Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives

A technology of bromomethylnaltrexone and naltrexone, applied in the field of naltrexone derivatives, can solve problems such as unmentioned chiral orientation rate, and achieve the effects of convenient industrial production, high yield and mild reaction conditions

Inactive Publication Date: 2013-06-26
天津康鸿医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction yield of this route is higher, but the problem of its chiral orientation rate is not mentioned

Method used

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  • Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives
  • Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives
  • Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1: Preparation of the first naltrexone derivative

[0073] This example is used to illustrate 3-[[2-(trimethylsilyl)ethoxymethyl]oxy]-4,5α-epoxy-14-hydroxyl-17-cyclopropylmethyl-6- Ketomorphinans and methods for their preparation.

[0074] (1) Dissolve 11 grams (ie 32 mmol) of naltrexone (ie 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-6-oxomorphinan) in 70 ml In dichloromethane, then add 5.6 grams (i.e. 34 mmol) 2-(trimethylsilyl) ethoxymethyl chloride (abbreviated as SEMCl), 100 mg of dimethylaminopyridine (abbreviated as DMAP) and 7 ml Triethylamine, stirred at room temperature until the reaction is complete;

[0075] (2) Pour the reaction solution obtained in step (1) into 100 milliliters of saturated aqueous sodium bicarbonate solution, stir for 5 minutes, let stand to separate layers, separate the upper water layer, and then use 50 milliliters of dichloromethane for the water layer to extract;

[0076] (3) Combine the dichloromethane layers in...

Embodiment 2

[0081] Embodiment 2: Preparation of the second naltrexone derivative

[0082] This example is used to illustrate the -14-hydroxy-6-ketomorphinan iodide and its preparation method.

[0083] To 10 g (ie 21.2 mmol) 3-[[2-(trimethylsilyl)ethoxymethyl]oxy]-4,5α-epoxy-14-hydroxyl-17-cyclopropylmethyl- 20 ml of methyl iodide was added to the 6-ketomorphinan, stirred evenly, and heated to 42° C. for 16 hours. Finally, excessive iodomethane was distilled off under reduced pressure (among them, iodomethane can be recycled and reused) to obtain 13 g of yellow powdery solid with a yield of 99.9%.

[0084] The proton nuclear magnetic resonance spectrum (abbreviation for short) of the yellow powdery solid that present embodiment makes 1 H-NMR) data are as follows: δ0.02(s,9H), 0.30(m,4H), 0.79(m,2H), 0.84(m,1H), 1.91(m,2H), 1.98(m,2H) , 2.22(m,2H), 3.20(m,2H), 3.24(t,2H), 3.30(m,3H), 3.40(t,2H), 3.75(m,1H), 4.79(s,1H), 6.02(s,2H), 6.33~6.46(q,2H), 9.04(s,1H). Among them, the above ...

Embodiment 3

[0089] This example is used to illustrate R-17,17-cyclopropylmethyl,methyl-3-hydroxy-4,5α-epoxy-14-hydroxy-6-ketomorphinan iodide / bromide and its preparation method.

[0090] To 10 g (ie 16.3 mmol) R-17,17-cyclopropylmethyl, methyl-3-[[2-(trimethylsilyl)ethoxymethyl]oxyl]-4,5α- Add 70 ml of methanol to epoxy-14-hydroxy-6-ketomorphinan iodide, stir to dissolve, and protect with nitrogen gas. At room temperature, 50 ml of 6% hydrobromic acid aqueous solution was added dropwise, and after the addition was completed, the temperature was raised to 60-70°C and the reaction was stirred for 5 hours. The reactant was concentrated under reduced pressure to obtain 6.8 g of light yellow solid.

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Abstract

The invention provides a preparation method of (R)-N-bromine-methyl naltrexone. The preparation method adopting naltrexone as the raw material comprises the following steps of: protecting 3-phenolic hydroxyl by adopting an organic silicon group to obtain a first naltrexone derivative; reacting the first naltrexone derivative with a methylation reagent CH3X to obtain a second naltrexone derivative; and removing the phenolic hydroxyl protective group from the second naltrexone derivative, and carrying out bromine anion exchange while necessary to obtain a target product. The invention further provides the two naltrexone derivatives related in the preparation method. The preparation method provided by the invention is high in directional rate and purity, less in steps, simple to operate, gentle in reaction conditions, low in device requirements and convenient to realize industrial production.

Description

technical field [0001] The invention relates to a preparation method of (R)-N-bromomethylnaltrexone and a naltrexone derivative as an intermediate of the preparation method. Background technique [0002] Methylnaltrexone (MNTX) is a quaternary ammonium salt derivative of the pure opioid antagonist naltrexone. Due to the addition of a methyl group, MNTX has a greater polarity and a smaller fat soluble. This feature makes it more difficult for MNTX to cross the blood-brain barrier, which acts more peripherally than centrally, with the advantage of not competing with the analgesic effects of opioids on the central nervous system. [0003] MNTX is a chiral molecule, and the chiral central quaternary ammonium nitrogen has two configurations, R and S. US patents 4176186, 4719215, 4861781, 5102887, 5972954, 6274591, 6559158 and 6608075, Chinese patents 200480009190.8, 2004800009191.2, 200680008123.3, 200680022957.X, etc. are all described. R-type isomer (R)-N-bromomethylnaltrexo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/08C07F7/18
CPCY02P20/55
Inventor 张晓军邹美香韩学文孙歆慧吴疆郭振华范巧云
Owner 天津康鸿医药科技发展有限公司
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