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Preparation method of antidiabetic dapagliflozin intermediate

A diabetes drug, dapagliflozin technology, applied in organic chemistry and other directions, can solve problems such as excessive waste and unfavorable industrialized production

Active Publication Date: 2014-09-24
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the zinc reagent and the lithium reagent used are all equivalent amounts, resulting in a lot of waste in the reaction system, which is not conducive to industrial production

Method used

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  • Preparation method of antidiabetic dapagliflozin intermediate
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  • Preparation method of antidiabetic dapagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0023] Example 1 (2R, 3R, 4R, 5S, 6S)-2-(acetylmethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran- Synthesis of 3,4,5-triacetyl ester (Ia)

[0024] Method 1): Add 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (4.9g, 15mmol) and 20mL of tetrahydrofuran to a 50mL three-necked flask, stir and cool to -5~0°C, drop slowly Add isopropyl magnesium chloride format reagent (8mL, 2mol / L), and keep the system at 0°C and stir for 2h. In another 100mL three-necked flask, add (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triacetyl ester (IIa, 4.1g, 10mmol), tetramethylethylenediamine (5wt%), cobalt triacetylacetonate (5wt%) and 20mL tetrahydrofuran, the system is cooled to 0°C. Slowly add the Grignard Reagent (IIIa) prepared in the previous 50mL bottle, after about 30min, the dripping is completed, the system is warmed to 25~30°C, the temperature is kept and stirred for 2h, the system is quenched with 1N hydrochloric acid aqueous solution, and the organic pha...

example 2

[0034] Example 2 (2S, 3S, 4R, 5R, 6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(pivaloyloxymethyl)tetrahydro-2H- Synthesis of pyran-3,4,5-tripivaloyl ester (Ib)

[0035] Add 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (4.9g, 15mmol) and 20mL of tetrahydrofuran to a 50mL three-neck flask, stir and cool to -5~0°C, slowly add isopropyl group dropwise Magnesium chloride format reagent (8mL, 2mol / L), the system was kept at 0°C and stirred for 2h. In another 100mL three-necked flask, add (2R,3R,4S,5R,6R)-2-bromo-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-tri Pivaloyl ester (IIb, 5.8g, 10mmol), tetramethylethylenediamine (5wt%), cobalt triacetylacetonate (5wt%) and 20mL tetrahydrofuran, the system is cooled to 0°C. Slowly add the format reagent in the previous 50mL bottle. After about 30 minutes, the addition is complete. The system is warmed to 25~30°C, kept and stirred for 2 hours. The system is quenched with 1N hydrochloric acid aqueous solution, and the organic phase is extracte...

example 3

[0037] Example 3 (2R, 3R, 4R, 5S, 6S)-3,4,5-tribenzyloxy-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl) ) Phenyl) tetrahydro-2H-pyran (Ic) synthesis

[0038] Add 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (4.9g, 15mmol) and 20mL of tetrahydrofuran to a 50mL three-neck flask, stir and cool to -5~0°C, slowly add isopropyl group dropwise Magnesium chloride format reagent (8mL, 2mol / L), the system was kept at 0°C and stirred for 2h. In another 100mL three-necked flask, add (2R,3R,4S,5R,6R)-3,4,5-tribenzyloxy-2-(benzyloxymethyl)-6-bromotetrahydro-2H-pyridine Cyan (IIc, 6.0g, 10mmol), tetramethylethylenediamine (5wt%), cobalt triacetylacetonate (5wt%) and 20mL tetrahydrofuran, the system is cooled to 0°C. Slowly add the format reagent in the previous 50mL bottle. After about 30 minutes, the addition is complete. The system is warmed to 25~30°C, kept and stirred for 2 hours. The system is quenched with 1N hydrochloric acid aqueous solution, and the organic phase is extracted with ...

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Abstract

The invention discloses a preparation method of antidiabetic dapagliflozin intermediate, hydroxyl protected ALPHA-D-bromo-glucopyranose as shown in formula II is used as a starting material for reacting with a Grignard reagent as shown in formula III, and the reaction is carried out in the presence of a cobalt catalyst and a ligand to prepare a dapagliflozin senior intermediate as shown in formula I. The raw material and reagents required in the preparation method are relatively cheap in price, and the preparation method has the advantages of simple operation, low cost, safe and convenient operation, good yield, less environmental pollution, and very good economic effect and is suitable for industrial production.

Description

Technical field [0001] The invention relates to a preparation method of an anti-diabetic drug dapagliflozin intermediate, in particular to a new synthesis method of an anti-type II diabetes drug dapagliflozin high-level intermediate shown in formula I. technical background [0002] The hypoglycemic drug Dapagliflozin is an oral, once-daily sodium-dependent glucose protein (SGLT) inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca. Its mechanism of action is to block the reabsorption of glucose in the kidneys, thereby expelling excess glucose from the body through urine, and to reduce blood sugar while further reducing the weight of the patient. [0003] Dapagliflozin advanced intermediate, its structure is shown in the following formula I: [0004] [0005] Wherein G is benzyl, acetyl, or pivaloyl. [0006] In the prior art, there are mainly the following methods for the synthesis of the intermediate of formula I: [0007] 1) The original research manufacturer Bristol-...

Claims

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Application Information

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IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 张念
Owner SHANGHAI FANGNAN PHARMA
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