Synthetic method of 3-aminomethyl-isoxazole hydrochloride

A technology of isoxazole hydrochloride and synthesis method, which is applied in the fields of chemical industry and medicine, can solve the problems of not being suitable for large-scale production, high cost, difficult preparation of starting materials, etc., and achieve shortened production process, mild conditions and high product purity Effect

Inactive Publication Date: 2013-08-14
苏州科捷生物医药有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0006] The starting material of this method is difficult to prepare, and the cost is high. At the same time, the first three steps of the reaction need to use toxic and dangerous reagents diisobutyl aluminum hydride, thionyl chloride and sodium hydride, and the last step of the reaction will use noble metal palladium. Not suitable for scale-up production

Method used

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  • Synthetic method of 3-aminomethyl-isoxazole hydrochloride
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  • Synthetic method of 3-aminomethyl-isoxazole hydrochloride

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Embodiment 1

[0019] Embodiment 1: Synthesis of 2,4-dichloro-2-butenone (compound 2)

[0020] Chloroacetyl chloride (120 g, 1.06 mol) was slowly added dropwise to anhydrous AlCl 3 (156g, 1.17mol) and CCl 4 (320mL), the mixture was cooled to -5°C, acetylene gas was introduced for 2 hours, the reactant was slowly poured into ice water, the organic layer was washed with cold water, dried over anhydrous sodium sulfate, and collected under reduced pressure at 78-83°C / 16mmHg The distillate obtained 65 g of oily product 2,4-dichloro-2-butenone, yield: 44.2%.

Embodiment 2

[0021] Embodiment 2: Synthesis of 3-chloromethyl-isoxazole (compound 3)

[0022] 2,4-Dichloro-2-butenone (50g, 0.36 mol), methanol (200mL) and hydroxylamine hydrochloride (25g, 0.36 mol), heated to reflux for 4 hours, distilled methanol under reduced pressure, Na 2 CO 3 The solution was adjusted to alkaline, extracted with ethyl acetate, washed with water, anhydrous Na 2 SO 4 Dry and distill under reduced pressure to obtain 26 g of oily 3-chloromethyl-isoxazole, yield: 61.5%.

[0023] 1 H-NMR (CDCl 3 , 300MHz): δ8.39(d, 1H), 6.46(d, 1H), 4.62(s, 2H).

Embodiment 3

[0024] Embodiment 3: Synthetic bis-Boc aminomethyl-isoxazole (compound 4)

[0025] 3-Chloromethyl-isoxazole (24g, 0.20mol), NH(Boc) 2 (43.4g, 0.20mol), K 2 CO 3 (27.6g, 0.20 mol), tetrabutylammonium bromide (1.6g, 0.005 mol) and acetonitrile (80mL), stirred and refluxed overnight, cooled, added water (250mL), extracted with ethyl acetate, anhydrous Na 2 SO 4 Dry and concentrate to obtain 42 g of oily bis-Boc aminomethyl-isoxazole, yield: 70.5%.

[0026] 1 H-NMR (CDCl 3 , 300MHz): δ8.33(d, 1H), 6.29(d, 1H), 4.87(s, 2H), 1.47(s, 18H).

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Abstract

The invention discloses a synthetic method of 3-aminomethyl-isoxazole hydrochloride. The synthetic method comprises the steps that with aluminium chloride as a catalyst, chloroacetyl chloride reacts with acetylene to obtain 2,4-dichloro-2-methyl vinyl ketone, then the 2,4-dichloro-2-methyl vinyl ketone and hydroxylamine hydrochloride carry out reflux ring closure in methanol to obtain 3-chloromethyl-isoxazole, then the 3-chloromethyl-isoxazole reacts with NH(Boc)2 in acetonitrile to obtain a key intermediate bi-Boc aminomethyl-isoxazole, and finally Boc is removed in a hydrochloric acid-methanol solution to obtain the target product 3-aminomethyl-isoxazole hydrochloride. The method is mild and simple in reaction conditions, low in cost, high in yield, simple and convenient to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis process of 3-aminomethyl-isoxazole hydrochloride, which belongs to the technical fields of medicine and chemical industry. Background technique [0002] Isoxazole compounds are widely used in medicine and chemical industry. [0003] 3-Aminomethyl-isoxazole hydrochloride is an important pharmaceutical and chemical intermediate, which can be used to synthesize hepatitis C virus inhibitors (WO2011156610), and can also be used to synthesize phosphodiesterase 10A inhibitors to treat schizophrenia (WO2011117264), p38MAP kinase inhibitors can also be synthesized to treat inflammatory diseases (WO2011021678), and drugs for treating tumors can also be synthesized (WO2011075383). [0004] The synthetic method (US5089499) of literature report is as follows: [0005] [0006] The starting material of this method is difficult to prepare, and the cost is high. At the same time, the first three steps of the reaction need to u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
Inventor 邵东黄传满
Owner 苏州科捷生物医药有限公司
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