CN113004352B - Preparation method of fondaparinux sodium and fondaparinux sodium monosaccharide intermediate - Google Patents
Preparation method of fondaparinux sodium and fondaparinux sodium monosaccharide intermediate Download PDFInfo
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Abstract
The invention discloses a fondaparinux sodium and a preparation method of a fondaparinux sodium monosaccharide intermediate, which takes glucosamine protected at C4 and C6 as raw materials, obtaining methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside through methylation, amidation and benzylation, then, a dehydroxylation protecting group protection reaction is carried out to obtain a fondaparinux sodium monosaccharide fragment intermediate methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, and the fondaparinux sodium is prepared from the intermediate methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside. The preparation method has the advantages of simple process, less side reaction impurities and high yield, and is suitable for large-scale preparation of fondaparinux sodium in order to meet the requirement of industrial production of fondaparinux sodium.
Description
The invention is a divisional application of Chinese patent application with application date of 2018, 11 and 16, application number of 2018113655419 and name of 'a preparation method of fondaparinux sodium monosaccharide intermediate'.
Technical Field
The invention belongs to the field of chemical synthesis of sugar, and particularly relates to fondaparinux sodium and a preparation method of a fondaparinux sodium monosaccharide intermediate.
Background
Fondaparinux sodium (Fondaparinux sodium) is an artificially synthesized heparin pentasaccharide drug and is the first indirect inhibitor of antithrombin dependent factor Xa developed by Sanofi Winthrop industries, france. The chemical structure is shown as the following formula (D, E, F, G, H represents 5 monosaccharide segments from left to right, respectively).
The total synthetic route of fondaparinux sodium is long, and the reaction steps are from 50 steps to over 70 steps. The main construction strategies at present are two (D + EF) + GH and D + (EF + GH), wherein the following structure (formula 1) is an important intermediate for introducing H monosaccharide fragment, the name methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (the name methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside):
the intermediate of the formula 1 forms a fondaparinux sodium molecular structure mainly through the following butt joints: the structure of formula 1 is first reacted with AcCl to afford protection of the-OH at C6: -OAc; the-OH at position C4 of formula 1 is docked with the-OH at position C1 of an intermediate of the G monosaccharide fragment to form an intermediate of the GH disaccharide fragment; docking an intermediate of the GH disaccharide fragment with an intermediate of the EF disaccharide fragment to form an intermediate of the EF + GH tetrasaccharide fragment; docking the intermediate of the EF + GH tetrasaccharide fragment with the intermediate of the D monosaccharide fragment to form an intermediate of D + (EF + GH) pentasaccharide; finally, preparing the fondaparinux sodium by a series of reactions such as deprotection, sulfonation and the like.
In the related reports of the synthesis method of the intermediate represented by formula 1 in the prior art, the synthesis method mainly uses D-glucosamine hydrochloride as a raw material, and the preparation method disclosed in US patent US20130005954 is as follows:
in the related synthetic route reported in the patent US20170015695, the protection of the dihydroxy at the C4 and C6 positions is obtained by using benzaldehyde dimethyl acetal and camphorsulfonic acid for reaction. The domestic literature ' journal of Chinese medicine industry, 2016, 47(10) ', pp.1235-1238 ' proposes a new synthetic route, the main difference is that MeOH is firstly used for methyl protection on hydroxyl at C1, and then Cbz group protection is carried out on amino, although reagents used for protecting double hydroxyl at C4 and C6 are changed into 2, 2-dimethoxypropane from benzaldehyde and benzaldehyde dimethyl acetal, a plurality of side reactions caused by the reaction of starting raw materials cannot be avoided, and various side reactions are generated due to the slight difference of each site in the structure of the starting raw materials, so that the whole preparation process generates more side reactions, generates various complex impurities, and brings intermediates and products of the next steps, thereby affecting the quality purity and the yield of the products.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art, and provide an improved preparation method of fondaparinux sodium monosaccharide intermediate methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, which can obtain more ideal product yield, has less three wastes and is suitable for industrial large-scale production.
The invention also provides a preparation method of fondaparinux sodium.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a preparation method of methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside represented by the formula (2), comprising the following steps:
methylating a compound represented by formula (5) with methanol in the presence of an acidic catalyst to produce a compound represented by formula (4);
(ii) subjecting the compound represented by the formula (4) and benzyl chloroformate to amidation reaction in a mixed system of an organic solvent and water in the presence of an alkaline reagent to produce a compound represented by the formula (3);
(iii) subjecting the compound represented by the formula (3) and benzyl halide to a benzylation reaction in a solvent in the presence of an alkaline reagent to produce a compound represented by the formula (2);
according to some preferred aspects of the invention, in step (i), the acidic catalyst is a combination of one or more selected from the group consisting of hydrochloric acid, concentrated sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, formic acid and hydrobromic acid. According to some embodiments of the invention, "concentrated sulfuric acid" refers to an aqueous solution of sulfuric acid having a mass percent of 70-98%.
According to some preferred aspects of the invention, in step (i), the compound represented by formula (5), the methanol and the acidic catalyst are fed in a molar ratio of 1: 1.5 to 50: 0.5 to 10.
According to some preferred aspects of the invention, in step (i), the methylation reaction is controlled to be carried out at a temperature of 55-65 ℃.
According to some preferred aspects of the invention, in step (i), the reaction time of the methylation reaction is controlled to be 24 to 48 hours.
According to some preferred aspects of the invention, in step (ii), the basic agent is a combination of one or more selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
According to some preferred aspects of the present invention, the organic solvent is one or more of an aprotic halogenated hydrocarbon solvent and a ketone solvent, wherein the aprotic halogenated hydrocarbon solvent is a combination of one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane and chlorobenzene, and the ketone solvent is acetone and/or cyclohexanone.
According to some preferred aspects of the present invention, in step (ii), the compound represented by formula (4), the benzyl chloroformate and the basic agent are fed in a molar ratio of 1: 1.2 to 2.0: 1.2 to 2.5.
According to some preferred aspects of the invention, in step (ii), the amidation reaction is controlled to be carried out at a temperature of 20-40 ℃.
According to some preferred aspects of the invention, in step (ii), the reaction time of the amidation reaction is controlled to be 12 to 24 hours.
According to some preferred aspects of the invention, in step (iii), the benzyl halide is benzyl bromide and/or benzyl chloride.
According to some preferred aspects of the invention, in step (iii), the basic agent is a combination of one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, lithium tert-butoxide, magnesium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.
According to some preferred aspects of the invention, in step (iii), the solvent is a combination of one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane and methyl tert-butyl ether.
According to some preferred aspects of the invention, in step (iii), the temperature of the benzylation reaction is controlled to be 20-40 ℃.
According to some preferred aspects of the present invention, in step (iii), the reaction time of the benzylation reaction is controlled to be 12 to 24 hours.
According to some preferred aspects of the present invention, in the step (iii), the compound represented by the formula (3), the benzyl halide and the basic agent are charged in a molar ratio of 1: 2.0 to 4.0: 2.0 to 5.5.
The invention provides another technical scheme that: a preparation method of methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside represented by the formula (1), comprising the steps of:
(a) preparing a compound represented by formula (2) according to the preparation method;
(b) subjecting the compound represented by the formula (2) to a hydroxyl group deprotection reaction in an acidic aqueous solution to produce methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside represented by the formula (1);
according to some particular aspects of the invention, step (b) is a conventional method and conditions of such reactions in the art.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the invention, the intermediate is obtained by performing benzyl subunit protection reaction on C4 and C6 positions of D-glucosamine and is used as an initial raw material, so that side reactions can be reduced in each step of the next reaction, reaction steps can be simplified and optimized, impurities in each step of the reaction are fewer and controllable, no pollutant is generated, the yield and the purity are high, and the green and environment-friendly effect is reflected; on the other hand, the starting raw materials and the used reagents are easy to obtain, the cost is low, and the method is suitable for the process amplification preparation so as to meet the industrial production of fondaparinux sodium.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified. The starting material, 4, 6-O-benzylidene-2-glucosamine, can be prepared by reacting D-glucosamine hydrochloride (CAS 1078691-95-8) with benzaldehyde dimethyl acetal (CAS 1125-88-8), see patent CN103588825 for the preparation of the same compounds. In the following, concentrated sulfuric acid refers to a 98% sulfuric acid aqueous solution by mass.
The synthetic route for fondaparinux sodium monosaccharide intermediate methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside in the following examples is as follows:
example 1
A) Preparation of methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside (compound represented by the formula (4)):
mixing and dissolving 4, 6-O-benzylidene-2-glucosamine (25g, a compound shown in a formula (5)) and methanol (75mL), adding hydrochloric acid (300mL, the mass fraction is 30%), heating to 60 ℃, reacting for 36h until the reaction is complete, cooling to room temperature, adjusting the pH value to 8-9 with potassium carbonate solution, cooling to 0 ℃, crystallizing for 6h, performing suction filtration, recrystallizing a filter cake with methanol to obtain methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside, wherein 23.7g of white solid is obtained, the yield is 90%, and the purity is 98.5%.
B) Preparation of methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (3)):
dissolving methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside (22.5g) in chloroform (300mL), adding 300mL of water, adding 22.1g of potassium carbonate, dropwise adding 20.5g of benzyl chloroformate, keeping the temperature at 40 ℃ for reacting for 18h until the reaction is complete, cooling to 10 ℃ for crystallization for 6h, performing suction filtration and vacuum drying to obtain the methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, wherein the white solid is 30.6g, the yield is 92 percent and the purity is 98.6 percent.
C) Preparation of methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (2)):
methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside (30g) is dissolved in N, N-dimethylformamide (280mL), sodium hydroxide (5.8g) is added, N-dimethylformamide solution of benzyl bromide (24.7g) is dropwise added, the temperature is kept at 40 ℃ for reaction for 12h till the reaction is complete, and after post-treatment, purification and vacuum drying, methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside is obtained, 34.7g of white solid, the yield is 95%, and the purity is 99.2%.
D) Preparation of methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (1)):
methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside (32g), water (63g) and acetic acid (95g) are added into a reaction bottle, the reaction is carried out for 5h at the temperature of 100 ℃ until the reaction is complete, and after post-treatment, purification and vacuum drying, the methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside is obtained, wherein the white solid is 25.4g, the yield is 96 percent, and the purity is 98.8 percent.
Example 2
A) Preparation of methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside (compound represented by the formula (4)):
mixing 4, 6-O-benzylidene-2-glucosamine (44g, a compound shown in formula (5)) and methanol (7.9g), heating to dissolve, adding concentrated sulfuric acid (8.1g), heating to 55 ℃, reacting for 48h until the reaction is complete, cooling to room temperature, adjusting the pH value to 8-9 with potassium carbonate solution, cooling to 0 ℃, crystallizing for 6h, filtering, recrystallizing a filter cake with methanol to obtain methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside, wherein 39.8g of white solid is obtained, the yield is 86%, and the purity is 97.7%.
B) Preparation of methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (3)):
dissolving methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside (35g) in acetone (500mL), dropwise adding an aqueous solution of sodium carbonate (15.8g) and benzyl chloroformate (25.5g), keeping the temperature at 20 ℃ for reaction for 24h until the reaction is complete, cooling to 10 ℃ for crystallization for 6h, performing suction filtration, and performing vacuum drying to obtain the methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, wherein the white solid is 46.5g, the yield is 90%, and the purity is 98.1%.
C) Preparation of methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (2)):
methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside (45.5g) is dissolved in 1, 4-dioxane (450mL), potassium hydroxide (24.6g) is added, 1, 4-dioxane solution of benzyl bromide (56.2g) is added dropwise, the temperature is kept at 30 ℃ for reaction for 16h till the reaction is complete, and after post-treatment, purification and vacuum drying, the methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside is obtained, 51.5g of white solid is obtained, the yield is 93 percent, and the purity is 98.7 percent.
D) Preparation of methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (1)):
adding methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside (50g), water (150g) and acetic acid (240g) into a reaction bottle, keeping the temperature at 100 ℃, reacting for 3.5h until the reaction is complete, and performing post-treatment, purification and vacuum drying to obtain the methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, wherein the white solid is 39.2g, the yield is 95%, and the purity is 98.6%.
Example 3
A) Preparation of methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside (compound represented by the formula (4)):
mixing and dissolving 4, 6-O-benzylidene-2-glucosamine (96g, a compound shown in a formula (5)) and methanol (575.4g), adding acetic acid (215.7g), raising the temperature to 65 ℃, reacting for 24h until the reaction is complete, cooling to room temperature, adjusting the pH to 8-9 by using a potassium carbonate solution, cooling to 0 ℃, crystallizing for 6h, performing suction filtration, recrystallizing a filter cake by using methanol to obtain methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside, 89.9g of white solid, 89% of yield and 97.9% of purity.
B) Preparation of methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (3)):
dissolving methyl 4, 6-O-benzylidene-2-amino-2-deoxy-alpha-D-glucopyranoside (88g) in 1.2-dichloroethane (1L), dropwise adding an aqueous solution of potassium bicarbonate (78.3g) and benzyl chloroformate (106.7g), keeping the temperature at 30 ℃ for reaction for 12h until the reaction is complete, cooling to 10 ℃ for crystallization for 6h, performing suction filtration and vacuum drying to obtain the methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, wherein the white solid is 120.9g, the yield is 93 percent and the purity is 98.0 percent.
C) Preparation of methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (2)):
dissolving methyl 4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside (120g) in methyl tert-butyl ether (1L), adding barium hydroxide (272.2g), dropwise adding a methyl tert-butyl ether solution of benzyl bromide (197.6g), keeping the temperature at 20 ℃ to react for 24h till the reaction is complete, and performing post-treatment, purification and vacuum drying to obtain methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside, wherein the white solid accounts for 131.4g, the yield is 90 percent, and the purity is 98.5 percent.
D) Preparation of methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside (compound represented by the formula (1)):
methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside (130g), water (325g) and acetic acid (552g) are added into a reaction bottle, the reaction is carried out for 4h at the temperature of 95 ℃ until the reaction is complete, and after post-treatment, purification and vacuum drying, the methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside is obtained, 104.1g of white solid is obtained, the yield is 97 percent, and the purity is 98.5 percent.
Comparative example 1
Basically, the method is the same as the method of the embodiment 1, and the method only differs from the method in that: the first methylation reaction (step (A)) and the second amidation reaction (step (B)) are exchanged in sequence, namely, the amidation reaction is firstly carried out, then the methylation reaction is carried out, and then the benzylation reaction and the hydroxyl-protecting group removing reaction are carried out, wherein the route is as follows:
the yields of the two reactions in this synthetic route were found to be 74.5% (purity 96.7%), 91% (purity 98.4%), respectively.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (10)
1. A preparation method of methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside represented by the formula (1), which comprises the following steps:
(a) preparation of methyl 3-O-benzyl-4, 6-O-benzylidene-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (2):
methylating a compound represented by formula (5) with methanol in the presence of an acidic catalyst to produce a compound represented by formula (4);
(ii) subjecting the compound represented by the formula (4) and benzyl chloroformate to amidation reaction in a mixed system of an organic solvent and water in the presence of an alkaline reagent to produce a compound represented by the formula (3);
(iii) subjecting the compound represented by the formula (3) and benzyl halide to a benzylation reaction in a solvent in the presence of an alkaline reagent to produce a compound represented by the formula (2);
(b) subjecting the compound represented by the formula (2) to a hydroxyl group deprotection reaction in an acidic aqueous solution to produce methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy-alpha-D-glucopyranoside represented by the formula (1);
2. the process for producing a methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1) according to claim 1, wherein in step (i), the acidic catalyst is one or more selected from the group consisting of hydrochloric acid, concentrated sulfuric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, formic acid and hydrobromic acid.
3. The process for producing methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1) according to claim 1, wherein in step (i), the compound represented by the formula (5), the methanol and the acidic catalyst are fed in a molar ratio of 1: 1.5 to 50: 0.5 to 10, and the methylation reaction is carried out at a temperature of 55 to 65 ℃ for 24 to 48 hours.
4. The process according to claim 1, wherein in step (ii), the basic agent is one or more selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
5. The process according to claim 1, wherein in step (ii), the organic solvent is one or more of an aprotic halogenated hydrocarbon solvent and a ketone solvent, wherein the aprotic halogenated hydrocarbon solvent is a combination of one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane and chlorobenzene, and the ketone solvent is acetone and/or cyclohexanone.
6. The process according to claim 1 for producing methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1), wherein in step (ii), the compound represented by the formula (4), the benzyl chloroformate and the basic agent are fed in a molar ratio of 1: 1.2 to 2.0: 1.2 to 2.5; the amidation reaction is carried out at a temperature of 20-40 ℃ and the reaction time of the amidation reaction is controlled to 12-24 h.
7. The process for producing methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1) according to claim 1, wherein in the step (iii), the compound represented by the formula (3), the benzyl halide and the basic agent are fed in a molar ratio of 1: 2.0 to 4.0: 2.0 to 5.5, and the reaction temperature of the benzylation reaction is controlled to 20 to 40 ℃ and the reaction time of the benzylation reaction is controlled to 12 to 24 hours, respectively.
8. The process for producing a methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1) according to claim 1, wherein in the step (iii), the benzyl halide is benzyl bromide and/or benzyl chloride; the alkaline reagent is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, lithium tert-butoxide, magnesium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate; the solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane and methyl tert-butyl ether.
9. The process for producing a methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1) according to claim 1, wherein the deprotection reaction of the hydroxyl group in step (b) is carried out in the presence of acetic acid.
10. A method for producing fondaparinux sodium, characterized by comprising a method for producing a methyl3-O-benzyl-2- (benzyloxycarbonyl) amino-2-deoxy- α -D-glucopyranoside represented by the formula (1) described in any one of claims 1 to 9.
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| CN202110199388.2A CN113004352B (en) | 2018-11-16 | 2018-11-16 | Preparation method of fondaparinux sodium and fondaparinux sodium monosaccharide intermediate |
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| CN201811365541.9A CN109369738B (en) | 2018-11-16 | 2018-11-16 | Preparation method of fondaparinux sodium monosaccharide intermediate |
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| Synthesis and Characterization of Monosaccharide-Derived Carbamates as Low-Molecular-Weight Gelators;Guijun Wang et al.;《Langmuir》;20090518;第25卷(第15期);全文 * |
| 氨基葡萄糖衍生物钌络合物催化苯乙酮氢化反应;刘晓晶等;《高等学校化学学报》;20141130;第35卷(第11期);全文 * |
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