Process for producing 4-thiazolylmethyl derivative

Details Process for producing 4-thiazolylmethyl derivative Process for producing 4-thiazolylmethyl derivative

2000-08-17

2003-01-14

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S202000

Reexamination Certificate

active

06506903

ABSTRACT:

TECHNICAL FIELD
This invention relates to a process for the production of a thiazolyl alanine derivative which is a nonnatural amino acid by a simple and economical method.
BACKGROUND ART
A thiazolyl alanine derivative such as 4-halomethylthiazole, 3-(4-thiazole) alanine, or the like is an important intermediate for the production of ES 6864 described in Synth. Commun., 20, 22, 3570 (1990) as a renin inhibitor and a TRH (thyrotropin-releasing hormone) derivative described in WO 98/08867 which is represented by the the formula (V):
wherein Y is optionally substituted alkyl. Further, a thiazolyl alanine derivative, a nonnatural amino acid, is useful as a tool of the combinatorial chemistry.
As a process for the production of a thiazolyl alanine derivative, two methods shown below have already been known. The first method consists of the following 3 steps:
(1) a reaction of formaldehyde with phosphorus pentoxide to give thioformamide (Synthesis, 149 (1973)) or
(1′) a reaction of formaldehyde with Lawesson's reagent to give thioformamide (Bull. Soc. Chim. Belg., 87, 3, 229 (1978)),
(2) a reaction of thioformamide with 1,3-dichloro-2-prooanone to give 4-chloromethylthiazole, and
(3) alkylation, decarboxylation, and optical resolution to give optically active 3-(4-thiazole)alanine (Synth. Commun., 20, 22, 3507(1990) and Chem. Pharm. Bull., 38, 1, 103(1990)).
Step (1) has some problems such as difficulty of waste disposal, because insoluble products in the reaction mixture have bad smell peculiar to sulfur compounds and do not dissolve in water and any organic solvent except for dimethylsulfoxide. The step (1′) is not appropriate for large scale synthesis because Lawesson's reagent is expensive. Further, as regards the step (2), 1,3-dichloro-2-propanone has a tearing property.
The second method for the production of a thiazolyl alanine derivative consists of the following 2 steps:
(1) a reaction of diethyl (3-bromo-2-oxo-propyl)acetamide malonate with thioformamide to give diethyl (4-thiazolylmethyl)acetamide malonate and
(2) hydrolysis, decarboxylation, and optical resolution using esterase to give optically active 3-(4-thiazole)alanine (U.S. Pat. No. 5,275,950).
In this method, use of thioformamide is also necessary as described in the above method.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a process for the simple and economical production of a thiazolyl alanine derivative which is a nonnatural amino acid. The thiazolyl alanine derivative is useful as an intermediate of medicaments and a tool of the combinatorial chemistry.
The present inventors have found a process, using 4-methylthiazole as a starting material, for the production of a thiazolyl alanine derivative, which is suitable for large scale synthesis.
This invention relates to A) a process for the production of a compound represented by the formula (I):
wherein R
1
is hydrogen or halogen and Hal is halogen, which comprises reacting 4-methylthiazole with N-halosuccinimide in a solvent in the presence of a radical initiator.
In more detail, the invention relates to B) a process for the production of a compound represented by the formula (II):
wherein R
2′
is hydrogen or an amino protective group, or the formula (IV):
wherein R
2″
is different from R
2′
and hydrogen or an amino protective group, which comprises,
(a) preparing a compound represented by the formula (I):
 wherein R
1
is hydrogen or halogen and Hal is halogen, by reacting 4-methylthiazole with N-halosuccinimide in a solvent in the presence of a radical initiator,
(b) preparing a compound represented by the formula (I):
 wherein R
1
is as defined above, R
2
is an amino protective group, and R
3
is lower alkyl, by reacting a compound represented by the formula (I) with R
2
NHCH(COOR
3
)
2,
wherein R
2
and R
3
are as defined above, in the presence of a base,
(c) dehalogenating the compound represented by the formula (II) when R
1
is halogen, and,
(d) preparing a compound represented by the formula (III) by subjecting the compound represented by the formula (II) to hydrolysis, decarboxylation, and optical resolution.
C) A process for the production of a compound represented by the formula (V):
wherein Y is optionally substituted alkyl, which comprises subjecting a compound represented by the formula (III) or (IV) to a peptide bond formation reaction.
D) A process as described in any one of A) to C) wherein the solvent is chlorobenzene, the radical initiator is 2,2-azobisisobutyronitrile, and N-halosuccinimide is N-chlorosuccinimide.
E) A process as described in any one of A) to C) wherein the solvent is carbon tetrachloride, the radical initiator is 2,2-azobisisobutyronitrile, and N-halosuccinimide is N-bromosuccinimide.
F) A process as described in any one of A) to C) wherein the solvent is carbon tetrachloride, the radical initiator is benzoyl peroxide, and N-halosuccinimide is N-bromosuccinimide.
G) A process for the production of 4-chloromethylthiazole comprising,
(e) reacting 4-methylthiazole with N-chlorosuccinimide in chlorobenzene in the presence of 2,2-azobisisobutyronitrile and
(f) treating the compound obtained in the step (e) with hydrochloric acid to give the corresponding hydrochloride, followed by decarboxylation.
H) A process for the production of a compound represented by the formula (III):
wherein R
2′
is as defined above, or the formula (IV):
wherein R
2″
is as defined above, which comprises,
(g) preparing 5-bromo-4-bromomethylthiazole by reacting 4-methylthiazole with N-bromosuccinimide in carbon tetrachloride in the presence of benzoyl peroxide,
(h) preparing a compound represented by the formula (VI):
 wherein R
2
and R
3
are as defined above, by reacting 5-bromo-4-bromomethylthiazole with R
2
NHCH(COOR
3
)
2,
wherein R
2
and R
3
are as defined above in the presence of a base, and
(i) subjecting the compound represented by the formula (VI) to dehalogenation, hydrolysis, decarboxylation, and optical resolution.
The above steps (d) and (i) are preferred to be carried out successively in order of hydrolysis, decarboxylation, and optical resolution.
The peptide bond formation reaction in the step C) is preferred to be carried out twice in appropriate order.
The term “halogen” herein used includes fluoro, chloro, bromo, and iodo. Preferred are chloro and bromo.
The term “lower alkyl” herein used includes straight or branched C
1
-C
6
chain alkyl. Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, and the like. Preferably, methyl and ethyl are exemplified.
Examples of “an amino protective group” are acetyl and n-butyryl.
The term “optionally substituted alkyl” herein used includes C
1
-C
6
straight or branched chain alkyl or C
3
-C
8
cycloalkyl which is optionally substituted at any possible position(s) with one or more substituents, for example, hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, carbamoyl, alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SO
P
R
A
(p is an integer of 1 to 3, and R
A
is hydrogen or alkyl), PO(OH)
2
or P(O)OH each is optionally substituted with alkyl, substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), optionally substituted aryl (e.g., phenyl and tolyl), optionally substituted heteroaryl, an optionally substituted non-aromatic heterocyclic group, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, non-aromatic heterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino, alkyloxyamino, formyl, and the lile. Examples of optionally substituted alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl, piperidinomethyl, N-meth

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