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Method for synthesizing morphine-6-Beta-D-glucuronide

A technology of glucuronide and morphine, which is applied in the field of medicinal chemistry, can solve the problems of difficult industrialization, difficult separation and purification, low yield and the like, and achieves the effect of simple and convenient operation.

Active Publication Date: 2013-12-04
YICHANG HUMANWELL PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Utilizing this method to synthesize M6G is also involved in the patent WO9938876, but there are also several deficiencies at the same time: first, when synthesizing the intermediate of thioglucoside-protected methyl glucuronate, glucuronolactone is used Ring-opening generates methyl glucuronate and then reacts with acid chloride, the yield is low, and it is not easy to separate and purify; second, the intermediate of morphine-6-β-D-glucuronide with protective group and the final product M6G are both Separation and purification by column chromatography is difficult for industrialization; third, no suitable deprotection and post-treatment methods are given

Method used

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  • Method for synthesizing morphine-6-Beta-D-glucuronide
  • Method for synthesizing morphine-6-Beta-D-glucuronide
  • Method for synthesizing morphine-6-Beta-D-glucuronide

Examples

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Embodiment 1

[0035] Example 1: Preparation of p-tolyl-2,3,4,6-tetra-O-pivaloyl-1-sulfhydryl-glucose (IV)

[0036] Method 1: In a 1L reaction flask, add 1,2,3,4,6-penta-pivaloyl glucose (36.8g, 61.2mmol), p-methylthiophenol (8.4g, 67.3mmol) and dichloro Methane 400ml, add boron trifluoride diethyl ether (99%, 10ml, 79.4mmol) under stirring at room temperature, react for 5 hours, add saturated sodium bicarbonate 200ml×2 to wash until neutral, separate the liquid and distill off the dichloride under reduced pressure Methane and crude ethanol were dissolved, cooled and crystallized, filtered and dried to obtain p-tolyl-2,3,4,6-tetra-O-pivaloyl-1-sulfhydryl-glucose with a yield of 31.8 g and a yield of 83%. 1 H-NMR: (300MHz, CDCl 3)δ=7.39(d, 2H), 7.11(d, 2H), 5.35(t, 1H), 4.96-5.10(m, 2H), 4.67(d, 1H), 4.22(d, 1H), 4.07(dd , 1H), 3.71-3.75 (m, 1H), 2.34 (s, 3H), 1.00-1.12 (m, 36H).

[0037] Method 2: In a 1L reaction flask, add 1,2,3,4,6-penta-pivaloyl glucose (36.8g, 61.2mmol), p-methylthio...

Embodiment 2

[0039] Example 2: Preparation of 3-acetyl-6-O-(2',3',4'-tripivaloyl-β-D-glucose)morphine (VI)

[0040] Method 1: In a 1L two-necked bottle, add p-tolyl-2,3,4,6-tetra-O-pivaloyl-1-sulfhydryl-glucose (36.6g, 58.8mmol), 3-acetylmorphine (19.2g , 58.8mmol) and dichloromethane 500ml, cooled to -10°C, added iodosuccinimide (13.2g, 58.8mmol), then added trifluoromethanesulfonic acid (2.6ml, 29.4mmol) dropwise, After the addition was completed, it was slowly raised to room temperature. After the reaction was completed, it was washed with saturated Na 2 S 2 o 4 solution, saturated NaHCO 3 solution and saturated NaCl solution, and after separation, dichloromethane was distilled off under reduced pressure, the crude product was dissolved in ethanol, cooled and crystallized, filtered and dried to obtain 3-acetyl-6-O-(2′,3′,4′-triptypentyl Acyl-β-D-glucose) morphine, yield 42.3g, yield 87%. 1 H-NMR: (300MHz, CDCl 3 )δ=6.73(d, 1H), 6.55(d, 1H), 5.71(d, 1H), 5.25-5.37(m, 3H), 5.07-5.14...

Embodiment 3

[0044] Embodiment 3: the preparation of morphine-6-β-D-glucoside (VII)

[0045] Method 1: Add 3-acetyl-6-O-(2′, 3′, 4′-tripivaloyl-β-D-glucose) morphine (22.0g, 26.6mmol), 5% NaOH40ml in the reaction flask and CH 3 OH200ml, stir overnight at 30°C, add activated 732 cation exchange resin to make the reaction solution neutral, filter the resin, filter the floc in the filtrate, dry to obtain morphine-6-β-D-glucoside, yield 11.0 g, 92% yield. 1 H-NMR: (300MHz, D 2 O) δ=6.65(d, 1H), 6.56(d, 1H), 5.74(d, 1H), 5.32(d, 1H), 4.61(d, 1H), 4.46(br, 1H), 4.09(br, 1H), 3.79(d, 1H), 3.61(dd, 1H), 3.00-3.44(m, 8H), 2.85-3.00(m, 6H), 2.05-2.20(m, 2H).

[0046] Method 2: Add 3-acetyl-6-O-(2′,3′,4′-tripivaloyl-β-D-glucose) morphine (22.0g, 26.6mmol) and 5% NaOH40ml into the reaction flask and CH 3 CH 2 OH200ml, stir overnight at 30°C, add activated 732 cation exchange resin to make the reaction solution neutral, filter the resin, filter the floc in the filtrate, dry to obtain morphine-6-...

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Abstract

The invention discloses a method for synthesizing morphine-6-Beta-D-glucuronide. According to the method, glucose and morphine serve as initial raw materials; morphine-6-Beta-D-glucose (VI), of which a key intermediate is provided with a protecting group, is synthesized in a three-dimensional selective manner; the protecting group is then removed; the primary hydroxyl group of glucose is oxidized in a selective manner, so as to obtain the target product morphine-6-Beta-D-glucuronide. The definition of substituent group in the formula (VI) is specified in the instruction manual. The method has the advantages that the raw materials are economical and easy to obtain; the synthesizing process is high in three-dimensional selectivity; the productivity of the target product is high; the synthesizing cost is low; the industrial value is higher.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a method for synthesizing morphine-6-beta-D-glucuronide from glucose and morphine. Background technique [0002] Morphine-6-β-D-glucuronide [Morphine-6-β-D-glucuronide, M6G for short, shown in formula (I) is the active metabolite of morphine in vivo. Morphine, as an opioid compound, is currently the most widely used narcotic analgesic for the treatment of moderate to severe pain, but studies have shown that morphine is not itself responsible for narcotic analgesia, but one of its main metabolites in the body—— M6G. Compared with morphine, M6G has stronger analgesic and analgesic effects, and greatly reduces side effects such as respiratory depression, nausea and vomiting caused by the use of morphine. [0003] [0004] At present, there are mainly three methods for the synthesis of M6G: [0005] Koenigs-Knorr (Koenigs-Knorr) glycoside method, the method is...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00
CPCY02P20/55
Inventor 吕金良尤启东汪淼符义刚李莉娥李杰徐华斌张建勋钱斌
Owner YICHANG HUMANWELL PHARMA