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Synthetic processes of intermediates for preparation of SGLT inhibitor

A technology for reagents and compounds, applied in the field of synthesizing SGLT inhibitors, can solve the problems of difficulty in meeting the needs of the pharmaceutical industry, high production costs, complex overall operations, etc., and achieve the effects of low cost, short route and low equipment requirements

Active Publication Date: 2020-12-18
DAEWOONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008]According to the above route, 22 steps of reaction are required from the starting material to the diphenylmethane derivative, and 14 and 15 steps are required to the key intermediate compound 1 and compound 2 respectively reaction, the overall operation is complicated, the production cost is high, and it is difficult to meet the needs of the pharmaceutical industry

Method used

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  • Synthetic processes of intermediates for preparation of SGLT inhibitor
  • Synthetic processes of intermediates for preparation of SGLT inhibitor
  • Synthetic processes of intermediates for preparation of SGLT inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Synthesis of 4,6-dibromo-2,3-dihydrobenzofuran-7-aniline

[0032]

[0033] In a 1000mL reaction flask, add 8.7g 2,3-dihydrobenzofuran-7-aniline, 200mL ethyl acetate, and then add 41.4g bromine (here bromine The added amount of bromine is the result of experimental optimization, if the added amount of bromine is too little, the reaction will not be complete; if the added amount is too high, the system will become complicated and the by-products will increase; controlling the reaction temperature is mainly to prevent the by-products from increasing). After the addition is complete, filter. Filter cake is added in the mixed solvent of the ethyl acetate of 100mL water and 100mL, is added dropwise 10% sodium hydroxide solution, adjusts pH between 8-10 (system is acidic after reaction, part product becomes salt, adjusts pH= 8-10 is for dissociation. If the pH is too low, the dissociation is not complete; if it is too high, more alkali will be consumed). The or...

Embodiment 2

[0034] Example 2: Synthesis of 4,6-dibromo-2,3-dihydrobenzofuran-7-aniline

[0035] In a 100mL reaction flask, add 5g of 2,3-dihydrobenzofuran-7-aniline, 100mL of N,N-dimethylformamide, cool to -5-0°C, and add 13.17g of N-bromosuccinimide (the advantage of N-bromosuccinimide is: N-bromosuccinimide is solid, easy to calculate and control; bromine is corrosive liquid, irritating , weighing and use are inconvenient), stirred and reacted for 30 minutes. The reaction solution was poured into 200 mL of water, extracted twice with ethyl acetate, the combined organic phase was washed with 10% sodium hydroxide, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.47 g of 4,6-dibromo-2,3 -Dihydrobenzofuran-7-aniline, yield 78.2%.

Embodiment 3

[0036] Example 3: Synthesis of 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran

[0037]

[0038] Add 10g of 4,6-dibromo-2,3-dihydrobenzofuran-7-aniline and 50mL of concentrated hydrochloric acid into a 250mL reaction flask, cool down to 0-5°C, add sodium nitrite solution (2.47g dissolved in 8mL of water). After the dropwise addition was completed, the reaction was incubated for 30 minutes, then 6.76 g of cuprous chloride was added in batches, and the temperature was raised to room temperature for 2 hours. Ethyl acetate was added for extraction, the organic layer was washed with 5% sodium hydroxide solution, concentrated to obtain a crude product, and 9.01 g of 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran was obtained by silica gel column chromatography , Yield 84.5%, white solid.

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Abstract

The invention discloses a method for preparing a compound 1 and a compound 2, the structure of the compound 1 and the structure of the compound 2 are shown in the specification.The method comprises the following steps: 1) carrying out selective dibromination on 2, 3-dihydrobenzofuran-7-aniline serving as a raw material by using a bromination reagent to obtain 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline; 2) subjecting the 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline obtained in the step 1) to a Sandmeyer reaction for chlorination to give 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran; 3-1) performing selective bromine removal on the 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran obtained in the step 2) by using a strong base, adding a formylation reagent to give the compound 1; and 3-2) performing selective bromine removal on the 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran obtained in the step 2) by using a strong base and then reacting with 4-cyclopropylbenzaldehyde to give the compound 2.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, and specifically relates to a method for synthesizing SGLT inhibitors using self-designed and innovative intermediates. Background technique [0002] Diabetes is one of the major diseases challenging human health in the 21st century. In 2019, an estimated 116 million adults in China had diabetes—and patients are also at risk of life-threatening complications. Of the estimated 116 million people, more than 65 million are undiagnosed and at very high risk. Worldwide, an estimated 463 million adults have diabetes, with 163 million in the Western Pacific region alone. [0003] Sodium-glucose cotransporter (SGLT) inhibitors are a new class of oral diabetes treatment drugs, which play a hypoglycemic effect by increasing the excretion of glucose in urine. [0004] U.S. Patent Publication No. 2015 / 0152075 discloses a diphenylmethane derivative compound with inh...

Claims

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Application Information

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IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 黄志宁叶伟平周章涛费安杰唐建王俊敬
Owner DAEWOONG PHARM CO LTD
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