Preparation method of canagliflozin intermediates

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...

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 not conducive to industrial production;

[0018] ②Reaction yield is low, only 50-55%

[0022] ① The raw materials used are not easy to buy, and the price is high;

[0023] ②The purity of the product is low

[0028] ① The raw material triethylsilane is expensive, and the yield is only 78%, so the cost is high;

[0029] ②Boron trifluoride ether and triethylsilane have a pungent smell, have high requirements for environmental protection, and are not conducive to industrial production

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