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Method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate

An oxazoline carboxylic acid, high-purity technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of high risk factor, unfavorable industrial production, and high cost, and achieve the effects of less three wastes, favorable production operation, and low cost

Pending Publication Date: 2020-02-28
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is that the existing method for preparing (R)-4-formyl-2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester has high risk factor and high cost, which is unfavorable for industrialization Production, the purpose is to provide a method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester, to solve the existing problem of preparing (R)-4-formyl -The problem that the method of 2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester is unfavorable for industrialized production

Method used

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  • Method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate
  • Method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate
  • Method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate

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Embodiment 1

[0053] like figure 1Shown, the present invention prepares the method for high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester, comprises the following steps:

[0054] S1. Preparation of compound 2 from compound 1: reacting compound 1 with thionyl chloride in methanol to obtain compound 2;

[0055] S2. Preparation of compound 3 from compound 2: reacting compound 2 with Boc anhydride under triethylamine to obtain compound 3;

[0056] S3. Compound 4 was prepared from compound 3: compound 4 was obtained by reacting compound 3 with 2,2-dimethoxypropane under boron trifluoride diethyl ether;

[0057] S4. Compound 5 was prepared from compound 4: compound 4 was reduced with DIBAL-H at -60 to -80°C to obtain a crude product, and then reacted with sodium sulfite to form a salt for purification to obtain high-purity (R)-4-formyl-2 , tert-butyl 2-dimethyl-3-oxazolinecarboxylate.

[0058] The synthetic route is as follows:

[0059]

[0060] The present ...

Embodiment 2

[0062] Based on Example 1, the present invention prepares the method for high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester, the specific steps are as follows:

[0063] S1, compound 2 is prepared from compound 1, the synthetic route is as follows:

[0064]

[0065] Add methanol (4.2L) and compound 1 (0.7kg, 6.66mol) into a 5L clean and dry four-neck flask at room temperature, under nitrogen protection, cool down to 0-5°C in an ice-salt water bath while stirring; maintain the system temperature at 0-5°C , dropwise added thionyl chloride (0.9075kg, 7.63 mol, took 6h), the system was white and turbid; after the dropwise addition, the system was slowly warmed to room temperature for 15 hours.

[0066] The reaction solution was transferred to a 5L clean and dry one-necked bottle and concentrated under reduced pressure until no obvious fraction flowed out to obtain compound 2 (1.036kg, 6.66mol, crude product yield=100%).

[0067] S2, prepare compo...

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Abstract

The invention discloses a method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate. The method comprises the following steps: carrying out a reaction on D-serine and thionyl chloride in methanol to obtain a compound 2; carrying out a reaction on the compound 2 and Boc anhydride under triethylamine to obtain a compound 3; carrying out a reaction on the compound3 and 2,2-dimethoxypropane under the action of boron trifluoride diethyl ether to obtain a compound 4; and reducing the compound 4 and DIBAL-H are at a temperature of -60 DEG C to -80 DEG C to obtaina crude product, carrying out a reaction on the crude product and sodium sulfite to form salt, and purifying to obtain the high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate. According to the invention, the salt forming is performed by using the properties of sodium sulfite and an aldehyde group, so that the purity of the salified product can reach 98%, the industrial standard is met, and the production operation is well facilitated.

Description

technical field [0001] The invention relates to a preparation method, in particular to a method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester. Background technique [0002] (R)-tert-butyl 4-formyl-2,2-dimethyl-3-oxazolinecarboxylate (compound I) is a widely used pharmaceutical intermediate and material intermediate. [0003] [0004] The current method for preparing the compound shown in formula I generally uses D-serine as a raw material, and the published documents are as follows: [0005] (1) Med.Chem.Commun., 2014, 5, 1693 published a synthetic method for preparing the compound of formula 1, the main steps are as follows: [0006] [0007] The main defect of this process is: the first step reaction uses a strong base, which may cause racemization of the compound, the solvent is tert-butanol, and the post-treatment concentration temperature is relatively high. The second step uses methyl iodide, which is highly to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/06
CPCC07D263/06C07B2200/07
Inventor 颜林何巍刘波李仟郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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