Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-04-12
2001-03-06
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S445000, C562S450000
Reexamination Certificate
active
06197998
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for efficiently producing N-glycyltyrosine including N-glycyl-L-tyrosine dehydrate, which is one of the dipeptides useful as an ingredient of infusions. The invention also relates to N-glycyl-L-tyrosine dihydrate having specific crystal structures and processes for producing the same.
Amino acids and dipeptides thereof have been conventionally used as ingredients of infusions. N-Glycyl-L-tyrosine is a derivative prepared for the purpose of improving the solubility of L-tyrosine, which has very low water-solubility.
A process for producing N-glycyl-L-tyrosine is disclosed in Berichte der Deutschen Chemischen Gesellschaft, p. 2486 (1904). In the process, L-tyrosine is subjected to a reaction with 1.1 equivalents of chloroacetyl chloride and an aqueous solution of sodium hydroxide to obtain N-chloroacetyl-L-tyrosine, which is then made to react with aqueous ammonia to prepare N-glycyl-L-tyrosine. This process gives N-chloroacetyl-L-tyrosine, which is an intermediate for the synthesis of N-glycyl-L-tyrosine, in a 50% yield. The above literature also discloses a process in which L-tyrosine ethyl ester is made to react with 1.0 equivalent of chloroacetyl chloride to form N-chloroacetyl-L-tyrosine ethyl ester, which is then hydrolyzed to prepare N-chloroacetyl-L-tyrosine. In this process, the overall yield of N-chloroacetyl-L-tyrosine based on L-tyrosine ethyl ester is 91%, and that based on L-tyrosine is 77% as the yield in the step of conversion into ethyl ester from L-tyrosine is 85%. The process for producing N-glycyl-L-tyrosine via L-tyrosine ethyl ester is thus advantageous in respect of yield over the process in which L-tyrosine is directly chloroacetylated. However, when applied to the production on an industrial scale, the former process which requires the steps of esterification and hydrolysis is inefficient compared with the latter process requiring a smaller number of steps.
Another process for producing N-haloacetyl-L-tyrosine by direct haloacetylation of L-tyrosine is disclosed in Journal of Organic Chemistry, 18, 127(1953) and ibid., 18, 1546(1953). In this process, N-haloacetyl-L-tyrosine is produced by a reaction of L-tyrosine with 1-2 equivalents of chloroacetyl chloride in ethyl acetate under reflux. This reaction must be carried out under severe conditions. Further, the yield of the reaction product is 59% and thus the process is not satisfactory in respect of efficiency.
The crystal structure of N-glycyl-L-tyrosine dehydrate is disclosed in Crystal Structure Communication, 1, 301 (1972).
Under the circumstances, a one-step process for producing N-haloacetyltyrosine from tyrosine in high yields is desired for the production of N-glycyltyrosine using N-haloacetyltyrosine as an intermediate.
An object of the present invention is to efficiently produce N-haloacetyltyrosine and to efficiently produce N-glycyltyrosine by ammonolysis of N-haloacetyltyrosine using ammonia, if necessary in the presence of inorganic salts. Another object of the invention is to provide a process for producing N-glycyl-L-tyrosine dihydrate having specific crystal structures suitable for use as an ingredient of pharmaceutical compositions.
SUMMARY OF THE INVENTION
The present invention relates to a process for producing N-glycyltyrosine represented by formula (III):
a salt thereof, or a solvate thereof, which comprises adding dropwise to an aqueous suspension of tyrosine or a salt thereof 2 equivalents or more of a haloacetyl halide represented by formula (I):
(wherein X
1
and X
2
, which may be the same or different, each represent chlorine, bromine or iodine) and an aqueous solution of an inorganic base simultaneously in the presence or absence of an organic solvent, to form N-haloacetyltyrosine represented by formula (II):
(wherein X
1
has the same meaning as defined above)(haloacetylation), and subjecting the resulting N-haloacetyltyrosine to a reaction with an ammonium ion.
In this process, the reaction temperature and pH of the reaction mixture in the step of haloacetylation of tyrosine are preferably maintained at −20 to 30° C. and at pH 8 to 14, respectively.
The invention relates to a process for producing N-haloacetyltyrosine represented by the above formula (II), a salt thereof, or a solvate thereof, which comprises adding dropwise to an aqueous suspension of tyrosine or a salt thereof 2 equivalents or more of a haloacetyl halide represented by the above formula (I) and an aqueous solution of an inorganic base simultaneously in the presence or absence of an organic solvent.
In this process, the reaction temperature and pH of the reaction mixture are preferably maintained at −20 to 30° C. and at pH 8 to 14, respectively.
The invention also relates to a process for producing N-glycyl-L-tyrosine dihydrate having the crystal structure giving the following diffraction pattern of the diffraction angle 2&thgr;° and the relative diffraction intensity shown in parentheses in terms of % I/I
0
in X-ray powder diffraction within the limit of experimental errors: 7.96 (22), 15.20 (26), 15.86 (16), 18.92 (26), 19.96 (14), 21.16 (54), 21.52 (24), 23.08 (17), 23.84 (100), 26.44 (17), 27.08 (22), 28.88 (20), 31.64 (20), 33.72 (9), 35.28 (11), which is characterized by comprising crystallizing the dehydrate from a water-ethanol mixed solvent (ethanol content:10-99 vol %)(hereinafter, the above crystal structure is referred to as crystal structure A).
Further, the invention relates to N-glycyl-L-tyrosine dehydrate having the crystal structure giving the following diffraction pattern of the diffraction angle 2&thgr;° and the relative diffraction intensity shown in parentheses in terms of % I/I
0
in X-ray powder diffraction within the limit of experimental errors: 7.36 (16), 9.48 (17), 10.12 (23), 11.24 (100), 13.80 (14), 14.72 (19), 15.32 (58), 22.16 (59), 22.56 (37), 23.08 (56), 25.56 (31), 26.84 (28), 28.76 (39), 29.72 (38), 33.12 (22), 34.16 (23), and to a process for producing the same, which is characterized by comprising crystallizing the same from water (hereinafter, the above crystal structure is referred to as crystal structure B).
DETAILED DESCRIPTION OF THE INVENTION
Tyrosine to be used in the production of N-glycyltyrosine may be in any of D-form, L-form and DL-form. In order to obtain N-glycyl-L-tyrosine, which is a dipeptide useful as an ingredient of infusions, L-tyrosine is used. Tyrosine may be used as such or in the form of a salt. Preferred salts include a disodium salt and a monohydrochloride.
Preferred organic solvents for the production of N-haloacetyltyrosine are aromatic hydrocarbons, halogenated hydrocarbons, fatty acid esters, cyclic or acyclic ether compounds, ketones, and mixtures thereof. Preferred inorganic bases to be added dropwise together with a haloacetyl halide are lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof. The haloacetyl halide is used in the reaction in an amount of 2 equivalents or more, preferably 2 to 6 equivalents based on tyrosine. The reaction temperature is preferably −20 to 30° C., more preferably −10 to 10° C. The reaction mixture is preferably kept at pH 8 to 14, more preferably at pH 11 to 13.
Chloroacetyl chloride is one of the preferred haloacetyl halides.
The haloacetylation of tyrosine is carried out in the presence or absence of an organic solvent. As the organic solvent, aromatic hydrocarbons (e.g., benzene, toluene and xylene), halogenated hydrocarbons (e.g., chloroform, methylene chloride and 1,2-dichloroethane), fatty acid esters (e.g., ethyl acetate and isopropyl acetate), cyclic or acyclic ether compounds (e.g., tetrahydrofuran and diethyl ether) and ketones (e.g. acetone and ethyl methyl ketone) can be used alone or in combination in an amount of 0.5 to 30 times, preferably 0.5 to 5 times, the amount of tyrosine (weight/weight). Water is used as a solvent in an amount of 1 to 30 times, preferably 3 to 5 times, the amount of tyrosine (weight/weight). The reaction is carried out at a temperature of −
Imai Eiichiro
Imai Takahiro
Kasai Masaji
Mimura Takashi
Ogasa Takehiro
Fitzpatrick ,Cella, Harper & Scinto
Killos Paul J.
Kyowa Hakko Kogyo Co. Ltd.
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