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Preparation method of alanine derivatives

A compound and chiral compound technology, applied in the field of preparation of alanine derivatives, can solve the problems of difficult realization, harsh production conditions, and difficult operation, and achieve the goal of reducing production difficulty, mild reaction conditions, and reducing production costs Effect

Active Publication Date: 2016-06-22
四川伊诺达博医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The starting material of this method is an achiral compound, and a chiral catalyst needs to be used to synthesize a chiral compound through asymmetric catalytic reduction. The chiral catalyst used in the literature [Rh(cod)(R,R-DIPAMP) + BF 4 - Very expensive, and reacting at high pressure of 1000psi for 14 days, its operation is very difficult and difficult to achieve
Therefore, in practice, this method is also difficult to apply industrially
[0018] It can be seen that for the preparation of alanine derivatives of opioid receptor modulator intermediates, the existing methods have higher production costs and harsh production conditions, and are difficult to adapt to the needs of large-scale industrial production

Method used

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  • Preparation method of alanine derivatives
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The preparation of embodiment 1L-tyrosine methyl ester hydrochloride (compound 11)

[0074]

[0075] Add L-tyrosine (110 g, 0.607 mol) into 500 mL of methanol, cool to 0° C., and add thionyl chloride (108.3 g, 0.91 mol) dropwise. After dropping, the temperature was raised to room temperature naturally, and then heated to reflux for 5 hours, and the reaction was monitored by TLC to complete. Cool to room temperature, filter, wash the filter cake with 420 mL of ethyl acetate, and dry to obtain 140.2 g of white solid, with a yield of 99.7%.

Embodiment 2

[0076] The preparation of embodiment 2N-tert-butoxycarbonyl-L-tyrosine methyl ester (compound 10)

[0077]

[0078] Potassium carbonate (250.9g, 1.815mol) was added to 1.0L of water, stirred evenly, compound 11 (140.2g, 0.605mol) was added under an ice-water bath, and then Boc 2 O (158.4 g, 0.726 mol) in ethanol (300 mL). After dropping, the temperature was naturally raised to room temperature for 2 h, and the reaction was monitored by TLC to complete. Extract with ethyl acetate (600mLX3), combine the organic phases, wash with 1N hydrochloric acid (400mL), tap water (400mL), saturated brine (400mLX2) successively, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a solid, which was washed with 300 mL of n-hexane and dried to obtain 175.8 g of a white solid with a yield of 98.4%.

Embodiment 3

[0079] Example 3 Preparation of N-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (compound 9)

[0080]

[0081] (1) Method 1:

[0082] Compound 10 (175.8g, 0.595mol) and 1.2L of dichloromethane were added to the reaction flask, after stirring evenly, pyridine (75.3g, 0.95mol) was added, and then trifluoromethanesulfonic anhydride (201.4g, 0.714mol). Continue to react at 0° C. for 1 h after the drop is complete, and monitor the completion of the reaction by TLC. Add 10% aqueous citric acid (200 mL) to quench the reaction, separate the layers, and wash the organic phase with 10% aqueous citric acid (200 mL) and tap water (200 mL×2), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and then 600 mL of methyl tert-butyl ether was added, frozen to 0°C for crystallization. After filtering, the filter cake was washed with 350 mL of n-hexane, and dried to obtain 239.5 g of lig...

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Abstract

The invention discloses a method for preparing alanine derivatives disclosed as Formula (I). The alanine derivatives can be used as a synthesis intermediate of an opioid receptor regulator, such as a synthesis intermediate of eluxadoline. By using the cheap and accessible chiral tyrosine as the initial raw material, the invention provides a brand-new synthesis route for preparing alanine derivatives. The whole reaction route has the advantages of high total yield, low cost and mild reaction conditions, is simple and safe for operation, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of alanine derivatives, in particular to the preparation of a class of intermediates of opioid receptor modulators, and in particular to the synthesis of esadoline intermediates. Background technique [0002] Patent CN1950342A discloses the following compounds as opioid receptor modulators and their preparation methods: [0003] [0004] Among these compounds, eluxadoline (compound 1) has been approved for marketing by the US FDA. [0005] [0006] For these compounds as modulators of opioid receptors, there are usually chiral alanine derivative structural fragments. Therefore, in order to prepare opioid receptor modulators with specific chirality, it is usually necessary to synthesize corresponding chiral alanine derivatives. For example, for Exadoline, N-tert-butoxycarbonyl-4-carboxamido-2,6-dimethyl-L-phenylalanine (compound 2) is its key preparation intermediate, and its structural formula is as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/22C07D233/64
CPCC07B2200/07C07C227/18C07C253/30C07C269/06C07D233/64C07C271/22C07C255/57C07C229/36
Inventor 付清泉张菊华林强唐敏张俊赵茂先
Owner 四川伊诺达博医药科技有限公司
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