A Titanium Catalyst Ligand Used in the Synthesis of Dexlansoprazole

A dexlansoprazole, titanium catalyst technology, applied in physical/chemical process catalyst, organic compound/hydride/coordination complex catalyst, organic chemistry, etc. Problems such as determination and complex process, to achieve the effect of high structural asymmetry, low temperature sensitivity, and stable catalyst performance

Active Publication Date: 2015-07-29
福州基石医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent DE403545 describes the preparation of dexlansoprazole by chemical resolution, which uses stereoselective nitrogen derivatization to resolve lansoprazole. The disadvantage of this method is that the racemic lansoprazole Azole needs two steps to produce optically pure lansoprazole, the reaction yield is only 40-50%, the process is complicated, and it is not suitable for industrial production
[0011] titanium( ) catalyst, Ti( i -PrO) 4 In coordination with the ligand L-diethyl tartrate, the Ti-O bond is extremely unstable, resulting in titanium ( ) The catalyst complex is unstable during the production process and is prone to failure, resulting in low yield and uncertain ee value of the product

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Take a 100mL coke bottle, pass nitrogen protection, put a medium-sized stirring bar, pass N 2 After 5 minutes, add 3.67g (99.5mmol) of titanium catalyst ligand, 40mL of toluene, 1.409g (49.75mmol) of tetraisopropyl titanate, stir at room temperature for 10min, then turn on the magnetic stirring heating button, slowly heat, and the temperature rises to 53.5°C. After incubating at this temperature for 42 minutes, add 20 μL (0.11 mmol) of purified water and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine]methyl]sulfanyl ]-1H-benzimidazole 8.00g (226mmol) was kept at the same temperature for 25min, then N,N-diisopropylethylamine 2.954g (228.85mmol) was added and kept for 14min. Put the reaction flask into a cold well at 5°C, stir for 15 minutes, then add 10.8 g (565 mmol) of cumene hydroperoxide, and react at 5°C for 7 hours. HPLC detection (chromatographic column: 250mm×20mm, 10μL C-18, column temperature: 40℃, mobile phase: acetonitrile / water / triethylamine=160 / 40 / 1,...

Embodiment 2

[0029] Take a 100mL coke bottle, pass nitrogen protection, put a medium stirring bar, pass N 2 After 5 minutes, add 3.67g (99.5mmol) of titanium catalyst ligand, 40mL of toluene, 1.69g (59.7mmol) of tetraisopropyl titanate, stir at room temperature for 10min, then turn on the magnetic stirring heating button, slowly heat, and the temperature rises to 54.5°C. After keeping at this temperature for 30 minutes, add 14.5 μL (0.0796 mmol) of purified water and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine]methyl]sulfur Base]-1H-benzimidazole 8.00g (226mmol), keep warm at the same temperature, add N,N-diisopropylethylamine 3.083g (238.8mmol) after 25min, keep warm for 20min. Put the reaction flask into a cold well at 5°C, stir and keep it warm for 15 minutes, then add 10.8 g (565 mmol) of cumene hydroperoxide, react at 5°C for 8 hours, and the conversion rate is 91.7%. With 40mL30%NaS 2 o 3 After the reaction was completed, the liquids were separated, and the organic phase ...

Embodiment 3

[0031] Take a 100mL coke bottle, protect it with nitrogen, put it into a medium-sized stirring bar, take 3.5g (99.5mmol) of titanium catalyst ligand, and pass through N 2 After 5 minutes, 40 mL of toluene and 1.83 g (64.68 mmol) of tetraisopropyl titanate were added. After stirring at room temperature for 10 minutes, the magnetic stirring heating button was turned on and heated slowly, and the temperature rose to 50.5°C in 20 minutes. After keeping at this temperature for 50 minutes, add 27.14 μL (0.149 mmol) of purified water and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine]methyl]sulfur Base]-1H-benzimidazole 8.00g (226mmol), keep warm at the same temperature, add N,N-diisopropylethylamine 3.339g (258.7mmol) after 30min, keep warm for 15min. Put the reaction flask into a cold well at 5°C, stir and keep warm for 15 minutes. Add 10.8 g (565 mmol) of cumene hydroperoxide, react at 5°C for 7 hours, and the conversion rate is 89.3%. With 40mL 30%NaS 2 o 3 After the re...

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PUM

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Abstract

The invention discloses a method for synthesizing dexlansoprazol by a titanium catalyst ligand. The chemical name of the titanium catalyst ligand is (1R,2S)-N-p-methylbenzene sulfonic acid-1,2-diphenyl ethylenediamine. The method comprises the following steps: mixing the ligand with tetraisopropyl titanate, N,N-diisopropylethylamine and purified water according to a certain ratio, and catalyzing 2-[[[3-methyl-4-(2,2,2 trifluoroethyoxyl)-2-pyridine]methyl]thioxo]-1H-benzimidazole by heating to synthesize dexlansoprazol. According to dexlansoprazol, the enantiomer excess is not less than 99.2% and the yield is not less than 80%. The process is good in stability and high in enantioselectivity, and can be better applied to industrialization production.

Description

technical field [0001] The invention belongs to the application field of chemical synthesis, and in particular relates to a titanium catalyst ligand used in the synthesis of D-lansoprazole. Background technique [0002] The new proton pump inhibitor dexlansoprazole is an anti-ulcer drug that inhibits gastric acid secretion, chemical name: 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2 -Pyridyl]methyl]sulfinyl]-1Hbenzimidazole, which was rated as one of the top ten best-selling drugs in the world by the American "Forbes" magazine in 2006, is clinically used for duodenal ulcer and gastric ulcer , anastomotic ulcer, reflux esophagitis and Zhuoi syndrome (also known as gastrinoma) and other diseases [Mao Yu et al., Chinese Journal of New Drugs, 2006，15 (1):17-20 ]. R-lansoprazole in the mixture has more significant proton pump inhibitory effect than S-lansoprazole, and the action time is longer. Its enteric-coated sustained-release capsules have been approved by the US FDA in 2009....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12B01J31/38
CPCC07D401/12
Inventor 陈忠鲁毅黄杨威赵学清魏宗有王娟
Owner 福州基石医药科技有限公司
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