阅读说明：本技术 (1r)-2-[[[2-(4-硝基苯基)乙基]氨基]甲基]苯甲醇盐酸盐的合成方法 (Synthesis method of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride ) 是由 高元 崔槐杰 宗杨磊 于 2019-11-18 设计创作，主要内容包括：本发明公开了一种(1R)-2-[[[2-(4-硝基苯基)乙基]氨基]甲基]苯甲醇盐酸盐的合成方法,包括以下加工步骤：S1、室温条件下,将将1R-2氯-1-苯乙醇、对硝基苯乙胺加入到甲醇中混合；S2、将混合液升温至60~65℃后,搅拌回流1~48h,降温；S3、在反应液中加入溶剂冷却,过滤得到(1R)-2-[[[2-(4-硝基苯基)乙基]氨基]甲基]苯甲醇盐酸盐,所述步骤S1中1R-2氯-1-苯乙醇和对硝基苯乙胺的摩尔比1:1～20,所述步骤S1中对硝基苯乙胺的甲醇溶液的溶度为25%～28%,其用量是1R-2氯-1-苯乙醇质量的1～1.5倍。本发明反应较为温和且操作简单,不仅没有使用具有刺激性的有机溶剂,也没有使用具有危险性的硼烷二甲硫醚,不仅反应过程绿色环保,实现了清洁生产,而且降低了成本,具有较好市场竞争力。(The invention discloses a synthesis method of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride, which comprises the following processing steps: s1, adding 1R-2 chloro-1-phenethyl alcohol and p-nitroanisole into methanol at room temperature, and mixing; s2, heating the mixed solution to 60-65 ℃, stirring and refluxing for 1-48 h, and cooling; s3, adding a solvent into the reaction liquid, cooling and filtering to obtain (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride, wherein the molar ratio of 1R-2 chloro-1-phenethyl alcohol to p-nitroanisole in the step S1 is 1: 1-20, and the solubility of the methanol solution of the p-nitroanisole in the step S1 is 25-28%, and the dosage of the methanol solution is 1-1.5 times of the mass of the 1R-2 chloro-1-phenethyl alcohol. The method has mild reaction and simple operation, does not use irritant organic solvent or dangerous borane dimethyl sulfide, is green and environment-friendly in reaction process, realizes clean production, reduces cost and has better market competitiveness.)

1. A method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride is characterized in that: the method comprises the following processing steps:

s1, adding 1R-2 chloro-1-phenethyl alcohol and p-nitroanisole into methanol at room temperature, and mixing;

s2, heating the mixed solution to 60-65 ℃, stirring and refluxing for 1-48 h, and cooling;

s3, adding a solvent into the reaction solution, cooling and filtering to obtain (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride.

2. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: in the step S1, the molar ratio of 1R-2 chloro-1-phenethyl alcohol to p-nitrophenyl ethylamine is 1: 1-20.

3. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: in the step S1, the solubility of the methanol solution of the p-nitroanisole is 25-28%, and the dosage of the methanol solution is 1-1.5 times of the mass of the 1R-2 chloro-1-phenylethyl alcohol.

4. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: in the step S3, the solvent is one or more of acetone, dichloromethane, chloroform, toluene, ethyl acetate, methyl tert-butyl ether, n-hexane and petroleum ether.

5. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: the dosage of the solvent in the step S3 is 4-5 times of the mass of the 1R-2 chloro-1-phenethyl alcohol.

6. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: the solvent in step S1 is methanol.

7. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: and in the step S2, the stirring reflux time is 8-12 h.

8. The method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride according to claim 1, wherein: the cooling temperature in the step S2 is 20-25 ℃.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride.

Background

Mirabegron, which is used for treating overactive bladder of adults. Clinical test data show that compared with the existing clinical treatment of overactive bladder of adults, the mirabegron has the characteristics of quick response, good tolerance, no sexual dysfunction to patients, small adverse reaction and the like. The chemical name of the compound is 2-amino-N- [4- [2- [ [ (2R) -2-hydroxy-2-phenylethyl ] amino ] ethyl ] phenyl ] -4-thiazole acetamide, and the chemical formula is as follows:

and (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride is an important intermediate for synthesizing mirabegron. The prior art literature on the synthesis of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride is filed by a patent application (publication number: EP1440969, 2004, A1) which relates to a process for the preparation of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride, comprising the following steps: a) Condensing D-mandelic acid and p-nitrophenylethylamine hydrochloride in an organic solvent at 25-45 ℃ to obtain (R) 2-hydroxy-N- [2- (4-nitro-phenyl) -ethyl ] -2-phenyl-acetamide; b) mixing (R) 2-hydroxy-N- [2- (4-nitro-phenyl) -ethyl ] -2-phenyl-acetamide and a solvent in an organic solvent, and reducing with borane dimethyl sulfide to obtain (R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol; c) The organic solvent is one or more of tetrahydrofuran, chloroform, dichloroethane, carbon tetrachloride, toluene, xylene, N-dimethylformamide and tetrahydrofuran. The chemical reaction formula is as follows:

the (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride prepared by the method has low yield, and borane dimethyl sulfide is adopted in the reaction step, wherein the borane dimethyl sulfide is harmful to human health, and the processing cost is high.

Disclosure of Invention

The invention aims to provide a method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride, which has the advantages of few reaction steps, high yield of final products and environmental protection.

In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride comprises the following processing steps:

s1, adding 1R-2 chloro-1-phenethyl alcohol and p-nitroanisole into methanol at room temperature, and mixing;

s2, heating the mixed solution to 60-65 ℃, stirring and refluxing for 1-48 h, and cooling;

s3, adding a solvent into the reaction solution, cooling and filtering to obtain (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride.

The technical scheme of further improvement in the technical scheme is as follows:

1. in the scheme, the molar ratio of the 1R-2 chloro-1-phenethyl alcohol to the p-nitrophenyl ethylamine in the step S1 is 1: 1-20.

2. In the scheme, the solubility of the methanol solution of the p-nitroanisole in the step S1 is 25-28%, and the dosage of the methanol solution is 1-1.5 times of the mass of the 1R-2 chloro-1-phenylethyl alcohol.

3. In the above scheme, the solvent in step S3 is one or more of acetone, dichloromethane, chloroform, toluene, ethyl acetate, methyl tert-butyl ether, n-hexane, and petroleum ether.

4. In the scheme, the dosage of the solvent in the step S3 is 4-5 times of the mass of the 1R-2 chloro-1-phenethyl alcohol.

5. In the above scheme, the solvent in step S1 is methanol.

6. In the scheme, the stirring reflux time in the step S2 is 8-12 h.

7. In the scheme, the cooling temperature in the step S2 is 20-25 ℃.

The chemical reaction formula of the synthetic method is as follows:

due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

1. the synthesis method of the invention uses 1R-2 chloro-1-phenethyl alcohol and p-nitroanisole as starting materials to synthesize the (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride with better yield, and has mild reaction and simple operation.

2. The synthesis method of the invention does not use any irritant organic solvent or dangerous borane dimethylsulfide, not only has green and environment-friendly reaction process, realizes clean production, but also reduces cost, and has better market competitiveness.

3. The method only uses methanol with environmental protection as a solvent in the whole synthesis process, and prepares the (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride through substitution reaction, has less reaction steps, high yield of final products and good quality, and is suitable for large-scale industrial production.

Drawings

FIG. 1 is a liquid chromatogram of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride prepared by the synthetic method of example 1 of the present invention.

Detailed Description

In the description of this patent, it is noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the present invention; the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance; furthermore, unless expressly stated or limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, as they may be fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The meaning of the above terms in this patent may be specifically understood by those of ordinary skill in the art.

The invention is further described below with reference to the following examples: