Preparation method of fondaparinux sodium related substance B

Abstract

The invention belongs to the technical field of organic medicine synthesis, and particularly relates to a preparation method of a fondaparinux sodium related substance B. The preparation method comprises the following steps: (1) mixing a compound B-0, a catalyst A, hydrogen and a solvent 1, and reacting to obtain a compound B-1; (2) mixing the compound B-1, organic alkali and a solvent 2, and reacting to obtain a compound B-2; and (3) mixing the compound B-2, a sulfonation reagent, a sodium phosphate aqueous solution and a solvent 3, reacting, adding an inorganic alkali solution, and stirring to obtain the related substance B. The method is simple and convenient to operate, high in route yield and high in product purity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic drug synthesis, and particularly relates to a method for preparing a fondaparinux sodium-related substance B. Background Art

[0002] Fondaparinux sodium is a pure chemically synthesized heparin pentasaccharide anticoagulant drug developed by Sanofi of France. It is the first new highly selective factor Xa inhibitor. It can be used to prevent and treat venous thrombosis and pulmonary embolism.

[0003] The Chinese chemical name of Fondaparinux sodium is: O-(2-deoxy-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-β-D-pyranoglucopyranosyl-(1→4)-O-(2-deoxy-2-sulfonylamino-3,6-di-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-(2-O-sulfonyl-α-L-iduronic acid)-(1→4)-2-deoxy-1-O-methyl-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranoside decasodium salt, and the chemical structure is as follows:

[0004]

[0005] Related substance B is included in the quality standard of fondaparinux sodium injection in the United States Pharmacopoeia. Its relative retention time under the related substance analysis method is 0.48. It is generally believed to be produced by the elimination of the sugar ring under heat and is a degradation impurity of fondaparinux sodium injection. The Chinese chemical name is: O-(2-O-sulfonyl-α-L-pyran-hex-4-ene-iduronic acid)-(1→4)-2-deoxy-1-O-methyl-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucoside tetrasodium salt, and the chemical structure is as follows:

[0006]

[0007] At present, there are few reports on the preparation methods of substance B. Among them, Chinese invention patent application CN104910217A reported a method for preparing crude products by high-temperature destruction and separation and purification, but the yield was extremely low and it was not easy to obtain impurity samples; Chinese invention patent application CN1097134757A proposed a synthetic route with relatively long steps and low overall yield.

[0008] Exploring new preparation methods, shortening the synthetic route, and obtaining the related substance B with high yield and high purity are of great significance for the quality research of fondaparinux sodium. Summary of the invention

[0009] In view of the deficiencies in the prior art, the present invention provides a method for preparing a fondaparinux sodium-related substance B.

[0010] In order to achieve the above-mentioned purpose of the present invention, the specific technical solution adopted by the present invention is:

[0011] A method for preparing a substance B related to fondaparinux sodium comprises the following steps:

[0012] (1) Compound B-0, catalyst A, hydrogen and solvent 1 are mixed and reacted to obtain compound B-1;

[0013] (2) mixing compound B-1, an organic base and solvent 2, and reacting to obtain compound B-2;

[0014] (3) Compound B-2, a sulfonating agent, a sodium phosphate aqueous solution and solvent 3 are mixed and reacted, and then an inorganic base solution is added and stirred to obtain the related substance B;

[0015] The structures of compounds B-0, B-1 and B-2 are shown below:

[0016]

[0017] Among them, R1, R2, and R4 are acetyl (Ac) or benzoyl (Bz); R3 and R5 are benzyl (Bn) or substituted benzyl (Bn).

[0018] Preferably, in step (1), the catalyst A is selected from one or more of palladium hydroxide, palladium carbon and palladium aluminum oxide, and the mass ratio of the catalyst A to the compound B-0 is 0.6-1.5:1.

[0019] Preferably, in step (1), the solvent 1 is selected from one or both of methanol and tetrahydrofuran, and the mass volume ratio of the compound B-0 to the solvent 1 is 1 g: 18-22 mL.

[0020] Preferably, the reaction temperature in step (1) is 15-60° C., the reaction pressure is 1-3 atmospheres, the reaction time is 5-7 hours, and after the reaction, the process further comprises the steps of suction filtration and concentrating the filtrate to dryness under reduced pressure.

[0021] Preferably, the organic base in step (2) is selected from one or more of 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,5,7-triazidebicyclo[4.4.0]dec-5-ene and tetramethylguanidine, and the molar ratio of the organic base to compound B-1 is 0.05-2.0:1.

[0022] Preferably, the solvent 2 in step (2) is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and the molar volume ratio of the organic base to the solvent 2 is 1 mol:30-35L.

[0023] Preferably, the reaction temperature in step (2) is 15-50° C., the reaction time is 7-9 hours, and after the reaction, the steps of adding water, stirring and concentrating to dryness under reduced pressure are also included.

[0024] Preferably, the sulfonating agent in step (3) is selected from one or more of sulfur trioxide triethylamine complex, sulfur trioxide pyridine complex, trimethylammonium sulfur trioxide complex and N-ethyldiisopropylamine sulfur trioxide complex, the molar concentration of the sodium phosphate salt aqueous solution is 0.8-1.2 mol / L, the molar ratio of the sulfonating agent to compound B-2 is 5-27:1, and the mass volume ratio of the sulfonating agent to the sodium phosphate salt aqueous solution is 1 g:3-4 mL.

[0025] Preferably, in step (3), the solvent 3 is selected from one or more of methanol, ethanol, purified water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the inorganic base is selected from one or more of cesium carbonate, potassium carbonate and sodium carbonate, the inorganic base solution is a saturated sodium carbonate aqueous solution, the volume ratio of the saturated sodium carbonate aqueous solution to the solvent 3 is 9-11:1, and the mass volume ratio of the sulfonating agent to the solvent 3 is 1g:3-4mL.

[0026] Preferably, in step (3), the reaction temperature is 20-35°C, the reaction time is 15-17h, the stirring temperature is 45-80°C, the stirring time is 11-13h, and after the reaction, the steps of concentrating to dryness under reduced pressure and purifying by column chromatography are also included.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention uses compound B-0 as a raw material and prepares compound B through reduction, elimination, O-sulfonation and saponification reactions. The method is simple to operate, the total yield of the route is ≥78.0%, and the product purity is ≥99.7%. DETAILED DESCRIPTION

[0029] The present invention will be further described in detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention. The experimental methods used in the following examples are generally conventional, unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available, unless otherwise specified.

[0030] Example 1

[0031] A method for preparing a related substance B of fondaparinux sodium:

[0032] (1) Take a sample of compound B-0 (5.00 g, 5.644 mmol) and dissolve it in methanol (100 ml). Stir at 600 rpm until it becomes clear. Add 10% palladium hydroxide (2.50 g). After nitrogen replacement, introduce hydrogen. Raise the temperature to 38°C and keep the reaction at 2 atmospheres for 6 hours.

[0033] The filtrate was filtered and concentrated to dryness under reduced pressure to obtain 3.11 g of compound B-1 with a purity of 91.7% and a yield of 96.3%.

[0034]

[0035] (2) The compound B-1 (3.11 g, 5.434 mmol) obtained in step (1) was dissolved in tetrahydrofuran (50 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (231 mg, 1.524 mmol) was added, and the reaction was stirred at 600 rpm at 30°C for 8 h. Purified water (5 ml) was added and stirred for 5 min. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase medium was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 2.37 g of compound B-2 with a purity of 99.2% and a yield of 85.4%.

[0036]

[0037] (3) The compound B-2 (2.37 g, 4.641 mmol) obtained in step (2) was dissolved in N,N-dimethylformamide (15 ml), sulfur trioxide pyridine complex (4.49 g, 28.22 mmol) and 1 M sodium phosphate aqueous solution (15 ml) with a pH of 10.0 were added, and the reaction was stirred at 600 rpm at 30°C for 16 h, and then a saturated sodium carbonate aqueous solution (150 ml) was added, the temperature was raised to 62°C, and stirring was continued for 12 h. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase medium was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 2.99 g of compound B with a purity of 99.9%, a yield of 94.8%, and a total yield of 78.0%.

[0038]

[0039] 1H-NMR(D2O,ppm)δ6.06~5.97(d,1H),5.572~5.485(d,1H),5.096~5.002(d,1H),4.637~4.544(m,1H),4.419~4.323(m,2H), 4.311~4.230(m,1H),4.063~3.982(m,1H),3.914~3.812(m,1H),3.790~3.694(m,1H),3.424(s,3H),3.356~3.272(dd,1H).

[0040] 13 C-NMR (D2O, ppm) δ171.99, 147.61, 109.79, 101.18, 99.81, 81.33, 77.97, 7 2.12,70.98,69.48,66.30,60.43,58.32.ESI-MS,m / z:611.96[M-3Na+2H] - .

[0041] Example 2

[0042] A method for preparing a related substance B of fondaparinux sodium:

[0043] (1) Take a sample of compound B-0 (5.00 g, 5.644 mmol) and dissolve it in methanol (90 ml). Stir at 500 rpm to dissolve it. Add 10% palladium hydroxide (5.0 g). After nitrogen replacement, introduce hydrogen. Heat to 15°C and keep the temperature at 3 atmospheres for 5 hours. Filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain 3.04 g of compound B-1 with a purity of 92.3% and a yield of 94.2%.

[0044] (2) The compound B-1 (3.04 g, 5.317 mmol) obtained in step (1) was dissolved in N,N-dimethylformamide (50 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (218 mg, 1.429 mmol) was added, and the reaction was stirred at 500 rpm at 15°C for 9 h. Purified water (6 ml) was added and stirred for 10 min. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase medium was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 2.38 g of compound B-2 with a purity of 99.0% and a yield of 87.6%.

[0045] (3) The compound B-2 (2.38 g, 4.656 mmol) obtained in step (2) was dissolved in dimethyl sulfoxide (15 ml), and N-ethyldiisopropylamine sulfur trioxide complex (31.9 g, 152.4 mmol) and 0.8 M sodium phosphate aqueous solution (128 ml) with a pH of 10.0 were added. The reaction was stirred at 500 rpm at 20°C for 17 h, and then a saturated sodium carbonate aqueous solution (135 ml) was added. The temperature was raised to 45°C, and the stirring was continued for 13 h. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase medium was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 3.11 g of compound B with a purity of 99.7%, a yield of 98.3%, and a total yield of 81.1%.

[0046] Example 3

[0047] A method for preparing a related substance B of fondaparinux sodium:

[0048] (1) Take a sample of compound B-0 (5.00 g, 5.644 mmol) and dissolve it in methanol (110 ml). Stir at 500 rpm to dissolve it. Add 10% palladium carbon (3.0 g). After nitrogen replacement, introduce hydrogen. Heat to 60°C and keep the temperature at 1 atmosphere for 7 hours. Filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain 3.10 g of compound B-1 with a purity of 90.8% and a yield of 96.0%.

[0049] (2) The compound B-1 (3.10 g, 5.418 mmol) obtained in step (1) was dissolved in tetrahydrofuran (50 ml), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) (255 mg, 1.667 mmol) was added. The mixture was stirred at 500 rpm at 50°C for 7 h. Purified water (5 ml) was added and stirred for 5 min. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain compound B-2 with a purity of 98.9% and a yield of 87.3%.

[0050] (3) The compound B-2 (2.42 g, 4.730 mmol) obtained in step (2) was dissolved in N-methylpyrrolidone (20 ml), sulfur trioxide triethylamine complex (16.4 g, 90.30 mmol) and 1.2 M sodium phosphate aqueous solution (50 ml) with a pH of 10.0 were added, and stirred at 500 rpm at 30°C for 15 h. Then, a saturated sodium carbonate aqueous solution (220 ml) was added, the temperature was raised to 80°C, and stirring was continued for 11 h. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase medium was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 3.07 g of compound B with a purity of 99.9%, a yield of 95.5%, and a total yield of 80.1%.

[0051] Comparative Example 1

[0052] The difference between this comparative example and Example 1 is that the reaction temperature in step (2) is different, specifically:

[0053] (2) The compound B-1 (3.11 g, 5.435 mmol) obtained in step (1) was dissolved in tetrahydrofuran (50 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (231 mg, 1.524 mmol) was added, and the mixture was reacted at 75° C. for 8 h. Purified water (5 ml) was added and stirred for 5 min. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 1.46 g of compound B-2 with a purity of 82.0% and a yield of 52.5%.

[0054] The overall preparation route finally prepared 1.84 g of compound B with a purity of 90.4% and a total yield of 47.9%.

[0055] Comparative Example 2

[0056] The difference between this comparative example and Example 1 is that the reaction temperature in step (2) is different, specifically:

[0057] (2) The compound B-1 (3.11 g, 5.435 mmol) obtained in step (1) was dissolved in tetrahydrofuran (50 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (231 mg, 1.524 mmol) was added, and the mixture was reacted at 10°C for 8 h. Purified water (5 ml) was added and stirred for 5 min. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 1.38 g of compound B-2 with a purity of 92.4% and a yield of 49.6%.

[0058] The overall preparation route finally prepared 1.74 g of compound B with a purity of 89.6% and a total yield of 45.4%.

[0059] Comparative Example 3

[0060] The difference between this comparative example and Example 1 is that the amount of sulfonating agent added in step (3) is different, specifically:

[0061] (3) The compound B-2 (2.37 g, 4.634 mmol) obtained in step (2) was dissolved in N,N-dimethylformamide (15 ml), sulfur trioxide pyridine complex (2.24 g, 14.11 mmol) and 1 M sodium phosphate aqueous solution (15 ml) with a pH of 10.0 were added, and the mixture was reacted at 30°C for 16 h. A saturated sodium carbonate aqueous solution (150 ml) was then added, the temperature was raised to 62°C, and the mixture was stirred for 12 h. The mixture was concentrated to dryness under reduced pressure and purified by column chromatography (the mobile phase was a mixed solution of methanol and water in a volume ratio of 26:74) to obtain 1.14 g of compound B with a purity of 88.3% and a yield of 36.2%.

[0062] The overall preparation route finally prepared compound B with a total yield of 29.8%.

[0063] Comparative Example 4

[0064] The difference between this comparative example and Example 1 is that the amount of catalyst added in step (1) is different, specifically:

[0065] (1) Take a sample of compound B-0 (5.00 g, 5.644 mmol) and dissolve it in methanol (100 ml). Stir at 600 rpm to dissolve it. Add 10% palladium hydroxide (1.50 g). After nitrogen replacement, introduce hydrogen. Heat to 38 ° C. and keep the temperature at 2 atmospheres for 6 hours. Filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain 0.89 g of compound B-1 with a purity of 91.7% and a yield of 27.6%.

[0066] The overall preparation route finally prepared 0.86 g of compound B with a purity of 86.7% and a total yield of 22.4%.

[0067] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for preparing a related substance B of fondaparinux sodium, characterized in that: The following steps are involved: (1) Compound B-0, catalyst A, hydrogen and solvent 1 are mixed and reacted to obtain compound B-1; (2) mixing compound B-1, an organic base and solvent 2, and reacting to obtain compound B-2; (3) Compound B-2, a sulfonating agent, a sodium phosphate aqueous solution and solvent 3 are mixed and reacted, and then an inorganic base solution is added and stirred to obtain the related substance B; The structures of compounds B-0, B-1 and B-2 are shown below: Wherein, R1, R2, and R4 are acetyl or benzoyl; and R3 and R5 are benzyl or substituted benzyl.

2. The preparation method according to claim 1, characterized in that: In step (1), the catalyst A is selected from one or more of palladium hydroxide, palladium carbon and palladium aluminum oxide, and the mass ratio of the catalyst A to the compound B-0 is 0.6-1.5:

1.

3. The preparation method according to claim 1, characterized in that: In step (1), the solvent 1 is selected from one or both of methanol and tetrahydrofuran, and the mass volume ratio of the compound B-0 to the solvent 1 is 1 g: 18-22 mL.

4. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is 15-60° C., the reaction pressure is 1-3 atmospheres, the reaction time is 5-7 hours, and after the reaction, the steps of suction filtration and concentrating the filtrate to dryness under reduced pressure are also included.

5. The preparation method according to claim 1, characterized in that: The organic base in step (2) is selected from one or more of 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,5,7-triazidebicyclo[4.4.0]dec-5-ene and tetramethylguanidine, and the molar ratio of the organic base to compound B-1 is 0.05-2.0:

1.

6. The preparation method according to claim 1, characterized in that: In step (2), the solvent 2 is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and the molar volume ratio of the organic base to the solvent 2 is 1 mol:30-35L.

7. The preparation method according to claim 1, characterized in that: The reaction temperature in step (2) is 15-50° C., the reaction time is 7-9 hours, and after the reaction, the steps of adding water for pulping and concentrating to dryness under reduced pressure are also included.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The sulfonating agent in step (3) is selected from one or more of sulfur trioxide triethylamine complex, sulfur trioxide pyridine complex, trimethylammonium sulfur trioxide complex and N-ethyldiisopropylamine sulfur trioxide complex, the molar concentration of the sodium phosphate aqueous solution is 0.8-1.2 mol / L, the molar ratio of the sulfonating agent to compound B-2 is 5-27:1, and the mass volume ratio of the sulfonating agent to the sodium phosphate aqueous solution is 1g:3-4mL.

9. The preparation method according to claim 1, characterized in that: In step (3), the solvent 3 is selected from one or more of methanol, ethanol, purified water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the inorganic base is selected from one or more of cesium carbonate, potassium carbonate and sodium carbonate, the inorganic base solution is a saturated sodium carbonate aqueous solution, the volume ratio of the saturated sodium carbonate aqueous solution to the solvent 3 is 9-11:1, and the mass volume ratio of the sulfonating agent to the solvent 3 is 1g:3-4mL.

10. The preparation method according to claim 1, characterized in that: The reaction temperature in step (3) is 20°C-35°C, the reaction time is 15-17h, the stirring temperature is 45-80°C, the stirring time is 11-13h, and after the reaction, the steps of reduced pressure concentration to dryness and column chromatography separation and purification are also included.

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