Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Process for preparing 1-deoxy-1-methylamino-d-glucitol 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate

A kind of technology of benzoxazole carboxylate, dichlorophenyl, be applied in the potassium salt of 2-benzoxazole-6-carboxylate, 6-carboxy-2--benzoxazole meglumine or chlorphenazole Meglumine acid, the preparation of key intermediate 4--3-hydroxybenzoic acid methyl ester, the field of the manufacture of meglumine meglumine salt of chlorphenazole acid, can solve the problems of lack of production methods, expensive drugs, increased cost and other problems

Pending Publication Date: 2021-12-31
INKE股份公司
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The lack of an efficient manufacturing process increases the cost of the final meglumine salt of meglumine salt and pharmaceutical compositions containing it, which has resulted in expensive drug

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process for preparing 1-deoxy-1-methylamino-d-glucitol 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate
  • Process for preparing 1-deoxy-1-methylamino-d-glucitol 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate
  • Process for preparing 1-deoxy-1-methylamino-d-glucitol 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0151] Reference Example 1: Preparation of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid methyl ester

[0152] Methyl 4-amino-3-hydroxybenzoate (2.0 g, 12.0 mmol) was dissolved in dry CH at a temperature of 20 °C to 25 °C 2 Cl 2To the suspension in (20 mL) was added pyridine (1.2 mL, 15.0 mmol). The mixture was cooled to a temperature between 0°C and 5°C for 15 minutes. Then, a solution of 3,5-dichlorobenzoyl chloride (2.7 g, 12.6 mmol) was added. The resulting suspension was warmed at a temperature between 20°C and 25°C and the reaction was stirred for 16 hours. Once the reaction was complete, the viscous suspension was filtered and washed with CH 2 Cl 2 washing. Suspend the obtained brown solid in acetone / HO 2 O in a mixture and the slurry was stirred at room temperature for one hour; the solid was filtered, washed with a mixture of acetone and water, and dried in an air oven at 45°C to afford HO as a light brown solid slightly purified by TLC. Methyl 4-(3,5-dichlo...

Embodiment 1

[0154] Example 1: Synthesis of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid methyl ester

[0155] To a suspension of methyl 4-amino-3-hydroxybenzoate (50.0 g, 300 mmol) in dry THF (400 mL) was added NaHCO at a temperature between 20 °C and 25 °C 3 (27.6 g, 330 mmol). The mixture was cooled to a temperature of 10°C to 15°C, and a solution of 3,5-dichlorobenzoyl chloride (65.8 g, 314 mmol) in dry THF (100 mL) was added dropwise, keeping the internal temperature below 20°C. Then, the temperature was adjusted to 20°C to 25°C, and the reaction mixture was stirred for 16 hours. Once the reaction was complete, the solvent was vacuum distilled and the resulting crude was resuspended in a 500 mL mixture of acetone (250 mL) and water (250 mL). The viscous suspension was stirred at room temperature for one hour and at 0°C to 5°C for another hour. The resulting solid was filtered, washed with a mixture of acetone and water, and dried in an air oven at 45°C to afford 4-(3,5-dichlorob...

Embodiment 2

[0157] Example 2: 2-(3,5-dichlorophenyl)benzo[d] Synthesis of oxazole-6-carboxylate methyl ester

[0158] P-toluenesulfonic acid monohydrate (4.5g, 23.52mmol) was added to 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid methyl ester (80g, 235.2mmol) obtained in Example 1 ) in suspension in toluene (1.6 L). The resulting mixture was heated at reflux and the reaction was stirred with elimination of water for 16 hours. The solution was cooled to 45°C and filtered. The solvent was distilled under vacuum and the resulting crude was resuspended in acetone (560 mL) and water (80 mL). The resulting viscous suspension was stirred at room temperature for one hour, the solid was filtered, washed with a mixture of acetone and water, and dried in an air oven at 45 °C to afford 2-(3,5-di Chlorophenyl) benzo[d] Azole-6-carboxymethyl ester (70.0 g, 217.0 mmol).

[0159] Yield: 92.4%

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to an improved process for the preparation of 1-deoxy-1-methylamino-D- glucitol 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate, also known as tafamidis meglumine. The process of the present invention is particularly suitable for industrial scale manufacture of tafamidis meglumine with excellent purity and high yields.

Description

technical field [0001] The present invention relates to the preparation of 1-deoxy-1-methylamino-D-glucitol 2-(3,5-dichlorophenyl)-6-benzo Azole carboxylate, also known as 6-carboxy-2-(3,5-dichlorophenyl)-benzo Improved method of meglumine or tafamidis meglumine. The method of the present invention is particularly suitable for the manufacture of meglumine salt of meglumine with high purity and high yield on an industrial scale. [0002] The present invention also relates to compounds that can be used for the preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzo in high yield and high purity. 2-(3,5-dichlorophenyl)benzo Potassium salt of azole-6-carboxylate. [0003] The present invention also describes an improved process for the preparation of the key intermediate methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate, which is suitable for the industrial scale preparation of this product. Background technique [0004] 6-carboxy-2-(3,5-dichlorophenyl)-benzo Meglumin...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/57A61K31/423
CPCC07D263/57
Inventor 塞尔吉奥·罗德里格斯罗佩罗琼·乌格特·克洛泰
Owner INKE股份公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products