Preparation method of 5-oxaspiro[2,4]heptane-6-one and intermediate thereof

An oxaspiro and solvent technology, which is applied in the field of preparation of 5-oxaspiro[2,4]heptan-6-one and its intermediates, can solve the problems of inability to realize industrialized production, complex reaction, difficult control of conditions and the like , to achieve the effects of cheap and easy-to-obtain starting materials, simple and easy process flow, and reduced production costs

Inactive Publication Date: 2014-07-23
SHANGHAI PUYI CHEM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although this method can prepare 5-oxaspiro[2,4]heptan-6-one (I), its disadvantages are obvious
First, 2-(3-(bromomethyl)oxetan-3-yl)methanol reacts with sodium cyanide to generate 2-(3-(hydroxymethyl)oxetan-3-yl)acetonitrile step , because the activity of bromine is low, so the reaction time is long, the yield is low, only 54%; Secondly, 2-(3-(hydroxymethyl) oxetan-3-yl) acetonitrile generates under the effect of hydrogen bromide The step reaction of 4,4-bis(bromomethyl)dihydrofuran-2(3H)-one is complex, the conditions are difficult to control, and many by-products will be produced; finally, the yield of the step of zinc powder ring closure is very low, Difficult post-processing, unable to realize industrial production
In short, this method only stays in the laboratory stage

Method used

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  • Preparation method of 5-oxaspiro[2,4]heptane-6-one and intermediate thereof
  • Preparation method of 5-oxaspiro[2,4]heptane-6-one and intermediate thereof
  • Preparation method of 5-oxaspiro[2,4]heptane-6-one and intermediate thereof

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preparation example Construction

[0023] The general synthetic route of the method for preparing 5-oxaspiro[2,4]heptan-6-one (I) of the present invention is as follows:

[0024]

[0025] Taking dibromoneopentyl glycol (V) as the starting material, cyclizing in the presence of zinc powder to obtain cyclopropyl dimethanol (IV), and then reacting with thionyl chloride to obtain cyclopropyl dimethanol sulfite (III); Cyclopropyldimethanol cyclosulfite (III) is ring-opened with cyanide to obtain nitrile alcohol compound (II), compound (II) is hydrolyzed under alkaline conditions, and the ring is closed under acidic conditions to obtain 5-oxygen Heterospiro[2,4]heptan-6-one (I).

Embodiment 1

[0027] Example 1: Preparation of cyclopropyl dimethanol (1-2)

[0028]

[0029] Dissolve 25 g of raw material dibromoneopentyl glycol (1-1) (Suzhou Jinghua Chemical) in 150 mL of ethanol, and add 10 g of zinc powder. Heat to 100°C under the protection of nitrogen and reflux for 4 hours until TLC (PE:EA=1:1 potassium permanganate color development) shows that the raw material points disappear. After the zinc powder is removed by suction filtration, ammonia gas is passed in at about 10°C, and a large amount of white solid is precipitated. Continue to pass in ammonia gas until ammonia overflows from the outlet. Incubate and stir for 30 minutes, filter with suction, and wash with a small amount of ethanol. The filtrate is concentrated to dryness to obtain a milky white oil, and 8.3 g of cyclopropyl dimethanol (1-2) can be obtained by distillation under reduced pressure with an oil pump as a colorless liquid. GC 98%, molar yield 85%. 1 H NMR(CDCl 3 ,500Hz)δ4.02(s,2H),3.56(s,4H),0.48(...

Embodiment 2

[0030] Example 2: Preparation of cyclopropyl dimethanol (1-2)

[0031]

[0032] Dissolve 25 g of raw material dibromoneopentyl glycol (1-1) (Suzhou Jinghua Chemical) in 150 mL of methanol, and add 10 g of zinc powder. Heat to 80°C under the protection of nitrogen and reflux for 6 hours until TLC (PE:EA=1:1 potassium permanganate color development) shows that the raw material points disappear. After the zinc powder is removed by suction filtration, ammonia gas is passed in at about 10°C, and a large amount of white solid is precipitated. Continue to pass in ammonia gas until ammonia overflows from the outlet. Incubate and stir for 30 minutes, filter with suction, and wash with a small amount of ethanol. The filtrate is concentrated to dryness to obtain a milky white oil. The oil pump vacuum distillation can obtain 7.3 g of cyclopropyl dimethanol (1-2), which is a colorless liquid. GC 99%, molar yield 75%. See Example 1 for spectrogram data.

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Abstract

The invention relates to a preparation method of 5-oxaspiro[2,4]heptane-6-one (I). The preparation method comprises the following steps: taking dibromoneopentyl glycol (V) as the primary raw material, carrying out a cyclization reaction in the presence of zinc powder so as to obtain cyclopropyl dimethanol (IV), subjecting the cyclopropyl dimethanol (IV) to react with thionyl chloride so as to obtain cyclopropyl dimethanol cyclicsulfite (III); carrying out a ring-opening reaction on the cyclopropyl dimethanol cyclicsulfite (III) in the presence of cyanide so as to obtain a nitrilo-alcohol compound (II); hydrolyzing the compound (II) under an alkaline condition, and then carrying out a ring-closing reaction under an acidic reaction so as to obtain the 5-oxaspiro[2,4]heptanes-6-one (I), whose structural formula is represented in the description. The preparation method has the advantages of smart design, cheap and available primary raw materials, simple and applicable technology process, benefit for industrial production, and suitability for large-scale promotion and application.

Description

Technical field [0001] The invention relates to the technical field of montelukast intermediates for the prevention and treatment of asthma, in particular to the technical field of 1-mercaptomethylcyclopropylacetic acid, and specifically refers to a 5-oxaspiro[2,4]heptane-6 -Preparation methods of ketones and their intermediates. Background technique [0002] 1-Mercaptomethylcyclopropylacetic acid (VI) is an important intermediate for the synthesis of Montelukast, and 5-oxaspiro[2,4]heptan-6-one (I) can be easily converted to 1-Mercaptomethylcyclopropylacetic acid (VI), as shown in Scheme 1. [0003] [0004] Route 1 [0005] Regarding the synthesis method of 5-oxaspiro[2,4]heptan-6-one (I), currently only US Patent No. 5,486,622A has reported it, as shown in Route 2. It uses dibromoneopentyl glycol (V) as a raw material, firstly it is closed to form 2-(3-(bromomethyl)oxetan-3-yl)methanol in the presence of a base, and then combined with sodium cyanide The reaction produces 2-(3-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/94C07D327/10
CPCC07D307/94C07D327/10
Inventor 李可来屠长刚王博
Owner SHANGHAI PUYI CHEM CO LTD
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