Preparation method of canagliflozin intermediates

A technology for an intermediate, fluorophenylthiophene, is applied in the field of synthesis of pharmaceutical intermediates, and can solve the problems of difficulty in purchasing, low reaction yield and high cost, and achieve the effects of easy control of operating conditions, high product purity and stable reaction.

Inactive Publication Date: 2015-10-21
CANGZHOU SENARY CHEM SCI TEC
View PDF8 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] ① Suzuki coupling requires the use of expensive Pd or Ni reagent catalysts, and the coupling of raw materials in the reaction is difficult to control, which is not suitable for industrial production;
[0011] ② Friedel-Crafts reaction is difficult to complete the reaction, the remaining raw materials are difficult to purify, and the resulting product has low purity and low yield
[0017] ① The raw materials used are expensive and difficult to purchase, which is n

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
  • Preparation method of canagliflozin intermediates
  • Preparation method of canagliflozin intermediates
  • Preparation method of canagliflozin intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: with Na 2 Add S (57.8g, 741mmol) into a 2L four-neck flask, then add 420ml of N,N-dimethylformamide to the system, and add N,N -Dimethylformamide (140ml) solution, dropwise, temperature controlled 65~75℃ and stirred for 1~2h, then slowly added dropwise 3-bromoacrolein (100g, 741mmol) in N,N-dimethylformamide (140ml) solution, the dropwise addition is completed and the temperature is controlled at 70-80°C to continue the reaction for 2-3 hours. After the HPLC detection is complete, the temperature is lowered to 0-10°C, and water (140ml) is dropped into the system. The system was filtered, the solid was recrystallized with methanol (420ml), cooled to 0-5°C for crystallization for 2 hours, filtered, and the solid was dried to obtain p-fluorophenylthiophene (122.8g, HPLC: 98.4%, yield 93%).

Embodiment 2

[0051] Embodiment 2: with Na 2 Add S (58.9g, 755mmol) into a 2L four-neck flask, then add 420ml of N,N-dimethylformamide to the system, and add N,N -Dimethylformamide (140ml) solution, dropwise, temperature controlled 65~75℃ and stirred for 1~2h, then slowly added dropwise 3-bromoacrolein (103g, 763mmol) in N,N-dimethylformamide (140ml) solution, the dropwise addition is completed and the temperature is controlled at 70-80°C to continue the reaction for 2-3 hours. After the HPLC detection is complete, the temperature is lowered to 0-10°C, and water (140ml) is dropped into the system. The system was filtered, the solid was recrystallized with methanol (420 ml), the temperature was lowered to 0-5°C for crystallization for 2 hours, and then filtered, and the solid was dried to obtain p-fluorophenylthiophene (125.4 g, HPLC: 98.9%, yield 95%) .

Embodiment 3

[0052] Embodiment 3: with Na 2Add S (60.7g, 778mmol) into a 2L four-neck flask, then add 420ml of N,N-dimethylformamide to the system, and add N,N -Dimethylformamide (140ml) solution, dropwise, temperature controlled 65~75℃ and stirred for 1~2h, then slowly added dropwise 3-bromoacrolein (110g, 815mmol) in N,N-dimethylformamide (140ml) solution, the dropwise addition is completed and the temperature is controlled at 70-80°C to continue the reaction for 2-3 hours. After the HPLC detection is complete, the temperature is lowered to 0-10°C, and water (140ml) is dropped into the system. The system was filtered, the solid was recrystallized with methanol (420 ml), the temperature was lowered to 0-5°C for crystallization for 2 hours, and then filtered, and the solid was dried to obtain p-fluorophenylthiophene (125.4 g, HPLC: 98.1%, yield 95%) .

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 invention relates to the technical field of preparation of medicine intermediates, and particularly discloses a preparation method of canagliflozin intermediates. High purity 2- ( 4- fluorophenyl)-5[(5- halogenating -2- methyl phenyl carbinol )]thiophene can be prepared, and the preparation method comprises the following steps of: adopting fluorine benzyl halide and 3- halogenating acrolein as raw materials, and under the existence of a sulfur reagent, obtaining 2-p-fluorophenyl thiophene; and enabling the 2-p-fluorophenyl thiophene and 5- halogenating -2- toluyl aldehyde to obtain a product of the 2- ( 4- fluorophenyl)-5[(5- halogenating -2- methyl phenyl carbinol )]thiophene under the condition of n-Butyllithium. Compared with the prior art, according to the method disclosed by the invention, the raw materials are easy to obtain, the yield is high, the reaction condition is easy to control, the product purity is high, the reaction is stable, and the commercialized production is easy.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Canagliflozin, also known as canagliflozin, is an effective blood sugar control drug developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It was approved by the U.S. Food and Drug Administration (FDA) on March 29, 2013. Glycemic control in adults with type 2 diabetes. Canagliflozin is a once-daily oral diabetes drug that belongs to a new class of selective sodium glucose co-transporter 2 (SGLT2) inhibitors, which block the reabsorption of blood sugar by the kidneys and increase Excretion of blood sugar in urine to lower blood sugar levels in the body. Its molecular formula is: [0003] [0004] In the current preparation route of the hypoglycemic drug canagliflozin, 2-(4-fluorophenyl)-5[(5-halo-2-methylphenylmethyl)]thiophene (compound Ⅱ) is used to synthesize An important intermediate of Canagliflozin. Th...

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
IPC IPC(8): C07D333/16
CPCC07D333/16
Inventor 张少平王平周文峰张伟刘劲松于淑玲
Owner CANGZHOU SENARY CHEM SCI TEC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap