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Method for preparing (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol and salts thereof

A technology of dimethylcyclopropanyl and aminomethyl, which is applied in the field of drug synthesis, can solve the problems of severe reduction reaction conditions, influence on industrial applications, and harsh temperature requirements, and achieve short reaction time, low risk, and mild reaction conditions. Effect

Inactive Publication Date: 2014-01-15
SHANGHAI DESANO CHEM PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Although this route has the advantage that the starting material is cheap and easy to obtain, this route needs to take a secondary reduction reaction when preparing (1R,3S)-3-aminomethyl-2,2-dimethylcyclopropanylmethanol, namely , at first utilizing lithium borohydride or sodium borohydride reduction ester group selected from alane, in the presence of trimethylsilyl chloride, and then using lithium aluminum hydride or triacetoxy sodium borohydride reduction amide group, the above reduction reaction conditions Vigorous, harsh temperature requirements, long reaction time, cumbersome post-treatment, and low safety, which affect the industrial application of this route

Method used

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  • Method for preparing (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol and salts thereof
  • Method for preparing (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol and salts thereof
  • Method for preparing (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol and salts thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] Under argon atmosphere, add formula I compound (69.3g, 0.35mol, 1.0eq) and 500mL tetrahydrofuran (THF) into 1L reaction bottle, ice bath cooling to 5~10 ℃; Add sodium borohydride (32.0g, 0.82mol , 2.3eq) and iodine (91g, 0.35mol, 1eq); heated to reflux; after reflux for 5-8 hours, cool the reaction solution to 5-10°C, add 100mL methanol to the reaction system to quench the reaction; filter, concentrate methanol in the dry filtrate; add 800mL ethyl acetate to the concentrated residue, and stir at room temperature for 2 to 3 hours; filter and concentrate the ethyl acetate in the dry filtrate to obtain (1R,3S)-3-aminomethyl- Crude 2,2-dimethylcyclopropanylmethanol; add excess benzoic acid to the above crude product at -5-10°C, stir for 2-3 hours to form a salt; filter, wash, and vacuum-dry at 40°C for 5- After 8 hours, 80.3 g of benzoate of (1R,3S)-3-aminomethyl-2,2-dimethylcyclopropanylmethanol was obtained (91.2% molar yield).

[0043] The obtained hydrogen ...

Embodiment 2

[0045] Under argon atmosphere, add formula I compound (69.3g, 0.35mol, 1.0eq) and 500mL dichloromethane into 1L reaction bottle, ice bath cooling to 5 ~ 10 ℃; add lithium borohydride (15.2g, 0.45mol, 1.3eq) and iodine (91g, 0.35mol, 1eq); heat to reflux; after reflux for 5-8 hours, cool the reaction solution to 5-10°C, add 100mL methanol to the reaction system to quench the reaction; filter and concentrate to dryness Methanol in the filtrate; add 800mL ethyl acetate to the concentrated residue, stir at room temperature for 3 to 5 hours; filter, concentrate and dry the ethyl acetate in the filtrate to obtain (1R,3S)-3-aminomethyl-2 , crude 2-dimethylcyclopropanylmethanol; add excess benzoic acid to the above crude product at -5-10°C, stir for 2-3 hours to form a salt; filter, wash, and vacuum-dry at 40°C for 5-8 hours, 77.3 g of benzoate of (1R,3S)-3-aminomethyl-2,2-dimethylcyclopropanylmethanol was obtained (molar yield: 87.2%).

[0046] The hydrogen spectrum data of the obtain...

Embodiment 3

[0048] Under argon atmosphere, add formula I compound (60g, 0.30mol, 1.0eq) and 500mL dioxane to 1L reaction bottle, cool to 5~10℃ in ice bath; add potassium borohydride (32.8g, 0.82mol, 2.0eq) and iodine (78g, 0.30mol, 1eq); heat to reflux; after reflux for 5-8 hours, cool the reaction solution to 5-10°C, add 80mL methanol to the reaction system to quench the reaction; filter, concentrate to dryness Methanol in the filtrate; add 500mL ethyl acetate to the concentrated residue, stir at room temperature for 3 to 5 hours; filter, concentrate and dry the ethyl acetate in the filtrate to obtain (1R,3S)-3-aminomethyl-2 , crude 2-dimethylcyclopropanylmethanol; add excess benzoic acid to the above crude product at -5-10°C, stir for 2-3 hours to form a salt; filter, wash, and vacuum-dry at 40°C for 5-6 hours, 63.5 g of benzoate of (1R,3S)-3-aminomethyl-2,2-dimethylcyclopropanylmethanol was obtained (molar yield: 83.0%).

[0049] The hydrogen spectrum data of the obtained benzoate of ...

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Abstract

The invention discloses a method for preparing (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol and salts thereof. The method comprises the following reduction reactions of simultaneously reducing the acylamino and ester group of a compound shown in a formula I or salt thereof in one step in the presence of hydroboron and iodine which are serving as reducing agents, wherein the compound is (1R, 3S)-3-methylamine acyl-2, 2-dimethyl cyclopropanecarboxylic acid allyl ester, and the specific reaction formula is shown in the specification. According to the method, cheap raw materials which are easy to get are utilized, the method is simple to operate, is carried out under mild reaction conditions, has low toxicity and low risk, can be used for synthesizing high-purity key intermediate (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol of Boceprevir and the salts of the key intermediate with low cost, can meet the requirement of large-scale industrial production of Boceprevir, is suitable for industrial application, and has practical value.

Description

technical field [0001] The invention relates to a method for preparing (1R,3S)-3-aminomethyl-2,2-dimethylcyclopropanylmethanol and salts thereof, belonging to the technical field of drug synthesis. Background technique [0002] Boceprevir (Boceprevir) is a hepatitis C virus (HCV) protease inhibitor, its specific chemical structural formula is as follows: [0003] The phase III SPRINT-2 study showed that compared with standard treatment, 24 weeks of boceprevir standard treatment can improve the SVR rate of HCV genotype 1 treatment-naïve patients. The antiviral efficacy of standard boceprevir treatment for 24 weeks was similar to that of boceprevir standard treatment for 44 weeks. [0004] At present, the synthesis of boceprevir mainly has the following routes: [0005] ①Synthetic route 1 disclosed in US patent US7012066 [0006] [0007] This route is to first amidate compound fragments A and B, then react with fragment C (tert-butyl isocyanate), and finally dock with...

Claims

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Application Information

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IPC IPC(8): C07C215/26C07C213/00
Inventor 李金亮赵楠王婷婷
Owner SHANGHAI DESANO CHEM PHARMA
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