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Preparation method of amenamevir and intermediate thereof

A compound and organic solvent technology, applied in the field of pharmaceutical chemical synthesis and preparation, can solve the problems of increased industrial production costs, long synthetic routes, unfavorable industrial production, etc., to solve the problems of double alkylation by-products, single substitution selectivity, and increase The Effect of Atom Utilization

Active Publication Date: 2018-10-09
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the second preparation method, the starting material 2,6-dimethylaniline is protected by Fmoc, and the protective group needs to be removed in the later stage. The preparation process route is extended, the production cycle is increased, and the generation of three wastes is increased, resulting in a large industrial production cost. Higher, not conducive to industrial production
[0010] In summary, the synthesis route of amonevir in the prior art has the disadvantages of long synthesis route, cumbersome operation, low yield, high production cost, and being unfavorable for industrialized production

Method used

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  • Preparation method of amenamevir and intermediate thereof
  • Preparation method of amenamevir and intermediate thereof
  • Preparation method of amenamevir and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1 Preparation of 1,1-dioxo-N-(2,6-dimethylphenyl)-2H-thiopyran-4-carboxylic acid amine

[0084] To 1,1-dioxo-hexahydrothiopyran-4-carboxylic acid (30.2g, 0.17mol) in 300ml tetrahydrofuran, add dropwise a tetrahydrofuran solution of oxalyl chloride (40.4g, 0.34mol) under stirring at room temperature, dropwise After completion, the reaction was stirred at 30° C. for 3 h, monitored by TLC, and the reaction was stopped after the disappearance of the raw materials. Spin to dry under reduced pressure, dissolve the concentrate in 250ml tetrahydrofuran, add dropwise 60ml of a tetrahydrofuran solution of the compound 2,6-dimethylaniline (61.6g, 0.5mol), and keep the reaction at 30°C for 2h after the dropwise reaction is completed. reaction. The reaction solution was poured into 2L of ice-cold 1M hydrochloric acid aqueous solution and stirred at 0-5°C for 0.5h, filtered, washed with ice water, and dried to obtain 42.0g of solid, 89.5%.

[0085] 1 H-NMR (400MHz, DMSO-d...

Embodiment 2

[0086] Example 2 Preparation of 1,1-dioxo-N-(2,6-dimethylphenyl)-2H-thiopyran-4-carboxylic acid amine

[0087] 1,1-dioxo-hexahydrothiopyran-4-carboxylic acid (30.2g, 0.17mol) in 300ml tetrahydrofuran was added dropwise with thionyl chloride (32.3g, 0.25mol) in tetrahydrofuran under stirring at room temperature , the reaction was stirred at 30° C. for 3 h after dropping, monitored by TLC, and the reaction was stopped after the disappearance of the raw materials. Spin to dry under reduced pressure, dissolve the concentrate in 250ml tetrahydrofuran, add 80ml of a tetrahydrofuran solution of the compound 2,6-dimethylaniline (82.3g, 0.68mol) dropwise, keep the reaction at 30°C for 2h after the dropwise reaction, and stop the reaction after TLC reaction. Pour the reaction solution into 2L of ice-cold 1M hydrochloric acid aqueous solution and stir at 0-5°C for 0.5h, filter, wash with ice water, and dry to obtain 40.8g of solid, 87.1%.

[0088] 1 H-NMR (400MHz, DMSO-d6): δ2.11 (6...

Embodiment 3

[0089] Example 3 N-(2,6-dimethylphenyl)-N-(1,1-dioxohexahydrothiopyran-4-formyl)glycine ethyl ester

[0090] 1,1-dioxo-N-(2,6-dimethylphenyl)-2H-thiopyran-4 carboxylic acid amine (5) (28.0g, 0.1mol) in tetrahydrofuran was stirred in batches and added to t Potassium butoxide (13.4 g, 0.13 mol) was stirred at room temperature for 1 h after the addition, ethyl bromoacetate (18.3 g, 0.11 mol) was added dropwise, stirred at room temperature for 3 h after the addition was completed, and the reaction was stopped after the TLC reaction was completed. The reaction solution was poured into water, extracted with EA, dried over magnesium sulfate, spin-dried and cooled to obtain 33.2 g of solid, 90.0%.

[0091] 1 H-NMR (400MHz, DMSO-d6): δ1.19 (3H, t, J = 7.2Hz), 1.86 (2H, dd, J = 14.0, 2.8Hz), 2.01 (2H, m), 2.26 (6H, s), 2.37 (1H, tt, J = 10.4, 3.6Hz), 3.01 (4H, m), 4.08 (2H, s), 4.10 (2H, q, J = 7.2Hz), 7.21 (3H, m).

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Abstract

The invention discloses a preparation method of amenamevir and an intermediate thereof. The invention provides a preparation method of a compound as shown in a formula (V). The preparation method comprises the following steps: adding a compound as shown in a formula (VII) into an organic solvent, dropwise adding a chlorating agent, and carrying out stirring reaction and vacuum concentration to prepare acyl chloride; adding a compound shown as a formula (VI) into the acyl chloride after the acyl chloride is dissolved into the organic solvent to obtain the compound shown as the formula (V). Theinvention aims at solving the problem of a bialkylation by-product and avoids refining; other protecting groups are prevented from being used, so that the atomic utilization rate is greatly improved;the preparation method has the advantages of mild conditions of a synthetic route, convenience in treatment, high yield and high suitability for industrial production. (The formula is shown in the description).

Description

1. Technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis and preparation, and specifically relates to a preparation method of amonavir, and also relates to a preparation method of an amonevir intermediate. 2. Background technology [0002] Amonevir is a non-nucleoside analog anti-herpes virus drug (treatment of herpes simplex virus infection and herpes zoster) with a novel mechanism of action (helicase-priming enzyme complex enzyme activity inhibitor) developed by Japan Astellas Pharma . On July 3, 2017, Amonevir was approved for marketing in Japan. The structural formula of amonevir is shown in the following formula (I). [0003] [0004] Chinese invention patent CN200480022258.6 discloses two preparation methods of amonevir. The first preparation method is to use 2,6-dimethylaniline (VI) as a starting material, first react with ethyl bromoacetate to obtain a compound of formula (VIII), and then condense with a compou...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D335/02
CPCC07D335/02C07D413/12Y02P20/55
Inventor 张绪猛赵显栋高超张志强陈敬金甄宜战
Owner SHANDONG BESTCOMM PHARMA CO LTD
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