Preparation method for (S)-(-)-alpha-methylaminopropiophenone

A technology of methylaminobenzene and methylbenzoyl tartaric acid, applied in the field of medicine and chemical industry, can solve the problems that mixed solvents cannot be directly recycled and applied, and affect production costs

Inactive Publication Date: 2014-10-29
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] 3) A large number of mixed solvents used in the split cannot be directly recycled and applied
The total yield of the above three steps is the highest and can only reach the total free base yield of 52.5-59.3% (the yield here refers to the yield of the three steps of "bromo-methylamination-resolution"), so these steps are Bottlenecks Affecting Production Costs

Method used

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  • Preparation method for (S)-(-)-alpha-methylaminopropiophenone
  • Preparation method for (S)-(-)-alpha-methylaminopropiophenone
  • Preparation method for (S)-(-)-alpha-methylaminopropiophenone

Examples

Experimental program
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Effect test

Embodiment 1

[0062] Embodiment 1: Preparation 1 of total double salt

[0063] Using propiophenone as raw material, dichloromethane as reaction solvent for bromination and methylation reaction, ethyl acetate and acetic acid as resolution solvent, (2R,3R)-dibenzoyl tartaric acid as resolution agent for α -Synthesis and resolution of methylaminopropiophenone.

[0064] At room temperature, 536g of propiophenone (4mol) was dissolved in 3L of dichloromethane. Add 640g (4mol) of liquid bromine dropwise to it under mechanical stirring, control the drop rate so that the temperature of the reaction system does not exceed 30°C, and absorb the escaped hydrogen bromide with water. After the dropwise addition, continue to react for 30 minutes, wash with 1L×2 liquid separations, collect the aqueous phase, and put about 3.5L of the organic phase directly into the next step.

[0065] Equipped with a spherical condenser, mechanical stirring and heating equipment, control the internal temperature to 40°C,...

Embodiment 2

[0074] Embodiment 2: the preparation 2 of total double salt

[0075] Adopt embodiment 1 method, reaction scale is with embodiment 1. The difference is that the amount of acetic acid added in one step of resolution becomes 316mL, and the resolution system is not heated, and the method of dropping at room temperature is adopted. Stirring was continued for 14 hours after the dropwise addition was complete. All the other operations are completely consistent with Example 1.

[0076] The double salt weight that obtains is 974.6g. The total yield calculated with propiophenone as raw material was 71.1%, and the salt-forming yield of resolving agent calculated with the amount of (2R,3R)-dibenzoyl tartaric acid was 87.9%. The purity of the total double salt was 99.0%, and the %de value was 86.1%.

[0077] Solvent recovery is the same as in Example 1.

Embodiment 3

[0078] Embodiment 3: the preparation 3 of total double salt

[0079] Using the method of Example 1, the reaction scale is 10% of Example 1 (that is, all materials are reduced to 10%, such as raw material propiophenone reduced to 53.6g). Ethyl acetate was used as the solvent for bromination and methylation, and other operations were unchanged.

[0080] The double salt weight that obtains is 83.7g. The purity of the total double salt was 98.0%, and the %de value was 91.7%.

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Abstract

The invention belongs to the field of medicinal chemical engineering, and relates to a preparation method for (S)-(-)-alpha-methylaminopropiophenone. The invention also relates to a composition, application thereof and a method of preparing ephedrine or pseudoephedrine. Concretely, the invention discloses preparation and a resolution purification technology of alpha-methylaminopropiophenone. Propiophenone or bromopropiophenone is taken as a raw material and is subjected to continuous synthesis, and resolution and purification of optically-pure alpha-methylaminopropiophenone are directly performed without performing synthesis and separation of alpha-methylaminopropiophenone hydrochloride, and the final product is obtained in the form of a [(S)-(-)-alpha-methylaminopropiophenone]2.(2R,3R)-dibenzoyltartaric acid derivative. Compared with the prior art, the preparation method is relatively simple in operation, relatively low in cost and relatively high in reaction yield and resolution efficiency, and all solvents are recyclable.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of (S)-(-)-α-methylaminopropiophenone. The present invention also relates to a composition and its application as well as a method for preparing ephedrine or pseudoephedrine. Background technique [0002] α-methylaminopropiophenone is an important pharmaceutical industry intermediate, and optically pure α-methylaminopropiophenone is an important intermediate raw material for many chiral drugs, of which (S)-(-)-α-methanol Aminopropiophenone can be used in the preparation of important drugs such as ephedrine and pseudoephedrine. [0003] In industrial production at present, preparation (S)-(-)-alpha-methylaminopropiophenone is mainly carried out through the following steps: [0004] [0005] Reducing (S)-(U)-α-methylaminopropiophenone obtained by the above preparation method, or directly forming a double salt of (S)-(-)-α-methylaminopropiophenon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/16
Inventor 聂爱华顾为
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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