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Preparation method of Dapagliflozin isomer impurities I

A technology for isomers and impurities, applied in the field of organic synthesis, to achieve the effects of cost reduction, good reproducibility and less by-products

Active Publication Date: 2018-07-24
SHENZHEN SUNGENING BIO-MEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] It can be seen that designing an efficient, directional, and specialized method for synthesizing I, reducing the generation of by-products and increasing the yield of the product is the key to the research of the entire preparation process, and the existing technology cannot meet the requirements.

Method used

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  • Preparation method of Dapagliflozin isomer impurities I
  • Preparation method of Dapagliflozin isomer impurities I
  • Preparation method of Dapagliflozin isomer impurities I

Examples

Experimental program
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Embodiment 1

[0032] The preparation of embodiment 1 compound A

[0033] Add 2-chloro-5-bromobenzoic acid (compound 2) (9.40g, 40mmol, 1.0eq) and dichloromethane (70mL) to a 250mL single-necked bottle, then add thionyl chloride (8.70mL, 120mmol, 3.0eq ) was stirred and reacted at 40° C. for 3 hours. After the reaction was completed, it was concentrated to dryness to obtain 10.20 g of compound A with a yield of 100%, which was directly used in the next reaction.

Embodiment 2

[0034] The preparation of embodiment 2 compound B

[0035] Add methoxymethylamine hydrochloride (9.75g, 100mmol, 2.5eq) and dichloromethane (90mL) into a 250mL single-necked bottle, stir and control the reaction temperature at -10-10°C, slowly add triethylamine ( 22mL, 160mmol, 4.0eq), after stirring for 30 minutes, slowly dropwise added the solution of the above compound A (10.20g, 40mmol, 1.0eq) dissolved in dichloromethane (15mL), after the dropwise addition was completed, continue to stir for 3 hours, recover At room temperature, the reaction solution was washed with 100 mL of water, separated, the organic phase was washed with 100 saturated sodium chloride, separated, the organic phase was dried over anhydrous Na2SO4, the solvent was removed under reduced pressure, and 11.0 g of white solid was obtained by vacuum drying, with a yield of 99% %, namely compound B.

[0036] The product has passed the identification of MS spectrum and 1HNMR spectrum: as figure 1 and figur...

Embodiment 3

[0039] Embodiment 3 Preparation of Dapagliflozin Isomer Impurity I

[0040] Under nitrogen protection, add compound C (2.01g, 10mmol, 1.eq) in anhydrous tetrahydrofuran (20mL) solution to a 100mL three-necked flask, stir and control the reaction temperature at -78°C, slowly add 1.6M n-butyl Lithium hexane solution (6.9mL, 11mmol, 1.1eq), after the dropwise addition, was stirred for 30 minutes, and compound B (3.06g, 11mmol, 1.1 eq) solution, after the dropwise addition, stir to return to room temperature, react for 2 hours, add 50mL ice water and 50mL n-hexane to the reaction solution, separate the liquids, extract the aqueous phase with 30mL n-hexane, combine the organic phases, dry over anhydrous Na2SO4, and decompress The solvent was removed, and the residue was separated by column chromatography (mobile phase: PE:DCM=3:1~1:1) to obtain 3.13g of a white solid with a purity of 99.6% and a yield of 92%, which was the isomer of dapagliflozin Impurity I.

[0041] MS (m / z): 33...

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Abstract

The invention discloses a preparation method of Dapagliflozin isomer impurities I. The preparation method comprises the following steps that a, 2-chlorine-5-bromobenzoic acid is dissolved in a first solvent; an acylation reagent is added; reaction is performed for 1 to 8h at 20 to 60 DEG C to generate a compound A; b, methoxyl methylamine hydrochloride is dissolved in a second solvent; alkali is added at -10 to 10 DEG C; then, the compound A capable of being dissolved in the second solvent is dropwise added; the temperature is maintained; stirring reaction is performed for 1 to 4h to obtain acompound B; c, a compound C is dissolved in a third solvent; a hexane solution of n-butyllithium is added at -78 DEG C; then, the compound B capable of being dissolved in the third solvent is dropwiseadded; after reaction, treatment is performed to obtain the Dapagliflozin isomer impurities I. The carbonyl substitution reaction is used, so that the reaction is exclusive; by-products are few; theoperation is simple; the process is stable; the repeatability is high; the total yield of the product is improved by 90 percent or higher; the cost is reduced; the commercialized production and the batch supply are facilitated.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a preparation method of medicine and medicine impurities, in particular to a preparation research of a dapagliflozin isomer impurity. Background technique [0002] Dapagliflozin (Dapagliflozin, trade name Forxiga, formula II), [0003] [0004] The chemical name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyridine Fum-3,4,5-triol is a sodium-glucoselinked transporter 2 (sodium-glucoselinked transporter 2, SGLT2) inhibitor hypoglycemic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. It was approved for marketing in the EU in November 2012. In January 2014, the US FDA approved 1 for improving blood sugar control in patients with type 2 diabetes. Its mechanism of action is to reduce the reabsorption of glucose in the kidney through the inhibition of SGLT2, and increase the excretion of glucose in the urine to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/45C07C49/84C07C259/10C07C51/60C07C63/70
CPCC07C45/455C07C51/60C07C259/10C07C49/84C07C63/70
Inventor 彭锦安李方林张琦珊肖奇才冯伟高理钱
Owner SHENZHEN SUNGENING BIO-MEDICAL CO LTD
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