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C-spirocycline analogue intermediate and preparation method thereof

A technology of analogues and intermediates, applied in the field of C-spirocycline analogue intermediates and their preparation, can solve problems such as difficult synthesis, difficult purification, and limited drug structure diversity

Active Publication Date: 2021-10-01
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] These drugs are all modified on the basis of the structure of dapagliflozin, especially the modification of the C ring is relatively large, but it is difficult to synthesize the BC ring intermediate with multiple functional groups on the B ring, which limits the structure of this type of drug Diversity
[0005] At present, most of the BC rings of the list drugs are ketone compounds obtained by F-C acylation reaction to obtain the BC ring, and the BC ring is obtained by reduction of triethylsilane and boron trifluoride ether system. The advantages are simple operation and short route, but The ortho-para isomer is formed in the F-C acylation reaction, which is difficult to purify, and the yield is only about 65%.

Method used

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  • C-spirocycline analogue intermediate and preparation method thereof
  • C-spirocycline analogue intermediate and preparation method thereof
  • C-spirocycline analogue intermediate and preparation method thereof

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preparation example Construction

[0027] A preparation method of a C-spirocycline analog intermediate, comprising the steps of:

[0028] (1) Steps for preparing 3-(4-ethylbenzyl)-2-methoxy-4-methylbenzaldehyde; raw material (3-bromo-2-methoxy-6-methylphenyl) (4'-Ethylphenyl)methane was dissolved in 20 mL of dry THF under argon protection. Cool to -65~-78°C, then add n-butyllithium dropwise, after the dropwise addition, react at -65~-78°C for 0.5-2 hours, then add dry N,N-dimethyl formaldehyde dropwise Amide, after the dropwise addition, continue to react at this temperature for 1-3 hours, then dropwise add saturated ammonium chloride to quench the reaction, then extract with dichloromethane, combine the organic phases, and wash with saturated brine, anhydrous sulfuric acid Dry over sodium and concentrate to dryness to obtain an oil, which is directly used in the next reaction. Among them, the molar ratio of (3-bromo-2-methoxy-6-methylphenyl)(4'-ethylphenyl)methane to n-butyllithium and N,N-dimethylformamide ...

Embodiment 1

[0032] Embodiment 1, the preparation of 2-(4-ethylbenzyl)-6-(1,3-dithian-2-yl)-3-methylphenol

[0033] First, the preparation of 3-(4-ethylbenzyl)-2-methoxy-4-methylbenzaldehyde, starting material 10 (1.6g, 5mmol) was dissolved in 20ml of dry tetrahydrofuran, under argon Under air protection. Cool to -78°C, then add n-butyllithium (1.6M, 3.8mL, 6.08mmol) dropwise, after the dropwise addition, react at -78°C for 0.5 hours, then add dry N,N-dimethyl Dimethyl formamide (1mL), after the dropwise addition was completed, the reaction was continued at this temperature for 1.5 hours, then saturated ammonium chloride was added dropwise to quench the reaction, then extracted with dichloromethane, the organic phases were combined, and washed with saturated brine, Dry over anhydrous sodium sulfate, concentrate to dryness, obtain 1.3 grams of oil, directly use in next step reaction, reaction formula is as follows:

[0034]

[0035] Next, the preparation of 3-(4-ethylbenzyl)-2-hydroxy-...

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Abstract

The invention relates to a C-spirocycline analogue intermediate and a preparation method thereof. The structural formula is shown in the specification. The preparation method comprises the following steps: by taking (3-bromo-2-methoxy-6-methylphenyl) (4'-substituted phenyl) methane as a raw material, carrying out butyl lithiation, then reacting with DMF to generate aldehyde, then carrying out demethylation through boron tribromide to generate phenol, and then reacting with 1,3-propanedimercapto alcohol under the catalysis of boron trifluoride diethyl etherate to generate an aldehyde group protection product. According to the invention, a short and convenient route for synthesizing the C-spirocycline analogue intermediate is designed, and the C-spirocycline analogue intermediate is efficiently synthesized.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a C-spirocycline analog intermediate and a preparation method thereof. Background technique [0002] In recent years, sodium glucose transporter 2 (sodium / glucose cotransporter 2, SGLT2) inhibitors have been hailed as a new hope for the treatment of diabetes. SGLT2 inhibitors mainly act on sodium glucose transporter 2 in the proximal tubule of the kidney. The filtered glucose is reabsorbed in the kidney, and the glucose can pass through the nephron, Bellini tube and ureter, and finally be excreted in the urine, so as to remove excess glucose in the urine and achieve the purpose of controlling hyperglycemia. Currently, the marketed drugs of SGLT2 inhibitors include canagliflozin, dapagliflozin (the following formula) and empagliflozin. [0003] [0004] These drugs are all modified on the basis of the structure of dapagliflozin, especially the modification of the C ring is r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D339/08
CPCC07D339/08
Inventor 吴岳林杨可莉汤文敏董莲吴晨
Owner SHANGHAI INST OF TECH