Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof

A technology of aminocyclohexyl and hydrochloride, applied in the field of medicine, can solve the problem of large amount of reducing agent, etc., and achieve the effect of simple operation, high yield and high purity

Active Publication Date: 2013-12-04
VALIANT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In this preparation route, the benzoyl group is used for protection, and the simultaneous reduction of the ester group and the amide is required, and the consumption of the reducing agent is relatively large.

Method used

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  • Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof
  • Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof
  • Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Synthesis of 4-aminocyclohexylcarboxylate (II)

[0054]In a 3L autoclave, add 400.0g of ethyl p-aminobenzoate, 24.1g of 5% ruthenium-carbon, 1600mL of tetrahydrofuran in sequence, nitrogen replacement, temperature 100-150°C, hydrogen filling to make the reaction system pressure 8-15MPa, no pressure drop Reaction 2 ~3h. TLC monitoring, no fluorescence absorption in the central area means the reaction is complete. The catalyst was filtered off to obtain a colorless clear liquid. Tetrahydrofuran was distilled off under reduced pressure and then distilled to obtain 320.0 g of a colorless clear liquid with a yield of 74.3% and a content of ≥98% as determined by GC.

Embodiment 2

[0055] Example 2: Synthesis of 4-substituted phthalimide cyclohexyl carboxylate (III)

[0056] In a 2L three-necked flask, add 85.5g of ethyl 4-aminocyclohexylcarboxylate, 855g of toluene, and 40.4g of triethylamine in sequence, and add 170.5g of tetrachlorophthalic anhydride in batches, and the system becomes a colorless transparent liquid. Heat the water and reflux for 6-10 hours. GC traced to complete conversion of starting material. Cool to room temperature, add 400.0g 3-4% NaOH solution, stir for 10-15min, and separate the toluene layer. Add 400.0 g of 3-4% HCl solution to the toluene layer, stir for 10-15 min, collect the toluene layer, and dry over anhydrous sodium sulfate to obtain a light yellow clear solution. Filter off the desiccant. The solvent was evaporated under reduced pressure to obtain 207.5 g of a colorless or yellow viscous liquid, with a yield of 95.0%, and the content measured by HPLC was ≥99%.

Embodiment 3

[0057] Example 3: Synthesis of trans-4-substituted phthalimide cyclohexyl carboxylate (IV)

[0058] Add 26.6g of potassium tert-butoxide and 600g of tetrahydrofuran into a 2L three-necked flask in sequence, and stir to dissolve. Under the protection of nitrogen, add a mixed solution of 160g compound III and 480g tetrahydrofuran, heat until the solid dissolves, evaporate the solvent tetrahydrofuran, raise the temperature to 180-220°C, and bake at high temperature for 4-20h. Add 2% aqueous solution of glacial acetic acid until the system pH=7, cool down and precipitate white crystals. Inner temperature 0~5℃, heat preservation and stirring for 0.5h, suction filtration to obtain a white flocculent solid, washed with water, dried, and recrystallized in a mixed solvent of cyclohexane and dichloromethane. 140.0 g of white crystals were obtained, the total yield was 83.6%, the content determined by HPLC was ≥99.5%, and the cis-isomer content was lower than the detection limit.

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Abstract

The invention relates to a method for preparing trans-4-amino cyclohexylmethanol hydrochloride, and belongs to the field of medicine. According to the method, 4-aminobenzoic ester is used as a raw material; catalytic hydrogenation, phthaloyl formylation, a conversion reaction, a hydrazinolysis reaction, amino protection, ester group reduction, amino deprotection and hydrogen chloride salification are carried out so as to obtain the trans-4-amino cyclohexylmethanol hydrochloride. The method and trans-4-amino cyclohexylmethanol hydrochloride have the advantages that the initial material is easy to obtain; the operation is simple; column chromatographic purification is not required; the yield and the purity are high; energy is saved; the environment is protected; suitability for industrialized production is realized.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a preparation method of trans-4-aminocyclohexylmethanol hydrochloride. Background technique [0002] Trans-4-aminocyclohexylmethanol hydrochloride is mainly used as an intermediate for the preparation of weight-loss drugs. There is no report on the preparation of this compound in China, and there are few reports on the preparation method of this compound abroad. There is no specific report on the preparation of the target product through transformation and reduction with cheap and easy-to-obtain starting materials, and there is no purity and cis-formation of the product. Body content reports. [0003] Panka j S.Patil et al. (Organic Process Research&Development 2009,13,1141 1144.) reported a Boc-protected trans -4 Aminocyclohexylcarboxylate isopropyl, but no reduction of the ester group was done in this document. [0004] [0005] The starting material of this route is 4-aminobenzoic a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/42C07C213/08C07C213/00
Inventor 孙宝佳杨光李炬吕作亮谷长虹鲁旭童张晓君孙蕊
Owner VALIANT CO LTD
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