A kind of synthetic method of 1-methyl-3-(piperidin-4-yl) urea hydrochloride

A synthetic method, n-boc-4-technology, applied in the field of organic chemical synthesis, can solve problems such as easy moisture absorption, and achieve the effects of easy operation, mild reaction conditions, and simple post-treatment

Active Publication Date: 2019-02-19
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The compound is highly hygroscopic and needs to be stored with an inert gas

Method used

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  • A kind of synthetic method of 1-methyl-3-(piperidin-4-yl) urea hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Dissolve 2.0kg (about 10mol) of N-Boc-4-aminopiperidine, 1.0kg (about 11mol) of methyl chloroformate and 3.1kg (about 31mol) of triethylamine in a suitable reactor into 20L of dichloromethane (the molar ratio of N-Boc-4-aminopiperidine, methyl chloroformate, and triethylamine is about 1:1.1:3.1), and stirred at 25°C for 2 hours. TLC tracking showed that the starting material disappeared. 10 L of water was added to the reaction solution, the organic layer was separated, and the aqueous phase was extracted with dichloromethane (2×5 L). The organic phases were combined, washed successively with water (4 L) and saturated brine (4 L), dried with 2 kg of anhydrous sodium sulfate, filtered, and concentrated to obtain 2.64 kg of N-Boc-4-[(methoxyacyl)amino ]piperidine (LCMS[M+Na] + 281.1), with a purity of about 95%, about 9.7 mol. This product was used directly in the next reaction.

[0032] (2) In a suitable reactor, mix 2.64kg (about 9.7mol) of N-Boc-4-[(methoxyacyl)a...

Embodiment 2

[0037] (1) Dissolve 20.0kg (about 100mol) of N-Boc-4-aminopiperidine, 12.3kg (about 130mol) of methyl chloroformate and 33.4kg (about 330mol) of triethylamine in a suitable reactor into 100L of dichloromethane (the molar ratio of N-Boc-4-aminopiperidine, methyl chloroformate and triethylamine is about 1:1.3:3.3), the mixture was stirred at 20°C for 3 hours, TLC Trace shows ingredients disappearing. 100L of water was added to the reaction solution, the organic layer was separated, and the aqueous phase was extracted with dichloromethane (2×50L). The organic phases were combined, washed with water (40L) and saturated brine (40L) successively, dried with 20kg of anhydrous sodium sulfate, filtered, and concentrated to obtain 25.83kg of N-Boc-4-[(methoxyacyl)amino]piperene Pyridine (LCMS [M+Na] + 281.1), the purity is about 94%, about 94mol. This product was used directly in the next reaction.

[0038] (2) 25.83kg (about 94mol) of N-Boc-4-[(methoxyacyl)amino]piperidine and 61.1...

Embodiment 3

[0043] (1) Dissolve 200.0kg (1000mol) of N-Boc-4-aminopiperidine, 141.8kg (1500mol) of methyl chloroformate and 303.6kg (3000mol) of triethylamine into 1200L diethylamine in a suitable reactor In methyl chloride (the molar ratio of N-Boc-4-aminopiperidine, methyl chloroformate, and triethylamine is about 1:1.5:3.5), stir at 25°C for 3 hours, TLC tracking shows that the raw materials disappear, and the reaction is complete 1000L of water was added to the final reaction liquid, the organic layer was separated, and the aqueous phase was extracted with dichloromethane (2×500L). Combine the organic phases, wash with water (500L) and saturated brine (400L) successively, then dry with 250kg of anhydrous sodium sulfate, filter, and concentrate to obtain 250.23kg of N-Boc-4-[(methoxyacyl)amino] Piperidine (LCMS[M+Na] + 281.1), the purity is about 96%, about 930mol. This product was used directly in the next reaction.

[0044] (2) In a suitable reactor, combine about 250.23kg (about ...

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Abstract

The invention relates to a synthesis method of 1-methyl-3-(piperidine-4-yl) urea hydrochloride. The synthesis method comprises the following steps: (1) reacting N-Boc-4-aminopiperidine with methylchloroformate in a solvent in the presence of organic alkali to generate N-Boc-4-[(methoxy acyl) amino] piperidine; (2) reacting N-Boc-4-[(methoxy acyl) amino] piperidine prepared in the step (1) with methylamine in the solvent in the presence of organic alkali to generate 1-methyl-3-(N-Boc-piperidine-4-yl) urea; and (3) reacting 1-methyl-3-(N-Boc-piperidine-4-yl) urea prepared in the step (2) with acetyl chloride in the solvent to obtain a final product which is 1-methyl-3-(piperidine-4-yl) urea hydrochloride. The method is easily available in raw materials, mild in reaction condition, easy to operate and high in total yield; the molar total yield of three steps of reaction, which is metered according to the raw material N-Boc-4-aminopiperidine, can reach not less than 87%; the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a synthesis method of 1-methyl-3-(piperidin-4-yl)urea hydrochloride, which belongs to the technical field of organic chemical synthesis. Background technique [0002] 1-Methyl-3-(piperidin-4-yl)urea hydrochloride can be used in the synthesis of a peptide amide ligand for the K opioid receptor. Drugs containing such peptide amide ligands are effective for the prevention and treatment of pain and inflammation associated with various diseases. The pains treated by these drugs mainly include visceral pain, neuropathic pain and hyperalgesia. Inflammatory aspects including IBD and IBS, eye and ear inflammation, other diseases such as skin itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma are effective in prevention and treatment with this drug . [0003] At present, there are few reports about the synthesis method of 1-methyl-3-(piperidin-4-yl)urea hydrochloride. Bioorganic & Medicinal Chemistr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 王治国李涛李超田贝贝
Owner SHANGHAI ZAIQI BIO TECH
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