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Process for the preparation of voglibose

A technology for voglibose and voglibose is applied in the field of preparing acid addition salts of voglibose and preparing crystalline hydrochloride of voglibose, and can solve the problem of low total product yield, Difficulty in separation process

Inactive Publication Date: 2006-12-20
RANBAXY LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overall yield of the product is low due to the difficulty of the separation process due to the prolonged heating required to recover large amounts of water

Method used

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  • Process for the preparation of voglibose
  • Process for the preparation of voglibose
  • Process for the preparation of voglibose

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1: Preparation of tetra-o-benzyl-5-[[2-hydroxyl-1-(hydroxymethyl)ethyl]amino]-1-C-(hydroxymethyl)-1,2,3,4 -Cyclohexanethritol

[0082] Add 2-amino-1,3-propanediol (20.1 g, 220 mmol) to tetra-o-benzyl-5-oxo-1-C-(hydroxymethyl)-1,2,3,4- Cyclohexanethritol (35.0 g, 63.4 mmol) in methanol (350 mL) and stirred for 60 minutes. Then, sodium cyanoborohydride (14 g, 222 mmol) was added to the reaction mixture. Concentrated hydrochloric acid was added to adjust the pH to about 8.0, and the reaction mixture was stirred overnight. The reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated to obtain the title compound as a light yellow syrup.

[0083] Yield: 38.6g

[0084] HPLC purity: 90.0%

[0085] 1 HNMR (CDCl 3 ), δ: 1.60 (1H, dd, J = 2.1, 15Hz), 1.92 (1H, dd, J = 2.7, 15Hz), 2.75 (1H, m), 3.20 (1H, d, J = 8.4Hz), 3.44 (1H, m), 3.50-3.69 (7H, m), 4.10 (1H, m), 4.39 (2H, ...

Embodiment 2

[0086] Embodiment 2: Preparation of voglibose hydrochloride

[0087] Add 5% palladium on carbon (13g) and 4% hydrogen chloride solution (20ml) to tetra-o-benzyl-5-[[2-hydroxyl-1-(hydroxymethyl)ethyl]amino]-1-C- (Hydroxymethyl)-1,2,3,4-cyclohexanetetrol (13.0g, 20.73mmol) in methanol and tetrahydrofuran (1:1, 260ml) solution, room temperature, 3.0-3.5Kg / cm 2 The mixture was hydrogenated with shaking for 3 hours. The solid was removed by filtration and washed with methanol. The combined filtrate and washes were concentrated. Then, ethanol was added to the obtained residue, and the solvent was completely recovered. This process is repeated several times to remove traces of water. Methanol (35 ml) was then added and stirred at room temperature for 1 hour. The product was filtered to obtain voglibose hydrochloride as a white crystalline solid.

[0088] Yield: 5.0g

[0089] 1 HNMR (D 2 O), δ: 1.94 (1H, d, J = 3.0, 16.2Hz), 2.33 (1H, d, J = 2.1, 16.2Hz), 3.60-3.70 (4H, m), 3...

Embodiment 3

[0091] Embodiment 3: Preparation of voglibose

[0092] 20% triethylamine in methanol was added to a suspension of voglibose hydrochloride (5.0 g, 16.47 mmol) in 40 ml of methanol to adjust the pH to about 8.8-9.0. The suspension became clear and then the free base crystallized. Stirring for 1 hour, filtration and washing with methanol afforded voglibose as a white crystalline solid which could be recrystallized from methanol.

[0093] Yield: 3.0g

[0094] HPLC purity: 99.9%

[0095] 1 HNMR (D 2 O), δ: 1.55 (1H, dd, J = 2.1, 15Hz), 2.10 (1H, dd, J = 2.7, 15Hz), 2.9 (1H, m), 3.40-3.55 (2H, m), 3.59 (2H , m), 3.64-3.80 (5H, m) 3.88 (1H, t, J=9.6Hz)

[0096] The XRD spectrum, IR spectrum and DSC pattern are similar to Figures IV, V and VI, respectively.

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PUM

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Abstract

The invention relates to processes for the preparation of pure voglibose. The invention also relates to the preparation of acid addition salts of voglibose. More particularly, it relates to the preparation of crystalline hydrochloride salt of voglibose. The invention also relates to pharmaceutical compositions that include the pure voglibose or voglibose hydrochloride and use of said compositions for treatment or prevention of hyperglycemic symptoms and various disorders caused by hyperglycemia such as diabetes, obesity, and hyperlipemia.

Description

field of invention [0001] The present invention relates to a process for the preparation of pure voglibose. The invention also relates to a process for the preparation of acid addition salts of voglibose. More specifically, the present invention relates to the preparation of crystalline hydrochloride salt of voglibose. The present invention also relates to a pharmaceutical composition comprising pure voglibose or crystalline voglibose hydrochloride and said composition is effective in treating or preventing hyperglycemia and various diseases caused by hyperglycemia such as diabetes, Use in obesity, obesity and hyperlipidemia. Background of the invention [0002] Chemically, voglibose is (1S)-(1(OH),2,4,5 / 1,3)-5-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino] -1-C-(hydroxymethyl)-1,2,3,4-cyclohexanethritol has excellent inhibitory activity on glucoside hydrolase. Several methods for the preparation of voglibose have been reported, for example in US Patents 4,701,559; 4,824,943;...

Claims

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Application Information

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IPC IPC(8): C07C215/44A61K31/133A61P3/06A61P3/10C07C213/00C07C213/10
CPCA61K31/133C07C215/44C07C213/10A61P3/06A61P3/10
Inventor C·H·坎杜拉伊J·S·巴布P·C·雷J·B·沙阿Y·库马
Owner RANBAXY LAB LTD
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