Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid

A technology of methylbenzoyl and methylbenzoyl chloride, which is applied in the field of chemical pharmacy, can solve the unsatisfactory problems of safety, yield, product quality and cost control, etc., and achieves the convenience of industrial production, rapid and mild reaction , the effect of high purity

Active Publication Date: 2011-06-15
天津天诚新药评价有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some relevant literatures have made some adjustments to the traditional process in many aspects such as starting materials, catalysts and reaction conditions, they are not satisfactory in terms of safety, yield, product quality and cost control.

Method used

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  • Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid
  • Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid
  • Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid

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Experimental program
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Effect test

Embodiment 1

[0028] 2-methyl-4-amino benzoate (100g, 0.61mol) and 2-methyl-4-nitrate phenyl chloride (85g, 0.55mol) are added to 5L reactive bottle, and dichlorobial (2L 2L), Ice and salt bath cool down to -10 to 0 ° C, stir until dissolved, slowly drip and dissolve with Agno 3 (93g, 0.55 mol) a tetrahydrofucleu solution 1.5L, the drip is completed, and the reaction is 5h.After the TLC detection reaction is complete, add the saturated solution of sodium bicarbonate (500ml) to the reaction solution, stir for 10 minutes, filter, wash with a small amount of dichloromethane (600ml × 2), combine organic phase, use saturated saline water(1.5L × 3) washing, dried sodium sodium sulfate, filtering.Filtering hyperthyroidism recovery solvents obtain 2-methyl-4-n- (2-methyl benzol) benzoate (104g, 66.7 %), purity 98.9 % (HPLC, naturalization method), MS (ESI)): M / Z = 284.13 (M+H) + Essence

Embodiment 2

[0030] 2-methyl-4-amino benzoate (100g, 0.61mol) and 2-methyl-4-nitrate phenyl chloride (142g, 0.92 mol) are added to a 5L reactor, and chloroform (2L) is added.Stir at room temperature until dissolved, and slowly drip adding silver -free stem (400g, 1.83 mol) solution of 1.5L of silver (400g, 1.83 mol).After the TLC detection reaction is complete, add the saturated solution of sodium carbonate to the reaction solution (500ml), stir for 10 minutes, filter, wash with a small amount of chlorine (1L × 2), combine organic phase, use saturated salt water (1.5L of 1.5L× 3) washing, dried sodium sodium sulfate, filtering.Filtering hydraulic recovery solvents obtain 2-methyl-4-n- (2-methyl benzol) benzoate (147g, 85.1 %), purity 99.8 % (HPLC, naturalization method), MS (ESI)): M / Z = 284.13 (M+H) + Essence

Embodiment 3

[0032]2-methyl-4-amino benzoate (100g, 0.61mol) and 2-methyl-4-nitrate phenyl chloride (123g, 0.79mol) are added to 5L reactive bottle, and dichlorotide (2.5L), heat to 40 ° C, stir until dissolved, slowly drip and dissolve silver sulfonate (310g, 1.22 mol) with trifluorosaine sulfonic acid (310g, 1.22mol), 1.5L.After the TLC detection reaction is complete, add the saturated solution of sodium bicarbonate (500ml) to the reaction solution, stir for 20 minutes, filter, wash with a small amount of dichloromethane (1L × 2), combine organic phase, use saturated saline water(2L × 3) washing, dried sodium sodium sulfate, filtering.Filtering hydraulic recovery solvents obtain 2-methyl-4-n- (2-methyl benzol) benzoate (146g, 84.6 %), purity 99.3 % (HPLC, naturalization method), MS (ESI)): M / Z = 284.13 (M+H) + Essence

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Abstract

The invention relates to a novel preparation method of a Tolvaptan intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid, which comprises the following step: carrying out N-acylation and hydrolysis on 2-methyl-4-amino methyl benzoate and 2-methyl benzoyl chloride which are used as initial raw materials, thereby obtaining the target compound 2-methyl-4-N-(2-methylbenzoyl)benzoic acid, wherein the N-acylation reaction is carried out under the action of silver salts. Compared with the preparation method provided in the existing literature, the method provided by the invention has the advantages of simple and accessible raw materials, mild reaction conditions, high yield and high purity, is easy and safe for operation, and lowers the requirements for equipment, thereby lowering the cost.

Description

Technical field [0001] The present invention is a chemical pharmaceutical technology field, especially involved a new type of arginine pluscin V 2 Remainor antagonist Tobutan intermediate 2-methyl-4-n- (2-methyl benzol) benzoic acid preparation method. Background technique [0002] 2-methyl-4-n- (2-methyl benzol) benzoic acid is an important intermediate of the synthetic drug Tosputan.Togurtan is a non -peptide selective V developed by OTSUKA Company (OTSUKA) Company 2 The receptor antagonist can reduce the load of the body fluid without affecting the electrolyte balance and renal function. It is an effective diuretic, which is suitable for the treatment of diseases such as hyponiasis. [0003] There are existing literature reports at home and abroad, such as Bioorganic & Medicinal Chemistry Letters.2007, 17 (23): 6455-6458 provides the following synthesis methods: [0004] 2-methyl-4-n- (2-methyl benzol) -1-bromine is preparation with carbon monoxide reactions under the action o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/81C07C231/12
Inventor 刘登科穆帅刘颖吴疆邹美香
Owner 天津天诚新药评价有限公司
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