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Acetylated methylnaltrexone bromide and preparation method therefor

A technology for acetylating methylnaltrexone and methylnaltrexone, which is applied in the field of medicinal chemical synthesis and can solve the problems such as the preparation method of Delta-7 bromnaltrexone is not disclosed.

Inactive Publication Date: 2016-07-20
PEKING UNIV FOUNDER GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The structure of Delta-7 methylnaltrexone bromide is disclosed in Chinese patent 200780050175.1, which is entitled "Methods for the synthesis of quaternary 4,5-epoxy-morphinane analogues and the separation of their N-stereoisomers ", the preparation method of Delta-7 bromidenaltrexone is not disclosed in this patent document

Method used

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  • Acetylated methylnaltrexone bromide and preparation method therefor
  • Acetylated methylnaltrexone bromide and preparation method therefor
  • Acetylated methylnaltrexone bromide and preparation method therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] Embodiment 1: the preparation of acetylated methylnaltrexone bromide

[0159] 10mL of dichloromethane and 150mg of methylnaltrexone bromide (0.39mmol, 1eq) were added to a 50mL round bottom flask, and 100mg of triethylamine (0.99mmol, 3eq) was added with stirring. The system was cooled to -10°C, and 61mg (0.78mmol, 2eq) of acetyl chloride solution was slowly added dropwise, then stirred for 1 hour, then slowly warmed to room temperature, and continued to stir for 1 hour. TLC (Thin Layer Chromatography) monitored the completion of the reaction. Stop the reaction, add 20 mL of dichloromethane, wash with tap water twice (20 mL×2), wash with saturated aqueous sodium chloride solution twice (20 mL×2), and dry over anhydrous sodium sulfate. After the organic layer was concentrated, 160 mg of the product was obtained with a yield of 86%, which was directly used in the next reaction.

[0160] 1 H-NMR (400MHz,D 2 O): δ7.09(d, 1H, J=8.0Hz), 7.01(s, 1H, J=8.0Hz), 5.15(s, 1H), ...

Embodiment 2

[0161] Embodiment 2: Preparation of acetylated Delta-7 bromidenaltrexone

[0162] Add 60mL of acetonitrile, 3.6g (12.85mmol, 3.07eq) of 2-iodanoylbenzoic acid, 1.6g (13.67mmol, 3.2eq) of N-methylmorpholine oxide into a 150mL round bottom flask, nitrogen protection, and stir at room temperature for 1.5 Hour. Add acetylated methylnaltrexone bromide 2g (4.19mmol, 1eq), dimethyl sulfoxide 0.6mL (8.46mmol, 2eq), and continue stirring for 24 hours. The reaction was stopped, the solvent was evaporated under reduced pressure, and the solid was purified by column chromatography (eluent: CH 2 Cl 2 / CH3 OH=6 / 1, volume ratio), 400 mg of crude product was obtained with a yield of 20.1%, which was further prepared and purified by HPLC.

Embodiment 3

[0163] Example 3: Purification of acetylated Delta-7 bromidenaltrexone and preparation of acetylated Delta-7 methylnaltrexone formate

[0164] Column: Gemini5uC18150×21.2mm

[0165] Mobile phase: A phase: 0.1% formic acid aqueous solution, B phase: acetonitrile.

[0166] Flow rate: 20mL / min

[0167] Detection wavelength: 214nm

[0168] According to the linear elution in Table 1, collect the first fraction:

[0169] Table 1

[0170]

[0171] The first component liquid is the component liquid that flows out in the first to three minutes, preferably the component liquid that flows out in the first 1.5 to 3 minutes.

[0172] HPLC spectrum see figure 1 .

[0173] NMR data of purified Delta-7 acetylated methylnaltrexone formate:

[0174] 1 H-NMR (400MHz,D 2 O): δ7.17(d, 1H, J=8.0Hz), 7.01(d, 1H, J=8.0Hz), 6.93(d, 1H, J=8.0Hz), 6.16(d, 1H, J=8.0 Hz), 5.11(s, 1H), 4.30(s, 1H), 4.01(d, 1H, J=12.0Hz), 3.83(d, 2H, J=12.0Hz), 3.72(s, 3H), 3.47( d,1H,J=12.0Hz),3.15(d,2H,J=12....

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Abstract

The invention provides acetylated methylnaltrexone bromide and a preparation method therefor. The acetylated methylnaltrexone bromide is prepared through acetylating methylnaltrexone bromide which serves as a raw material.

Description

technical field [0001] The present invention relates to a synthetic preparation method of Delta-7 bromidenaltrexone, and acetylated bromidenaltrexone, acetylated Delta-7 bromidenaltrexone, and acetylated Delta-7 methylnaltrexone formic acid Salt, the preparation method of Delta-7 methylnaltrexone formate. The invention belongs to the technical field of pharmaceutical chemical synthesis. Background technique [0002] Methylnaltrexone bromide (methylnaltrexone bromide, methylnaltrexonebromide) is a mu opioid receptor antagonist jointly researched and developed by Wyeth Pharmaceuticals and Progenics. In 2008, the U.S. FDA approved methylnaltrexonebromide (Relistor) to be launched on the market, the trade name is Rdistor, which is used for the treatment of opioid-induced constipation (OIC) and the use of laxatives is ineffective. [0003] The structure of methylnaltrexone bromide is as follows: [0004] [0005] Delta-7 methylnaltrexone bromide is a compound with potential...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/08
Inventor 易崇勤刘鹏许恒韩方斌
Owner PEKING UNIV FOUNDER GRP CO LTD