Synthetic method for pharmaceutical intermediate

A synthesis method and intermediate technology, applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as low product conversion rate, harsh reaction conditions, and low production safety, and achieve simple production process, simple purification treatment, and low preparation cost Effect

Active Publication Date: 2015-09-23
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the reaction route is long, the reaction steps are numerous, the reaction conditions are harsh, the production safety is low, and the product conversion rate is low, so it is not suitable for industrial production.

Method used

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  • Synthetic method for pharmaceutical intermediate
  • Synthetic method for pharmaceutical intermediate
  • Synthetic method for pharmaceutical intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Dissolve compound Ⅰ (6.99g, 30mmol) in anhydrous DMSO (90ml), add bis-valeryl diboron (15.24g, 60mmol), potassium acetate (12g, 120mmol) and PdCl in sequence 2 (DPPF)-DCM (1.2 g, 1.5 mmol). After the reaction solution was degassed, it was stirred at 80°C overnight (12-20 hours). TLC spots the plate, and the raw material is completely reacted. The reaction solution was filtered through celite, and the filter residue was washed with ethyl acetate (500ml). The filtrate was washed with 10% ammonium chloride solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 7.9 g of white solid with a yield of 94%.

[0039] Compound III (3.28g, 20mmol, X=Br) was dissolved in a mixture of DMSO (50ml) and water (10ml), and compound II (7.87g, 28.1mmol) and potassium carbonate (11g, 80mmol) were added in sequence. After the reaction solution was degass...

Embodiment 2

[0041] Under nitrogen protection, compound Ⅰ (11.7g, 50.2mmol) was dissolved in anhydrous THF (100ml), cooled to -78°C, and 2.5M n-BuLi solution (24ml, 60.2mmol) was added dropwise, keeping the temperature below - Stir at 70°C for 1h, add trimethyl borate (3.86g, 75.3mmol) dropwise, and stir at -70°C for 2h. TLC spots the plate, and the raw material is completely reacted. Slowly lower to room temperature, add 10% hydrochloric acid solution (40ml) dropwise, and stir for 30min. Stand still, separate the organic layer, extract the aqueous layer with ethyl acetate (100ml*3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain 8.96 g of solids with a yield of 90.1 %.

[0042] Compound Ⅲ (3.28g, 20mmol, X=Br) was dissolved in a mixture of DMSO (50ml) and water (10ml), and compound Ⅱ (5.56g, 28.1mmol), potassium carbonate (11g, 80mmol), PdCl 2 (DPPF)-DCM (0.8 g, 1 mmol)....

Embodiment 3

[0044] Compound Ⅰ (6.99g, 30mmol) was dissolved in anhydrous DMSO (90ml), and dimethylpropanediol diboronic acid ester (15.97g, 60mmol), potassium acetate (12g, 120mmol) and PdCl were added successively 2(DPPF)-DCM (1.2 g, 1.5 mmol). After the reaction solution was degassed, it was stirred at 80°C overnight (12-20 hours). TLC spots the plate, and the raw material is completely reacted. The reaction solution was not processed and directly entered into the next reaction.

[0045] Compound III (3.28g, 20mmol, X=Br) was dissolved in a mixture of DMSO (50ml) and water (10ml), and the reaction solution obtained in the previous step and potassium carbonate (11g, 80mmol) were added in sequence. After the reaction solution was degassed, the temperature was raised to 80°C and stirred overnight (12-20 hours). TLC spots the plate, and the raw material is completely reacted.

[0046] The reaction solution was filtered through celite, and the filter residue was washed with ethyl acetate...

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Abstract

The invention relates to the field of medical chemistry, particularly the field of pharmaceutical synthesis and more particularly a synthetic method for a pharmaceutical intermediate. The synthetic method comprises the steps: by taking 4-bromobiphenyl as an initial raw material, carrying out reaction with boride to obtain a compound II; and further synthesizing a target compound by directly taking a post-reaction solution as a raw material by treating or not treating a reaction liquid of the compound II. By adopting the synthetic route disclosed by the invention, the production process is simple, the product yield is high, the purification treatment is simple, the product purity is high after simple treatment, and the preparation cost is low, and the synthetic method is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to the field of drug synthesis, more specifically to a method for synthesizing a drug intermediate. Background technique [0002] The chemical structure of compound IV is as follows: [0003] [0004] It is an important class of pharmaceutical intermediates. [0005] At present, L-pyroglutamic acid is used as a raw material in the prior art, and it undergoes multi-step reactions such as carboxyl activation, Grignard reagent coupling reaction, carbonyl reduction, chiral methylation, ring opening reaction, esterification reaction and amidation condensation. Finally, the target product is obtained. [0006] However, the reaction route is long, the reaction steps are numerous, the reaction conditions are harsh, the production safety is low, and the product conversion rate is low, so it is not suitable for industrial production. Contents of the invention [0007] Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/267C07F5/04C07F5/02
CPCC07D207/267C07F5/025C07F5/04
Inventor 陈本顺
Owner JIANGSU ALPHA PHARM CO LTD
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