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Method for preparing 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride

A technology of methoxymethylpiperidine and phenylpropanamide, which is applied in the field of preparation of 4--4-methoxymethylpiperidine hydrochloride, can solve the problems of unfavorable long-term storage and transportation, large discharge of three wastes, Resolve problems such as low reaction purity, and achieve the effects of facilitating storage and transportation, reducing three waste pollution, and improving purity and yield

Inactive Publication Date: 2011-07-20
ZHEJIANG LANGHUA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above process, highly toxic raw materials such as potassium cyanide and sodium cyanide and other raw materials with great safety hazards are used. It is difficult to post-process during industrial scale-up production, and the discharge of three wastes is relatively large.
In the synthesis process, methyl iodide is used twice, and the production cost is relatively high
And in the 7th step, use propionyl chloride as reaction reagent, reaction purity is correspondingly lower
In addition, the target product 4-(N-phenylpropanamide)-4-methoxymethylpiperidine is a free oily substance with poor stability, which is not conducive to long-term storage and transportation needs

Method used

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  • Method for preparing 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Acetic acid (1600g), 1-phenyl-4-piperidone (500g, 2.64mol) and aniline (270.6g, 2.91mol) were added to a 5L reaction flask, and the solution was an orange-yellow clear liquid. After cooling in an ice bath to below 30°C, trimethylcyanosilane (275 g, 2.78 mol) was added dropwise, and the dropping temperature was controlled below 40°C. After the dropwise reaction was stirred at room temperature for 2 hours, TLC (petroleum ether: ethyl acetate = 3: 1) monitored the complete reaction of the raw material 1-phenyl-4-piperidone. Pour ammonia water into the reaction bottle, adjust the pH to around 9, and a large amount of white solids are precipitated. After standing for half an hour, the solid was collected by filtration, rinsed with 300ml of water, and dried to obtain 720g of off-white solid (I), with a yield of 93.5% (GC purity 98.5%, largest single impurity 0.3%). The product was directly put into the next step reaction without further purification.

[0031] Pre...

Embodiment 2

[0032] Example 2: Compound (I) (500g, 1.72mol) was added to a 3L reaction flask, concentrated H 2 SO 4 (4kg), control the temperature between 20-30°C, react at room temperature for 20h, TLC (petroleum ether: ethyl acetate = 3: 1) to monitor the complete reaction of raw materials, add ice cubes (3kg), a large amount of heat release, stir for 30min Afterwards, a white solid precipitated out. After cooling to 10°C, filter, and dissolve the collected white solid in a mixed solution (3.5 L) of isopropanol: water = 1: 8, and pour ammonia water to adjust the pH to about 9. After standing for 1 hour to cool to room temperature, filter and rinse with 150ml of water, and dry to obtain 490g of off-white solid (II), with a yield of 92.5% (GC purity 99.4%, largest single impurity 0.1%). Compound (II) does not need to be processed again, and is directly dropped into the next step reaction.

[0033] The present embodiment replaces the concentrated sulfuric acid with hydrochloric acid or p...

Embodiment 3

[0035] Example 3: Add compound (II) (450g, 1.46mol), 1,2-propanediol (1.55kg), potassium hydroxide (326g, 5.82mol) into the reaction flask, heat and control the temperature at 170°C for 12h, TLC (Ethyl acetate) After monitoring the complete reaction of raw materials, add 2000ml of water. Remove insoluble inorganic salts by filtration, adjust the pH of the aqueous layer to 5-6 with about 700ml of concentrated HCl, cool to 10°C, and let it stand for about 2 hours, a large amount of off-white solids precipitated. The off-white solid was collected by filtration and dried to obtain 388 g of product (Ⅲ), with a yield of 86% (HPLC purity 98.6%, maximum single impurity 0.8%). The white solid was directly put into the next reaction without further purification.

[0036] Present embodiment replaces potassium hydroxide with sodium hydroxide, replaces propylene glycol with ethylene glycol, all can obtain same result.

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Abstract

The invention discloses a method for preparing 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride, which belongs to the technical field of preparation of medicinal intermediates. The 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride is synthesized by using 1-phenyl-4-piperidone and aniline as initiative raw materials and by seven reactions. In raw materials used in the invention, trimethyl cyanato silane is used in place of potassium cyanide or sodium cyanide which is a highly toxic raw material to make the operation and management more convenient; potassium tert-butoxide and other alkalis are used in place of sodium hydride which is a dangerous and flammable reagent to improve the safety of scale-up production; propionic anhydride is used in place of highly irritant propionyl chloride to improve the safety, purity and yield of experiments; dimethyl sulfate is used in place of expensive methyl iodide to further control the production cost; and the high-pressure liquid chromatography (HPLC) purity of the obtained 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride product can reach 99.7 percent, the single impurity content is less than 0.1 percent, the total yield can reach 23 percent, and the product is a hydrochloride which is favorable for storage and transport.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, in particular to the co-synthesis intermediate 4-(N-phenylpropanamide)-4-methoxymethylpiperene of alfentanil and sufentanil opioid receptor agonists The preparation method of pyridine hydrochloride. Background technique [0002] Fentanyl is a synthetic opioid receptor agonist widely used clinically. It is mainly used for sedation and analgesia before, during and after anesthesia, and also for pain caused by various reasons. Studies have found that the analgesic activity of fentanyl is mainly derived from its 4-aniline piperidine skeleton structure. Through structural modification, an ether group is introduced at the 4-position of fentanyl, which also has good analgesic activity, such as alfentanil and sulfentanil. Compared with fentanyl, alfentanil has a shorter duration of action, and sufentanil has 5-10 times the analgesic activity, which also greatly enric...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
Inventor 石予白李军敏林邦平
Owner ZHEJIANG LANGHUA PHARMA
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