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A kind of preparation method of 3-oxetane formic acid

A technology of oxetane and formic acid, applied in the field of preparation of 3-oxetanecarboxylic acid, can solve the problems of unreported preparation method, unfavorable industrial amplification, low total reaction yield and the like, and achieves high market value, Ease of operation and the effect of shortening the reaction route

Active Publication Date: 2019-04-23
SHANGHAI BALMXY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] 3-Oxetanecarboxylic acid is an important intermediate, which can be used as the side chain of spiro compounds, thereby changing the structure of spiro compounds and expanding the new properties of compounds, so it has a wide range of applications, but its preparation method barely reported
[0005] However, the reaction steps in this route are relatively long, reaching a ten-step reaction, resulting in a low overall reaction yield, and the key steps need to be purified by column chromatography, which is not conducive to industrial scale-up, thus limiting the application of this route

Method used

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  • A kind of preparation method of 3-oxetane formic acid
  • A kind of preparation method of 3-oxetane formic acid
  • A kind of preparation method of 3-oxetane formic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] This embodiment prepares 3-oxetane formic acid through the following steps

[0067] (1) prepare 3-hydroxypropionate ethyl ester by 3-hydroxypropionitrile, concrete reaction formula is as follows:

[0068]

[0069] Put ethanol (1L) into a three-necked flask, stir, cool to 0°C, and slowly add concentrated hydrochloric acid (80mL) dropwise. Thionyl chloride (132 mL) was slowly added dropwise, and the system slowly rose to room temperature. 3-Hydroxypropionitrile (250 g) was slowly added dropwise, and the system was refluxed for 6 hours after dropping, and a large amount of white powder appeared. The system was cooled to 0°C, and the pH was adjusted to about 7 with solid sodium carbonate. After filtration, the filtrate was concentrated and distilled to obtain 208 g of ethyl 3-hydroxypropionate with a yield of 50%.

[0070] 1 H NMR (300MHz, CDCl 3 )δ4.20(dd,2H)3.84(t,J=6.1Hz,2H); 2.76(brs,1H,OH);2.55(td,J=5.8,1.6Hz,2H),1.25(t,3H) .

[0071] (2) prepare 3-hydroxy-2-...

Embodiment 2

[0091] This embodiment prepares 3-oxetane formic acid through the following steps

[0092] (1) prepare 3-hydroxypropionate ethyl ester by 3-hydroxypropionitrile, concrete reaction formula is as follows:

[0093]

[0094] Put ethanol (875mL) into a three-neck flask, stir, cool to 0°C, and slowly add concentrated hydrochloric acid (80mL) dropwise. Thionyl chloride (130 mL) was slowly added dropwise, and the system slowly rose to room temperature. 3-Hydroxypropionitrile (250 g) was slowly added dropwise, and the system was refluxed for 5 hours after dropping, and a large amount of white powder appeared. The system was cooled to 0°C, and the pH was adjusted to about 7 with solid sodium carbonate. After filtration, the filtrate was concentrated and distilled to obtain 200 g of ethyl 3-hydroxypropionate with a yield of 48.1%.

[0095] 1 H NMR (300MHz, CDCl 3 )δ4.20(dd,2H)3.84(t,J=6.1Hz,2H); 2.76(brs,1H,OH);2.55(td,J=5.8,1.6Hz,2H),1.25(t,3H) .

[0096] (2) prepare 3-hydroxy...

Embodiment 3

[0116] This embodiment prepares 3-oxetane formic acid through the following steps

[0117] (1) prepare 3-hydroxypropionate ethyl ester by 3-hydroxypropionitrile, concrete reaction formula is as follows:

[0118]

[0119] Put ethanol (1.25L) into a three-neck flask, stir, cool to 0°C, and slowly add concentrated hydrochloric acid (80mL) dropwise. Thionyl chloride (150 mL) was slowly added dropwise, and the system slowly rose to room temperature. 3-Hydroxypropionitrile (250 g) was slowly added dropwise, and the system was refluxed for 8 hours after dropping, and a large amount of white powder appeared. The system was cooled to 0°C, and the pH was adjusted to about 7 with solid sodium carbonate. After filtration, the filtrate was concentrated and distilled to obtain 205 g of ethyl 3-hydroxypropionate with a yield of 49.3%.

[0120] 1 H NMR (300MHz, CDCl 3 )δ4.20(dd,2H)3.84(t,J=6.1Hz,2H); 2.76(brs,1H,OH);2.55(td,J=5.8,1.6Hz,2H),1.25(t,3H) .

[0121] (2) prepare 3-hydroxy...

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Abstract

The invention provides a preparation method of 3-oxetane carboxylic acid. The preparation method is characterized by carrying out hydrolytic esterification reaction, hydrogen pulling reaction and reduction reaction by taking 3-hydroxypropionitrile as a raw material, thus obtaining 2-benzyloxymethyl-1,3-propanediol; carrying out cyclization reaction, debenzylation reaction and oxidation reaction on2-benzyloxymethyl-1,3-propanediol, thus obtaining 3-oxetane carboxylic acid. According to the preparation method of 3-oxetane carboxylic acid, provided by the invention, a key intermediate 2-benzyloxymethyl-1,3-propanediol can be prepared just through three-steps reaction by taking 3-hydroxypropionitrile as the raw material, and 3-oxetane carboxylic acid can be prepared just through six-steps reaction in a final integral route, so that the reaction route is greatly shortened, and reaction steps are reduced; compared with a preparation method requiring ten-steps reaction in the prior art, theyield is higher, the operation is easy, and industrial production can be favorably realized.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of 3-oxetane formic acid. Background technique [0002] 3-Oxetanecarboxylic acid is an important intermediate, which can be used as the side chain of spiro compounds, thereby changing the structure of spiro compounds and expanding the new properties of compounds, so it has a wide range of applications, but its preparation method Little to no coverage. [0003] US2008 / 0021032 A1 discloses a pyrazole glucokinase agonist, wherein 3-oxetanecarboxylic acid can be used as a side chain of the pyrazole glucokinase agonist, which can improve the effect of the agonist, and the disclosed 3-oxetane The synthetic method of butane formic acid mainly takes malonic acid diester as raw material, and prepares through ten steps of reaction, and concrete reaction formula is as follows: [0004] [0005] However, the reaction steps in this route are lon...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/08
CPCC07D305/08
Inventor 柴腾林增明
Owner SHANGHAI BALMXY PHARMA CO LTD