CN110872234B - Synthesis method of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride - Google Patents
Synthesis method of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride Download PDFInfo
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- CN110872234B CN110872234B CN201911128423.0A CN201911128423A CN110872234B CN 110872234 B CN110872234 B CN 110872234B CN 201911128423 A CN201911128423 A CN 201911128423A CN 110872234 B CN110872234 B CN 110872234B
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Abstract
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.
Description
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 temperature is reduced to 20-25 ℃ in the step S2.
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:
example 1: under the condition of room temperature, 500ml of methanol, 156.6 g of 1R-2 chloro-1-phenethyl alcohol and 170g of p-nitroanisole are added into a reaction bottle, the mixed solution is heated to 60-65 ℃, stirred and refluxed for 8h, cooled to 20-25 ℃, added with 500g of ethyl acetate, cooled to 0 degree and filtered to obtain 317g of similar white solid (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride, the yield is 98.4 percent and the purity is 99.32 percent.
Example 2: under the condition of room temperature, 500ml of methanol, 156 g of 1R-2 chloro-1-phenethyl alcohol and 170g of p-nitroanisole are added into a reaction bottle, the mixed solution is heated to 60-65 ℃, stirred and refluxed for 8h, cooled to 20-25 ℃, added with 500g of acetone, cooled to 0 degree and filtered to obtain 230g of white solid (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride with the yield of 71 percent and the purity of 96.1 percent.
Example 3: under the condition of room temperature, 500ml of methanol, 156.6 g of 1R-2 chloro-1-phenethyl alcohol and 190g of p-nitroanisole are added into a reaction bottle, the mixed solution is heated to 40-45 ℃, stirred and refluxed for 8 hours, cooled to 20-25 ℃, 500g of n-hexane is added, the temperature is reduced to 0 degree, and filtration is carried out to obtain 117g of white-like solid (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride, wherein the yield is 36.3 percent and the purity is 81 percent.
Then, a sample of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride prepared by the synthesis method of example 1 of the present invention was sampled and detected by liquid chromatography.
Detection conditions are as follows: the instrument comprises the following steps: agilent 1100 hplc;
a chromatographic column: luna C18,4.6mm × 250mm,5 μm;
column temperature: 25 ℃;
flow rate: 1.0 ml/min;
detection wavelength: 235 nm;
sample introduction volume: 5 ul;
mobile phase: acetonitrile: 0.1% aqueous phosphoric acid =60:40 (v/v);
operating time: and (3) 30 min.
The liquid chromatogram of the detected sample is shown in FIG. 1; the analysis results are shown in table 1.
Table 1: the chromatographic analysis result of a sample of (1R) -2- [ [ [2- (4-nitrophenyl) ethyl ] amino ] methyl ] benzyl alcohol hydrochloride prepared by the synthetic method of inventive example 1.
TABLE 1
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (7)
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: and in the step S2, the stirring reflux time is 8-12 h.
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, cooling to a temperature of 20-25 ℃.
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| CN108658797A (en) * | 2018-06-19 | 2018-10-16 | 安徽德信佳生物医药有限公司 | A kind of synthesis of Mirabegron intermediate (R) -2- (4- nitrophenethyls amino) -1- phenylethanol hydrochlorides |
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| CN108658797A (en) * | 2018-06-19 | 2018-10-16 | 安徽德信佳生物医药有限公司 | A kind of synthesis of Mirabegron intermediate (R) -2- (4- nitrophenethyls amino) -1- phenylethanol hydrochlorides |
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