Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide

A technology of glucuronide and synthesis method, applied in the field of medicinal chemistry synthesis, can solve the problems of reduced yield, low yield, low feasibility of amplification and industrialization, etc.

Active Publication Date: 2014-06-18
YICHANG HUMANWELL PHARMA
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  • Summary
  • 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-band-protected glucuronide methyl ester, glucuronolactone is used to develop Cycling 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 all passed through The separation and purification of column chromatography is difficult for industrialization; thirdly, no suitable deprotection and post-treatment methods are given
[0012] (1) The perchloric acid and 3-pivaloylmorphine in the catalyst form a salt and precipitate, resulting in catalyst deactivation
[0013] (2) Column chromatography is used to purify the product in the post-treatment of the glycoside reaction, and the feasibility of later amplification and industrialization is not high
It can be seen that the conversion rate of this reaction is very low, and the raw materials and products are not easy to separate. Column chromatography is used to purify the product, which further reduces the yield, and there are problems in the industrialization of this method
[0015] In summary, the above-mentioned several methods of M6G all have the same problem: (1) the conversion rate of the key step glycoside reaction is low
(2) The purification of the products all adopts the method of column chromatography, and there are problems in industrialization
(3) The purity and residue on ignition of the product are difficult to meet the quality requirements

Method used

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  • Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide
  • Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide
  • Synthesis method and intermediate compound of morphine-6-Beta-D-glucuronide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] (1) Synthesis of Intermediate III (P1 and P2 are different protecting groups)

[0066] Dissolve 20 g of the compound shown in formula III (both P1 and P2 are isobutyryl, R is methyl) in acetic acid, add 10 g of trifluoroacetic anhydride, add 0.1 ml of boron trifluoride, react at 30-40 ° C, pour into ice In water, filtered, and the filter cake was dried under reduced pressure at 45-50°C to obtain (P1 is isobutyryl, P2 is trifluoroacetyl, R is methyl) 20.5 g of the compound represented by formula III, with a yield of 97.6%;

[0067] 1 H-NMR: (300MHz, CDCl 3 )δ=5.75(d, 1H), 5.11~5.16(m, 3H), 4.17(d, 1H), 3.74(s, 3H), 2.02(s, 9H).

[0068] (2) Synthesis of Intermediate IV

[0069] Dissolve 10 g of acetylmorphine (compound represented by formula II) and 20 g of compound represented by formula III (P1 is isobutyryl, P2 is trifluoroacetyl, R is methyl) in methyl tert-butyl ether, 10-25 ° C Add 5g of zinc bromide, react until complete at 55-60°C, filter, extract with dichlo...

Embodiment 2

[0079] 1) Synthesis of intermediate III (P1 and P2 are different protecting groups)

[0080] Dissolve 20 g of the compound shown in formula III (both P1 and P2 are acetyl, R is methyl) in benzoic acid, add 12 g of trichloromethanesulfonic anhydride, add 0.05 ml of boron trifluoride, react at 30-40 ° C, pour into Filter in ice water, and dry the filter cake under reduced pressure at 50-60°C to obtain 21.5 g of the compound represented by formula III (P1 is acetyl, P2 is trifluoromethanesulfonyl, R is methyl) with a yield of 97.5%;

[0081] 1 H-NMR: (300MHz, CDCl 3 )δ=6.42(d, 1H), 5.24~5.79(m, 3H), 4.44(d, 1H), 3.73(s, 3H), 2.46~2.54(m, 3H), 1.12(d, 18H).

[0082] (2) Synthesis of Intermediate IV

[0083] Dissolve 10 g of acetylmorphine (compound represented by formula II) and 18 g of compound represented by formula III (P1 is acetyl, P2 is trifluoromethanesulfonyl, R methyl) in dichloromethane, and add trifluoride Boron ether solution 15ml, 35 ~ 40 ° C until the reaction is...

Embodiment 3

[0088] (1) Synthesis of Intermediate III (P1 and P2 are different protecting groups)

[0089] Dissolve 20 g of the compound shown in formula III (both P1 and P2 are isopropionyl, R is ethyl) in benzoic acid, add 9 g of trifluoromethanesulfonic anhydride, add 3 g of zinc chloride, react at 70-80 ° C, pour into ice In water, filtered, and the filter cake was dried under reduced pressure at 50-60°C to obtain 20 g of the compound represented by formula III (P1 is isopropionyl, P2 is trifluoromethanesulfonyl, R is ethyl) with a yield of 96.5%;

[0090] (2) Synthesis of Intermediate IV

[0091] Dissolve 10 g of acetylmorphine (compound represented by formula II) and 16 g of compound represented by formula III (P1 is isopropionyl, P2 is trifluoromethanesulfonyl, R is ethyl) in chloroform, and add chlorine at 10-25 ° C Aluminum 12g, reacted at 40-45°C until complete, filtered, the filtrate was extracted with ethyl acetate, washed with water and saturated brine, concentrated to drynes...

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Abstract

The invention discloses a synthesis method and an intermediate compound of morphine-6-Beta-D-glucuronide. The synthesis method comprises the following steps: (1) carrying out a reaction on 3-acetyl morphine and acyl-protected glucuronate in an organic solvent 1 under the catalysis of lewis acid so as to obtain an intermediate shown as a formula (IV); (2) hydrolyzing the intermediate shown as the formula (IV) with lithium hydroxide and neutralizing the intermediate shown as the formula (IV) with hydrobromic acid in a mixture solvent of C1-C4 alkanol and water; and washing the intermediate with the C1-C4 alkanol and drying, thereby obtaining the intermediate compound of the morphine-6-Beta-D-glucuronide, wherein the definitions of substituent groups in the formula (III) and the formula (IV) are shown in the specification. The synthesis method has the advantages of moderate condition and high yield, and is simple to operate and easy to industrialize.

Description

technical field [0001] The invention relates to a method for synthesizing analgesics, belonging to the field of chemical synthesis of medicines, in particular to a method for synthesizing morphine-6-β-D-glucuronide and an intermediate compound thereof. Background technique [0002] Morphine-6-β-D-glucuronide [Morphine-6-β-D-glucuronide, referred to as M6G], shown in formula (I), is the active metabolite of morphine in vivo. Morphine as an opioid is currently the most widely used narcotic analgesic for the treatment of moderate to severe pain, but studies have shown that it is not morphine itself that acts as an analgesic. Morphine is mainly combined with glucuronide in the liver and produces two metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G can bind to opioid receptors, and animal experiments show that its analgesic effect is stronger than that of morphine, and its adverse reactions are milder. M3G has a low affinity with opioid receptors ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H13/06C07H1/00
CPCC07H1/00C07H13/06C07H17/00
Inventor 郭建锋张国龙王孟华吕金良符义刚田峦鸢李莉娥李仕群郑炜
Owner YICHANG HUMANWELL PHARMA
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