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Preparation method of fondaparinux sodium monosaccharide intermediate

A technology of reaction time and glucopyranoside, applied in the field of preparation of fondaparinux sodium monosaccharide intermediates, can solve the problems of affecting product quality, purity and yield, and many side reactions, so as to reduce the generation of side reactions and the cost Low, less impurity effect

Active Publication Date: 2019-02-22
江苏美迪克化学品有限公司
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  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

The domestic literature "Chinese Journal of Pharmaceutical Industry, 2016, 47(10), pp.1235-1238" proposes a new synthetic route. The main difference is that MeOH is first used to methylate the hydroxyl group at the C1 position, and then to attach the amino group. Cbz group protection, although the reagents used for the protection of dihydroxyl groups on the C4 and C6 positions are changed from benzaldehyde and benzaldehyde dimethyl acetal to 2,2-dimethoxypropane, but still cannot avoid the reaction of starting materials. Many side reactions, due to the small differences in each site in the structure of the starting material, various side reactions occur, so that the whole preparation process produces more side reactions and generates various complex impurities, which are brought to the intermediates and products in the next steps , thus affecting the quality, purity and yield of the product

Method used

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  • Preparation method of fondaparinux sodium monosaccharide intermediate
  • Preparation method of fondaparinux sodium monosaccharide intermediate
  • Preparation method of fondaparinux sodium monosaccharide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] A) Preparation of methyl 4,6-O-benzylidene-2-amino-2-deoxy-α-D-glucopyranoside (compound shown in formula (4)):

[0048] 4,6-O-benzylidene-2-glucosamine (25g, the compound represented by formula (5)) was mixed with methanol (75mL) and dissolved, and hydrochloric acid (300mL, mass fraction was 30%) was added, and the temperature was raised to 60°C React for 36 hours until the reaction is complete, lower to room temperature, adjust the pH value to 8-9 with potassium carbonate solution, cool to 0°C for crystallization for 6 hours, filter with suction, and recrystallize the filter cake with methanol to obtain methyl 4,6-O -Benzylidene-2-amino-2-deoxy-α-D-glucopyranoside, white solid 23.7g, yield 90%, purity 98.5%.

[0049] B) Preparation of methyl 4,6-O-benzylidene-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside (compound represented by formula (3)):

[0050] Dissolve methyl 4,6-O-benzylidene-2-amino-2-deoxy-α-D-glucopyranoside (22.5g) in chloroform (300mL), add wat...

Embodiment 2

[0056] A) Preparation of methyl 4,6-O-benzylidene-2-amino-2-deoxy-α-D-glucopyranoside (compound shown in formula (4)):

[0057] 4,6-O-benzylidene-2-glucosamine (44g, the compound represented by formula (5)) was mixed with methanol (7.9g), heated to dissolve, added concentrated sulfuric acid (8.1g), raised to 55°C for reaction After 48 hours until the reaction is complete, cool down to room temperature, adjust the pH value to 8-9 with potassium carbonate solution, cool to 0°C and crystallize for 6 hours, filter with suction, and recrystallize the filter cake with methanol to obtain methyl 4,6-O- Benzylidene-2-amino-2-deoxy-α-D-glucopyranoside, white solid 39.8g, yield 86%, purity 97.7%.

[0058] B) Preparation of methyl 4,6-O-benzylidene-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside (compound represented by formula (3)):

[0059] Methyl 4,6-O-benzylidene-2-amino-2-deoxy-α-D-glucopyranoside (35 g) was dissolved in acetone (500 mL), and an aqueous solution of sodium car...

Embodiment 3

[0065] A) Preparation of methyl 4,6-O-benzylidene-2-amino-2-deoxy-α-D-glucopyranoside (compound shown in formula (4)):

[0066] 4,6-O-benzylidene-2-glucosamine (96g, the compound represented by formula (5)) and methanol (575.4g) were mixed and dissolved, and acetic acid (215.7g) was added, raised to 65°C for 24h to react complete, lowered to room temperature, adjusted to pH 8-9 with potassium carbonate solution, cooled to 0°C for crystallization for 6 hours, filtered with suction, and the filter cake was recrystallized with methanol to obtain methyl 4,6-O-benzylidene- 2-Amino-2-deoxy-α-D-glucopyranoside, white solid 89.9g, yield 89%, purity 97.9%.

[0067] B) Preparation of methyl 4,6-O-benzylidene-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside (compound represented by formula (3)):

[0068] Methyl 4,6-O-benzylidene-2-amino-2-deoxy-α-D-glucopyranoside (88g) was dissolved in 1.2-dichloroethane (1L), potassium bicarbonate (78.3 g) and benzyl chloroformate (106.7g), kee...

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Abstract

The invention discloses a preparation method of a fondaparinux sodium monosaccharide intermediate. The preparation method includes using methyl glucose protected by C4 and C6 positions as a raw material to obtain methyl 3-O-benzyl-4,6-O-benzylidene-2-(benzyloxycarbonyl)amino-2-deoxy-alpha-D-glucopyranoside by methylation, amidation and benzylation, and then conducting dehydroxylation protection group protection reaction to obtain the fondaparinux sodium monosaccharide fragment intermediate methyl-3-O-benzyl-2-(benzyloxycarbonyl)amino-2-deoxy-alpha-D-glucopyranoside. The preparation method is simple in process, less in side reaction impurities, high in yield and suitable for process amplification preparation to meet the industrial production of fondaparinux sodium.

Description

technical field [0001] The invention belongs to the field of sugar chemical synthesis, and in particular relates to a preparation method of fondaparinux sodium monosaccharide intermediate. Background technique [0002] Fondaparinux sodium (Fondaparinux sodium) is a synthetic heparin pentasaccharide drug, which is the first indirect inhibitor of antithrombin-dependent factor Xa developed and produced by Sanofi Winthrop Industrie in France. The chemical structural formula is as follows (D, E, F, G, H are used to represent 5 monosaccharide fragments from left to right). [0003] [0004] The total synthetic route of fondaparinux sodium is relatively long, and the number of reaction steps varies from 50 steps to more than 70 steps. At present, the main construction strategies are (D+EF)+GH and D+(EF+GH). Among them, the following structure (Formula 1) is an important intermediate for introducing H monosaccharide fragments, and the Chinese name is methyl 3- O-benzyl-2-(benzy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H1/00
CPCC07H1/00C07H15/18C07H15/04Y02P20/55
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
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