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L-alanine derivative preparation method

A technology of derivatives and alanine, applied in the field of preparation of L-alanine derivatives, can solve the problems of high production cost of intermediates, low chiral purity of products, complicated operations, etc., and achieves improved yield and reduced processing cost, the effect of speeding up production

Active Publication Date: 2019-08-06
SYNCOZYMES SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The technical problem to be solved by this invention is to provide a kind of preparation method of L-alanine derivatives, solve the present (S)-2-tert-butoxycarbonylamino-(2,6-dimethyl 3-cyano)benzene Methyl propionate, (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid and related intermediates have high production costs, complex operations, and high production costs. The problem of low chiral purity

Method used

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Examples

Experimental program
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Embodiment 1

[0052] The preparation of embodiment 1 compound 2

[0053]

[0054] Dissolve compound 1 (22g, 0.1mol) in 220g of methanol, pass ammonia gas into the above mixture until it is saturated, place it in a polytetrafluoroethylene-lined tank and heat it to 80°C for 24 hours, stop heating after detecting that the reaction is complete , cooled to room temperature, the reaction solution was decompressed to remove the solvent, and the obtained product was directly used in the next step without further purification.

Embodiment 2

[0055] The preparation of embodiment 2 compound 3

[0056]

[0057] Dissolve triphenylphosphine (26.2g, 0.1mol) and imidazole (6.8g, 0.1mol) in 340ml of dichloromethane, add iodine (25.4g, 0.1mol) into the above system in three batches, and stir at room temperature for 10 minute, cooled to 0°C, dissolved the crude product obtained in Example 1 in 150mL of dichloromethane and dropped it into the above system within 30 minutes, kept stirring at 0°C for 1h, raised to room temperature and stirred for 1.5h, added 200mL of water, and slowly added 1M hydrochloric acid, The pH value was adjusted to 4, the liquid was separated, the organic phase was concentrated to about 80 mL, and the product compound 3 (24.5 g, 0.078 mol) was obtained by silica gel column chromatography (ethyl acetate: petroleum ether 3: 1). The step yield is 78%.

Embodiment 3

[0058] The preparation of embodiment 3 compound 6

[0059]

[0060]Zinc powder (64 g, 1 mol) and 196 ml of N,N-dimethylformamide were added into the reaction flask, and nitrogen was replaced three times. Add 1,2-dibromoethane (13.9 g, 0.074 mol), raise the temperature of the reaction solution to 85±2° C., and keep the temperature for ten minutes. Cool in an ice bath to 25±2°C, add trimethylchlorosilane (4.8 g, 0.044 mol), and keep warm at 25±2°C for 10 minutes. The reaction solution was cooled to 10-15°C, and volatile substances were removed under reduced pressure. Compound 3 (24.5 g, 0.078 mol) prepared in Example 2 was dissolved in DMF (196 ml) to form a solution. The solution was added dropwise to the reaction solution at 20° C. under temperature control. Stir for 2 hours after the dropwise addition, prepare the zinc reagent and refrigerate for future use.

[0061] Add 2,5-dimethyl-4-cyanoiodobenzene (20.6g, 0.08mol) and P(o-tol) successively in the four-neck flask ...

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Abstract

The invention relates to the preparation of pharmaceutical intermediates, and belongs to the field of organic synthesis, particularly to an L-alanine derivative preparation method, which comprises: carrying out a Negishi reaction on a compound 3 to obtain a zinc reagent solution containing an intermediate state compound 4; carrying out a palladium-catalyzed coupling reaction on the zinc reagent solution and a compound 5 to obtain a compound 6; and hydrolyzing the compound 6 to convert into a compound 7. According to the present invention, in the six-step reaction of the route, only the products of the three steps are required to be separately purified, and the products of other steps can be directly poured into the next reaction through the direct one-pot method or after the pressure reducing drying, such that the post-treatment cost of the reaction is substantially saved, the production is accelerated, and the production efficiency is improved; and by using the compound 3 as the starting raw material, the overall yield of the target compound 7 is not less than 46.7%, such that the atomic economy rate is high, the process is environmentally friendly, and the production cost is low.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of L-alanine derivatives. Background technique [0002] On May 27, 2017, the U.S. FDA approved Furiex Pharmaceuticals' new drug for diarrhea-predominant irritable bowel syndrome, Eluxadoline, with the trade name Viberzi. As a mu-opioid receptor agonist, iludoline acts on mu-opioid receptors to treat diarrhea-predominant irritable bowel syndrome (IBS-D). Is a first-in-class orally active, locally acting therapeutic drug with a unique mechanism of action; the drug has mixed opioid receptor activity, is a μ receptor antagonist, and is also a delta opioid receptor agonist and kappa receptor agonist agent. Taking the drug while eating can significantly reduce the symptoms of abdominal pain and diarrhea in IBS-D patients. Ilupolyline molecular structure is shown in formula I: [0003] [0004] In the synthetic technique of iludoline, the compound (S)-2-tert-...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22
CPCC07B2200/07C07C269/06C07C271/22
Inventor 田松川竺伟
Owner SYNCOZYMES SHANGHAI
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