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The preparation method of 2-(4-methylthiazol-5-yl) ethyl nitrate hydrochloride

A technology of methylthiazole and hydrochloride, applied in the field of compound preparation, can solve the problems of increased production difficulty and cost, small preparation amount, poor economy and the like, and achieves the advantages of avoiding column chromatography separation and purification, mild reaction conditions, and avoiding explosion risks. Effect

Active Publication Date: 2021-12-07
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI +1
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Problems solved by technology

[0013] (2) In verification test 1, the raw material 4-methyl-5-hydroxyethylthiazole cannot be completely reacted, which leads to the need for column chromatography purification, and the yield is low
[0014] (3) In verification test 2, although the reaction of the raw material 4-methyl-5-hydroxyethylthiazole is complete, the yield is low, and the experimental process involves two temperature control processes of heating and cooling, and the complicated operation is not conducive to a large amount of Production; the raw material urea used needs to be dried, which also increases the difficulty and cost of production
[0018] Although the method shown in Table 1 can realize the synthesis of 2-(4-methylthiazol-5-yl)ethyl nitrate, there are obvious deficiencies, such as raw material 4-methyl-5-hydroxyethylthiazole in verification test 1 The reaction cannot be completed completely, and the product needs to be purified by column chromatography, etc.; the reaction operation in verification test 2 is cumbersome, and urea, one of the raw materials, needs to be dried and pretreated, etc.
The preparation method of comprehensive literature report all has problems such as preparation amount is little, reaction operation complexity, yield is low and economy is poorer, so above-mentioned literature technique is not suitable for industrialized production nitric acid 2-(4-methylthiazol-5-yl) ethyl ester
And the preparation of 2-(4-methylthiazol-5-yl) ethyl nitrate hydrochloride has no bibliographical information

Method used

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  • The preparation method of 2-(4-methylthiazol-5-yl) ethyl nitrate hydrochloride
  • The preparation method of 2-(4-methylthiazol-5-yl) ethyl nitrate hydrochloride
  • The preparation method of 2-(4-methylthiazol-5-yl) ethyl nitrate hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0044] Put 21.46g (0.15mol) of 4-methyl-5-hydroxyethylthiazole in a 1000ml three-necked flask, add 210ml of dichloromethane, cool in an ice-salt bath, and keep the internal temperature below 0°C, add 56.7ml (0.6mol) Acetic anhydride, keep the internal temperature below 0°C, add 25.4ml (0.6mol) fuming nitric acid dropwise, keep 0-4°C for 2 hours after the addition, and the reaction is complete. Add 100ml of water to the solution, keep the internal temperature below 0°C, add dropwise 60% NaOH (about 120ml) aqueous solution to adjust pH≈7~8, separate the water layer, extract with dichloromethane (100ml×2 times), and combine the organic layers , washed with water (100ml × 2 times), washed with saturated brine (100ml × 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26.33g of 2-(4-methylthiazol-5-yl)ethyl nitrate, Yield: 93%.

Embodiment 2

[0046]Put 7.15g (0.05mol) of 4-methyl-5-hydroxyethylthiazole in a 500ml three-neck flask, add 70ml of dichloromethane, cool in an ice-salt bath, and keep the internal temperature below 5°C, add 7.3ml (0.08mol) Acetic anhydride, keep the internal temperature below 5°C, add 8.5ml (0.2mol) fuming nitric acid dropwise, keep the internal temperature below 5°C after the addition and react for 2 hours, the reaction is complete, add 33ml of water to the solution, maintain the internal temperature at 5°C Next, add 60% NaOH aqueous solution dropwise to adjust the pH to ≈7~8, separate the aqueous layer, extract with dichloromethane (30ml×2 times), combine the organic layers, wash with water (30ml×2 times), and wash with saturated brine (30ml×2 times). 1 time), dried over anhydrous sodium sulfate, added 0.9 g of activated carbon for decolorization, filtered, and concentrated to obtain 9.10 g of 2-(4-methylthiazol-5-yl)ethyl nitrate, yield: 96.8%.

Embodiment 3

[0048] Put 7.15g (0.05mol) of 4-methyl-5-hydroxyethylthiazole in a 500ml three-necked flask, add 35ml of dichloromethane, cool in an ice-salt bath, and keep the internal temperature below 5°C, add 7.6ml (0.08mol) Acetic anhydride, keep the internal temperature below 5°C, add 8.5ml (0.2mol) fuming nitric acid dropwise, keep the internal temperature below 5°C after adding and react for 3 hours, the reaction is complete, keep the internal temperature below 5°C, add 30% NaOH dropwise Adjust the pH of the aqueous solution to ≈7~8 (about 60ml), separate the aqueous layer, extract with dichloromethane (30ml×2 times), combine the organic layers, wash with water (30ml×2 times), and wash with saturated brine (30ml×1 time) , dried over anhydrous sodium sulfate, decolorized by adding 0.9 g of activated carbon, filtered, and concentrated to obtain 8.94 g of 2-(4-methylthiazol-5-yl)ethyl nitrate, yield: 95.1%. Dissolve the obtained 2-(4-methylthiazol-5-yl)ethyl nitrate in 55ml of ethyl acet...

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Abstract

The invention provides a kind of preparation method of 2-(4-methylthiazol-5-yl) ethyl nitrate hydrochloride, which is characterized in that it comprises the following steps: (1) using 4-methyl-5-(2-hydroxy Ethyl) thiazole is that starting material obtains nitrate 2-(4-methylthiazole-5-yl) ethyl ester through nitration reaction; (2) nitrate 2-(4-methylthiazole-5-yl) ethyl ester in solvent React with hydrochloric acid to make nitrate 2-(4-methylthiazole-5-yl) ethyl ester hydrochloride crude product; (3) to nitrate 2-(4-methylthiazole-5-yl) ethyl ester hydrochloride The crude product was recrystallized to obtain a qualified product. The method has the advantages of simple operation, mild reaction conditions, high yield and good product purity, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to a preparation method of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride. Background technique [0002] The compound 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is recorded in the literature Journal of Alzheimer's Disease 2004, 6, S75-S84; Current Alzheimer Research, 2006, 3, 237-245; Neuropsychopharmacology, 2007, 32,505–513; Pharmacology, Biochemistry and Behavior 2009, 91,495–502; ACS Medicinal Chemistry Letter, 2011, 2,656–661; US20090252704; WO2014013338. The compound is code-named GT-1061 in the literature and has the molecular formula C 6 h 9 ClN 2 o 3 S, the molecular weight is 224.66, and the structural formula is as follows. Literature reports show that 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride has anti-senile dementia (AD) effect. [0003] [0004] GT-1061 documents WO2000054756, WO2001049275, WO2005105065, US6310052, Pharmace...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/24
CPCC07D277/24
Inventor 黄海洪张东峰林紫云王晓良彭英
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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