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Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester

A biphenylalanine alkyl ester, DL-4 technology, applied in the preparation of amino hydroxyl compounds, organic chemical methods, cyanide reaction preparation, etc., can solve the problems of no description, use of expensive palladium catalyst, etc., and achieve easy Application, cheap effect

Inactive Publication Date: 2018-12-21
AMINOLOGICS
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these methods are disadvantageous due to the necessity to use expensive and difficult-to-handle palladium catalysts
[0012] In addition, a method for preparing optically active acyl 4,4'-biphenylalanine has been disclosed, wherein the acyl 4,4'-biphenylalanine is subjected to optical resolution to form salts followed by hydrolysis (European Patent No. 2387558 (2010)), but the exact optical purity of the resulting acyl 4,4'-biphenylalanine is not described

Method used

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  • Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester
  • Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester
  • Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester

Examples

Experimental program
Comparison scheme
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preparation example 1

[0101] Preparation example 1 prepares DL-4,4'-biphenylalanine methyl ester

[0102] Add 50g DL-4,4'-biphenylalanine to 500mL methanol at 0°C, then add 49.3g thionyl chloride, heat to 75°C and stir for 3 hours, then slowly cool to room temperature. The solution was concentrated, whereby 60.3 g of DL-4,4'-biphenylalanine methyl ester hydrochloride was obtained.

[0103] use 1 H-NMR analysis of DL-4,4'-biphenylalanine methyl ester hydrochloride. The result is as follows.

[0104] 1 H-NMR (DMSO-d 6 ,400MHz):δ3.18(m,2H),3.68(s,3H),4.29(t,1H),7.33(m,3H),7.45(t,2H),7.63(t,4H),8.69( br,3H).

[0105] 250 mL of water, 350 mL of dichloromethane and 14 g of potassium hydroxide were added to DL-4,4'-biphenylalanine methyl ester hydrochloride, and stirred for 1 hour. Then, the dichloromethane layer was concentrated to obtain 59.1 g of DL-4,4'-biphenylalanine methyl ester.

[0106] use 1 The DL-4,4'-biphenylalanine methyl ester thus obtained was analyzed by H-NMR. The result is a...

Embodiment 1

[0112] Embodiment 1 prepares D-4,4'-biphenylalanine methyl ester

[0113] Add 10 g of DL-4,4'-biphenylalanine methyl ester and 7.6 g of di-p-toluoyl-D-tartaric acid to 150 mL of methanol, heat to 70 ° C, stir for 2 hours, and then slowly cool to room temperature .

[0114] Then, 8.3 g of a precipitated salt of D-4,4'-biphenylalanine methyl ester and di-p-toluoyl-D-tartaric acid (L / D ratio=10 / 90) were obtained by filtration.

[0115] use 1 H-NMR analysis of the salt of D-4,4'-biphenylalanine methyl ester and di-p-toluoyl-D-tartaric acid. The result is as follows.

[0116] 1 H-NMR (DMSO-d 6 ,400MHz):δ2.34(s,6H),3.04(d,2H),3.23(s,3H),4.13(t,1H),5.63(s,2H),7.27(m,6H),7.34( t,1H), 7.45(t,2H), 7.58(m,4H), 7.81(d,4).

[0117]To the salt of D-4,4'-biphenylalanine methyl ester and di-p-toluoyl-D-tartaric acid were added 41.5 mL of water, 58.1 mL of dichloromethane and 2.5 g of potassium hydroxide, and stirred for 30 minutes. Then, the dichloromethane layer was concentrated to...

Embodiment 2

[0118] Embodiment 2 prepares D-4,4'-biphenylalanine methyl ester

[0119] Add 15.0 g of DL-4,4'-biphenylalanine methyl ester, 23.2 g of dibenzoyl-D-tartaric acid and 0.56 g of 3,5-di Chloro-salicylaldehyde, heated to 65°C and stirred for 20 hours, then slowly cooled to room temperature.

[0120] Then, 23.4 g of a precipitated salt of D-4,4'-biphenylalanine methyl ester and dibenzoyl-D-tartaric acid (L / D ratio=8 / 92) were obtained by filtration.

[0121] use 1 The salt of D-4,4'-biphenylalanine methyl ester and dibenzoyl-D-tartaric acid thus obtained was analyzed by H-NMR. The result is as follows.

[0122] 1 H-NMR (DMSO-d 6 ,400MHz):δ3.09(m,2H),3.64(s,3H),4.14(t,1H),5.67(s,2H),7.28(d,2H),7.34(t,1H),7.48( m,6H), 7.62(m,6H), 7.92(d,4H).

[0123] To the salt of D-4,4'-biphenylalanine methyl ester and dibenzoyl-D-tartaric acid were added 117 mL of water, 163.8 mL of dichloromethane and 7.5 g of potassium hydroxide, and stirred for 1 hour. Thereafter, the dichloromethane l...

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Abstract

The present invention relates to a method for preparing a D-4,4'-biphenylalanine alkyl ester or an L-4,4'-biphenylalanine alkyl ester by optically splitting a DL-4,4'-biphenylalanine alkyl ester usinga chiral diaroyl tartaric acid as an optical splitter.

Description

technical field [0001] The invention relates to a method for preparing D-4,4'-biphenylalanine alkyl ester or L-4,4'-biphenylalanine from DL-4,4'-biphenylalanine alkyl ester The method for alkyl alanine ester, and more specifically, relates to a kind of use chiral diaroyl tartaric acid as optical resolution agent to prepare D-4,4'-biphenylalanine alkyl ester or L- 4,4'-Biphenylalanine alkyl ester method. Background technique [0002] Alkyl 4,4'-biphenylalanine is a chiral compound having a chiral carbon (chiral center) represented by Chemical Formula 1 below. [0003] [chemical formula 1] [0004] [0005] In Chemical Formula 1, * is a chiral carbon (chiral center), and [0006] R is C 1 ~C 4 alkyl. [0007] D-4,4'-biphenylalanine is a key material for the preparation of neutral endopeptidase inhibitors (such as Sacubitril) used as a therapeutic agent for heart failure. [0008] In conventional techniques, the problem with the preparation of optically active 4,4'-bi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C219/22C07C213/10C07B55/00
CPCC07C69/78C07B57/00C07C227/34C07C229/36C07B2200/07C07C213/08C07C219/22C07C213/10C07B55/00C07C2601/16C07C69/86C07C227/32
Inventor 边一锡刘哲焕金元燮
Owner AMINOLOGICS