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A Stereoselective Synthesis Method of 6β-Hydroxy-7,8-Dihydro-morphine Derivatives

A synthesis method and derivative technology, applied in organic chemistry and other directions, can solve problems such as unreported synthesis methods, and achieve the effects of improving accurate positioning and characterization, cheap raw materials, and simple operation.

Active Publication Date: 2021-11-23
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Literature Quarry, Mary Ann; Williams, Reed C.; Sebastian, DoloresS. Determination of degradation products in nalbuphine hydrochloride injection by high performance liquid chromatography. Journal of Liquid Chromatography & Related Technologies (1998), 21 (18), 2841-2852, R.Cill. ; Edwards, J.F.; Ainsworth, C.R. Analysis of diastereoisomer impurities in chiral pharmaceutical compounds by capillary electrophoresis. Chromatographia (1994), 38(7-8), 441-6, Chatterjie, Nithiananda; Umans, Jason G.; Inturrisi, Charles E. Reduction of 6-βketones of the morphine series with formamidine sulfinic acid. Stereoselectivity opposite to that of hydride reductions. Journal ofOrganic Chemistry (1976), 41(22), 3624-5. Only the structure of the β-nalbuphine isomer is given , and no synthetic method has been reported

Method used

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  • A Stereoselective Synthesis Method of 6β-Hydroxy-7,8-Dihydro-morphine Derivatives
  • A Stereoselective Synthesis Method of 6β-Hydroxy-7,8-Dihydro-morphine Derivatives
  • A Stereoselective Synthesis Method of 6β-Hydroxy-7,8-Dihydro-morphine Derivatives

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] The synthesis of embodiment 1β-nalbuphine isomer (formula I-1 compound)

[0108] S1: Add 300ml of chloroform, 28.5g of morphine, and 42.7g of potassium bicarbonate into a 500ml three-necked bottle, stir at room temperature, add 85.5ml of ethyl chloroformate dropwise, after the addition is complete, heat up to reflux until the reaction is complete, cool down to room temperature, and react Pour the solution into 500ml of water, separate the layers, extract the aqueous layer with 300ml of dichloromethane, combine the organic phases, wash with 300ml of water and 200ml of saturated aqueous sodium chloride solution, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain the residue Thing 43g, promptly obtains formula II compound (R 1 and R 3 Both are ethoxycarbonyl), this intermediate does not need to be purified, it is directly used in the next step with a yield of more than 100%, which may contain ethyl chloroformate.

[0109] S2: A...

Embodiment 2

[0122] S1: Add 300ml of chloroform, 28.5g of morphine, and 42.7g of sodium bicarbonate into a 500ml three-necked flask, stir at room temperature, add 85.5ml of methyl chloroformate dropwise, after the addition is complete, heat up to reflux until the reaction is complete, cool down to room temperature, and react Pour the solution into 500ml of water, separate the layers, extract the aqueous layer with 300ml of dichloromethane, combine the organic phases, wash with 300ml of water and 200ml of saturated aqueous sodium chloride solution, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain the residue Thing 42g, promptly obtains formula II compound (R 1 and R 3 Both are methoxycarbonyl), this intermediate is directly used in the next step without purification, and the yield is over 100%, which may contain methyl chloroformate.

[0123] S2: Add acetone 500ml, S1 formula II compound (R 1 and R 3 Both are methoxycarbonyl), stir to dissolv...

Embodiment 3

[0132] Preparation of β-6-hydroxyhydromorphone (as shown in formula (I-2))

[0133] S1: Add 28.5g of hydromorphone, 300ml of acetonitrile, and 10.2g of triethylamine into a 500ml three-necked bottle, cool down to 0°C, add 10.2g of acetic anhydride dropwise, after the dropwise addition, return to room temperature naturally, and the reaction is completed. The solution was poured into 300ml of ice water, extracted twice with 500ml of dichloromethane, washed with saturated aqueous sodium bicarbonate until neutral, washed with saturated aqueous sodium chloride, dried overnight with anhydrous magnesium sulfate, filtered, and concentrated to dryness to obtain 330g of white Solid (Intermediate VI-2, R 1 is acetyl, R 3 For methyl), this solid may contain part of the solvent, but it does not affect the next step reaction and can be directly used in the next step reaction.

[0134] S2: Add the compound of formula VI-2 (R 1 is acetyl, R 3 methyl), 560ml of anhydrous methanol, 1.5ml of...

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Abstract

The invention discloses a stereoselective synthesis method of 6β-hydroxyl-7,8-dihydro-morphine derivatives. The synthesis method comprises the following steps: (i) the compound of formula VI is in a hydrophilic organic solvent, In the presence of a catalytic amount of C1-C4 alkanoic acid, it is reduced to a compound of formula VII by sodium borohydride; (ii) the compound of formula VII obtained in step (i) is separated to obtain a compound of formula VIII; here, in formula VI, formula VII and VIII For the definition of substituents, please refer to the specification.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a stereoselective synthesis method of 6β-hydroxyl-7,8-dihydro-morphine derivatives. Background technique [0002] Nalbuphine hydrochloride is a mixed opioid receptor agonist-antagonist. It is clinically used for the analgesic treatment of moderate to severe pain caused by various diseases, such as tumor, cancer, liver and gallbladder pain, and postoperative PCA patient-controlled analgesia. Compared with other opioid analgesics, nalbuphine hydrochloride has the characteristics of less adverse reactions and lower toxic and side effects. As a powerful analgesic, nalbuphine hydrochloride can antagonize μ receptors, stimulate k receptors, and has a weak agonistic effect on σ receptors, so there is little discomfort, and no blood pressure and heart rate increase. It is widely used clinically as an adjuvant in balanced anesthesia, for preoperative, postoperati...

Claims

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Application Information

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IPC IPC(8): C07D489/08C07D489/02
CPCC07D489/02C07D489/08
Inventor 李莉娥周园林廖宗权李杰杜文涛田峦鸢吕金良曲龙妹朱圣姬郭建锋
Owner YICHANG HUMANWELL PHARMA
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