large reaction kettle of thousands of liters is very difficult to implement. While the fourth method, although avoiding the ultra-low temperature reaction, requires two grignard reactions. Particularly, in the first Grignard reaction, two bromines exist on a reaction substrate, so that the selectivity is poor under the condition of magnesium powder, the yield is low, and the impurity removal is difficult. Thus, current processes limit the large scale production of bedaquiline to some extent.

Disclosure of Invention

In order to improve the technical problems, the invention firstly provides a compound shown as the following formula III,

the invention also provides a preparation method of the compound shown in the formula III, which comprises the following steps:

step a): reacting a compound N- (4- (1, 3-diketoisoindol-2-yl) phenyl) -3-hydrocinnamide shown as a formula II in DMF and POCl₃Under the action of the compound of the formula III,

according to an embodiment of the present invention, the reaction time in step a) may be 2 to 10 hours.

According to an embodiment of the present invention, in the step a), the reaction temperature may be 10 to 120 ℃, for example, 30 to 110 ℃, 50 to 100 ℃, for example, 80 ℃.

According to an embodiment of the invention, in step a), N- (4- (1, 3-diketoisoindol-2-yl) phenyl) -3-phenylacrylamide is reacted with DMF and POCl₃The molar ratio of (1) - (10) - (1-10) may be 1 (2) - (9) (2-9), 1 (3) - (8) (3-8), 1 (4) - (7) (4-7), such as 1:5:5, 1:6:5, 1:5:6, 1:5:7, 1:7:5, etc.

According to an embodiment of the present invention, step a) may be carried out in a suitable organic solvent which may be any suitable solvent including, but not limited to, toluene, chlorobenzene, acetonitrile.

In one embodiment, the compound of formula II, N- (4- (1, 3-diketoisoindol-2-yl) phenyl) -3-phenylpropanamide, can be prepared by the following step 1):

step 1): reacting 2- (4-aminophenyl) isoindole-1, 3-dione shown in formula I with phenylpropionyl chloride under the action of alkali to obtain a compound shown in formula II,

the reaction time of step 1) may be 1 to 10 hours, for example, 1 to 8 hours, 2 to 7 hours, preferably 2 to 3 hours.

The reaction temperature in step 1) may be 0 ℃ to 80 ℃, and more preferably 10 ℃ to 30 ℃, for example, room temperature.

The base in step 1) may be an inorganic base, which may be, for example, one, two or more of lithium carbonate, potassium carbonate, sodium carbonate, tripotassium phosphate and trisodium phosphate, or an organic base. The organic base may be, for example, one, two or more of triethylamine, tributylamine, pyridine, 4-dimethylaminopyridine and DBU.

In the step 1), the molar ratio of the compound 2- (4-aminophenyl) isoindole-1, 3-dione represented by the formula I to the phenylpropionyl chloride and the base may be 1 (1-2) to (1-4), such as 1 (1.01-1.9) to (1.1-3.5), 1 (1.02-1.8) to (1.2-3), 1 (1.03-1.7) to (1.3-2.5), 1 (1.04-1.6) to (1.4-2), 1 (1.05-1.6) to (1.5-1.9), such as 1:1.05: 1.5.

The reaction of step 1) may be carried out in any suitable organic solvent, which may be, for example, one, two or more of dichloromethane, 1, 2-dichloroethane, toluene, chlorobenzene, dioxane, acetonitrile, THF, DMF, DMSO, N-dimethylacetamide and N-methylpyrrolidone.

In one embodiment, the compound 2- (4-aminophenyl) isoindole-1, 3-dione of formula I can be prepared by the following step 0):

step 0): reacting phthalic anhydride with p-phenylenediamine to obtain a compound shown in a formula I;

the reaction time of step 0) may be 1 to 5 hours, preferably 3 hours;

the reaction temperature in step 0) may be 10 to 150 ℃, for example 10 to 130 ℃.

In the reaction of step 0), the molar ratio of phthalic anhydride to p-phenylenediamine may be 1 (1-2), for example, 1 (1.05-1.9), 1 (1.1-1.8), 1 (1.15-1.7), 1 (1.2-1.6), for example, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, etc.

The reaction of step 0) may be carried out in any suitable organic solvent, which may be, for example, one, two or more of 1, 2-dichloroethane, toluene, chlorobenzene, dioxane, DMF, DMSO, N-dimethylacetamide and N-methylpyrrolidone.

The invention also provides the application of the compound shown in the formula III in preparing the compound shown in the formula IV,

the present invention also provides a compound of formula IV as described above,

the invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps:

step b): reacting the compound shown in the formula III with sodium methoxide to obtain a compound shown in a formula IV,

according to an embodiment of the invention, in step b), the reaction time may be 2 to 10 hours, for example 8 hours.

According to an embodiment of the present invention, in step b), the temperature of the reaction may be 10 to 80 ℃, for example 15 to 70 ℃, for example 65 ℃.

According to an embodiment of the invention, in step b), the molar ratio of 2- (3-benzyl-2-chloro-quinolin-6-yl) isoindole-1, 3-dione to sodium methoxide may be 1 (1 to 10), such as 1 (1.5 to 9), 1 (2 to 8), 1 (2.5 to 7), 1 (3 to 6), such as 1:3, 1:4, 1:5 or 1: 6.

According to an embodiment of the present invention, in step b), the reaction may be carried out in any suitable organic solvent, which may be, for example, one, two or more of methanol, dioxane, THF and methyltetrahydrofuran, preferably methanol.

The invention also provides the use of a compound of formula IV in the preparation of compound V,

the invention also provides a compound of formula V as described above,

the invention also provides a preparation method of the compound shown in the formula V, which comprises the following steps:

step c): reacting a compound 2- (3-benzyl-2-methoxy-quinoline-6-yl) isoindole-1, 3-dione shown in a formula IV under the action of hydrazine hydrate or methylamine to obtain a compound shown in a formula V,

according to an embodiment of the invention, in step c), the molar ratio of 2- (3-benzyl-2-methoxy-quinolin-6-yl) isoindole-1, 3-dione to hydrazine hydrate may be 1 (1 to 5), such as 1 (1.5 to 4.5), 1 (2 to 4), such as 1:2.

According to an embodiment of the present invention, in step c), the reaction time may be 5 to 30 hours, such as 6 to 20 hours, such as 7 to 15 hours, such as 8 hours.

According to an embodiment of the present invention, in the step c), the temperature of the reaction may be 10 to 100 ℃, for example, 10 to 80 ℃, 10 to 60 ℃, for example, 10 to 30 ℃.

According to an embodiment of the present invention, in step c), the reaction may be carried out in any suitable organic solvent, which may be, for example, one, two or more of dichloromethane, methanol, ethanol, dioxane, acetonitrile, THF, DMF, DMSO, N-dimethylacetamide and N-methylpyrrolidone, preferably methanol or a mixture of ethanol and dichloromethane.

The invention also provides the use of a compound of formula V for the preparation of compound VI,

the present invention also provides a compound of formula VI as described above,

the invention also provides a preparation method of the compound shown as the formula VI, which comprises the following steps:

step d): reacting the compound 3-benzyl-6-amino-2-methoxy-quinoline shown in the formula V with benzyl halide to obtain a compound shown in a formula VI,

according to an embodiment of the present invention, in step d), the benzyl halide may be benzyl chloride, benzyl bromide or a mixture of the two in any ratio.

According to an embodiment of the present invention, in the step d), the reaction time may be 4 to 12 hours, for example, 5 to 11 hours, 6 to 10 hours, for example, 7 hours, 8 hours, 9 hours or 10 hours.

According to an embodiment of the present invention, in the step d), the temperature of the reaction may be 10 to 100 ℃, for example 20 to 90 ℃, 30 to 80 ℃, for example 40 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃.

According to an embodiment of the present invention, in step d), the reaction may be carried out in the presence of a base, which may be an inorganic base or an organic base, including but not limited to lithium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, tripotassium phosphate, trisodium phosphate, pyridine, DBU.

According to an embodiment of the invention, in step d), the molar ratio of 3-benzyl-6-amino-2-methoxy-quinoline to benzyl halide may be 1 (2 to 4), such as 1 (2.1 to 3.9), 1 (2.2 to 3.8), 1 (2.3 to 3.7), 1 (2.4 to 3.6), 1 (2.5 to 3.5), such as 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3:4, 1: 3.5.

According to an embodiment of the invention, the molar ratio of 3-benzyl-6-amino-2-methoxy-quinoline to benzyl halide and base in step d) may be 1 (2-4) to (2-5), e.g. 1:3: 4.

According to an embodiment of the present invention, in step d), the reaction may be carried out in any suitable organic solvent, which may be, for example, one, two or more of toluene, dioxane, acetonitrile, THF, DMF, DMSO, N-dimethylacetamide, N-methylpyrrolidone, and the like.

The invention also provides the application of the compound shown in the formula VI in preparing the compound VIII,

the present invention also provides a compound of formula VIII as described above,

the invention also provides a preparation method of the compound shown in the formula VIII, which comprises the following steps:

step e): reacting the compound 3-benzyl-6- (N, N-dibenzylamino) -2-methoxy-quinoline shown as the formula VI with the compound 3-dimethylamino-1- (naphthyl-5-yl) -1-acetone shown as the formula VII to obtain a compound shown as the formula VIII,

according to an embodiment of the invention, in step e), the reaction time may be 1 to 5 hours, for example 1 to 4 hours.

According to an embodiment of the invention, the temperature of the reaction in step e) may be in the range of-20 ℃ to 30 ℃, e.g. 0 ℃ to 30 ℃.

According to an embodiment of the present invention, in step e), the reaction may be carried out in any suitable organic solvent, which may be, for example, tetrahydrofuran or 2-methyltetrahydrofuran.

According to an embodiment of the invention, in step e), the reaction may be carried out under the action of LDA. According to an embodiment of the present invention, in step e), the molar ratio of compound VI to compound VII may be 1 (1 to 3), such as 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1: 3.0.

According to an embodiment of the present invention, in step e), the molar ratio of the compound VI to the compound VII to the LDA is 1 (1-3) to (1-2), such as 1 (1-2) to (1-1.5), such as 1:1.3: 1.1.

The invention also provides the application of the compound shown in the formula VIII in preparing the compound IX,

the present invention also provides a compound of formula IX as described above,

the present invention also provides a process for the preparation of a compound of formula IX as described above, comprising the steps of:

step f): reacting a compound 1- (6- (N, N-dibenzylamino) -2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol represented by formula VIII under Pd/C catalytic hydrogenation conditions to obtain a compound represented by formula IX,

according to an embodiment of the present invention, in step f), the reaction time may be 1 to 8 hours, such as 2 to 7 hours, such as 4 to 5 hours.

According to an embodiment of the present invention, in the step f), the temperature of the reaction may be 10 to 60 ℃, for example, 10 to 30 ℃.

According to an embodiment of the invention, in step f), the weight ratio of the compound 1- (6- (N, N-dibenzylamino) -2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol of formula VIII to Pd/C may be 1:0.01 to 0.2, e.g. 1:0.01 to 1: 0.05.

According to an embodiment of the present invention, in step f), the reaction may be carried out in any suitable organic solvent, which may be, for example, one, two or more of methanol, ethanol, ethyl acetate, toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

The invention also provides application of the compound shown in the formula IX in preparation of a bedaquiline racemate shown in the formula X.

The invention also provides a preparation method of the bedaquiline racemate shown in the formula X, which comprises the following steps:

step g): reacting the compound shown in the formula IX with copper bromide or cuprous bromide to obtain the bedaquiline racemate shown in the formula X,

according to an embodiment of the present invention, in step g), the reaction time may be 1 to 5 hours, such as 2 to 4 hours, such as 3 hours.

According to an embodiment of the invention, the temperature of the reaction in step g) may be from 0 ℃ to 70 ℃, such as from 0 ℃ to 50 ℃, such as from 0 ℃ to 20 ℃.

According to an embodiment of the invention, in step g), the reaction is carried out in the presence of tert-butyl nitrosonitrite or isoamyl nitrite.

According to an embodiment of the invention, in step g), the molar ratio of the compound 1- (6-amino-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol of formula IX to nitroso-tert-butyl ester or isoamyl nitrite and cupric bromide or cuprous bromide may be 1 (1-3) to (1-3), preferably 1:1.5: 2.

According to an embodiment of the present invention, in step g), the reaction may be carried out in a solvent, which may be any suitable solvent that dissolves the reactants but does not react with the reactants, including but not limited to DMF, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, water, acetone, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof.

As one embodiment, the bedaquiline racemate represented by the formula X is prepared by the following method,

the method comprises the following steps:

step a): reacting a compound N- (4- (1, 3-diketoisoindol-2-yl) phenyl) -3-hydrocinnamamide shown as a formula II with DMF and POCl₃Reacting to obtain a compound shown in a formula III;

step b): reacting the compound shown in the formula III with sodium methoxide to obtain a compound shown in a formula IV;

step c): reacting a compound 2- (3-benzyl-2-methoxy-quinoline-6-yl) isoindole-1, 3-dione shown in a formula IV under the action of hydrazine hydrate or methylamine to obtain a compound shown in a formula V;

step d): reacting the compound 3-benzyl-6-amino-2-methoxy-quinoline shown in the formula V with benzyl halide to obtain a compound shown in a formula VI;

step e): reacting the compound 3-benzyl-6- (N, N-dibenzylamino) -2-methoxy-quinoline shown in the formula VI with the compound 3-dimethylamino-1- (naphthyl-5-yl) -1-acetone shown in the formula VII to obtain a compound shown in the formula VIII;

step f): reacting the compound 1- (6- (N, N-dibenzylamino) -2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol represented by the formula VIII under the Pd/C catalytic hydrogenation condition to obtain a compound represented by the formula IX; and

step g): and (3) reacting the compound shown as the formula IX with copper bromide or cuprous bromide to obtain the bedaquiline racemate shown as the formula X.

Advantageous effects

The invention provides Bedaquinoline key intermediates (compounds III-VIII) with novel structures and preparation methods of the intermediates. The invention also provides a novel method for preparing the bedaquiline racemate according to the intermediate, so that the bedaquiline racemate can be industrially produced more conveniently, efficiently and economically. The advantages of the invention are embodied in:

1. the preparation method of the bedaquiline racemate thoroughly changes the ultralow temperature reaction of the prior art, and carries out the ultralow temperature reaction which is difficult to realize in the prior industry at the conventional temperature, so that the large-scale industrialization is possible.

2. The method greatly improves the conversion rate of the reaction substrate, improves the reaction yield, enables the product to be easier to crystallize and purify, and simultaneously reduces the production cost.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.