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Preparation method of tetrahydro-2-furoic acid

A tetrahydrofuran and formic acid technology, applied in the field of biocatalysis, can solve problems such as complex operation

Active Publication Date: 2019-06-11
弈柯莱生物科技(集团)股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method requires multi-step recrystallization, and the operation is more complicated.

Method used

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  • Preparation method of tetrahydro-2-furoic acid
  • Preparation method of tetrahydro-2-furoic acid
  • Preparation method of tetrahydro-2-furoic acid

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Experimental program
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Effect test

Embodiment 12- 4

[0089] The preparation of embodiment 1.2- methyl tetrahydrofuran carboxylate

[0090] Add 10.0 g of 2-tetrahydrofurancarboxylic acid, 0.1 g of concentrated sulfuric acid, and 30 ml of anhydrous methanol into the three-neck flask, heat to reflux, and react for 16 hours. The reaction is complete as monitored by GC. Add 0.1 g of sodium carbonate, pH = 4.60, stir for 10 min, the pH remains unchanged, continue to add sodium carbonate, the pH reaches up to 5.80, filter, and the filtrate is spin-dried to obtain 11.2 g of methyl 2-tetrahydrofurancarboxylate as a yellow liquid.

[0091]

Embodiment 22- 4

[0092] The preparation of embodiment 2.2-ethyl tetrahydrofuran formate

[0093] 10.0 g of 2-tetrahydrofurancarboxylic acid, 0.1 g of concentrated sulfuric acid, and 30 ml of absolute ethanol were added to the three-necked flask, heated to reflux, and reacted for 16 hours, and the reaction was complete as monitored by GC. Add 0.1 g of sodium carbonate, pH = 4.60, stir for 10 minutes, the pH remains unchanged, continue to add sodium carbonate, the highest pH reaches 5.80, filter, and spin the filtrate to give 12.4 g of ethyl 2-tetrahydrofurancarboxylate as a yellow liquid.

[0094]

Embodiment 3

[0095] Example 3. Enzyme-catalyzed preparation of (S)-2-tetrahydrofurancarboxylic acid

[0096] 3.1 In the reaction system, add 9g of methyl 2-tetrahydrofurancarboxylate obtained in Example 1, 10uL of Candida antarctica lipase B, 100mL of phosphate buffer solution pH=8, react at 20°C for 40min, and detect the conversion rate by GC. The raw materials for the reaction, the water phase is adjusted to pH = 2, the product is extracted by MTBE, and the product is obtained by rotary evaporation and solvent removal. The test results are shown in Table 1.

[0097] 3.2 In the reaction system, add 9 g of methyl 2-tetrahydrofurancarboxylate obtained in Example 1, 10 uL of Aspergillus honey protease (from Nagase ChemteX Company, Pretease XP-488), 100 mL of phosphate buffer solution pH=8, react at 20°C for 40 min, and GC The conversion rate was detected, unreacted raw materials were extracted by MTBE, the water phase was adjusted to pH=2, the product was extracted by MTBE, and the product ...

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Abstract

The present invention provides a preparation method of tetrahydro-2-furoic acid. Specifically, the invention provides an (S)-tetrahydro-2-furoic acid preparation method with low cost, high efficiencyand high optical purity. The method utilizes lipase (such as candida antarctica lipase B (CALB)) to prepare (S)-tetrahydro-2-furoic acid with very high efficiency and high stereoselectivity (ee valueis greater than or equal to 98%). The method provided by the invention not only reduces the cost, but also reduces the refining process, thereby greatly improving the conversion efficiency (the conversion rate can reach up to about 48% or above), shortening the reaction time and reducing the production cost. The method has the advantages of high yield, high conversion rate, low cost, short production period, simple process, easiness in amplification, suitability for large-scale production and the like.

Description

technical field [0001] The invention relates to the field of biocatalysis, in particular to a preparation method of tetrahydrofuran-2-carboxylic acid. Background technique [0002] Cefovecin is a semi-synthetic third-generation cephalosporin developed by SmithKline Beecham. In the mid-1990s, after Pfizer Animal Health acquired the animal health division of SmithK-line Beecham, it developed the sodium salt of cefotaxime, namely cefotaxime sodium, which greatly reduced production costs and allowed cefotaxime to be formed Commercial scale production (trade name: Kangweining, Convenia). Cefotaxime is mainly used for dogs and cats. It has the characteristics of rapid absorption, slow elimination, high bioavailability, long duration of drug effect, and high therapeutic index. It can be used as a long-acting antibiotic for dogs and cats. [0003] (S)-Tetrahydrofuran-2-acetyl (cas: 131328-27-3) is the key intermediate, and its structural formula is as follows: [0004] [0005...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/04C12N1/21C12R1/19
Inventor 程占冰孙传民田振华
Owner 弈柯莱生物科技(集团)股份有限公司