Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-08-16
2002-04-16
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S553000, C562S444000, C562S445000
Reexamination Certificate
active
06372941
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of producing a &bgr;-halogeno-&agr;-aminocarboxylic acid or a salt thereof, which is useful as a raw material for the production of medicinals, among others. The invention also relates to a method of producing an optically active N-protected S-phenyl-L-cysteine or a salt thereof, which is useful as an intermediate of medicinals, in particular anti-AIDS drugs, and to a method of producing an intermediate thereof.
BACKGROUND ART
The following methods, among others, are known for producing &bgr;-halogeno-&agr;-aminocarboxylic acids:
(1) The method which comprises derivatizing a &bgr;-hydroxy-&agr;-aminocarboxylic acid into the corresponding &bgr;-hydroxy-&agr;-aminocarboxylic acid ester, then halogenating the hydroxyl group thereof with a phosphorus halide to give the corresponding &bgr;-halogeno-&agr;-aminocarboxylic acid ester, and hydrolyzing the ester group using a hydrohalogenic acid to give the objective &bgr;-halogeno-&agr;-aminocarboxylic acid. Specifically, serine is derivatized into serine methyl ester hydrochloride, the ester salt is then treated with phosphorus pentachloride to give &agr;-amino-&bgr;-chloropropionic acid methyl ester hydrochloride, which is further hydrolyzed with hydrochloric acid. The resulting &agr;-amino-&bgr;-chloropropionic acid hydrochloride is isolated by concentrating the reaction mixture to dryness, followed by crystallization of the residue from a mixture of 1-propanol and hydrochloric acid [e.g. CHIRALITY, 8:197-200 (1996)]; and
(2) The method which comprises treating &bgr;-phenylserine monohydrate with thionyl chloride and then with concentrated hydrochloric acid to give &bgr;-chloro-&bgr;-phenylalanine [Gazzetta Chimica Italiana, 119 (1989) p. 215].
However, in the above method (1), the halogenation of the hydroxyl group in &bgr; position usually involves three reaction steps, namely protection of the carboxyl group, halogenation of the hydroxyl group in &bgr; position and deprotection of the carboxyl group. In this case, many difficulties are encountered, for example the multiplicity of steps required, procedural complexity and low yields.
In the above method (2), such difficulties arise as the use of thionyl chloride in large amounts for the same to serve also as a solvent and the resulting complicatedness of procedure. As a result of investigations made by the present inventors, it was further found that the method is hardly applicable to the chlorination of serine, threonine or the like.
Thus, no efficient technology has been established for producing &bgr;-halogeno-&agr;-aminocarboxylic acids on a commercial scale.
On the other hand, such methods of producing optically active S-phenylcysteine derivatives as mentioned below are known in the art:
<Derivatization from Serine>
1) The method comprising reacting serine with thiophenol in the presence of tryptophan synthase (EP 754759);
2) The method which involves lactonization of a serine derivative with an azodicarboxylic acid ester [J. Am. Chem. Soc., 1985, vol. 107, p. 7105; Synth. Commun., 1995, vol. 25 (16), p. 2475];
3) The method comprising converting the hydroxyl group of an N-protected serine ester derivative to a sulfonyloxy group and substituting a thiophenyl group therefor [Tetrahedron Lett., 1987, vol. 28, p. 6069; ibid., 1993, vol. 34, p. 6607; EP 604185 A1];
<Derivatization from Starting Compounds other than Serine>
4) The method comprising reacting cysteine with a phenyldiazonium salt in the presence of a copper salt [J. Org. Chem., 1958, vol. 23, p. 1251];
5) The method comprising derivatizing from an aziridinecarboxylic acid derivative in the presence of boron trifluoride-ethyl ether complex [Bull. Chem. Soc. Jpn, 1983, vol. 56, p. 520];
6) The method comprising reacting cysteine with iodobenzene in the presence of a copper salt [Aust. J. Chem., 1985, vol. 38, p. 899]; and
7) The method comprising reacting dehydroalanine with a chiral nickel complex [Tetrahedron, 1988, vol. 44, p. 5507].
Since optically active serine, in particular L-serine, is a readily available compound, a practical method would be provided if the starting material L-serine could be converted efficiently to an optically active S-phenylcysteine derivative. However, the method 1), in which a particular enzyme is utilized, and the method 2), in which a lactone derivative is used as an intermediate, have problems from the viewpoint of operability, productivity, safety in reagents handling, and economy, among others. The method 3), in which the hydroxyl group of an N-protected serine ester derivative is converted to a sulfonyloxy group and the resulting product is then subjected to substitution reaction using the sodium salt of a thiol in N,N-dimethylformamide, is also disadvantageous in that because it involves the use of a reagent relatively difficult to handle, for example sodium hydride or potassium hydride, as a base, it does not always give the desired N-protected S-phenylcysteine ester in high yield and, in particular, the optical purity is decreased, as revealed by a study made by the present inventors.
On the other hand, the methods 4) through 7), which comprise derivatization from other starting compounds than serine, cannot be said to be industrially advantageous, either, since, for example, the waste treatment is troublesome, materials requiring caution in handling or expensive materials are used and the yield and productivity are low.
In view of the above state of the art, the primary object of the present invention is to provide a method of producing &bgr;-halogeno-&agr;-aminocarboxylic acids in an industrially advantageous manner and a method of producing optically active S-phenylcysteine derivatives from optically active serine, which is readily available commercially, in an industrially advantageous manner.
SUMMARY OF THE INVENTION
As a result of their intensive investigations made in an attempt to develop an industrially advantageous method of producing &bgr;-halogeno-&agr;-aminocarboxylic acids, the present inventors have surprisingly found an industrially advantageous production method according to which &bgr;-halogeno-&agr;-aminocarboxylic acids can be synthesized in an efficient manner by treating a&bgr;-hydroxy-&agr;-aminocarboxylic acid or a salt thereof with an acid with a halogenating agent.
On the other hand, in efficiently producing optically active S-phenylcysteine derivatives from optically active serine, namely L- or D-serine, the point is how to prevent the optical purity from decreasing in thiophenylating the activated compound derived from optically active serine by converting its hydroxyl group to a leaving group. The present inventors thought that there would be the possibility of attaining the above object in an industrially advantageous manner while preventing racemization if an adequately activated carboxylic acid derivative could be synthesized from optically active serine by activating the hydroxyl group thereof in the form of a leaving group and if the thiophenylation could be realized efficiently. Based on this way of thinking, they made intensive investigations and, as a result, found that optically active &bgr;-chloroalanine can be synthesized in an efficient manner when the above method of producing &bgr;-halogeno-&agr;-aminocarboxylic acids is utilized. There are no prior art findings teaching or suggesting that optically active &bgr;-chloroalanine can be produced by directly chlorinating optically active serine or a salt thereof. The relevant method of production is thus novel.
In addition, it was found that the optically active &bgr;-chloroalanine obtained in the above manner can be converted to an optically active N-protected-&bgr;-chloroalanine by treatment with an amino-protecting agent and that said compound can be converted to an optically active N-protected-S-phenylcysteine by reacting with thiophenol under a basic condition. Based on these and other findings, the present invention has now been complete
Inoue Kenji
Kinoshita Koichi
Murao Hiroshi
Ueda Yasuyoshi
Yamashita Koki
Chaudhry Mahreen
Connolly Bove Lodge & Hutz LLP.
Geist Gary
Kaneka Corporation
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