Method for preparing dapagliflozin intermediate by one-pot method

A technology for an intermediate, chlorobenzoic acid, applied in the field of one-pot preparation of dapagliflozin intermediates, can solve problems such as complicated steps and environmental pollution, and achieve the effects of improving product purity, simple post-processing operations, and reducing pollution

Pending Publication Date: 2021-06-08
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Purpose of the invention: In order to solve the above-mentioned problems existing in the prior art, the present invention provides a one-pot method for preparing dapagliflozin intermediates

Method used

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  • Method for preparing dapagliflozin intermediate by one-pot method
  • Method for preparing dapagliflozin intermediate by one-pot method
  • Method for preparing dapagliflozin intermediate by one-pot method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Add 20 mL of 1,4-dioxane, 5-bromo-2-chlorobenzoic acid (2.35 g), red phosphorus (123.89 mg), sodium bromide (51.44 mg), anhydrous sodium carbonate powder ( 105.99mg), α-Fe 2 o 3 (128.00mg), potassium persulfate (5.40g) and 4A type molecular sieve (2.00g), after stirring evenly at 40°C, after adding phenetole (1.83g) dropwise at 0.184mL per minute, react at 40°C After 4 hours, after quenching, layering, drying and concentrating, recrystallization was carried out by absolute ethanol to obtain a white powdery solid, i.e. (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) ketone ( 3.04g, the yield is 90%, and the purity monitored by HPLC is 99.5%, and its hydrogen spectrum and carbon spectrum results are as figure 1 with figure 2 shown.

[0035] 1 H NMR (400MHz, DMSO-d 6 )δ7.77–7.73(m,2H),7.70–7.67(m,2H),7.56(d,J=8.4Hz,1H),7.09–7.05(m,2H),4.13(q,J=7.0Hz ,2H),1.35(t,J=7.0Hz,3H);

[0036] 13 C NMR (101MHz, DMSO-d 6 )δ191.65, 163.95, 140.97, 134.49, 132.69, 132.19, 131.53, 1...

Embodiment 2

[0038] Add 20 mL of 1,4-dioxane, 5-bromo-2-chlorobenzoic acid (2.35 g), red phosphorus (123.89 mg), sodium bromide (51.44 mg), anhydrous sodium carbonate powder ( 105.99mg), α-Fe 2 o 3 (128.00mg), potassium persulfate (5.40g) and A4 molecular sieve (2.00g), after stirring evenly at 10°C, after adding phenetole (1.83g) dropwise at 0.184mL per minute, react at 10°C for 5 After 1 hour, quench, separate layers, dry and concentrate, and then recrystallize from absolute ethanol to obtain a white powdery solid, which is detected as (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (2.63 g, 72% yield, 99.0% purity by HPLC).

Embodiment 3

[0040] Add 20 mL of 1,4-dioxane, 5-bromo-2-chlorobenzoic acid (2.35 g), red phosphorus (123.89 mg), sodium bromide (51.44 mg), anhydrous sodium carbonate powder ( 105.99mg), α-Fe 2 o 3(128.00mg), potassium persulfate (5.40g) and A4 molecular sieve (2.00g), after stirring evenly at 60°C, after adding phenetole (1.83g) dropwise at 0.184mL per minute, react at 60°C for 3 Hours later, after quenching, layering, drying and concentrating, recrystallization by absolute ethanol gave a white powdery solid, i.e. (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) ketone (2.70 g, the yield is 80%, and the yield monitored by HPLC is 99.0%).

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Abstract

The invention discloses a method for preparing a dapagliflozin intermediate by a one-pot method, and the method comprises the following steps: reacting 5-bromo-2-chlorobenzoic acid with phenetole in the presence of an oxidant and a catalyst for a period of time, and performing purifying to obtain the dapagliflozin intermediate (5-bromo-2-chlorphenyl) (4-ethoxyphenyl) ketone. The method provided by the invention is high in yield, simplifies the process steps of the traditional synthesis method, makes the process simpler, reduces the reaction cost and impurity content, improves the purity and yield, and better conforms to the industrialization standard of benefit maximization.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for preparing a dapagliflozin intermediate by a one-pot method. Background technique [0002] Dapagliflozin is a reversible and highly selective hypoglycemic drug named Farxiga jointly developed by Bristol-Myers Squibb and AstraZeneca in the United States. Important choice for use as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It can significantly reduce HbA1c and fasting blood glucose in patients with type 2 diabetes, the incidence of adverse reactions is similar to that of placebo, the risk of hypoglycemia is low, and it can reduce body weight. Its chemical structure is as follows: [0003] [0004] In the prior art, the synthesis of dapagliflozin mainly adopts the important intermediate (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone as the initial raw material, after reduction, coupling, reduction an...

Claims

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Application Information

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IPC IPC(8): C07C45/45C07C45/81C07C49/84
CPCC07C45/455C07C45/81C07C49/84
Inventor 杨博丁同俊
Owner 安庆奇创药业有限公司
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