Method for preparing (S)-2',6'-dimethyl tyrosine and derivative of (S)-2',6'-dimethyl tyrosine, and derivative

Abstract

The invention belongs to the field of medicines, and particularly relates to a method for preparing (S)-2',6'-dimethyl tyrosine and a derivative of (S)-2',6'-dimethyl tyrosine, and the derivative. The preparation method of (S)-2',6'-dimethyl tyrosine comprises the following step that a) a protecting group of a structural compound as shown in Formula (I) is removed to form (S)-2',6'-dimethyl tyrosine, wherein R is selected from benzyl, silicyl or acyl. The preparation method of (S)-2',6'-dimethyl tyrosine is not involved with reaction conditions easily causing chiral inversion such as strong acid and strong alkali in a preparation process, and high-chiral-purity (S)-2',6'-dimethyl tyrosine can be obtained. An experimental result proves that the HPLC (high performance liquid chromatography) purity of (S)-2',6'-dimethyl tyrosine prepared by the method is above 97%, and an ee (enantiomeric excess) value is above 99%.

Description

technical field

[0001] The invention belongs to the field of medicines, and in particular relates to a method for preparing (S)-2',6'-dimethyltyrosine and derivatives thereof and the derivatives. Background technique

[0002] (S)-2',6'-Dimethyltyrosine is a non-natural chiral amino acid, which is a derivative of tyrosine, and (S)-2',6'-dimethyltyrosine can detect Topological conformation of biologically active peptides, improving the enzymatic stability and biological activity of peptides.

[0003] Xuejun Tang et al. provided a method for preparing (S)-2'6'-dimethyltyrosine with a chiral ligand of nickel metal as a chiral reagent. The specific reaction scheme is as follows:

[0004]

[0005] The method uses 2,3-dimethylbenzyl bromide as a starting material and sodium hydroxide as a deprotonating reagent, separates two chiral intermediates R and S through column chromatography, and finally obtains the target product after hydrochloric acid treatment. Since the starting m...

Examples

preparation example Construction

[0048] The invention provides a method for preparing (S)-2',6'-dimethyltyrosine, comprising the following steps:

[0049] a) Deprotection of the structural compound shown in formula (I) to obtain (S)-2',6'-dimethyltyrosine;

[0050]

[0051] In formula (I), R is selected from benzyl, silyl or acyl.

[0052] The preparation method provided by the invention utilizes the structural compound represented by formula (I) to obtain (S)-2',6'-dimethyltyrosine by removing the protecting group. Wherein, in the compound represented by the formula (I), R is selected from benzyl, silyl or acyl, preferably from benzyl, trimethylsilyl, triethylsilyl, dimethylisobutylsilyl, Acetyl, trifluoroacetyl, propionyl or butyryl, more preferably selected from benzyl, acetyl or trifluoroacetyl.

[0053] In the present invention, the compound of structure shown in (I) is preferably prepared according to the following steps:

[0054] (S)-2-phthalimido-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl) p...

Embodiment 1

[0101] Preparation of (S)-2-phthalimido-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)propionamide

[0102] Add 17.8g (0.2mol) of alanine, 29.6g (0.2mol) of phthalic anhydride and 450mL of toluene into a three-neck round-bottomed glass flask, stir the mixture for 5 minutes and add 2.8mL (2.0g, 0.02mol) of triethyl amine. The resulting mixture was heated to reflux for 18 hours, and TLC detection (ninhydrin color development) showed that alanine was completely consumed, and a large amount of white solids were separated out in the system, filtered, 50mL toluene washed the filter cake, and the filter cake was added to 300mL of dichloromethane, The mixture was stirred at room temperature, and after it was completely dissolved, 4 mL of concentrated hydrochloric acid was added, the mixture was washed once with 100 mL of water and 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 42.3 g of a white solid....

Embodiment 2

[0105] (S)-2-phthalimide-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-3-(2,6-dimethyl-4 -Preparation of benzyloxyphenyl) propanamide

[0106] 43.5g (100mmol) of (S)-2-phthalimido-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)propane obtained in Example 1 Amide was added to a container containing 1000mL 1,2-dichloroethane, and after stirring at room temperature for 10 minutes, 5g (15mmol) palladium trifluoroacetate, 2.8g (30mmol) 2-picoline, 56g (200mmol) carbonic acid Silver and 2.3g (20mmol) trifluoroacetic acid were sequentially added to the above 1,2-dichloroethane solution, and the mixed system continued to stir for 30 minutes. 51 g (150 mmol) of 2,6-dimethyl-4-benzyloxyiodobenzene was added to the mixed solution. The resulting mixed system was transferred to a high-pressure reactor, and the used container was washed twice with 500 mL of 1,2-dichloroethane so that the material was completely transferred into the high-pressure reactor, and replaced with nitrogen three...

technical field

[0001] The invention belongs to the field of medicines, and in particular relates to a method for preparing (S)-2',6'-dimethyltyrosine and derivatives thereof and the derivatives. Background technique

[0002] (S)-2',6'-Dimethyltyrosine is a non-natural chiral amino acid, which is a derivative of tyrosine, and (S)-2',6'-dimethyltyrosine can detect Topological conformation of biologically active peptides, improving the enzymatic stability and biological activity of peptides.

[0003] Xuejun Tang et al. provided a method for preparing (S)-2'6'-dimethyltyrosine with a chiral ligand of nickel metal as a chiral reagent. The specific reaction scheme is as follows:

[0004]

[0005] The method uses 2,3-dimethylbenzyl bromide as a starting material and sodium hydroxide as a deprotonating reagent, separates two chiral intermediates R and S through column chromatography, and finally obtains the target product after hydrochloric acid treatment. Since the starting m...

Examples

preparation example Construction

[0048] The invention provides a method for preparing (S)-2',6'-dimethyltyrosine, comprising the following steps:

[0049] a) Deprotection of the structural compound shown in formula (I) to obtain (S)-2',6'-dimethyltyrosine;

[0050]

[0051] In formula (I), R is selected from benzyl, silyl or acyl.

[0052] The preparation method provided by the invention utilizes the structural compound represented by formula (I) to obtain (S)-2',6'-dimethyltyrosine by removing the protecting group. Wherein, in the compound represented by the formula (I), R is selected from benzyl, silyl or acyl, preferably from benzyl, trimethylsilyl, triethylsilyl, dimethylisobutylsilyl, Acetyl, trifluoroacetyl, propionyl or butyryl, more preferably selected from benzyl, acetyl or trifluoroacetyl.

[0053] In the present invention, the compound of structure shown in (I) is preferably prepared according to the following steps:

[0054] (S)-2-phthalimido-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl) p...

Embodiment 1

[0101] Preparation of (S)-2-phthalimido-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)propionamide

[0102] Add 17.8g (0.2mol) of alanine, 29.6g (0.2mol) of phthalic anhydride and 450mL of toluene into a three-neck round-bottomed glass flask, stir the mixture for 5 minutes and add 2.8mL (2.0g, 0.02mol) of triethyl amine. The resulting mixture was heated to reflux for 18 hours, and TLC detection (ninhydrin color development) showed that alanine was completely consumed, and a large amount of white solids were separated out in the system, filtered, 50mL toluene washed the filter cake, and the filter cake was added to 300mL of dichloromethane, The mixture was stirred at room temperature, and after it was completely dissolved, 4 mL of concentrated hydrochloric acid was added, the mixture was washed once with 100 mL of water and 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 42.3 g of a white solid....

Embodiment 2

[0105] (S)-2-phthalimide-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-3-(2,6-dimethyl-4 -Preparation of benzyloxyphenyl) propanamide

[0106] 43.5g (100mmol) of (S)-2-phthalimido-N-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)propane obtained in Example 1 Amide was added to a container containing 1000mL 1,2-dichloroethane, and after stirring at room temperature for 10 minutes, 5g (15mmol) palladium trifluoroacetate, 2.8g (30mmol) 2-picoline, 56g (200mmol) carbonic acid Silver and 2.3g (20mmol) trifluoroacetic acid were sequentially added to the above 1,2-dichloroethane solution, and the mixed system continued to stir for 30 minutes. 51 g (150 mmol) of 2,6-dimethyl-4-benzyloxyiodobenzene was added to the mixed solution. The resulting mixed system was transferred to a high-pressure reactor, and the used container was washed twice with 500 mL of 1,2-dichloroethane so that the material was completely transferred into the high-pressure reactor, and replaced with nitrogen three...

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