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Synthetic method of acotiamide hydrochloride

A technology of acotiamide hydrochloride and a synthesis method, which is applied in the synthesis field of acotiamide hydrochloride, can solve the problems of many side reactions, poor reaction selectivity, high toxicity, etc., and achieves less operation steps, less side reactions, and high selectivity. high effect

Active Publication Date: 2014-03-26
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantages of this patent are: (1) the use of thionyl chloride and ethylene dichloride are highly toxic and environmentally destructive substances; (2) the yield of demethylation is low (reported as 64.6%-86 %)
[0015] Among the above-mentioned patents, the CN1084739 reaction reagent uses dichloroethane, which is highly toxic and destructive to the environment, and the total reaction yield is low, which is not conducive to industrial production; the second-step demethylation reaction mentioned in the patent CN102030654B will produce Many by-products, it is difficult to selectively remove only the 2-hydroxyl protecting group, the reaction selectivity is poor, and there are many side reactions

Method used

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  • Synthetic method of acotiamide hydrochloride
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  • Synthetic method of acotiamide hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Synthesis of 2-tert-butyldimethylsiloxy-4,5-dimethoxybenzoic acid (2a)

[0048] Dissolve 2-hydroxy-4,5-dimethoxybenzoic acid (100g) in anhydrous toluene (400ml), slowly add TBSOTf (160g) to the solution at room temperature, stir for 5 hours, add purified water to wash To neutrality, take the organic phase, add anhydrous sodium sulfate (20 g) and dry for 8 hours, filter, and evaporate to dryness under reduced pressure to obtain 134 g of the title compound, yield 85%, melting point: 235°C

[0049] H1-NMR(DMSO, 400 MHz) δ: 0.08(s, 3H,-SiCH3), 0.09(s, 3H,-SiCH3), 0.14(s, 3H, -CH3); 0.22(s, 3H, -CH3) , 0.35(s,3H, -CH3), 4.59(s, 3H,-CH3), 4.68(s, 3H,-CH3), 7.26(s, 1H,ArH), 7.63(s, 1H,ArH), 11.27 (s, 1H, COOH).

Embodiment 2

[0051] Synthesis of 2-tert-Butoxycarbonyl-4,5-dimethoxybenzoic acid (2b)

[0052] Dissolve 2-hydroxy-4,5-dimethoxybenzoic acid (100g) in anhydrous toluene (400ml), add Boc2O (132g) at room temperature and stir at room temperature for 3 hours, add 10% citric acid aqueous solution (100ml) washed three times, washed with purified water until neutral, added with anhydrous sodium sulfate (20g) and dried for 8 hours, filtered and evaporated to dryness under reduced pressure to obtain the title compound (135g), yield 90%, melting point: 190℃

[0053] H1-NMR(DMSO, 400 MHz) δ: 1.34(s,3H), 1.37(s,3H), 1.40(s,3H), 3.77(s,3H), 3.82(s, 3H), 7.17(s, 1H), 7.50(s, 1H), 13.45-13.70(bs, 1H).

Embodiment 3

[0055] Step 1: Preparation of 2-[N-(2-tert-butyldimethylsilyloxy-4,5-dimethoxybenzoyl)amino]-4-methoxycarbonyl-1,3-thiazole

[0056] Dissolve 2-hydroxy-4,5-dimethoxybenzoic acid (100g) in anhydrous toluene (400ml), slowly add TBSOTf (160g) to the solution at room temperature, stir for 5 hours, add purified water to wash To neutrality, take the organic phase, add anhydrous sodium sulfate (20g) and dry for 8 hours, filter, add thionyl chloride (60g) and N,N-dimethylformamide (0.18ml) to the filtrate, Stir at 80°C for 4 hours, add 2-amino-4-methoxycarbonyl-1,3-thiazole (80g) to the compound, stir at 100°C for 5 hours, after the reaction is over, cool to room temperature, and filter the precipitate Crystals, crystals were added to 1.6 liters of water, 400 grams of ice was added to stir, and 10% by mass sodium hydroxide aqueous solution was added, the pH of the aqueous solution was adjusted to 7.5, and then stirred at room temperature for 3 hours. The crystals were collected by filtra...

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Abstract

The invention relates to a synthetic method of acotiamide hydrochloride. The synthetic route of the acotiamide hydrochloride comprises the following steps: protecting hydroxyl vicinal to carboxyl in a formula (1) compound to obtain a formula (2) compound, performing acylating chlorination on the formula (2) compound to obtain a formula (3) compound, condensing the formula (3) compound with a formula (4) compound to obtain a formula (5) compound, condensing the formula (5) compound with a formula (6) compound to obtain a formula (7) compound, removing protection of 2-site hydroxyl of a benzene ring from the formula (7) compound, and salifying the compound to obtain the acotiamide hydrochloride. The synthetic method has the benefits that the formula (2) compound is not extracted but directly used for the next reaction to form the formula (5) compound in a one-pot method; the method is high in selectivity, low in side effect and high in yield; in the meantime, the formula (5) compound to the formula (8) compound can be prepared with the one-pot method; the method is high in the protection removal selectivity, low in side effect, less in the operation steps, and easy for realizing industrialization.

Description

Technical field [0001] The invention belongs to the field of chemical engineering, in particular to the technical field of organic synthesis, and in particular to a method for synthesizing acotiamide hydrochloride. Background technique [0002] Acotiamide hydrochloride, chemical name: N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino] -1,3-thiazole-4-carboxamide hydrochloride, the structure is as follows: [0003] [0004] Acotamide hydrochloride is an acetylcholinesterase inhibitor gastrokinetic drug jointly developed by Japan’s Zeria Pharmaceutical Company and Astellas, that is, a drug for the treatment of functional dyspepsia. It is the first drug approved for the treatment of FD in the world, 2013 It was launched in Japan for the first time in June 2006 under the trade name Acofide. Functional dyspepsia (FD) refers to a group of common symptoms including upper abdominal fullness, early satiety, burning sensation, belching, nausea and vomiting, and indescr...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07C69/96C07C68/00C07H15/256C07H1/00
Inventor 黄建金
Owner CHINA RESOURCES SAIKE PHARMA
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