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Synthetic method of anesthetic analgesic drug

A synthetic method and drug technology, applied in the direction of organic chemistry, can solve the problems that are not conducive to industrial production, cumbersome operation, low yield, etc.

Active Publication Date: 2019-12-17
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] It can be seen from the synthesis methods disclosed in the above documents that both remifentanil and carfentanil were synthesized using highly toxic cyanide. There are many potential safety hazards; in addition, when carrying out piperidine 4-carboxymethyl esterification, we find that the reaction time is too long, and it will be refluxed in methanol for more than 90 hours, and the reaction of the reactant is not complete, only about 70% Therefore, the yield of this step is extremely low, only about 50%, so the total yield of the whole route is very low, only about 10%
The synthetic route is long and the operation is cumbersome, which is unfavorable for industrialized production

Method used

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  • Synthetic method of anesthetic analgesic drug
  • Synthetic method of anesthetic analgesic drug
  • Synthetic method of anesthetic analgesic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] (1) compound of formula (III) (R 2 for hydrogen, R 1 for -CH 2 -CH 2 -C(O)-O-CH 3 )Synthesis

[0071] Formula (II)(R 2 Hydrogen) compound 129g, dissolved in 800ml of acetonitrile, added 175g of methyl acrylate, heated to 85 ° C, refluxed for 5 hours, the reaction was completed, the reaction solution was concentrated under reduced pressure, the solvent and the remaining methyl acrylate were removed, and the residue was washed with methanol Recrystallized and dried under reduced pressure at 40°C to obtain 195.6 g of white solid, yield: 91%.

[0072] 1 H-NMR (400MHz, CDCl 3 ), δ=1.59-1.95 (m, 4H), 2.35-2.57 (m, 7H), 3.62 (s, 3H), 3.76-3.83 (m, 2H).

[0073] (2) compound of formula (IV) (R 2 for hydrogen, R 1 for -CH 2 -CH 2 -C(O)-O-CH 3 )Synthesis

[0074] Formula (III) compound (R 2 for hydrogen, R 1 for -CH 2 -CH 2 -C(O)-O-CH 3) 191.7g dissolved in 2L 2-methyltetrahydrofuran, lower the temperature, control the internal temperature at 0-10°C, add 107.1g...

Embodiment 2

[0085] (1) compound of formula (III) (R 2 for hydrogen, R 1 for the synthesis of 2-phenylethyl)

[0086] Formula (II) compound (R 2 Hydrogen) 129g, dissolved in 800ml tetrahydrofuran, temperature controlled at about 0°C, 185-200g of β-phenethyl bromide was added dropwise, reacted at 30-40°C, after the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was washed with isopropyl The alcohol was recrystallized and dried under reduced pressure at 40°C to obtain 207.3 g of white solid, yield: 89%.

[0087] 1 H-NMR (400MHz, CDCl 3 ), δ=1.56-1.87 (m, 4H), 2.23-2.55 (m, 5H), 2.67-2.71 (t, 4H), 7.17-7.28 (m, 5H), 10.62 (s, 1H).

[0088] (2) compound of formula (IV) (R 2 for hydrogen, R 1 for the synthesis of 2-phenylethyl)

[0089] Formula (III) compound (R 2 for hydrogen, R 1 Dissolve 198g of 2-phenylethyl) in 2.7L of acetone, lower the temperature, control the internal temperature at 0-10°C, add 101.2g of thionyl chloride dr...

Embodiment 3

[0100] (1) compound of formula (III) (R 2 for hydrogen, R 1 for -CH 2 -CH 2 -C(O)-NH 2 )Synthesis

[0101] Formula (II) compound (R 2 (hydrogen) 129g, dissolved in 800ml of acetone, add 108g of acrylamide, heat up to 50-60°C, reflux reaction for 7 hours, after the reaction is completed, the reaction solution is concentrated under reduced pressure, the solvent and the remaining acrylamide are removed, and the residue is washed with methanol The tert-butyl ether was purified by pulping, and dried under reduced pressure at 40°C to obtain 173 g of white solid, yield: 86%.

[0102] 1 H-NMR (400MHz, DMSO-d 6), δ=1.63-1.92 (m, 4H), 2.33-2.59 (m, 7H), 3.62-3.65 (d, 2H), 7.53 (s, 2H), 12.45 (s, 1H).

[0103] (2) compound of formula (IV) (R 2 for hydrogen, R 1 for -CH 2 -CH 2 -C(O)-NH 2 )Synthesis

[0104] Formula (III) compound (R 2 for hydrogen, R 1 for -CH 2 -CH 2 -C(O)-NH 2 ) 170g dissolved in 1.7L acetonitrile, lower the temperature, control the internal temperat...

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Abstract

The invention discloses a synthetic method of an anesthetic analgesic drug. According to the synthetic method, 4-piperidinecarboxylic acid is used as a raw material and subjected to alkylation, bromination, methylation, acylation and the like to prepare the anesthetic analgesic drug. The method avoids the usage of highly toxic cyanide, so the safety and controllability of operation are improved; the method avoids an elimination reaction in reaction process, thereby accelerating reaction speed and shortening reaction time; and the method reduces reaction temperature, shortens the reaction time,and is more suitable for industrial production.

Description

technical field [0001] The present invention relates to but not limited to the technical field of medicinal chemistry, in particular to but not limited to a synthesis method of narcotic and analgesic drugs, especially a synthesis method of remifentanil and carfentanil. Background technique [0002] Remifentanil is the latest μ opioid receptor agonist, a new type of powerful analgesic, with definite curative effect, strong drug effect, rapid onset, small dose and easy control, low toxicity, safe and reliable. It was released in 1996 It was approved for clinical use in the United States. Carfentanil (carfentanil), the chemical name is 1-(2-phenylethyl)-4-(N-propionyl-N-phenylamino)-4-piperidinecarboxylic acid methyl ester, which is fentanyl The analogue is a high-strength and short-acting narcotic analgesic. Their chemical structures are as follows: [0003] [0004] At present, there are mainly the following two routes in the literature of synthesizing remifentanil and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 李莉娥郭建锋曹路陈雷周园林李杰杜文涛汪淼田峦鸢吕金良廖宗权曲龙妹李禹琼
Owner YICHANG HUMANWELL PHARMA
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