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Synthesis method of dapagliflozin

A synthetic method and technology of synthetic route, applied in the direction of organic chemistry, etc., can solve the problem of unclear root cause, and achieve the effects of easy extraction and separation, high yield, and mild reaction conditions.

Inactive Publication Date: 2015-04-01
SUZHOU JONATHAN NEW MATERIALS TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] About 100 million people worldwide suffer from type II diabetes (NIDDM - non-insulin-dependent diabetes mellitus), characterized by hyperglycemia due to excess hepatic glucose production and peripheral insulin resistance, but the underlying cause is unknown

Method used

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  • Synthesis method of dapagliflozin
  • Synthesis method of dapagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1: preparation compound 2

[0019] Add 50g of raw material 4, 0.5ml of anhydrous DMF and 250ml of DCM to the three-necked flask, add dropwise 30ml of oxalyl chloride (or 25ml of thionyl chloride), drop it for 5 hours, react for 3 hours, concentrate, add 100ml of DCM to the residue, and cool to -10~ 0°C, add 20g of phenethyl ether and 30g of anhydrous aluminum trichloride, after addition, react for 3h at 0°C, add the reaction solution into ice water, separate and extract, wash the organic phase with acid, alkali, water, dry, and concentrate to obtain 62.2 g compound 2, yield: 86.2%, purity 97.9%.

Embodiment 2

[0020] Embodiment 2: preparation compound 3

[0021] Add 50g of compound 2, 300ml of ethanol and 10g of sodium borohydride into the three-necked flask, react for 1 hour, then cool down to -10~0°C, add 50g of anhydrous aluminum trichloride, rise to 0~5°C for 5 hours, then reflux for 12 hours, Cooled, concentrated, added to ice water, extracted with EA, the organic phase was acid-washed, washed with water, dried, and concentrated to obtain 45.1 g of compound 3 with a yield of 94.1% and a purity of 95.2%.

Embodiment 3

[0022] Embodiment 3: preparation compound 5

[0023] Add 50g of compound 3 and 300ml THF to the three-necked flask, cool down to -78°C, add 120ml of 2mol / L butyllithium dropwise, stir for 1h, add the above reaction solution dropwise to 110g of compound 4 in toluene (260ml) solution, the reaction temperature React at -78°C for 3 hours, add 200ml of 1mol / L methanol solution of methanesulfonic acid dropwise, rise to room temperature for reaction, add sodium carbonate to adjust the pH value to 7-8, separate liquid extraction, wash the organic phase with water, dry and concentrate to obtain 68.1g Compound 5 has a crude yield of 101% and a purity of 92.1%.

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Abstract

The invention provides a synthesis method of dapagliflozin. A synthesis route of the synthesis method is shown as the following formulae which are as shown in the specification. The synthesis method of dapagliflozin comprises the following steps: (1) carrying out friedel-crafts acylation on a raw material 1 to generate a compound 2; (2) carrying out reduction reaction on the compound 2 to generate a compound 3; (3) carrying out condensation reaction on the compound 3 and a compound 4 to generate a compound 5; (4) removing methoxy of the compound 5 to generate a compound 6; and (5) carrying out deprotection on the compound (6) to generate a compound 7. The synthesis method of dapagliflozin at least has the following beneficial effects of being simple in operation steps and mild in reaction condition; the dapagliflozin is easy to extract and separate and high in yield; the production cost is greatly reduced; the industrial production is facilitated.

Description

technical field [0001] The invention relates to a method for synthesizing raw materials, in particular to a method for synthesizing dapagliflozin. Background technique [0002] Approximately 100 million people worldwide suffer from type II diabetes (NIDDM - non-insulin-dependent diabetes mellitus), characterized by hyperglycemia due to excess hepatic glucose production and peripheral insulin resistance, but the underlying cause is unknown. Hyperglycemia is considered a major risk factor for the development of diabetic complications and may be directly related to the impaired insulin secretion that occurs in late NIDDM. It is expected that normalization of blood glucose in NIDDM patients will improve insulin action and counteract the development of diabetic complications. Inhibitors of the sodium-dependent glucose transporter SGLT2 in the kidney are expected to contribute to normalization of plasma glucose levels and perhaps body weight by increasing glucose excretion. Dapa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 李卓才李苏杨
Owner SUZHOU JONATHAN NEW MATERIALS TECH