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Tetrabenzyl voglibose crystallizing and preparing process

A technology of benzyl and benzyloxymethyl, which is applied in the field of crystallization of tetrabenzyl voglibose, can solve the problems of difficult removal of impurities, cumbersome separation process of Jinggang mycylamine, a large amount of labor and energy consumption, etc.

Inactive Publication Date: 2007-03-21
PHARMAXYN LAB
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Problems solved by technology

[0004] The chemical name of voglibose is (1S)-(1(hydroxyl),2,4,5 / 1,3)-[(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) through fermentation, and then use it as a raw material for chemical synthesis method manufacturing (patent document EP56194); but the preparation and separation process of Jinggang mycylamine is loaded down with trivial details, needs a large amount of labor and energy consumption, and the impurity in the product prepared by this method is not easy to remove, needs loaded down with trivial details column chromatography to carry out refining work again

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
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Effect test

Embodiment 1

[0048] Example 1 Oily (1S)-(1(hydroxyl),2,4,5 / 1,3)-2,3,4-tri-oxo-benzyl-5-[(2-hydroxyl-1-( Hydroxymethyl) ethyl) amino]-1-carbon-benzyloxymethyl-1,2,3,4-cyclohexanetetraol (abbreviated as tetrabenzyl voglibose (the same below), (II )) (with reference to the literature J.Org.Chem.1992,57,3651 method)

[0049](1S)-(1(hydroxyl),2,4,5 / 1,3)-2,3,4-tri-oxo-benzyl-1-carbon-benzyloxymethyl-5-oxo-1 , 2,3,4-cyclohexanetetraol (6.0g, 10.8mmol) and 2-amino-1,3-propanediol (3.0g, 33mmol) were dissolved in 30ml of methanol, and cyanoboron was added in portions at room temperature Sodium hydride (1.5g, 24mmol), after adding, continue to stir at room temperature for 16 hours, concentrate the reaction solution, dissolve the residue with 300ml of ethyl acetate, wash with 100ml of water, and wash twice with 100ml of 1% aqueous hydrochloric acid solution, 5% Wash twice with 100 ml of aqueous sodium carbonate solution, twice with 100 ml of saturated brine, and dry over anhydrous sodium sulfate. ...

Embodiment 2

[0050] Example 2 Preparation of tetrabenzyl voglibose (II) crystals

[0051] Dissolve 1.0 g of oily tetrabenzyl voglibose in 2.5 ml of ethyl acetate, add 6 ml of cyclohexane under stirring, and stir the solution at room temperature for 1.5 hours to form colorless granular crystals, continue to Stand for 5 hours, then place at 0-5°C for 5 hours, filter, and dry the crystals in vacuum 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°C; [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=8.6Hz), 3.62-3.73(6H, m), 4.13(1H, t, J=9.6Hz), 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

[0052] Example 3 Preparation of tetrabenzyl voglibose (II) crystals

[0053] Dissolve 3.0 g of oily tetrabenzyl voglibose in 10 ml of isopropyl ether, add 25 ml of n-hexane while stirring, and stir the solution at room temperature for 1 hour to form colorless granular crystals, and continue to stand at room temperature for 1 hour. hours, and 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°C; [α]22D+30.6° (cl, chloroform), and the hydrogen spectrum data are consistent with those in 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 to treat diabetes effective drugs. The present invention also relates to a method for preparing the crystal. Background technique [0002] Voglibose is an α-glucosidase inhibitor developed by Japan's Takeda Pharmaceutical Company (EP56194), and has been marketed in Japan, South 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(hydroxyl),2,4,5 / 1,3)-[(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) through fermentation, and then use it as a raw material for chemical synthesis method (patent document EP56194); but the preparation and separation process ...

Claims

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Application Information

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IPC IPC(8): C07C215/44C07C213/10
CPCC07C215/44A61P3/10
Inventor 刘立刚李瑞文
Owner PHARMAXYN LAB
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