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Morphinone quaternary ammonium salt derivatives and preparation method thereof

A compound and mixture technology, applied in the field of morphinone quaternary ammonium salt derivatives and its preparation, can solve the problems of cumbersome process routes, limited sources, expensive prices, etc., and achieve the goals of fewer process steps, low production costs, and reduced relapse rate Effect

Active Publication Date: 2012-01-11
HANGZHOU ADAMERCK PHARMLABS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Due to the limited source of thebaine and its high price, EP0158476, US5922876, US6008354 and WO03 / 018588 have reported the use of cheap morphine as a raw material to synthesize the key intermediate noroxymorphone of morphinone derivatives, after demethylation and benzyl etherification , oxidation to ketone, 14-position hydroxylation, hydrogenation to remove the 3-position methyl group, acidic hydrolysis to remove the 17-position protecting group to obtain the target product, but the process route is cumbersome and the yield is low

Method used

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  • Morphinone quaternary ammonium salt derivatives and preparation method thereof
  • Morphinone quaternary ammonium salt derivatives and preparation method thereof
  • Morphinone quaternary ammonium salt derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Synthesis of 3,17-bis(2,2,2-trichloroethyl formate)normorphine (compound b1)

[0034]

[0035] At room temperature, morphine (28.53g, 0.1mol), trichloroethyl chloroformate (42.37g, 0.2mol) and a certain amount of pyridine were added to the reaction flask, and the mixture was reacted and stirred overnight. After the reaction was complete, water was added to precipitate out. After washing and drying, 3,17-bis(2,2,2-trichloroethyl formate) normorphine was obtained.

[0036] The compound H NMR spectrum (D6-DMSO+D2O): δ1.88, 1.63 (CH 2 , m, 2H), 2.88 (CH, m, H), 3.19, 2.94 (CH 2 , m, 2H), 3.39, 3.29 (CH 2 , m, 2H), 3.73 (CH, m, H), 4.19 (CH, s, H), 4.30 (CH, s, H), 4.84 (CH 2 , s, 2H), 4.92 (CH 2 , s, 2H), 5.59 (2CH, m, 2H), 6.54 (CH, d, H), 6.63 (CH, d, H) ppm.

Embodiment 2

[0038] Synthesis of 3,17-bis(2,2,2-trichloroethyl formate) normorphone (compound c1)

[0039]

[0040] 3,17-bis(2,2,2-trichloroethyl formate) normorphine (14.3 g, 0.023 mol) was dissolved in 60 ml of trichlorethylene, and 28 ml of water was added. The pH was adjusted to 5 with sulfuric acid, the mixture was heated to reflux, and then Jones reagent (7.5g sodium dichromate dihydrate dissolved in 22ml water and 6ml sulfuric acid) was slowly added for 1 hour, and the oxidation reaction was carried out under reflux for 1.5 hours, Excess oxidizing agent was destroyed by adding 6 ml of 2-propanol. The layers were separated, and the organic layer was washed with 10% aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. Concentrate to dryness, and dissolve the residue in ethanol to obtain 3,17-bis(2,2,2-trichloroethyl formate)normorphone.

[0041] The compound H nuclear magnetic resonance spectrum (D6-DMSO+D2O): δ1.88, 1.63 (CH 2, m, 2H), 2.88 (C...

Embodiment 3

[0043] Synthesis of 14-hydroxy-3,17-bis(2,2,2-trichloroethyl formate)normorphone (compound d1)

[0044]

[0045] Dissolve 3,17-bis(2,2,2-trichloroethyl formate) normorphone (13.02g, 0.021mol) in 135ml of ethanol, heat to 60°C, add 2.6g (0.0147 mol) cobalt acetate and 0.5g (0.006mol) sodium acetate and pass into air, TLC traces until the reaction is complete, and the reaction solution is treated with activated carbon (0.3g) and filtered. Concentrate to volume (8.91 g 14-hydroxy-3,17-bis(2,2,2-trichloroethyl carboxylate)normorphone in 50 ml ethanol) and proceed directly to the next step.

[0046] The compound H NMR spectrum (D6-DMSO+D2O): δ1.88, 1.63 (CH 2 , m, 2H), 3.19, 2.94 (CH 2 , m, 2H), 3.39, 3.29 (CH 2 , m, 2H), 3.81(CH, t, H), 4.84(CH 2 , s, 2H), 4.92(CH, s, H), 4.92(CH 2 , s, 2H), 6.34 (CH, d, H), 6.54 (CH, d, H), 6.63 (CH, d, H), 7.01 (CH, d, H) ppm.

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Abstract

The invention provides morphinone quaternary ammonium salt derivatives which are prepared through the following steps: obtaining morphinone derivatives from morphine as the starting material through demethylation, oxidation, reduction, condensation and other chemical reactions; and obtaining the morphinone quaternary ammonium salt derivatives from the morphinone derivative through the reaction with halocarbon. The preparation method of the invention has the characteristics of few technological steps, low production cost, simple operation, stable quality and the like. The compounds provided by the invention have obvious contraction effect on the morphine-dependent guinea pig ilea, thereby promoting the intestinal peristalsis, the compounds are applicable to the preparation of drugs for curing constipation and intestinal obstruction; and the compounds provided by the invention further have obvious inhibiting effect on the conditioned place preference (CPP) of morphine-induced rats to the drug-paired compartment, therefore, the compounds can be used for preparing anti-relapsing drugs and effectively reducing the relapse rate, and the invention is favorable for the all-round promotion of rehabilitation and anti-relapsing work.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to morphinone quaternary ammonium salt derivatives and a preparation method thereof. technical background [0002] There are many varieties of morphinone derivatives on the market, such as naltrexonehydrochloride, naloxone hydrochloride, naltrexone hydrochloride and methylnaltrexone. [0003] The disclosed method of synthesizing morphinone derivatives is to take thebaine (thebaine) as starting material, obtain oxycodone (oxycodone) through oxidation and hydrogenation reduction; Obtain 14-acetyl oxycodone (14- Acetyloxycodone); acidic hydrolysis after reacting with chloroformate to remove the 17-position methyl group to obtain noroxycodone (noroxycodone); remove the 3-position methyl group by boron tribromide to obtain noroxymorphone (noroxymorphone ); react with cyclopropyl bromide to give naltrexone; react with allyl bromide to give naloxone. [0004] Due to the limite...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/02C07D489/00A61K31/485A61P1/10A61P25/30
Inventor 漆又毛揭清张冯敏顾颖
Owner HANGZHOU ADAMERCK PHARMLABS INC
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