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Preparation method of carboxylic acid compound and metal salt derivative thereof

A technology of compounds and carboxylic acids, which is applied in the field of preparation of carboxylic acid compounds and their metal salt derivatives, can solve problems such as non-industrial synthesis methods, achieve high practical value, broad application prospects, and mild reaction conditions

Pending Publication Date: 2022-04-05
ENZYMEWORKS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This method requires high pressure and noble metal catalysis, so it is not an ideal industrial synthesis method

Method used

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  • Preparation method of carboxylic acid compound and metal salt derivative thereof
  • Preparation method of carboxylic acid compound and metal salt derivative thereof
  • Preparation method of carboxylic acid compound and metal salt derivative thereof

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preparation example Construction

[0052] Due to existing compound 1 and compound 2 The preparation method of the present invention has problems such as cumbersome steps, expensive raw materials or harsh reaction conditions, which leads to high production costs, is not suitable for industrial production, and restricts the development of some medicines. Therefore, the inventor has carried out a large number of experiments, and proposes a new preparation method of carboxylic acid compounds, which uses raw materials from a wide range of sources, and has a simple process and mild reaction conditions.

[0053] Reaction equation of the present invention is:

[0054]

[0055] In the above reaction formula, R 1 Is halogen or sulfonic acid group; R 2 for C 1 ~C 6 Alkyl; R 3 is cyano or -COOR 4 , R 4 for C 1 ~C 4 Alkyl group, M is monovalent metal ion such as Na, K, etc., the yield of carboxylic acid compound can reach 70% and above, and the yield of its metal salt derivative can reach 67%.

Embodiment 1

[0058] 1) D-tert-butyl lactate sulfonylation

[0059]

[0060]Add 80ml of dichloromethane, 14.2g (100mmol) of D-tert-butyl lactate, 12.3g (120mmol) of triethylamine, 21.9g (115mmol) of p-toluenesulfonyl chloride into the reaction flask, and react at 30°C-35°C for 5 hours. Add 50 g of water to wash the organic layer, add anhydrous sodium sulfate to the organic layer to dry, filter off the desiccant, concentrate, add 50 ml of tetrahydrofuran to dilute and directly use in the next reaction.

[0061] 2) Preparation of (R)-3-methyl-4-tert-butoxy-4-oxobutanoic acid

[0062]

[0063] Add 80ml of tetrahydrofuran, 14.5 grams (110mmol) of dimethyl malonate, 3.8 grams of 60% sodium hydrogen (110mmol) in the reaction flask, and dropwise add the tetrahydrofuran solution prepared in Example 1 at 35 ° C. After the dropwise addition, 50 ℃ for another 3 hours, concentrated under reduced pressure to remove the solvent, added 50ml of toluene and 60ml of 4N sodium hydroxide solution, react...

Embodiment 2

[0067]

[0068] Add 80ml of tetrahydrofuran, 14.5 grams (110mmol) of dimethyl malonate, 3.8 grams of 60% sodium hydrogen (110mmol) into the reaction flask, and add 16.6 grams (100mmol) of (R)-2-tert-butyl chloropropionate dropwise at 35°C After the addition of the ester, react at 50°C for another 3 hours, concentrate under reduced pressure to remove the solvent, add 50ml of toluene and 60ml of 4N sodium hydroxide solution, react at room temperature for 2 hours, add hydrochloric acid dropwise to neutralize to PH=1-2, and heat to reflux 1 hour, cooled to room temperature, separated the water layer, concentrated the organic layer, added petroleum ether to precipitate a solid, filtered, and dried to obtain 14.1 g of the product, with a purity of 98% and an optical purity of ee% of 97%.

[0069] Product hydrogen spectrum:

[0070] 1 H NMR (400MHz, CDCl 3 ):11.0(s,1H),2.92-2.77(m,2H),2.64-2.53(m,1H),1.38(s,9H),1.19(s,3H).

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Abstract

The invention relates to a preparation method of carboxylic acid compounds and metal salt derivatives thereof. The preparation method comprises the following steps: carrying out condensation reaction on a compound shown in a formula I and a compound shown in a formula II to obtain a compound shown in a formula III, carrying out hydrolysis decarboxylation on the compound shown in the formula III to obtain a carboxylic acid compound shown in a formula IV, and in the formula, R1 is halogen or sulfonic acid group; r2 is alkyl of C1 to C6; r3 is a cyano group or-COOR4, and R4 is a C1-C4 alkyl group. The method has the advantages of wide raw material source, low cost, simple reaction steps, mild reaction conditions, no need of expensive and highly dangerous metal catalyst, high practical value, and wide application prospect, and is especially suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of carboxylic acid compounds and metal salt derivatives thereof. Background technique [0002] Compound 1 and compound 2 As a starting material or an important intermediate, it is widely used in the production and synthesis of some medicines. [0003] Regarding the preparation method of compound 1, although there are reports in the prior art, it is not suitable for industrial production, such as Organic Letters, 15 (6), 1266-1269; 2013 reports the following synthetic route: [0004] [0005] 2-Methylbutyrolactone undergoes multi-step reactions such as ring opening, benzyl protection, esterification, chiral resolution, and then oxidation to obtain the target product. The steps are complicated and cumbersome; the synthesis steps disclosed in WO2006074940 are as follows: [0006] The starting material chiral monomethyl succinate...

Claims

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Application Information

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IPC IPC(8): C07C67/343C07C67/32C07C69/34C07C253/30C07C255/22C07C255/19C07C303/28C07C309/73
Inventor 李庆毅
Owner ENZYMEWORKS
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