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Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile

A hydroxymethyl cyclopropyl acetonitrile and acetylation technology is applied in the field of preparation of 1-hydroxymethyl cyclopropyl acetonitrile, and can solve the problems of long distillation time, difficulty in rectifying and purifying the product, and increasing process cost. The effect of reducing the number of processing steps, shortening the reaction time, and reducing the production cost

Pending Publication Date: 2022-01-18
NENTER & CO
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] 1) Cyclic sulfite is synthesized from cyclopropyl dimethanol, and cyanide is used to open the ring to obtain 1-hydrocarbon methyl cyclopropyl acetonitrile. Due to the low nucleophilic reactivity of the cyano group, this step requires a long time at a higher temperature of 90 Reaction at ℃, at the same time need to add a phase transfer catalyst (tetrabutylammonium bromide, potassium iodide, etc.) to promote the reaction, increasing the wastewater treatment process and increasing the process cost
[0015] 2) Selectively protect the single hydroxyl group of cyclopropyldimethanol, and convert it into 1-hydrocarbonmethylcyclopropylacetonitrile through multi-steps. This method has the disadvantage of poor selectivity of the hydroxyl protection reagent, and the by-products of the reaction are more , which affects the yield and product quality, and there are certain difficulties in the rectification and purification of the product
[0016] 3) In the method of preparing 1-hydroxymethylcyclopropylacetonitrile with tribromoneopentyl alcohol, the use of ammonia quenching affects the yield and product quality; after the cyano group substitution and hydrolysis reactions, distillation and desolventization are carried out respectively, and the distillation time is long, High energy consumption, affecting product quality, complex processing procedures, resulting in increased risk of leakage of toxic substances

Method used

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  • Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile
  • Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile
  • Preparation method of 1-hydroxymethyl cyclopropyl acetonitrile

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Embodiment Construction

[0040] In order to understand the technical content of the present invention more clearly, the following examples are given for detailed description, and the provided examples should not be construed as limiting the protection scope of the present invention. The raw material of compound VI pentaerythritol in the examples is a commercially available product.

[0041] Step 1: Preparation of tribromoneopentyl acetate (compound Ⅳ)

[0042] Add 200g of pentaerythritol (compound VI), 880g of hydrobromic acid (48%), 200g of concentrated sulfuric acid and 800g of acetic acid into a 3L three-neck flask, stir and raise the temperature (100-140°C) to react, and the reaction is completed in about 20 hours. The temperature was lowered to 50°C, and the layers were allowed to stand, and 100 g of acetic anhydride was added to the lower organic phase, and stirred and reacted at 60°C for 6 hours. Add 200g of water to the reaction solution, stir for half an hour, stand to separate the layers, a...

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Abstract

The invention relates to a preparation method of 1-hydroxymethyl cyclopropyl acetonitrile, and belongs to the technical field of synthesis of medical intermediates. According to the method, pentaerythritol is used as a raw material, tribromoneopentyl alcohol is obtained through bromination reaction, then 3-bromo-2, 2-bis (bromomethyl) propyl acetate is obtained through acetylation reaction, pentaerythritol is used as a starting material, the reaction temperature is reduced to 50 DEG C from 90 DEG C, the reaction time is shortened to about 10 hours from about 35 hours, the reaction time is shortened, the reaction temperature is reduced, and the production cost is greatly reduced; in the reaction process, a bromine-containing material is used mechanically, so that the bromine element is recycled, the output of wastes is greatly reduced, and the problem that only one hydroxyl group needs to be selectively protected due to the fact that cyclopropyl dimethyl carbinol contains two hydroxyl groups is solved; in addition, a cyanide solution is adopted to replace a cyanide solid, so that the risk of direct contact between an operator and a cyanide-containing material is reduced. The raw materials are simple and easy to obtain, the technological process is simple, and the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation method of 1-hydroxymethylcyclopropylacetonitrile, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] 1-Hydroxymethylcyclopropylacetonitrile, English chemical name: 1-(Hydroxymethyl) cyclopropaneacetonitrile, CAS registration number: 152922-71-9, molecular formula: C 6 h 9 NO, molecular weight: 111.14, chemical structural formula as follows: [0003] [0004] 1-Hydroxymethylcyclopropylacetonitrile is an important intermediate in the synthesis of montelukast sodium. Montelukast sodium was developed by Merck & Co., USA, and its trade name is "Singulaer". It is a selective leukotriene D4 receptor antagonist, which can selectively bind to leukotriene in the airway. Combining and blocking the effect of allergic reaction, improving respiratory inflammation and unblocking the airway, it is an anti-asthma anti-inflammatory and anti-allergic drug with high efficien...

Claims

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Application Information

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IPC IPC(8): C07C253/14C07C253/30C07C255/31C07C67/08C07C67/297C07C69/63C07C29/62C07C31/36
CPCC07C253/14C07C253/30C07C67/08C07C67/297C07C29/62C07C2601/02C07C31/36C07C69/63C07C255/31
Inventor 乔建成周显亮王文鹏
Owner NENTER & CO
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