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Method for preparing lafutidine from hydroxylamine hydrochloride

A technology of hydroxylamine hydrochloride and lafutidine, which is applied in the direction of organic chemistry, can solve problems such as increasing costs, and achieve the effects of improving safety, improving product quality and total yield, and increasing synthesis yield

Inactive Publication Date: 2013-06-05
北京国联诚辉医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, adding more compounds will inevitably increase the cost

Method used

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  • Method for preparing lafutidine from hydroxylamine hydrochloride
  • Method for preparing lafutidine from hydroxylamine hydrochloride
  • Method for preparing lafutidine from hydroxylamine hydrochloride

Examples

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Embodiment 1

[0039] Embodiment 1: N-[cis-4-[4-(N-piperidinylmethyl)pyridine-2-oxygen]-2-buten-1-yl]phthalimide (compound of formula 4) preparation of

[0040] Take 100g (0.197mol) of maleate salt (compound of formula 5), ​​add 1 liter of water, stir at room temperature for 15 minutes, add sodium hydroxide to adjust the pH to about 12, extract with 500mL of dichloromethane, separate layers, and then use 250mL of dichloromethane Extract with methyl chloride, combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the solvent to give 74.7g of viscous liquid (Compound 4), with a yield of 96.8% (based on crude product)

Embodiment 2

[0041] Example 2: Preparation of N-[cis-4-[4-(N-piperidinylmethyl)pyridine-2-oxygen]-2-butene-1-amine (compound of formula 2)

[0042]In a 500mL three-necked flask, 20 g (0.05 mol) of the imine (the compound of formula 4 prepared in Example 1), 94 g of ethanol, and 21.4 g (0.31 mol) of hydroxylamine hydrochloride were added to produce a large amount of white solid, and then aqueous sodium hydroxide ( Contains sodium hydroxide 51g, 1.27mol), react at room temperature for about 1 hour. After the TLC detection reaction was complete, add 400 mL of water to the reaction solution, extract 200 mL × 2 with dichloromethane, combine the organic phase, wash 200 mL with water, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain 13.2 g of light yellow oil ( Compound 2) has a yield of 95.5%, HPLC 98.9%, and is used in the next step without further purification.

Embodiment 3

[0043] Example 3: (+ / –)-2-[(2-furylmethyl)sulfinyl]-N-[4-[4-(1-piperidinylmethyl)-2-pyridyl]oxy Synthesis of Sub-(Z)-2-butenyl]acetamide (compound of formula 1, lafutidine)

[0044] Add 70 mL of ethyl acetate to 13.2 g (0.05 mol) of the oily enamine (compound of formula 2) obtained in Example 2, stir to dissolve, and then add p-nitrophenol 2-furan methanesulfonyl acetate (compound of formula 3 ) 15.6g (0.05mol, HPLC purity 99.5%), stirred and reacted at room temperature for 3-4 hours, TLC detected that the reaction was complete. Add 100 mL of water, adjust the pH to 4 with concentrated hydrochloric acid, filter, and separate layers. Add 150 mL of dichloromethane to the water phase, add potassium carbonate to adjust the pH to about 10, and separate layers. Add 80 mL of dichloromethane to the water layer for extraction. Combine the organic phases, wash with 30% potassium carbonate solution (100mL×4), wash with water (100mL×5), separate the organic phase, dry over anhydrous sodi...

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Abstract

The invention relates to a novel chemical synthetic method for lafutidine, and in particular relates to a method for preparing the lafutidine from hydroxylamine hydrochloride serving as aminolysis reagent. The method comprises the following steps of: (1) reacting a compound in a formula 4 with the hydroxylamine hydrochloride and sodium hydroxide so as to obtain a compound in a formula 2; (2) carrying out condensation on the compound in the formula 2 and a compound in a formula 3 so as to obtain the lafutidine in a formula 1. The whole preparation process is as shown in the specification. When in preparation of the key intermediate the compound in the formula 2, the hydroxylamine hydrochloride is chosen for substituting other reagents for aminolysis reaction, and the prepared lafutidine product has higher purity and can reach 99.88%; compared with the condition that the aminolysis reagent is removed from the intermediate, the hydroxylamine is easier to remove; and furthermore, the hydroxylamine hydrochloride is a solid reagent, has high purity and high stability, and industrial production is more easily realized.

Description

technical field [0001] The invention relates to a new chemical synthesis method of lafutidine, more specifically a method for preparing lafutidine by using hydroxylamine hydrochloride as an aminolysis reagent. Background technique [0002] Lafutidine, chemical name: (+ / –)-2-[(2-furylmethyl)sulfinyl]-N-[4-[4-(1-piperidinylmethyl)-2 -pyridyl]oxo-(Z)-2-butenyl]acetamide, molecular formula: C 22 h 29 N 3 o 4 S, molecular weight: 431.55, structural formula as follows: [0003] [0004] Lafutidine is a potent, long-acting second-generation histamine H 2 Receptor antagonists, jointly developed by Japan's Fujirebio and Taiho, are marketed under the trade names Storga and Protecadin respectively. [0005] Fuji's original patents JP56434, EP0282077, US4912101 and the subsequent improved method JP05-59045 reported the method for preparing lafutidine. These patents all adopt the Gabriel synthesis method to prepare primary amines, and then condense with active lipid intermediat...

Claims

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Application Information

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IPC IPC(8): C07D405/12
Inventor 罗宣德王高翔赵寅堡
Owner 北京国联诚辉医药技术有限公司
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