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Tetrabenzyl voglibose crystallizing and preparing process

A technology of tetrabenzyl voglibose and crystallization, which is applied to an effective drug for the treatment of diabetes, and the preparation of the crystallization field can solve the problems of a lot of labor and energy consumption, difficult removal of impurities, complicated preparation and separation process of Jinggangmemamine, etc.

Inactive Publication Date: 2008-06-11
PHARMAXYN LAB
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The chemical name of voglibose is (1S)-(1(hydroxyl),2,4,5 / 1,3)-5-[(2-hydroxy-1-(hydroxymethyl)ethyl)amino] -1-carbon-hydroxymethyl-1, 2, 3, 4-cyclohexanetetraol, there are several ways to make it, the earliest is to produce Jinggang mycamine (Valienamine) by fermentation, and then use this as raw material to carry out Manufactured by chemical synthesis method (patent document EP56194); but the preparation and separation process of Jinggang mycylamine is cumbersome, requires a lot of labor and energy consumption, and the impurities in the product prepared by this method are not easy to remove, and cumbersome column chromatography is required for refining.

Method used

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  • Tetrabenzyl voglibose crystallizing and preparing process
  • Tetrabenzyl voglibose crystallizing and preparing process
  • Tetrabenzyl voglibose crystallizing and preparing process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1 Oily (1S)-(1(hydroxy),2,4,5 / 1,3)-2,3,4-tris-oxy-benzyl-5-[(2-hydroxy-1-( (Hydroxymethyl)ethyl)amino]-1-carbon-benzyloxymethyl-1,2,3,4-cyclohexanetetraol (abbreviated as tetrabenzyl voglibose (the same hereinafter), (II )) preparation (refer to the literature J.Org.Chem.1992,57,3651 method)

[0064] (1S)-(1(hydroxy), 2,4,5 / 1,3)-2,3,4-tris-oxy-benzyl-1-carbon-benzyloxymethyl-5-oxy-1 , 2,3,4-Cyclohexanetetraol (6.0g, 10.8mmol) and 2-amino-1,3-propanediol (3.0g, 33mmol) were dissolved in 30ml methanol, and cyanoboron was added in batches at room temperature. Sodium hydride (1.5g, 24mmol), after the addition, continue to stir at room temperature for 16 hours, the reaction solution was concentrated, the residue was dissolved in 300ml of ethyl acetate, washed with 100ml of water, and then washed twice with 100ml of 1% hydrochloric acid aqueous solution, 5% Wash twice with 100 ml of sodium carbonate aqueous solution, twice with 100 ml of saturated brine, and dry with anhy...

Embodiment 2 4

[0065] Example 2 Preparation of tetrabenzyl voglibose (II) crystal

[0066] Dissolve 1.0 g of oily tetrabenzyl voglibose in 2.5 ml of ethyl acetate, add 6 ml of cyclohexane while stirring, and stir the solution at room temperature for 1.5 hours to form colorless granular crystals. Continue at room temperature Placed for 5 hours, then placed at 0-5°C for 5 hours, filtered, and the crystals were vacuum dried at room temperature for 10 hours to obtain 0.76 g of colorless granular crystals. Content determined by HPLC method: 98.5%; mp88.2-90.8℃; [α] 22 D +30.8°(cl, chloroform); 1 H NMR(CDCl 3 , 500Hz), δ: 1.63 (1H, dd, J=2.8, 15.1Hz), 1.91 (1H, dd, J=2.9, 15.1Hz), 2.78 (1H, m), 3.19 (1H, d, J=8.6 Hz), 3.39 (1H, m), 3.54 (1H, d, J = 8.6 Hz), 3.62-3.73 (6H, m), 4.13 (1H, t, J = 9.6 Hz), 4.39 (2H, s), 4.59 (1H, d, J = 11.1), 4.64 (1H, d, J = 11.4), 4.72 (1H, d, J = 11.4), 4.82 (1H, d, J = 10.6), 4.91 (1H, d, J=11.2), 4.93 (1H, d, J=10.7), 7.24-7.35 (20H, m)

Embodiment 3 4

[0067] Example 3 Preparation of tetrabenzyl voglibose (II) crystal

[0068] Dissolve 3.0g of oily tetrabenzyl voglibose in 10ml of isopropyl ether, add 25ml of n-hexane with stirring, and stir the solution at room temperature for 1 hour to form colorless granular crystals. Continue to stand at room temperature for 1 Hours, then placed at 0-5°C for 3 hours, filtered, and the crystals were vacuum dried at room temperature for 12 hours to obtain 2.5 g of colorless granular crystals. Content determined by HPLC method: 98.7%; mp88.5-90.7℃; [α] 22 D +30.6° (cl, chloroform), the hydrogen spectrum data is consistent with that of Example 2.

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Abstract

The present invention relates to crystallized (1S)-(1(hydroxy), 2, 4, 5 / 1, 3)-2, 3, 4-tri-oxo-benzyl-5-[(2-hydroxy-1-(hydroxymethyl) ethyl) amino]-1-carbo-methylbenzylmethyl-1, 2, 3, 4-cyclohexane tetrol, which has smelting point of 89.7 deg.c; monocrystalline X ray diffraction data of orthorhombic system, P2(1)2(1)2(1) space groupp, unit cell parameters a=7.8487, b=20.746, c=20.988 and R 0.0748; and X ray diffraction peak of crystal powder of 16.76, 18.90 and 24.00+ / -0.15 deg. It is prepared through dissolving oily tetrabenzyl voglibose in one kind of polar non-protonic solvent, adding one other kind of non-polar solvent via stirring at room temperature to crystallize, stilling, filtering and vacuum drying to obtain the crystal. Compared with oily tetrabenzyl voglibose, the crystallized tetrabenzyl voglibose has higher purity, convenient transportation and maintenance and easy application.

Description

Technical field [0001] The present invention relates to a crystal of tetrabenzyl voglibose, which can be used to prepare high-purity α-glucosidase inhibitor-voglibose, which is currently used for the treatment of diabetes Effective drugs. The invention also relates to a method for preparing the crystal. Background technique [0002] Voglibose is an α-glucosidase inhibitor developed by Takeda Pharmaceutical Company of Japan (EP56194). It has been marketed in Japan, Korea and China for the treatment of diabetes. Its structure is shown in formula (I): [0003] [0004] The chemical name of voglibose is (1S)-(1(hydroxy),2,4,5 / 1,3)-5-[(2-hydroxy-1-(hydroxymethyl)ethyl)amino] -1-Carbon-hydroxymethyl-1,2,3,4-cyclohexanetetraol. There are several manufacturing methods for it. The first was to produce Valienamine through fermentation, which was then used as a raw material. Manufactured by chemical synthesis method (Patent Document EP56194); but the preparation and separation process of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/44C07C213/10
CPCC07C215/44A61P3/10
Inventor 刘立刚李瑞文
Owner PHARMAXYN LAB
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