JPH10101655A - Oxazoline compound, its production and production of threo-3-aromatic serine using the compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a racemic or optically active oxazoline compound useful as an intermediate for a threo-3-aromatic serine by oxidizing the 3-site of a racemic or optically active 3-aromatic alanine derivative by a new method. SOLUTION: The objective compound of the formula II is produced by reacting a racemic or optically active 3-aromatic alanine derivative of the formula I (Ar is an aromatic group; R<1> is an alkyl or phenyl; R<2> is a carboxylic acid protecting group) with a ceric salt (e.g. ceric ammonium nitrate) or a persulfate (e.g. potassium persulfate) in the presence or absence of a copper catalyst (e.g. cuprous chloride). For example, (4S, 5R)-5-(furan-2-yl)-2-phenyl-2- oxazoline-4-carboxylic acid methyl ester is produced as the compound of the formula II by using (2S)-benzoylamino-3(furan-2-yl)propanoic acid methyl ester as the compound of the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the following general formula (2):
The present invention relates to a racemic or optically active oxazoline represented by the formula:

[0002]

2. Description of the Related Art Conventionally, as a method for producing oxazolines, 1) a method of cycloaddition of a nitrile to an epoxide (J.
Am. Chem. Soc., 89, 4456 (1967)) 2) A method of condensing an aromatic aldehyde with an isocyanate (Helvetica Chimica Acta, 72, 1038 (198)
9)) etc. are known.

[0003]

However, in the above method 1), when an aromatic epoxide is used as a raw material, a nitrogen atom of a nitrile is added to the benzyl position, so that oxygen is introduced to the 3-position. It is difficult. In the method (2), an expensive aromatic aldehyde is excessively used as a raw material, and complicated operations are required. was there.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve such problems, and as a result, have obtained a novel method of obtaining oxazoline by oxidizing the 3-position of a 3-aromatic alanine derivative. The present invention finds that a threo-3-aromatic serine represented by the following general formula (3) can be efficiently produced by opening the ring and removing the protecting group, and the present invention. Reached.

That is, the present invention provides a compound represented by the general formula (1)(In the formula, Ar represents an aromatic group which may have a substituent.
Then R¹Is an alkyl group which may have a substituent or
A phenyl group which may have a substituent; ^TwoHa
Shows a protective group for rubonic acid. ) Racemic or light
Biologically active 3-aromatic alanine derivative and ceric salt or
Reacts with persulfate in the presence or absence of a copper catalyst
General formula (2)(Where Ar, R¹And R^TwoHas the same meaning as above
You. Racemic or optically active oxazolines represented by)
And a general formula (3) using the same(In the formula, Ar has the same meaning as described above.)
Industry of racemic or optically active threo-3-aromatic serines
It provides an excellent production method.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
I do. 3-aromatic alanine derivative represented by the general formula (1)
In the formula, Ar represents (a) 4 or less substituents (R
^Three, R^Four, R ^Five, R⁶Phenyl) optionally substituted with
Group, 2-biphenyl group, 3-biphenyl group, 4-biphenyl
Group, 1-naphthyl group, 2-naphthyl group, 1-anthranyl group,
2-anthranyl group, 9-anthranyl group, 1-indenyl
Group, 2-indenyl group, 3-indenyl group, 4-indenyl
Group, 5-indenyl group, 6-indenyl group, 7-indenyl
Group, pyrrol-2-yl group, pyrrol-3-yl group, India
2-yl, indole-3-yl, indole-4
-Il group, Indole-5-Il group, Indole-6-Il
Group, indole-7-yl group, benzofuran-2-yl group,
Benzofuran-3-yl group, benzofuran-4-yl group,
Benzofuran-5-yl group, benzofuran-6-yl group, ben
Zofuran-7-yl group, benzimidazol-2-yl group,
Benzimidazole-4-yl group, benzimidazole-5
-Yl, benzothiazol-2-yl, benzothiazo
4-yl group, benzothiazol-5-yl group, benzo
Thiazol-6-yl group or benzothiazole-7-
Yl group or (b) three or less substituents (R^Three, R^Four,
R^Five)) 2-furyl group, 3-furyl
Group, 2-thienyl group, or 3-thienyl group, or
(C) up to two substituents (R^Three, R ^Four)
2-thiazolyl group, 4-thiazolyl group, or 5-
A thiazolyl group (where R^Three, R^Four, R^Five, R⁶Are the same
Or differently, a linear or branched alkyl having 1 to 7 carbon atoms
Kill group, cycloalkyl group having 1 to 7 carbon atoms, 1 to 7 carbon atoms
7 alkoxyalkyl groups, C 1-10 amino groups
Alkyl group, halogenated alkyl group having 1 to 7 carbon atoms, carbon
An alkoxy group having 1 to 7 carbon atoms and an aromatic ox having 6 to 12 carbon atoms
Si group, alkylamino group having 1 to 7 carbon atoms, 1 to 7 carbon atoms
A cyclic alkylamino group having 6 to 12 carbon atoms
Group, an alkylsulfonylamino group having 1 to 7 carbon atoms, charcoal
An aromatic sulfonylamino group having a prime number of 6 to 12, a nitro group,
Or a halogen atom. However, Ar is a phenyl group
Is not an alkoxy group having 1 to 6 carbon atoms. )

[0007] More specific examples of Ar include the following groups. (A) phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 3-methoxymethylphenyl, 4-methoxymethylphenyl, 3-ethoxymethylphenyl, 4-ethoxymethylphenyl, 3-dimethylaminomethylphenyl,
4-dimethylaminomethylphenyl, 3-[(piperidine-1-
Yl) methyl] phenyl, 4-[(piperidin-1-yl) methyl] phenyl, 3-[(pyrrolidin-1-yl) methyl] phenyl, 4-[(pyrrolidin-1-yl) methyl] phenyl,
3-[(azepin-1-yl) methyl] phenyl, 4-[(azepin-1-yl) methyl] phenyl, 4-chloromethylphenyl, 4-dichloromethylphenyl, 4-trichloromethylphenyl, 2-methoxyphenyl Phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methyl-4-methoxyphenyl, 4-methyl-3-methoxyphenyl, 4-phenoxyphenyl, 4- (furan-2-yloxy) phenyl, 3-dimethylamino Phenyl, 4-dimethylaminophenyl, 3- (
Piperidin-1-yl) phenyl, 4- (piperidin-1-yl) phenyl, 3- (pyrrolidin-1-yl) phenyl, 4-
(Pyrrolidin-1-yl) phenyl, 3- (azepin-1-yl) phenyl, 4- (azepin-1-yl) phenyl, 4-diphenylaminophenyl, 3-methanesulfonylaminophenyl, 4-methanesulfonylaminophenyl , 3- (4-toluenesulfonylamino) phenyl, 4- (4-toluenesulfonylamino) phenyl, 3- (2-nitrobenzenesulfonylamino) phenyl, 4- (2-nitrobenzenesulfonylamino) phenyl, 2-biphenyl, 2 '-Methyl-2-
Biphenyl, 3'-methyl-2-biphenyl, 4'-methyl-2-
Biphenyl, 2 ', 4'-dimethyl-2-biphenyl, 2', 3'-
Dimethyl-2-biphenyl, 3 ', 4'-dimethyl-2-biphenyl, 2', 3 ', 4'-trimethyl-2-biphenyl, 3'-methoxymethyl-2-biphenyl, 4'-methoxymethyl-2 -Biphenyl, 3'-ethoxymethyl-2-biphenyl, 4'-ethoxymethyl-2-biphenyl, 3'-dimethylaminomethyl-
2-biphenyl, 4'-dimethylaminomethyl-2-biphenyl, 3-biphenyl, 2'-methyl-3-biphenyl, 3'-
Methyl-3-biphenyl, 4'-methyl-3-biphenyl,
2 ', 4'-dimethyl-3-biphenyl, 2', 3'-dimethyl-3-biphenyl, 3 ', 4'-dimethyl-3-biphenyl, 2', 3 ', 4'-
Trimethyl-3-biphenyl, 3'-methoxymethyl-3-biphenyl, 4'-methoxymethyl-3-biphenyl, 3'-ethoxymethyl-3-biphenyl, 4'-ethoxymethyl-3-
Biphenyl, 3'-dimethylaminomethyl-3-biphenyl, 4'-dimethylaminomethyl-3-biphenyl, 4-biphenyl, 2'-methyl-4-biphenyl, 3'-methyl-4-biphenyl, 4'-methyl -4-biphenyl, 2 ', 4'-dimethyl
-4-biphenyl, 2 ', 3'-dimethyl-4-biphenyl, 3',
4'-dimethyl-4-biphenyl, 2 ', 3', 4'-trimethyl-4-
Biphenyl, 3'-methoxymethyl-4-biphenyl, 4'-
Methoxymethyl-4-biphenyl, 3'-ethoxymethyl-
4-biphenyl, 4'-ethoxymethyl-4-biphenyl,
3'-dimethylaminomethyl-4-biphenyl, 4'-dimethylaminomethyl-4-biphenyl, naphth-1-yl, 2-methylnaphth-1-yl, 3-methylnaphth-1-yl, 4-methylnaphth-1-yl Yl, 5-methylnaphth-1-yl, 6-methylnaphth-1-yl, 7-methylnaphth-1-yl, 8-methylnaphth-1-yl, 2,4-dimethylnaphth-1-yl, 2,3-dimethyl Naphth-1-yl, 3,4-dimethylnaphth-1-yl, 2,
3,4-trimethylnaphth-1-yl, 3-methoxymethylnaphth-1-yl, 4-methoxymethylnaphth-1-yl, 3-ethoxymethylnaphth-1-yl, 4-ethoxymethyl-naphtho
-1-yl, 3-dimethylaminomethylnaphth-1-yl, 4-
Dimethylaminomethylnaphth-1-yl, naphth-2-yl, 1-methylnaphth-2-yl, 3-methylnaphth-2-yl, 4-methylnaphth-2-yl, 5-methylnaphth-2-yl, 6-methylnaphtho 2-yl, 7-methylnaphth-2-yl, 8-methylnaphth-2-yl, 1,4-dimethylnaphth-2-yl
Yl, 1,3-dimethylnaphth-2-yl, 3,4-dimethylnaphth-2-yl, 1,3,4-trimethylnaphth-2-yl, 3-methoxymethylnaphth-2-yl, 4-methoxy Methyl naphtho-2
-Yl, 3-ethoxymethylnaphth-2-yl, 4-ethoxymethyl-naphth-2-yl, 3-dimethylaminomethylnaphth-2-yl, 4-dimethylaminomethylnaphth-2-yl,
Anthra-1-yl, 2-methylanthra-1-yl, 3-methylanthra-1-yl, 4-methylanthra-1-yl, 5-methylanthra-1-yl, 6-methylanthra-1-yl , 7-
Methylanthra-1-yl, 8-methylanthra-1-yl,
9-methylanthra-1-yl, 10-methylanthra-1-yl, 2,4-dimethylanthra-1-yl, 2,3-dimethylanthra-1-yl, 3,4-dimethylanthra-1-yl , 2,3,4-
Trimethylanthra-1-yl, 3-methoxymethylanthra-1-yl, 4-methoxymethylanthra-1-yl, 3-ethoxymethylanthra-1-yl, 4-ethoxymethyl-anthra-1-yl, 3- Dimethylaminomethylanthra-1-
Yl, 4-dimethylaminomethylanthra-1-yl, anthra-2-yl, 1-methylanthra-2-yl, 3-methylanthra-2-yl, 4-methylanthra-2-yl,
5-methylanthra-2-yl, 6-methylanthra-2-
Il, 7-methylanthra-2-yl, 8-methylanthra
-2-yl, 9-methylanthra-2-yl, 10-methylanthra-2-yl, 1,4-dimethylanthra-2-yl, 1,3-dimethylanthra-2-yl, 3,4-dimethyl Anthra-2-yl, 1,3,4-trimethylanthra-2-yl, 3-methoxymethylanthra-2-yl, 4-methoxymethylanthra-2-yl, 3-ethoxymethylanthra-
2-yl, 4-ethoxymethyl-anthra-2-yl, 3
-Dimethylaminomethylanthra-2-yl, 4-dimethylaminomethylanthra-2-yl, anthra-9-yl, 1-methylanthra-9-yl, 2-methylanthra-
9-yl, 3-methylanthra-9-yl, 4-methylanthra-9-yl, 5-methylanthra-9-yl, 6-methylanthra-9-yl, 7-methylanthra-9-yl,
8-methylanthra-9-yl, 10-methylanthra-9
-Yl, 2,4-dimethylanthra-9-yl, 2,3-dimethylanthra-9-yl, 3,4-dimethylanthra-9-yl, 2,3,4-trimethylanthra-9-yl, 3 -Methoxymethylanthra-9-yl, 4-methoxymethylanthra
-9-yl, 3-ethoxymethylanthra-9-yl, 4-
Ethoxymethyl-anthra-9-yl, 3-dimethylaminomethylanthra-9-yl, 4-dimethylaminomethylanthra-9-yl, inden-1-yl, 2-methylinden-1-yl, 3-methylindene 1-yl, 4-methylinden-1-yl, 5-methylinden-1-yl, 6-methylinden-1-yl, 7-methylinden-1-yl, 2,4-dimethylinden-1-yl Yl, 2,3-dimethylinden-1-yl, 3,4-dimethylinden-1-yl, 2,3,4-trimethylinden-1-yl, 3-methoxymethylinden-1-yl, 4-methoxy Methylinden-1-yl, 3-ethoxymethylinden-1-yl, 4-ethoxymethyl-indene-1
-Yl, 3-dimethylaminomethylinden-1-yl, 4-
Dimethylaminomethylinden-1-yl, indene-2-
Yl, 1-methylindene-2-yl, 3-methylindene-2
-Yl, 4-methylindene-2-yl, 5-methylindene
2-yl, 6-methylinden-2-yl, 7-methylinden-2-yl, 1,4-dimethylinden-2-yl, 1,3-dimethylinden-2-yl, 3,4-dimethyl Inden-2-yl, 1,3,4-trimethylinden-2-yl, 3-methoxymethylinden-2-yl, 4-methoxymethylinden-2-yl
Yl, 3-ethoxymethylinden-2-yl, 4-ethoxymethyl-inden-2-yl, 3-dimethylaminomethylinden-2-yl, 4-dimethylaminomethylindene-2-yl
Il, inden-3-yl, 1-methylinden-3-yl,
2-methylinden-3-yl, 4-methylinden-3-yl, 5-methylinden-3-yl, 6-methylinden-3-yl
Yl, 7-methylinden-3-yl, 2,4-dimethylinden-3-yl, 1,2-dimethylinden-3-yl, 1,4-dimethylinden-3-yl, 1,2,4- Trimethylindene-3-
Yl, 1-methoxymethylindene-3-yl, 4-methoxymethylindene-3-yl, 1-ethoxymethylindene-3
-Yl, 4-ethoxymethyl-inden-3-yl, 1-dimethylaminomethylinden-3-yl, 4-dimethylaminomethylinden-3-yl, inden-4-yl, 1-methylinden-4-yl , 2-methylinden-4-yl, 3-methylinden-4-yl, 5-methylinden-4-yl, 6-methylinden-4-yl, 7-methylinden-4-yl, 1,
2-dimethylindene-4-yl, 1,3-dimethylindene-4
-Yl, 2,3-dimethylinden-4-yl, 1,2,3-trimethylinden-4-yl, 1-methoxymethylindene-4-
Yl, 3-methoxymethylinden-4-yl, 1-ethoxymethylinden-4-yl, 3-ethoxymethyl-indene
-4-yl, 1-dimethylaminomethylinden-4-yl,
3-dimethylaminomethylinden-4-yl, indene-5
-Yl, 1-methylindene-5-yl, 2-methylindene
-5-yl, 3-methylindene-5-yl, 4-methylindene-5-yl, 6-methylindene-5-yl, 7-methylindene-5-yl, 2,4-dimethylindene-5- Yl, 2,3-dimethylindene-5-yl, 3,4-dimethylindene-5-yl, 2,3,4-trimethylindene-5-yl, 3-methoxymethylindene-5-yl, 4-methoxy Methylindene-5-
Yl, 3-ethoxymethylindene-5-yl, 4-ethoxymethyl-indene-5-yl, 3-dimethylaminomethylindene-5-yl, 4-dimethylaminomethylindene-5-yl
Il, inden-6-yl, 1-methylinden-6-yl,
2-methylindene-6-yl, 3-methylindene-6-yl, 4-methylindene-6-yl, 5-methylindene-6-yl
Yl, 7-methylindene-6-yl, 2,4-dimethylindene-6-yl, 2,3-dimethylindene-6-yl, 3,4-dimethylindene-6-yl, 2,3,4- Trimethylindene-6-
Yl, 3-methoxymethylindene-6-yl, 4-methoxymethylindene-6-yl, 3-ethoxymethylindene-6
-Yl, 4-ethoxymethyl-indene-6-yl, 3-dimethylaminomethylindene-6-yl, 4-dimethylaminomethylindene-6-yl, inden-7-yl, 1-methylindene-7-yl , 2-methylinden-7-yl, 3-methylinden-7-yl, 4-methylinden-7-yl, 5-methylinden-7-yl, 6-methylinden-7-yl, 2,
4-dimethylindene-7-yl, 2,3-dimethylindene-7
-Yl, 3,4-dimethylinden-7-yl, 2,3,4-trimethylinden-7-yl, 3-methoxymethylindene-7-
Yl, 4-methoxymethylindene-7-yl, 3-ethoxymethylindene-7-yl, 4-ethoxymethyl-indene
-7-yl, 3-dimethylaminomethylindene-7-yl,
4-dimethylaminomethylindene-7-yl, pyrrole-2
-Yl, 1-methylpyrrole-2-yl, 3-methylpyrrole
2-yl, 4-methylpyrrole-2-yl, 1,4-dimethylpyrrole-2-yl, 1,3-dimethylpyrrole-2-yl, 3,4-
Dimethylpyrrole-2-yl, 1,3,4-trimethylpyrrole
2-yl, 4-methoxymethylpyrrole-2-yl, 5-methoxymethylpyrrole-2-yl, 4-ethoxymethylpyrrole-2-yl, 5-ethoxymethylpyrrole-2-yl, 4-dimethylaminomethyl Pyrrol-2-yl, 5-dimethylaminomethylpyrrole-2-yl, 4-[(piperidin-1-yl)
Methyl] pyrrole-2-yl, 5-[(piperidin-1-yl)
Methyl] pyrrole-2-yl, 4-[(pyrrolidin-1-yl)
Methyl] pyrrole-2-yl, 5-[(pyrrolidin-1-yl)
Methyl] pyrrole-2-yl, 4-[(azepin-1-yl) methyl] pyrrole-2-yl, 5-[(azepin-1-yl) methyl] pyrrole-2-yl, 5-chloromethylpyrrole- 2-yl, 5-dichloromethyl, 5-trichloromethyl, 5-methoxypyrrole-2-yl, 4-methoxypyrrole-2-yl, 5-
Methoxypyrrole-2-yl, 4-methyl-5-methoxypyrrole-2-yl, 4-methyl-5-methoxypyrrole-2-yl, 4-chloropyrrol-2-yl, 5-chloropyrrole-2-yl
Il, pyrrole-3-yl, 1-methylpyrrole-3-yl,
2-methylpyrrole-3-yl, 4-methylpyrrole-3-yl, 1,4-dimethylpyrrole-3-yl, 1,2-dimethylpyrrole-3-yl, 2,4-dimethylpyrrole-3-yl , 1,2,4-
Trimethylpyrrole-3-yl, 4-methoxymethylpyrrole-3-yl, 5-methoxymethylpyrrole-3-yl, 4-ethoxymethylpyrrole-3-yl, 5-ethoxymethylpyrrole-3-yl, 4-dimethyl Aminomethylpyrrole-3-yl, 5-dimethylaminomethylpyrrole-3-yl, 4-[(piperidin-1-yl) methyl] pyrrole-3-yl, 5-[(piperidin-1-yl) methyl] pyrrole -3-yl, 4-[(pyrrolidin-1-yl) methyl] pyrrole-3-yl, 5-[(pyrrolidin-1-yl) methyl] pyrrole-3-yl, 4-[(azepin-1-yl) ) Methyl] pyrrole-3-yl, 5-[(azepin-1-yl) methyl] pyrrole-3-yl, 5-chloromethylpyrrole-3-yl, 5-dichloromethyl, 5-trichloromethyl, 5-methoxy Pyrrole-3-yl, 4-methoxypyrrole-3-yl, 5-methoxypyrrole-3-yl, 4-methyl-5-methoxypyrrole-3 -Yl, 4-methyl-5-methoxypyrrole-3-yl, 4-chloropyrrole-3-yl, 5-chloropyrrole-3-yl, indol-2-yl, 1-methylindol-2-yl, 3 -Methylindole-2-yl, 4-
Methylindol-2-yl, 5-methylindol-2-yl, 6-methylindol-2-yl, 7-methylindole
2-yl, 1,4-dimethylindole-2-yl, 1,3-dimethylindole-2-yl, 3,4-dimethylindole-2-
Yl, 1,3,4-trimethylindol-2-yl, 3-methoxymethylindol-2-yl, 4-methoxymethylindol-2-yl, 3-ethoxymethylindol-2-yl,
4-ethoxymethyl-indole-2-yl, 3-dimethylaminomethylindol-2-yl, 4-dimethylaminomethylindol-2-yl, indol-3-yl, 1-methylindol-3-yl, 2- Methylindol-3-yl, 4-
Methylindol-3-yl, 5-methylindol-3-yl, 6-methylindol-3-yl, 7-methylindole
-3-yl, 2,4-dimethylindole-3-yl, 1,2-dimethylindole-3-yl, 1,4-dimethylindole-3-
Yl, 1,2,4-trimethylindol-3-yl, 1-methoxymethylindol-3-yl, 4-methoxymethylindol-3-yl, 1-ethoxymethylindol-3-yl,
4-ethoxymethyl-indole-3-yl, 1-dimethylaminomethylindol-3-yl, 4-dimethylaminomethylindol-3-yl, indol-4-yl, 1-methylindol-4-yl, 2- Methylindole-4-yl, 3-
Methylindole-4-yl, 5-methylindole-4-yl, 6-methylindole-4-yl, 7-methylindole
-4-yl, 1,2-dimethylindole-4-yl, 1,3-dimethylindole-4-yl, 2,3-dimethylindole-4-yl
Yl, 1,2,3-trimethylindol-4-yl, 1-methoxymethylindol-4-yl, 3-methoxymethylindol-4-yl, 1-ethoxymethylindol-4-yl,
3-ethoxymethyl-indole-4-yl, 1-dimethylaminomethylindol-4-yl, 3-dimethylaminomethylindol-4-yl, indol-5-yl, 1-methylindole-5-yl, 2- Methylindole-5-yl, 3-
Methylindole-5-yl, 4-methylindole-5-yl, 6-methylindole-5-yl, 7-methylindole
-5-yl, 2,4-dimethylindole-5-yl, 2,3-dimethylindole-5-yl, 3,4-dimethylindole-5-
Yl, 2,3,4-trimethylindole-5-yl, 3-methoxymethylindole-5-yl, 4-methoxymethylindole-5-yl, 3-ethoxymethylindole-5-yl,
4-ethoxymethyl-indole-5-yl, 3-dimethylaminomethylindole-5-yl, 4-dimethylaminomethylindole-5-yl, indol-6-yl, 1-methylindole-6-yl, 2- Methylindole-6-yl, 3-
Methylindole-6-yl, 4-methylindole-6-yl, 5-methylindole-6-yl, 7-methylindole
-6-yl, 2,4-dimethylindole-6-yl, 2,3-dimethylindole-6-yl, 3,4-dimethylindole-6-
Yl, 2,3,4-trimethylindole-6-yl, 3-methoxymethylindole-6-yl, 4-methoxymethylindole-6-yl, 3-ethoxymethylindole-6-yl,
4-ethoxymethyl-indole-6-yl, 3-dimethylaminomethylindole-6-yl, 4-dimethylaminomethylindole-6-yl, indol-7-yl, 1-methylindole-7-yl, 2- Methylindole-7-yl, 3-
Methyl indol-7-yl, 4-methyl indol-7-yl, 5-methyl indol-7-yl, 6-methyl indole
-7-yl, 2,4-dimethylindole-7-yl, 2,3-dimethylindole-7-yl, 3,4-dimethylindole-7-
Yl, 2,3,4-trimethylindol-7-yl, 3-methoxymethylindol-7-yl, 4-methoxymethylindol-7-yl, 3-ethoxymethylindol-7-yl, 4
-Ethoxymethyl-indole-7-yl, 3-dimethylaminomethylindol-7-yl, 4-dimethylaminomethylindol-7-yl, benzofuran-2-yl, 3-methylbenzofuran-2-yl, 4-methyl Benzofuran-2-yl, 5-methylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 7-methylbenzofuran-2-yl, 3,4-dimethylbenzofuran-2-yl, 3-methoxymethylbenzofuran- 2-yl, 4-methoxymethylbenzofuran-2-yl, 3-ethoxymethylbenzofuran-2-yl, 4-ethoxymethyl-benzofuran-2-yl, 3-dimethylaminomethylbenzofuran-2-yl, 4-dimethylamino Methylbenzofuran-2-yl, benzofuran-3-yl, 2-methylbenzofuran-3-yl, 4-methylbenzofuran-3-yl, 5-methylbenzofuran-3-yl, 6-methylbenzofuran-3-yl , 7-Methylbenzofuran-3-yl, 2,4-dimethylbenzofuran-3-yl, 2-methoxymethylbenzofuran-3-yl, 4-methoxymethylbenzofuran-3-yl, 2-ethoxymethylbenzofuran-3-yl , 4-ethoxymethyl-benzofuran-3-yl, 2-dimethylaminomethylbenzofuran-3-yl, 4-dimethylaminomethylbenzofuran-3-yl, benzofuran-4-yl, 2-methylbenzofuran-4-yl, 3 -Methylbenzofuran-4-yl, 5-methylbenzofuran-4-yl, 6-methylbenzofuran-4-yl, 7-methylbenzofuran-4-yl, 2,3-dimethylbenzofuran-4-yl, 2-methoxymethyl Benzofuran-4-yl, 3-methoxymethylbenzofuran-4-yl, 2-ethoxymethylbenzofuran-4-yl, 3-ethoxymethyl-benzofuran-4-yl, 2-dimethylaminomethylbenzofuran-4-i , 3-dimethylaminomethylbenzofuran-4-yl, benzofuran-5-yl, 2-methylbenzofuran-5-yl, 3-methylbenzofuran-5-yl, 4-methylbenzofuran-5-yl, 6-methylbenzofuran- 5-yl, 7-methylbenzofuran-5-yl, 2,4-dimethylbenzofuran-5-yl, 2,3-dimethylbenzofuran-5-yl, 3,4-dimethylbenzofuran-5-yl, 2,3,
4-trimethylbenzofuran-5-yl, 3-methoxymethylbenzofuran-5-yl, 4-methoxymethylbenzofuran
-5-yl, 3-ethoxymethylbenzofuran-5-yl, 4-
Ethoxymethyl-benzofuran-5-yl, 3-dimethylaminomethylbenzofuran-5-yl, 4-dimethylaminomethylbenzofuran-5-yl, benzofuran-6-yl, 2-
Methylbenzofuran-6-yl, 3-methylbenzofuran-6
-Yl, 4-methylbenzofuran-6-yl, 5-methylbenzofuran-6-yl, 7-methylbenzofuran-6-yl, 2,
4-dimethylbenzofuran-6-yl, 2,3-dimethylbenzofuran-6-yl, 3,4-dimethylbenzofuran-6-yl,
2,3,4-trimethylbenzofuran-6-yl, 3-methoxymethylbenzofuran-6-yl, 4-methoxymethylbenzofuran-6-yl, 3-ethoxymethylbenzofuran-6-yl, 4-ethoxymethyl-benzofuran- 6-yl, 3-dimethylaminomethylbenzofuran-6-yl, 4-dimethylaminomethylbenzofuran-6-yl, benzofuran-7-yl, 2-methylbenzofuran-7-yl, 3-methylbenzofuran-7-yl, 4-methylbenzofuran-7-yl, 5-methylbenzofuran-7-yl, 6-methylbenzofuran-7-yl, 2,4-dimethylbenzofuran-7-yl, 2,3-dimethylbenzofuran-7-yl, 3 , 4-dimethylbenzofuran-7-
Yl, 2,3,4-trimethylbenzofuran-7-yl, 3-methoxymethylbenzofuran-7-yl, 4-methoxymethylbenzofuran-7-yl, 3-ethoxymethylbenzofuran-7-yl
Yl, 4-ethoxymethyl-benzofuran-7-yl, 3-
Dimethylaminomethylbenzofuran-7-yl, 4-dimethylaminomethylbenzofuran-7-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
4-methylbenzimidazol-2-yl, 5-methylbenzimidazol-2-yl, 6-methylbenzimidazol-2
-Yl, 7-methylbenzimidazol-2-yl, 1,4-dimethylbenzimidazol-2-yl, 4-methoxymethylbenzimidazol-2-yl, 5-methoxymethylbenzimidazol-2-yl, 4-ethoxy Methylbenzimidazol-2-yl, 5-ethoxymethyl-benzimidazol-2-yl, 4-dimethylaminomethylbenzimidazol-2-yl, 5-dimethylaminomethylbenzimidazol-2-yl, benzimidazol-4-yl , 1-methylbenzimidazol-4-yl, 2-methylbenzimidazol-4-yl, 5-methylbenzimidazol-4-yl, 6-
Methylbenzimidazol-4-yl, 7-methylbenzimidazol-4-yl, 1,2-dimethylbenzimidazole
-4-yl, 1-methoxymethylbenzimidazol-4-yl, 5-methoxymethylbenzimidazol-4-yl, 1-
Ethoxymethylbenzimidazol-4-yl, 5-ethoxymethyl-benzimidazol-4-yl, 1-dimethylaminomethylbenzimidazol-4-yl, 5-dimethylaminomethylbenzimidazol-4-yl, benzimidazole-5- Yl, 1-methylbenzimidazole-5-yl, 2-methylbenzimidazole-5-yl, 4-methylbenzimidazole-5-yl, 6-methylbenzimidazole-5-yl, 7-methylbenzimidazole-5-yl Il, 2,
4-dimethylbenzimidazol-5-yl, 1-methoxymethylbenzimidazol-5-yl, 4-methoxymethylbenzimidazol-5-yl, 1-ethoxymethylbenzimidazol-5-yl, 4-ethoxymethyl-benzimidazole -5-yl, 1-dimethylaminomethylbenzimidazol-5-yl, 4-dimethylaminomethylbenzimidazol-5-yl, benzothiazol-2-yl, 3-methylbenzothiazol-2-yl, 4-methylbenzo Thiazole
2-yl, 5-methylbenzothiazol-2-yl, 6-methylbenzothiazol-2-yl, 7-methylbenzothiazol-2-yl, 4-methoxymethylbenzothiazol-2-yl, 5-methoxymethyl Benzothiazol-2-yl, 4-ethoxymethylbenzothiazol-2-yl, 5-ethoxymethyl-benzothiazol-2-yl, 4-dimethylaminomethylbenzothiazol-2-yl, 5-dimethylaminomethylbenzothiazole- 2-yl, benzothiazol-4-yl, 2-methylbenzothiazol-4-yl, 3-methylbenzothiazol-4-yl, 5-methylbenzothiazol-4-
Yl, 6-methylbenzothiazol-4-yl, 7-methylbenzothiazol-4-yl, 2-methoxymethylbenzothiazol-4-yl, 2-ethoxymethylbenzothiazole-4
-Yl, 2-dimethylaminomethylbenzothiazole-4-
Yl, benzothiazol-5-yl, 2-methylbenzothiazol-5-yl, 4-methylbenzothiazol-5-yl,
6-methylbenzothiazol-5-yl, 7-methylbenzothiazol-5-yl, 2,4-dimethylbenzothiazol-5-yl
Yl, 2-methoxymethylbenzothiazol-5-yl, 4-
Methoxymethylbenzothiazol-5-yl, 2-ethoxymethylbenzothiazol-5-yl, 4-ethoxymethyl-
Benzothiazol-5-yl, 3-dimethylaminomethylbenzothiazol-5-yl, 4-dimethylaminomethylbenzothiazol-5-yl, benzothiazol-6-yl, 2-
Methylbenzothiazol-6-yl, 4-methylbenzothiazol-6-yl, 5-methylbenzothiazol-6-yl,
7-methylbenzothiazol-6-yl, 2,4-dimethylbenzothiazol-6-yl, 2-methoxymethylbenzothiazol-6-yl, 4-methoxymethylbenzothiazol-6-yl
Yl, 2-ethoxymethylbenzothiazol-6-yl, 4-
Ethoxymethyl-benzothiazol-6-yl, 2-dimethylaminomethylbenzothiazol-6-yl, 4-dimethylaminomethylbenzothiazol-6-yl, benzothiazol-7-yl, 1-methylbenzothiazol-7-yl , 2-
Methylbenzothiazol-7-yl, 3-methylbenzothiazol-7-yl, 4-methylbenzothiazol-7-yl,
5-methylbenzothiazol-7-yl, 6-methylbenzothiazol-7-yl, 2,4-dimethylbenzothiazole-7-yl
Yl, 2,3-dimethylbenzothiazol-7-yl, 3,4-dimethylbenzothiazol-7-yl, 2,3,4-trimethylbenzothiazol-7-yl, 3-methoxymethylbenzothiazol-7-yl , 4-methoxymethylbenzothiazole-7
-Yl, 3-ethoxymethylbenzothiazol-7-yl,
4-ethoxymethyl-benzothiazol-7-yl, 3-dimethylaminomethylbenzothiazol-7-yl, 4-dimethylaminomethylbenzothiazol-7-yl,

(B) Furan-2-yl, 3-methylfuran-2
-Yl, 4-methylfuran-2-yl, 5-methylfuran-2-
Yl, 3,4-dimethylfuran-2-yl, 3,5-dimethylfuran-2-yl, 4,5-dimethylfuran-2-yl, 3,4,5-trimethylfuran-2-yl, 4- Methoxymethylfuran-2-yl, 5-methoxymethylfuran-2-yl, 4-ethoxymethylfuran-2-yl, 5-ethoxymethylfuran-2-yl,
4-dimethylaminomethylfuran-2-yl, 5-dimethylaminomethylfuran-2-yl, 4-[(piperidin-1-yl)
Methyl] furan-2-yl, 5-[(piperidin-1-yl) methyl] furan-2-yl, 4-[(pyrrolidin-1-yl) methyl] furan-2-yl, 5-[(pyrrolidin-yl) 1-yl) methyl]
Furan-2-yl, 4-[(azepin-1-yl) methyl] furan-2-yl, 5-[(azepin-1-yl) methyl] furan
2-yl, 4-chloromethylfuran-2-yl, 5-chloromethylfuran-2-yl, 4-dichloromethylfuran-2-yl, 5-dichloromethylfuran-2-yl, 4-trichloromethylfuran 2-yl, 5-trichloromethylfuran-2-yl, 3-methoxyfuran-2-yl, 4-methoxyfuran-2-yl
Yl, 5-methoxyfuran-2-yl, 4-methyl-5-methoxyfuran-2-yl, 5-methyl-4-methoxyfuran-2-yl, 5-phenoxyfuran-2-yl, 5- (furan -2-yloxy) furan-2-yl, 4-dimethylaminofuran-2-
Yl, 5-dimethylaminofuran-2-yl, 4- (piperidin-1-yl) furan-2-yl, 5- (piperidin-1-yl) furan-2-yl, 4- (pyrrolidin-1-yl) ) Franc
2-yl, 5- (pyrrolidin-1-yl) furan-2-yl,
4- (azepin-1-yl) furan-2-yl, 5- (azepine
-1-yl) furan-2-yl, 4-methanesulfonylaminofuran-2-yl, 5-methanesulfonylaminofuran-2-yl
Yl, 4- (4-toluenesulfonylamino) furan-2-yl, 5- (4-toluenesulfonylamino) furan-2-yl, 4- (2-nitrobenzenesulfonylamino) furan-2
-Yl, 5- (2-nitrobenzenesulfonylamino) furan-2-yl, 5-fluorofuran-2-yl, 5-chlorofuran-2-yl, 5-bromofuran-2-yl, 5-nitrofuran
-2-yl, furan-3-yl, 2-methylfuran-3-yl,
4-methylfuran-3-yl, 5-methylfuran-3-yl, 2,
4-dimethylfuran-3-yl, 2,5-dimethylfuran-3-yl, 4,5-dimethylfuran-3-yl, 2,4,5-trimethylfuran-3-yl, 4-methoxymethylfuran- 3-yl, 5-methoxymethylfuran-3-yl, 4-ethoxymethylfuran
-3-yl, 5-ethoxymethylfuran-3-yl, 4-dimethylaminomethylfuran-3-yl, 5-dimethylaminomethylfuran-3-yl, 4-[(piperidin-1-yl) methyl]
Furan-3-yl, 5-[(piperidin-1-yl) methyl] furan-3-yl, 4-[(pyrrolidin-1-yl) methyl] furan-3-yl, 5-[(pyrrolidin-1- Yl) methyl] furan-
3-yl, 4-[(azepin-1-yl) methyl] furan-3-
Yl, 5-[(azepin-1-yl) methyl] furan-3-yl, 4-chloromethylfuran-3-yl, 5-chloromethylfuran-3-yl, 4-dichloromethylfuran-3-yl, 5-dichloromethylfuran-3-yl, 4-trichloromethylfuran-3-yl, 5-trichloromethylfuran-3-yl, 3-methoxyfuran-3-yl, 4-methoxyfuran-3-yl, 5-
Methoxyfuran-3-yl, 4-methyl-5-methoxyfuran
-3-yl, 5-methyl-4-methoxyfuran-3-yl, 5-phenoxyfuran-3-yl, 5- (furan-2-yloxy)
Furan-3-yl, 4-dimethylaminofuran-3-yl, 5-
Dimethylaminofuran-3-yl, 4- (piperidin-1-yl) furan-3-yl, 5- (piperidin-1-yl) furan
-3-yl, 4- (pyrrolidin-1-yl) furan-3-yl,
5- (pyrrolidin-1-yl) furan-3-yl, 4- (azepin-1-yl) furan-3-yl, 5- (azepin-1-yl)
Furan-3-yl, 4-methanesulfonylaminofuran-3-
Yl, 5-methanesulfonylaminofuran-3-yl, 4- (4
-Toluenesulfonylamino) furan-3-yl, 5- (4-
Toluenesulfonylamino) furan-3-yl, 4- (2-nitrobenzenesulfonylamino) furan-3-yl, 5- (2
-Nitrobenzenesulfonylamino) furan-3-yl,
5-fluorofuran-3-yl, 5-chlorofuran-3-yl,
5-bromofuran-3-yl, 5-nitrofuran-3-yl, thiophen-2-yl, 3-methylthiophen-2-yl, 4-methylthiophen-2-yl, 5-methylthiophen-2-yl, 3,4-dimethylthiophen-2-yl, 3,5-dimethylthiophen-2-yl, 4,5-dimethylthiophen-2-yl,
3,4,5-trimethylthiophen-2-yl, 4-methoxymethylthiophen-2-yl, 5-methoxymethylthiophen-2
-Yl, 4-ethoxymethylthiophen-2-yl, 5-ethoxymethylthiophen-2-yl, 4-dimethylaminomethylthiophen-2-yl, 5-dimethylaminomethylthiophen-2-yl, 4-[(piperidine -1-yl) methyl] thiophen-2-yl, 5-[(piperidin-1-yl) methyl] thiophen-2-yl, 4-[(pyrrolidin-1-yl) methyl]
Thiophene-2-yl, 5-[(pyrrolidin-1-yl) methyl] thiophen-2-yl, 4-[(azepin-1-yl) methyl] thiophen-2-yl, 5-[(azepin-1- Yl) methyl] thiophen-2-yl, 4-chloromethylthiophene-2
-Yl, 5-chloromethylthiophen-2-yl, 4-dichloromethylthiophen-2-yl, 5-dichloromethylthiophen-2-yl, 4-trichloromethylthiophen-2-yl, 5-trichloromethylthiophen-2 -Yl, 3-methoxythiophen-2-yl, 4-methoxythiophen-2-yl, 5-methoxythiophen-2-yl, 4-methyl-5-methoxythiophen-2-yl, 5-methyl-4-methoxy Thiophen-2-yl, 5-phenoxythiophen-2-yl, 5- (
Furan-2-yloxy) thiophen-2-yl, 4-dimethylaminothiophen-2-yl, 5-dimethylaminothiophen-2-yl, 4- (piperidin-1-yl) thiophen-2
-Yl, 5- (piperidin-1-yl) thiophen-2-yl, 4- (pyrrolidin-1-yl) thiophen-2-yl, 5-
(Pyrrolidine-1-yl) thiophen-2-yl, 4- (azepin-1-yl) thiophen-2-yl, 5- (azepin-1-yl)
Yl) thiophen-2-yl, 4-methanesulfonylaminothiophen-2-yl, 5-methanesulfonylaminothiophen-2-yl, 4- (4-toluenesulfonylamino) thiophen-2-yl, 5- (4- Toluenesulfonylamino) thiophen-2-yl, 4- (2-nitrobenzenesulfonylamino) thiophen-2-yl, 5- (2-nitrobenzenesulfonylamino) thiophen-2-yl, 5-fluorothiophen-2-yl, 5 -Chlorothiophen-2-yl, 5-bromothiophen-2-yl, 5-nitrothiophen-2-yl, thiophen-3-yl, 2-methylthiophen-3-yl, 4-methylthiophen-3-yl, 5-methylthiophen-3-yl, 2,4-dimethylthiophen-3-yl, 2,5-dimethylthiophen-3-yl, 4,5-dimethylthiophen-3-yl,
2,4,5-trimethylthiophen-3-yl, 4-methoxymethylthiophen-3-yl, 5-methoxymethylthiophen-3
-Yl, 4-ethoxymethylthiophen-3-yl, 5-ethoxymethylthiophen-3-yl, 4-dimethylaminomethylthiophen-3-yl, 5-dimethylaminomethylthiophen-3-yl, 4-[(piperidine 1-yl) methyl] thiophen-3-yl, 5-[(piperidin-1-yl) methyl] thiophen-3-yl, 4-[(pyrrolidin-1-yl) methyl]
Thiophen-3-yl, 5-[(pyrrolidin-1-yl) methyl] thiophen-3-yl, 4-[(azepin-1-yl) methyl] thiophen-3-yl, 5-[(azepin-1- Yl) methyl] thiophen-3-yl, 4-chloromethylthiophene-3
-Yl, 5-chloromethylthiophen-3-yl, 4-dichloromethylthiophen-3-yl, 5-dichloromethylthiophen-3-yl, 4-trichloromethylthiophen-3-yl, 5-trichloromethylthiophen-3 -Yl, 3-methoxythiophen-3-yl, 4-methoxythiophen-3-yl, 5-methoxythiophen-3-yl, 4-methyl-5-methoxythiophen-3-yl, 5-methyl-4-methoxy Thiophen-3-yl, 5-phenoxythiophen-3-yl, 5- (
Furan-2-yloxy) thiophen-3-yl, 4-dimethylaminothiophen-3-yl, 5-dimethylaminothiophen-3-yl, 4- (piperidin-1-yl) thiophen-3
-Yl, 5- (piperidin-1-yl) thiophen-3-yl, 4- (pyrrolidin-1-yl) thiophen-3-yl, 5-
(Pyrrolidin-1-yl) thiophen-3-yl, 4- (azepin-1-yl) thiophen-3-yl, 5- (azepin-1-yl)
Yl) thiophen-3-yl, 4-methanesulfonylaminothiophen-3-yl, 5-methanesulfonylaminothiophen-3-yl, 4- (4-toluenesulfonylamino) thiophen-3-yl, 5- (4- Toluenesulfonylamino) thiophen-3-yl, 4- (2-nitrobenzenesulfonylamino) thiophen-3-yl, 5- (2-nitrobenzenesulfonylamino) thiophen-3-yl, 5-fluorothiophen-3-yl, 5 -Chlorothiophen-3-yl, 5-bromothiophen-3-yl, 5-nitrothiophen-3-yl,

(C) Thiazol-2-yl, 4-methylthiazol-2-yl, 5-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 4-methoxymethylthiazol-2-yl , 5-methoxymethylthiazol-2-yl, 4-
Ethoxymethylthiazol-2-yl, 5-ethoxymethylthiazol-2-yl, 4-dimethylaminomethylthiazol-2-yl, 5-dimethylaminomethylthiazol-2-yl, 4-[(piperidin-1-yl) Methyl] thiazole-2-
Yl, 5-[(piperidin-1-yl) methyl] thiazole-2
-Yl, 4-[(pyrrolidin-1-yl) methyl] thiazole
2-yl, 5-[(pyrrolidin-1-yl) methyl] thiazol-2-yl, 4-[(azepin-1-yl) methyl] thiazol-2-yl, 5-[(azepin-1-yl) ) Methyl] thiazol-2-yl, 4-chloromethylthiazol-2-yl, 5-chloromethylthiazol-2-yl, 4-dichloromethylthiazol-2-yl, 5-dichloromethylthiazol-2-yl, 4 -Trichloromethylthiazol-2-yl, 5-trichloromethylthiazol-2-yl, 4-methoxythiazole
2-yl, 5-methoxythiazol-2-yl, 4-methyl-5
-Methoxythiazol-2-yl, 5-methyl-4-methoxythiazol-2-yl, 5-phenoxythiazol-2-yl, 5- (furan-2-yloxy) thiazol-2-yl,
4-dimethylaminothiazol-2-yl, 5-dimethylaminothiazol-2-yl, 4- (piperidin-1-yl) thiazol-2-yl, 5- (piperidin-1-yl) thiazole-
2-yl, 4- (pyrrolidin-1-yl) thiazol-2-yl, 5- (pyrrolidin-1-yl) thiazol-2-yl, 4-
(Azepin-1-yl) thiazol-2-yl, 5- (azepin-1-yl) thiazol-2-yl, 4-methanesulfonylaminothiazol-2-yl, 5-methanesulfonylaminothiazol-2-yl, 4- (4-toluenesulfonylamino) thiazol-2-yl, 5- (4-toluenesulfonylamino) thiazol-2-yl, 4- (2-nitrobenzenesulfonylamino) thiazol-2-yl, 5- (2- Nitrobenzenesulfonylamino) thiazol-2-yl, 5-fluorothiazol-2-yl, 5-chlorothiazol-2-yl,
5-bromothiazol-2-yl, 5-nitrothiazol-2-
Yl, thiazol-4-yl, 2-methylthiazol-4-yl, 5-methylthiazol-4-yl, 2,5-dimethylthiazol-4-yl, 2-methoxymethylthiazol-4-yl,
5-methoxymethylthiazol-4-yl, 2-ethoxymethylthiazol-4-yl, 5-ethoxymethylthiazol-4
-Yl, 2-dimethylaminomethylthiazol-4-yl,
5-dimethylaminomethylthiazol-4-yl, 2-[(piperidin-1-yl) methyl] thiazol-4-yl, 5-[(piperidin-1-yl) methyl] thiazol-4-yl, 2-
[(Pyrrolidin-1-yl) methyl] thiazol-4-yl,
5-[(pyrrolidin-1-yl) methyl] thiazol-4-yl, 2-[(azepin-1-yl) methyl] thiazol-4-yl, 5-[(azepin-1-yl) methyl] thiazole- 4-yl, 2-chloromethylthiazol-4-yl, 5-chloromethylthiazol-4-yl, 2-dichloromethylthiazol-4
-Yl, 5-dichloromethylthiazol-4-yl, 2-trichloromethylthiazol-4-yl, 5-trichloromethylthiazol-4-yl, 2-methoxythiazol-4-yl,
5-methoxythiazol-4-yl, 2-methyl-5-methoxythiazol-4-yl, 5-methyl-2-methoxythiazole
-4-yl, 5-phenoxythiazol-4-yl, 5- (furan-4-yloxy) thiazol-4-yl, 2-dimethylaminothiazol-4-yl, 5-dimethylaminothiazole
-4-yl, 2- (piperidin-1-yl) thiazol-4-yl, 5- (piperidin-1-yl) thiazol-4-yl, 2-
(Pyrrolidin-1-yl) thiazol-4-yl, 5- (pyrrolidin-1-yl) thiazol-4-yl, 2- (azepin-1-yl)
Il) Thiazol-4-yl, 5- (azepin-1-yl)
Thiazol-4-yl, 2-methanesulfonylaminothiazol-4-yl, 5-methanesulfonylaminothiazole-4
-Yl, 2- (4-toluenesulfonylamino) thiazole
-4-yl, 5- (4-toluenesulfonylamino) thiazol-4-yl, 2- (2-nitrobenzenesulfonylamino)
Thiazol-4-yl, 5- (2-nitrobenzenesulfonylamino) thiazol-4-yl, 5-fluorothiazole-4
-Yl, 5-chlorothiazol-4-yl, 5-bromothiazol-4-yl, 5-nitrothiazol-4-yl, thiazol-5-yl, 2-methylthiazol-5-yl, 4-methylthiazol- 5-yl, 2,4-dimethylthiazol-5-yl,
2-methoxymethylthiazol-5-yl, 4-methoxymethylthiazol-5-yl, 2-ethoxymethylthiazole-5
-Yl, 4-ethoxymethylthiazol-5-yl, 2-dimethylaminomethylthiazol-5-yl, 4-dimethylaminomethylthiazol-5-yl, 2-[(piperidin-1-yl) methyl] thiazole-5 -Yl, 4-[(piperidine-1-
Yl) methyl] thiazol-5-yl, 2-[(pyrrolidine-1-
Yl) methyl] thiazol-5-yl, 4-[(pyrrolidine-
1-yl) methyl] thiazol-5-yl, 2-[(azepine-
1-yl) methyl] thiazol-5-yl, 4-[(azepine-
1-yl) methyl] thiazol-5-yl, 2-chloromethylthiazol-5-yl, 4-chloromethylthiazole-5-
Yl, 2-dichloromethylthiazol-5-yl, 4-dichloromethylthiazol-5-yl, 2-trichloromethylthiazol-5-yl, 4-trichloromethylthiazol-5-yl, 2-methoxythiazol-5-yl , 4-methoxythiazol-5-yl, 2-methyl-4-methoxythiazol-5-yl, 4-methyl-2-methoxythiazol-5-yl, 4-phenoxythiazol-5-yl, 4- (furan- 5-yloxy) thiazol-5-yl, 2-dimethylaminothiazole
-5-yl, 4-dimethylaminothiazol-5-yl, 2-
(Piperidin-1-yl) thiazol-5-yl, 4- (piperidin-1-yl) thiazol-5-yl, 2- (pyrrolidine
-1-yl) thiazol-5-yl, 4- (pyrrolidin-1-yl) thiazol-5-yl, 2- (azepin-1-yl) thiazol-5-yl, 4- (azepin-1-yl) Thiazole-5
-Yl, 2-methanesulfonylaminothiazol-5-yl, 4-methanesulfonylaminothiazol-5-yl, 2-
(4-toluenesulfonylamino) thiazol-5-yl,
4- (4-toluenesulfonylamino) thiazol-5-yl, 2- (2-nitrobenzenesulfonylamino) thiazol-5-yl, 4- (2-nitrobenzenesulfonylamino)
Thiazol-5-yl, 4-fluorothiazol-5-yl,
4-chlorothiazol-5-yl, 4-bromothiazole-5-
Yl or 4-nitrothiazol-5-yl.

In the compounds represented by the general formulas (1) and (2), the optionally substituted alkyl group for R ¹ includes, for example, methyl group, ethyl group, n-propyl group, i-propyl Group, butyl group, pentyl group, hexyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, trifluoromethyl group, methoxymethyl group, methoxyethoxymethyl group, methoxypropyl group, etc. Examples of the optionally substituted phenyl group include a phenyl group, an o-, m-, p-tolyl group, an o-, m-, p-methoxyphenyl group, an o-,
m-, p-chlorophenyl group, p-nitrophenyl group and the like.

In the compounds represented by the general formulas (1) and (2), R ² represents a carboxylic acid protecting group, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group. Alkyl groups having 1 to 6 carbon atoms, such as benzyl group, naphthylmethyl group, etc.
1 aralkyl group; and an aromatic group having 6 to 10 carbon atoms such as a phenyl group, a tolyl group, and a naphthyl group.

Specific examples of the 3-aromatic alanine derivative (1) include, for example, 2-acetylamino-3- (5-methylfuran-2)
-Yl) methyl propanoate, 2-acetylamino-3- (5-ethylfuran-2-yl) ethyl propanoate, 2-benzoylamino-3- (5-methylfuran-2-yl) methyl propanoate, 2 -Benzoylamino-3- (furan-2-yl) methyl propanoate, 2-benzoylamino-3- (5-chlorofuran-2-
Yl) Methyl propanoate, 2-benzoylamino-3- (5-bromofuran-2-yl) methyl propanoate, 2-acetylamino-3- (5-methylthiophen-2-yl) methyl propanoate, 2-acetyl Ethyl amino-3- (5-ethylthiophen-2-yl) propanoate, 2-benzoylamino-3- (5-methylthiophen-2-yl) methyl propanoate, 2-benzoylamino-3- (thiophen-2 -Yl) methyl propanoate,
2-benzoylamino-3- (5-chlorothiophen-2-yl)
Racemic and optically active forms such as methyl propanoate and methyl 2-benzoylamino-3- (5-bromothiophen-2-yl) propanoate are exemplified.

The 3-aromatic alanine derivative (1) is
It can be synthesized according to the method described in Tetrahedron Asymmetry, 4, 1833 (1993).

The optically active oxazoline compound (2) of the present invention is prepared by reacting the corresponding 3-aromatic alanine derivative (1) with a ceric salt or persulfate in the presence or absence of a copper catalyst. It can be manufactured by the following.

The cerium salt includes, for example, ceric ammonium nitrate, ceric hydroxide, ceric sulfate, ceric ammonium sulfate and the like. The amount of the second cerium salt to be used is generally 1 to 6 times, preferably 2 to 5 times, the molar amount of the 3-aromatic alanine derivative (1). In addition, by allowing the copper catalyst to coexist with the second cerium salt, the reaction can proceed more efficiently.

Examples of the persulfate include sodium persulfate, potassium persulfate, and ammonium persulfate. The amount of the persulfate to be used is generally 1 to 6 moles, preferably 2 to 5 moles per mole of the 3-aromatic alanine derivative (1).
It is molar times. In addition, by allowing the copper catalyst to coexist with the persulfate, the reaction can proceed more efficiently.

The copper catalyst used in combination with the second cerium salt or persulfate includes, for example, cuprous chloride, cupric chloride, copper acetate, copper sulfate, copper hydroxide and the like. Its usage is
Usually 0.01 to 3-aromatic alanine derivative (1)
To 100 mol%, preferably 0.1 to 50 mol%.

The reaction for obtaining oxazolines from the 3-aromatic alanine derivative (1) is usually carried out in the presence of a solvent. Halogenated hydrocarbons such as chloroform, carbon tetrachloride, and monochlorobenzene; ketones such as acetone and methyl ethyl ketone; esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile; ethers such as tetrahydrofuran and dioxane , Acetic acid, organic acids such as propanoic acid, water, carbon disulfide, and mixtures thereof. The amount used is not particularly limited.

The reaction temperature is usually -30 to 100 ° C., preferably -20 to 50 ° C. when a ceric salt is used, and usually 20 to 130 ° C., preferably 50 to 100 ° C. when a persulfate is used. ° C. The reaction time is not particularly limited, and the end point can be the disappearance of the raw material compound (1) or the stop of the reduction.

After completion of the reaction, if necessary, the remaining cerium salt or the like is deactivated with sodium thiosulfate or hydroquinone, and then the reaction solution is poured into water, and the organic layer is separated or toluene, ethyl acetate, diethyl ether or the like is removed. , Extracted with a normal extraction solvent such as dichloromethane,
The organic layer is separated and concentrated to obtain the oxazoline compound (2) of the present invention. If necessary, purification can be carried out by a conventional method such as column chromatography or recrystallization.

Specific examples of the racemic or optically active oxazoline compound (2) obtained by the production method of the present invention include 5-
Methyl phenyl-2-methyl-2-oxazoline-4-carboxylate, methyl 5- (4-methylphenyl) -2-methyl-2-oxazoline-4-carboxylate, 5- (4-methoxyphenyl) -2-
Methyl methyl 2-oxazoline-4-carboxylate, methyl 2,5-diphenyl-2-oxazoline-4-carboxylate, 5- (4
-Methylphenyl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (4-methoxyphenyl) -2-phenyl
Methyl-2-oxazoline-4-carboxylate, 5-phenyl-2
-Ethyl methyl-2-oxazoline-4-carboxylate, 5- (4
-Methylphenyl) -2-methyl-2-oxazoline-4-carboxylate, 5- (4-methoxyphenyl) -2-methyl-2-
Oxazoline-4-ethyl carboxylate, 2,5-diphenyl-2
-Ethyl oxazoline-4-carboxylate, 5- (4-methylphenyl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (4-methoxyphenyl) -2-phenyl-2-oxazoline-4 -Ethyl carboxylate, 5-phenyl-2-methyl-2
-Benzyl oxazoline-4-carboxylate, 5- (4-methylphenyl) -2-methyl-2-oxazoline-4-carboxylate, 5- (4-methoxyphenyl) -2-methyl-2-oxazoline-4 -Benzyl carboxylate, benzyl 2,5-diphenyl-2-oxazoline-4-carboxylate, benzyl 5- (4-methylphenyl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (4-methoxy Phenyl) -2-phenyl-2-oxazoline-4-benzyl carboxylate, 5- (1-methylpyrrole
-2-yl) -2-methyl-2-oxazoline-4-methyl carboxylate, 5- (1,5-dimethylpyrrol-2-yl) -2-methyl-2
-Methyl oxazoline-4-carboxylate, 5- (5-bromo-1
-Methylpyrrole-2-yl) -2-methyl-2-oxazoline
Methyl -4-carboxylate, 5- (1-methylpyrrol-2-yl) -2-phenyl-2-oxazoline-4-methyl carboxylate, 5- (1,5-dimethylpyrrol-2-yl) -2 -Phenyl-2
-Methyl oxazoline-4-carboxylate, 5- (5-bromo-1
-Methyl pyrrol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, ethyl 5- (1-methylpyrrol-2-yl) -2-methyl-2-oxazoline-4-carboxylate,
Ethyl 5- (1,5-dimethylpyrrol-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-bromo-1-methylpyrrol-2-yl) -2-methyl- Ethyl 2-oxazoline-4-carboxylate, ethyl 5- (1-methylpyrrol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (1,5
-Dimethylpyrrole-2-yl) -2-phenyl-2-oxazoline-4-ethyl carboxylate, 5- (5-bromo-1-methylpyrrol-2-yl) -2-phenyl-2-oxazoline-4- Ethyl carboxylate, 5- (1-methylpyrrol-2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (1,5-
Dimethylpyrrole-2-yl) -2-methyl-2-oxazoline
Benzyl-4-carboxylate, 5- (5-bromo-1-methylpyrrole-2-yl) -2-methyl-2-oxazoline-4-benzylcarboxylate, 5- (1-methylpyrrole-2-yl) Benzyl-2-phenyl-2-oxazoline-4-carboxylate, 5- (1,5-
Benzyl dimethylpyrrole-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (5-bromo-1-methylpyrrol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate Benzyl, 5- (1-methylindol-2-yl) -2-
Methyl-2-oxazoline-4-carboxylate, 5- (5-
Methyl bromo-1-methylindol-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (1-methylindol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate Methyl, 5- (5-bromo-1-methylindol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, methyl 5- (1-methylindol-2-yl) -2-methyl Benzyl-2-oxazoline-4-carboxylate, 5- (5-bromo-1-
Methylindole-2-yl) -2-methyl-2-oxazoline
-4-benzyl carboxylate, 5- (1-methylindole-2-
Yl) -2-phenyl-2-oxazoline-4-benzyl carboxylate, 5- (5-bromo-1-methylindole-2-yl) -2-
Benzyl phenyl-2-oxazoline-4-carboxylate, 5-
(Benzofuran-2-yl) -2-methyl-2-oxazoline-4
-Methyl carboxylate, methyl 5- (5-bromobenzofuran-2-yl) -2-methyl-2-oxazoline-4-carboxylate,
Methyl 5- (benzofuran-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (5-bromobenzofuran-2
-Yl) -2-phenyl-2-oxazoline-4-carboxylate methyl, 5- (benzofuran-2-yl) -2-methyl-2-oxazoline-4-carboxylate benzyl, 5- (5-bromobenzofuran- 2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (benzofuran-2-yl) -2-phenyl-2
-Benzyl oxazoline-4-carboxylate, 5- (5-bromobenzofuran-2-yl) -2-phenyl-2-oxazoline-4
-Benzyl carboxylate, 5- (1-methylbenzimidazol-2-yl) -2-methyl-2-oxazoline-4-methyl carboxylate, 5- (5-bromo-1-methylbenzimidazole-2
-Yl) -2-methyl-2-oxazoline-4-carboxylate methyl, 5- (1-methylbenzimidazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate methyl, 5- (5 -Methyl bromo-1-methylbenzimidazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (1-methylbenzimidazol-2-yl) -2-methyl-2-oxazoline- Benzyl 4-carboxylate, 5- (5-bromo-1-methylbenzimidazol-2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (1-methylbenzimidazol-2-yl Benzyl) -2-phenyl-2-oxazoline-4-carboxylate, benzyl 5- (5-bromo-1-methylbenzimidazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- Methyl (benzothiazol-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-bromobenzothiazol-2-yl) -2- Methyl-2-oxazoline-4-carboxylate, 5- (benzothiazole-2-
Yl) -2-phenyl-2-oxazoline-4-carboxylate methyl, 5- (5-bromobenzothiazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate methyl, 5- (benzothiazole -2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (5-bromobenzothiazole-2-
Benzyl) -2-methyl-2-oxazoline-4-carboxylate, benzyl 5- (benzothiazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (5-bromobenzothiazole -2-yl) -2-phenyl-2-oxazoline-4-
Benzyl carboxylate, 5- (5-methylfuran-2-yl) -2
-Methyl-2-oxazoline-4-carboxylate, 5- (5-
(Ethylfuran-2-yl) -2-methyl-2-oxazoline-4-
Methyl carboxylate, 5- (5-methylfuran-2-yl) -2-
Methyl phenyl-2-oxazoline-4-carboxylate, 5- (
Methyl furan-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- {5-[(azepin-1-yl) methyl] -furan-2-yl} -2-phenyl-2- Methyl oxazoline-4-carboxylate, 5- (5-chlorofuran-2-yl) -2-methyl
Methyl 2-oxazoline-4-carboxylate, 5- (5-bromofuran-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-chloromethylfuran-2-yl) Methyl 2-methyl-2-oxazoline-4-carboxylate, 5- (5-nitromethylfuran-2-yl) -2-methyl-2-oxazoline
-4-Methyl carboxylate, 5- (5-methylfuran-2-yl)-
Ethyl 2-methyl-2-oxazoline-4-carboxylate, 5- (5
-Ethylfuran-2-yl) -2-methyl-2-oxazoline-4
-Ethyl carboxylate, 5- (5-methylfuran-2-yl) -2-
Ethyl phenyl-2-oxazoline-4-carboxylate, 5- (
Ethyl furan-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- {5-[(azepin-1-yl) methyl] -furan-2-yl} -2-phenyl-2- Ethyl oxazoline-4-carboxylate, 5- (5-chlorofuran-2-yl) -2-methyl
Ethyl-2-oxazoline-4-carboxylate, 5- (5-bromofuran-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-chloromethylfuran-2-yl) Ethyl 2-methyl-2-oxazoline-4-carboxylate, 5- (5-nitromethylfuran-2-yl) -2-methyl-2-oxazoline
-4-Ethyl carboxylate, 5- (5-methylfuran-2-yl)-
Benzyl 2-methyl-2-oxazoline-4-carboxylate, 5-
(5-Ethylfuran-2-yl) -2-methyl-2-oxazoline
Benzyl-4-carboxylate, 5- (5-methylfuran-2-yl) -2-phenyl-2-oxazoline-4-benzylcarboxylate, 5- (furan-2-yl) -2-phenyl-2- Oxazoline
-4-benzyl carboxylate, 5- ｛5-[(azepin-1-yl)
Methyl] -furan-2-yl｝ -2-phenyl-2-oxazoline-4-carboxylate benzyl, 5- (5-chlorofuran-2-yl) -2-methyl-2-oxazoline-4-carboxylate benzyl Benzyl, 5- (5-bromofuran-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-chloromethylfuran-2-yl) -2-methyl-2-oxazoline-4 -Benzyl carboxylate, 5- (5-nitromethylfuran-2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (5-
Methylthiophen-2-yl) -2-methyl-2-oxazoline
Methyl-4-carboxylate, 5- (5-ethylthiophen-2-yl) -2-methyl-2-oxazoline-4-methylcarboxylate,
Methyl 5- (5-methylthiophen-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, methyl 5- (thiophen-2-yl) -2-phenyl-2-oxazoline-4-carboxylate , 5- ｛5-[(azepin-1-yl) methyl] -thiophene-2
-Methyl yl-2-phenyl-2-oxazoline-4-carboxylate, 5- (5-chlorothiophen-2-yl) -2-methyl-2-
Methyl oxazoline-4-carboxylate, 5- (5-bromothiophen-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-chloromethylthiophen-2-yl) -2 -Methyl-2-oxazoline-4-carboxylate, 5
-(5-nitromethylthiophen-2-yl) -2-methyl-2-
Methyl oxazoline-4-carboxylate, 5- (5-methylthiophen-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-ethylthiophen-2-yl) -2- Ethyl methyl-2-oxazoline-4-carboxylate, 5- (5-methylthiophen-2-yl) -2-phenyl-2-oxazoline-4
-Ethyl carboxylate, 5- (thiophen-2-yl) -2-phenyl-2-oxazoline-4-ethyl carboxylate, 5- ｛5-
[(Azepin-1-yl) methyl] -thiophen-2-yl｝ -2
-Ethyl phenyl-2-oxazoline-4-carboxylate, 5-
Ethyl (5-chlorothiophen-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-bromothiophen-2
-Yl) -2-methyl-2-oxazoline-4-ethyl carboxylate, 5- (5-chloromethylthiophen-2-yl) -2-methyl
Ethyl-2-oxazoline-4-carboxylate, 5- (5-nitromethylthiophen-2-yl) -2-methyl-2-oxazoline
Ethyl -4-carboxylate, 5- (5-methylthiophen-2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (5-ethylthiophen-2-yl) -2-methyl Benzyl-2-oxazoline-4-carboxylate, 5- (5-methylthiophen-2-yl) -2-phenyl-2-oxazoline-4-benzyl carboxylate, 5- (thiophen-2-yl) -2- Phenyl
Benzyl-2-oxazoline-4-carboxylate, 5- ｛5-[(azepin-1-yl) methyl] -thiophen-2-yl｝ -2-phenyl-2-oxazoline-4-carboxylate, 5- (Five-
Chlorothiophen-2-yl) -2-methyl-2-oxazoline-4-carboxylate benzyl, 5- (5-bromothiophene-2
-Benzyl) -2-methyl-2-oxazoline-4-carboxylate, benzyl 5- (5-chloromethylthiophen-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5 -Nitromethylthiophen-2-yl) -2-methyl-2-oxazoline-4-carboxylate benzyl, methyl 5- (thiazol-2-yl) -2-methyl-2-oxazoline-4-carboxylate,
Methyl 5- (4-bromothiazol-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (5-bromothiazole
-2-yl) -2-methyl-2-oxazoline-4-carboxylate methyl, 5- (4-methylthiazol-2-yl) -2-methyl-2-
Methyl oxazoline-4-carboxylate, 5- (5-methylthiazol-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (thiazol-2-yl) -2-phenyl-2 -
Methyl oxazoline-4-carboxylate, 5- (4-bromothiazol-2-yl) -2-phenyl-2-methyl oxazoline-4-carboxylate, 5- (5-bromothiazol-2-yl) -2- Methyl phenyl-2-oxazoline-4-carboxylate, 5- (4-
Methylthiazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate, 5- (5-methylthiazole-2-
Methyl yl) -2-phenyl-2-oxazoline-4-carboxylate, benzyl 5- (thiazol-2-yl) -2-methyl-2-oxazoline-4-carboxylate, 5- (4-bromothiazole-2
-Yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (5-bromothiazol-2-yl) -2-methyl-2-
Benzyl oxazoline-4-carboxylate, 5- (4-methylthiazol-2-yl) -2-methyl-2-oxazoline-4-benzyl carboxylate, 5- (5-methylthiazol-2-yl) -2-
Benzyl methyl-2-oxazoline-4-carboxylate, 5- (
Thiazol-2-yl) -2-phenyl-2-oxazoline-4-
Benzyl carboxylate, benzyl 5- (5-bromothiazol-2-yl) -2-phenyl-2-oxazoline-4-carboxylate and the like can be mentioned.

The oxazoline compound (2) thus obtained can be converted to the corresponding racemic or optically active threo-3-aromatic serine (3) by ring opening and deprotection. Ring opening and deprotection can be carried out according to known methods, for example, by the following methods, but are not limited thereto. The order of ring opening and deprotection is not particularly limited, and they may be performed simultaneously.

First, the ring opening reaction will be described. The oxazoline moiety is mixed with an appropriate solvent such as water, hydrated methanol, hydrated ethanol, or hydrated acetone, and reacted with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as formic acid, methanesulfonic acid, or trifluoroacetic acid. It is easily hydrolyzed and can be opened to the corresponding amino alcohol. The amount of the mineral acid or the organic acid to be used is generally 0.001 to 100 mol times, preferably 0.01 to 10 mol times, relative to the oxazolines (2), and the reaction time is not particularly limited. Instead, the end point can be the termination of disappearance or reduction of the starting compound. The reaction temperature is generally -30 to 150C, preferably 0 to 120C.

Next, the deprotecting group for R ² will be described. R ²
Is an alkyl group, it can be deprotected by hydrolysis under acidic or basic conditions. Under acidic conditions, acids such as hydrochloric acid, sulfuric acid and nitric acid are used, and under basic conditions, bases such as lithium hydroxide, sodium hydroxide and barium hydroxide are used. The amount of the acid or the base used is, respectively, the oxazoline (2)
The molar ratio is usually 0.001 to 100 times, preferably 0.01 to 10 times the molar amount. The reaction time is not particularly limited, and the end point can be the termination of disappearance or reduction of the starting compound. The reaction temperature is usually -3
The temperature is 0 to 150 ° C, preferably 0 to 120 ° C.

When R ² is an aralkyl group, it can be deprotected by hydrogenolysis in the presence of a noble metal catalyst such as palladium. The amount of the noble metal catalyst used is usually 0.00001 to 1 with respect to the oxazoline (2).
It is by weight, preferably 0.001 to 0.1 times by weight. The hydrogen pressure is usually 0.1 to 200 atm, preferably 1 to 50 atm, and the reaction time is not particularly limited, and the end point can be termination of disappearance or reduction of the starting compound. The reaction temperature is usually -30 to 15
0 ° C, preferably 0 to 120 ° C.

[0026]

The racemic or optically active oxazolines (2) of the present invention are useful as pharmaceutical intermediates and can be derived, for example, into the corresponding threo-3-aromatic serines (3). Further, according to the production method of the present invention, a threo-3-aromatic serine can be easily produced by a three-stage reaction by passing an oxazoline (2) from a 3-aromatic alanine derivative (1). This is particularly advantageous as an industrial production method.

[0027]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[Reference Example 1- (1)] 15-20 ° C. under stirring
With hippuric acid 10.00 g (55.81 mmol) and potassium bicarbonate
In a solution of 2.24 g (22.37 mmol) suspended in acetic anhydride 25 ml,
After adding 7.14 g (63.66 mmol) of 2-thiophenecarboxaldehyde, the mixture was stirred at the same temperature for 3 hours. The resulting viscous liquid is
It was poured into water at room temperature under stirring. The obtained solid is separated by filtration,
After drying, recrystallize with ethanol to give 2-phenyl
7.06 g (yield 50%) of -4- (2-thienylmethylene) -5 (4H) -oxazolone was obtained. ¹ H-NMR (δ): 7.14-7.18 (m, 1H), 7.
47-7.64 (m, 5H), 7.70-7.74 (m, 1H), 8.14-8.18 (m, 2H)

Reference Example 1- (2) 2-Phenyl-4- (2-thienylmethylene) -5 (4
To a suspension of 3.00 g (11.75 mmol) of H) -oxazolone in 45 ml of methanol was added 0.11 g (0.57 mmol) of sodium methoxide,
The mixture was stirred at room temperature for 3 hours. During this time the suspension becomes a clear solution. Then, the reaction solution was concentrated under reduced pressure to remove methanol, and the residue was extracted by adding water and ethyl acetate. The organic layer was washed with saturated saline, dried, concentrated under reduced pressure, and hexane: ethyl acetate = 1: 1. (1) By recrystallization from a mixed solvent, (Z) -2-benzoylamino-3- (thiophen-2-yl)
2.59 g (77% yield) of methyl propenoate was obtained. ¹ H-NMR (δ)
: 3.80 (s, 3H), 7.03-7.07 (m, 1H), 7.31-7.33 (m, 1H)
, 7.42-7.60 (m, 5H), 7.85 (s, 1H), 7.94-8.08 (m, 2H)

[Reference Example 1- (3)] (+)-DI under stirring at room temperature
OP [(+)-2,3-O-isopropylidene-2,3-dihydroxy-
1,4-bis (diphenylphosphino) butane) 20 mg (0.04
mmol) and bis (1,5-cyclooctadiene) rhodium
(I) To a solution of 15 mg of tetrafluoroborate hydrate ((0.04 mmol) in 30 ml of methanol) was added 1.12 g (3.90 mmol) of methyl (Z) -2-benzoylamino-3- (thiophen-2-yl) propenoate, After replacing the reaction system with hydrogen, pressurized to 10 atm with hydrogen,
Hydrogenation was performed at room temperature for 18 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove methanol, and the residue was subjected to silica gel column chromatography (mobile phase: toluene / ethyl acetate = 1/1) to remove the origin component, and then hexane: ethyl acetate = 1: 1. (2S) -2 by recrystallization from a mixed solvent
-1.03 g (91% yield) of methyl benzoylamino-3- (thiophen-2-yl) propanoate was obtained. Optical rotation [α] _D ²⁰ 44.0 ° (C = 1, EtOH) ¹ H-NMR (δ): 3.51 (dd, 2H, J = 3.6 Hz, 3.9 Hz), 3.80 (s, 3)
H), 5.09 (ddd, 1H, J = 3.3Hz, 3.6Hz, 3.9Hz), 6.80 (d, 1H, J =
3.3Hz), 6.81 (d, 1H, J = 3.6Hz), 6.94 (dd, 1H, J = 3.6Hz,
5.3Hz), 7.18 (d, 1H, J = 5.3Hz), 7.40-7.53 (m, 3H),
7.77-7.81 (m, 2H)

(Reference Example 2) If the reaction was carried out in the same manner as in Reference Example 1 except that furfural was used instead of 2-thiophenecarboxaldehyde, (2S) -2-benzoylamino-3- ( Furan-2-yl) methyl propanoate is
It was obtained in a yield of 33% based on furfural. Methyl (2S) -2-benzoylamino-3- (furan-2-yl) propanoate ¹ H-NMR (δ): 3.30-3.33 (m, 2H), 3.79 (s, 3H), 5.01-
5.08 (m, 1H), 6.09-6.11 (m, 1H), 6.28-6.30 (m, 1H),
6.78-6.83 (m, 1H), 7.33-7.55 (m, 4H), 7.74-7.79 (m, 2
H)

(Reference Example 3) If the reaction was carried out in the same manner as in Reference Example 1 except that 5-methylfurfural was used instead of 2-thiophenecarboxaldehyde, (2S) -2
-Methyl benzoylamino-3- (5-methylfuran-2-yl) propanoate is 43% relative to 5-methylfurfural
Was obtained in a yield of Methyl (2S) -2-benzoylamino-3- (5-methylfuran-2-yl) propanoate ¹ H-NMR (δ): 2.23 (s, 3H), 3.19-3.28 (m, 2H), 3.79
(s, 3H), 4.97-5.05 (m, 1H), 5.85 (d, 1H, J = 3.3Hz), 5.9
8 (d, 1H, J = 3.3Hz), 6.81 (d, 1H, J = 7.3Hz), 7.40-7.55 (m, 3
H), 7.75-7.80 (m, 2H)

Reference Example 4 The reaction was carried out in the same manner as in Reference Example 1 except that 5-methyl-2-thiophenaldehyde was used instead of 2-thiophenecarboxaldehyde, and (2S) -2 was used. -Methyl benzoylamino-3- (5-methylthiophen-2-yl) propanoate was obtained in a yield of 51% relative to 5-methyl-2-thiophenaldehyde. (2S) -2-benzoylamino-3- (5-methylthiophen-2-
Yl) Methyl propanoate ¹ H-NMR (δ): 2.41 (s, 3H), 3.37-3.47 (m, 2H), 3.79
(s, 3H), 5.02-5.12 (m, 1H), 6.55-6.58 (m, 2H), 6.75-
6.85 (m, 1H), 7.31-7.54 (m, 3H), 7.77-7.81 (m, 2H)

Reference Example 5 10 ml of an acetic acid-acetonitrile (1: 1) solution and (2S) -2-benzoylamino-3 under ice-cooling and stirring.
-(Thiophen-2-yl) methyl propanoate 100mg (0.364m
mol), 66.3 mg (0.415 mmol) of bromine were added dropwise thereto, and stirring was continued at the same temperature for 1 hour. Next, an aqueous solution of sodium thiosulfate was added to deactivate excess bromine, and the mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the residue for extraction, and the organic layer was washed with saturated saline, dried, concentrated under reduced pressure, and then subjected to silica gel chromatography to give (2S) -2-benzoylamino-3- (5- 123.6 mg (96% yield) of methyl bromothiophen-2-yl) propanoate was obtained. ¹ H-NMR (δ): 3.41-3.50 (m, 2H), 3.80 (s, 3H), 5.01-
5.08 (m, 1H), 6.56 (d, 1H, J = 3.6Hz), 6.85-6.90 (m, 2H)
, 7.41-7.54 (m, 3H), 7.77-7.82 (m, 2H)

Example 1 Under stirring, a suspension of 802.4 mg (1.46 mmol) of ceric ammonium nitrate and 199 mg (1.83 mmol) of sodium acetate in 10 ml of acetonitrile cooled to 0 ° C. was stirred at the same temperature for (2S). -2-Benzoylamino-3- (furan-2
-Yl) 100 mg (0.366 mmol) of methyl propanoate was added and 3
Stirring was continued for hours. Dilute the reaction mass with ethyl acetate,
After adding 0.1N sodium thiosulfate to deactivate the remaining oxidizing agent, the mixture was filtered through celite. The organic layer of the filtrate was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
By purifying with silica gel chromatography,
42.7 mg (yield 43%) of methyl (4S, 5R) -5- (furan-2-yl) -2-phenyl-2-oxazoline-4-carboxylate was obtained.
^{1 H-NMR (δ):} 3.84 (s, 3H), 5.13 (d, 1H, J = 7.6Hz), 5.92
(d, 1H, J = 7.6Hz), 6.40 (dd, 1H, J = 1.7Hz, 3.3Hz), 6.52
(d, 1H, J = 3.3Hz) 7.37-7.51 (m, 4H) 、 7.98-8.03 (m, 2H)

(Example 2) In Example 1, (2S) -2-
Example 3 except that methyl (2S) -2-benzoylamino-3- (5-methylfuran-2-yl) propanoate was used instead of methyl benzoylamino-3- (furan-2-yl) propanoate (2S) -2-Benzoylamino-3
Methyl 5- (5-methylthiophen-2-yl) propanoate
Obtained in 6% yield. (4S, 5R) -5- (5-Methylfuran-2-yl) -2-phenyl-2-
Methyl oxazoline-4-carboxylate ¹ H-NMR (δ): 2.29 (s, 3H), 3.83 (s, 3H), 5.12 (d, 1H, J =
8.1Hz), 5.85 (d, 1H, J = 8.1Hz), 5.98 (d, 1H, J = 3.0Hz), 6.
40 (d, 1H, J = 3.0Hz), 7.37-7.53 (m, 3H), 7.98-8.02 (m, 2
H)

Example 3 In Example 1, (2S) -2-
Methyl benzoylamino-3- (furan-2-yl) propanoate, methyl (4S, 5R) -5- (5-methylfuran-2-yl) -2-phenyl-2-oxazoline-4-carboxylate By reacting in the same manner as in Example 3 except for using (4S, 5R) -5- (5
-Methylthiophen-2-yl) -2-phenyl-2-oxazoline-4-carboxylate was obtained in a yield of 68%. (4S, 5R) -5- (5-methylthiophen-2-yl) -2-phenyl
-2-oxazoline-4-carboxylic acid methyl ¹ H-NMR (δ): 2.47 (s, 3H), 3.84 (s, 3H), 4.95 (d, 1H, J =
7.6Hz), 6.05 (d, 1H, J = 7.6Hz), 6.65 (d, 1H, J = 3.6Hz), 6.
96 (d, 1H, J = 3.6Hz), 7.41-7.55 (m, 3H), 7.99-8.03 (m, 2
H)

Example 4 (4S, 5R) -5- (5
-Methylthiophen-2-yl) -2-phenyl-2-oxazoline-4-carboxylate (100 mg, 0.332 mmol) was added to 2N aqueous hydrochloric acid (10 ml), and the mixture was heated under reflux with stirring for 16 hours.
After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the reaction mass was neutralized with a 1N aqueous solution of sodium hydroxide, and the precipitated crystals were collected by filtration to obtain L-threo-3- (5-methylthiophen-2- Yl) Serine 61 mg (91% yield) was obtained.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07B 53/00 C07B 53/00 C C07C 227/12 C07C 227/12 229/36 229/36 C07D 413/04 307 C07D 413/04 307 333 333 // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (10)

[Claims] 1. The general formula (1)(In the formula, Ar represents an aromatic group which may have a substituent.
Then R¹Is an alkyl group which may have a substituent or
A phenyl group which may have a substituent; ^TwoHa
Shows a protective group for rubonic acid. ) Racemic or light
Biologically active 3-aromatic alanine derivative and cerium salt 2
Reacts with persulfate in the presence or absence of a copper catalyst
General formula (2)(Where Ar, R¹And R^TwoHas the same meaning as above
You. Racemic or optically active oxazolines represented by)
Manufacturing method. 2. A 3-aromatic alanine represented by the general formula (1)
Of derivatives and oxazolines represented by the general formula (2)
Ar is (a) 4 or less substituents (R^Three, R^Four, R^Five,
R⁶) Optionally substituted phenyl group, 2-biphenyl
Group, 3-biphenyl group, 4-biphenyl group, 1-naphthyl
Group, 2-naphthyl group, 1-anthranyl group, 2-anthranyl
Group, 9-anthranyl group, 1-indenyl group, 2-indenyl
Group, 3-indenyl group, 4-indenyl group, 5-indenyl
Group, 6-indenyl group, 7-indenyl group, pyrrole-2-a
Group, pyrrol-3-yl group, indole-2-yl group, a
Indole-3-yl, Indole-4-yl, Indore
Le-5-yl, indole-6-yl, indole-7-
Yl group, benzofuran-2-yl group, benzofuran-3-a
Group, benzofuran-4-yl group, benzofuran-5-yl
Group, benzofuran-6-yl group, benzofuran-7-yl
Group, benzimidazole-2-yl group, benzimidazo
4-yl group, benzimidazole-5-yl group, benzo
Thiazol-2-yl group, benzothiazol-4-yl group,
Benzothiazol-5-yl group, benzothiazole-6-a
Or a benzothiazol-7-yl group, or
(B) up to three substituents (R ^Three, R^Four, R^FiveReplaced by)
Optionally 2-furyl, 3-furyl, 2-thienyl
Group, or 3-thienyl group, or (c) no more than two
Substituent (R^Three, R^Four2-) thiazoly which may be substituted
Group, 4-thiazolyl group or 5-thiazolyl group (here
And R^Three, R^Four, R^Five, R⁶Are the same or different, charcoal
A linear or branched alkyl group of 1 to 7 carbon atoms, 1 to 1 carbon atoms
7 cycloalkyl groups, C1-7 alkoxyalkali
Kill group, aminoalkyl group having 1 to 10 carbon atoms, 1 carbon atom
Alkyl halides having 1 to 7 carbon atoms, alkoxy having 1 to 7 carbon atoms
Si group, C6-C12 aromatic oxy group, C1-C7
An alkylamino group having 1 to 7 carbon atoms
Group, an aromatic amino group having 6 to 12 carbon atoms, 1 to 7 carbon atoms
Alkylsulfonylamino group, aromatic having 6 to 12 carbon atoms
Group sulfonylamino group, nitro group or halogen atom
Show. However, when Ar is a phenyl group,
It is not an alkoxy group of 1 to 6. 2. The method according to claim 1, wherein
For producing racemic or optically active oxazolines. 3. The method according to claim 1, wherein the 3-aromatic alanine derivative represented by the general formula (1) and the oxazoline represented by the general formula (2) have (a) four or less substituents (R ³ , R ⁴ , R ⁵ ,
R ⁶ ) optionally substituted with a phenyl group, 1-naphthyl group, 2-naphthyl group, 1-anthranyl group, 2-anthranyl group, 9-anthranyl group, or (b) 3 or less substituents (R ^3, R ^4, R ⁵⁾ in optionally substituted 2-furyl, 3-furyl group, 2-thienyl or 3-thienyl group ^{(wherein,, R 3, R 4,} R 5, R 6 Represents the same meaning as described above.) The process for producing racemic or optically active oxazolines according to claim 1, wherein 4. The process for producing a racemic or optically active oxazoline according to claim 1, wherein the ceric salt is ceric ammonium nitrate. 5. The process for producing a racemic or optically active oxazoline according to claim 1, wherein the persulfate is sodium persulfate, potassium persulfate or ammonium persulfate. 6. The copper catalyst according to claim 1, 2, 3 or 7, wherein the copper catalyst is cuprous chloride, cupric chloride, copper acetate, copper sulfate, or copper hydroxide. For producing racemic or optically active oxazolines. 7. A racemic or optically active oxazoline represented by the general formula (2) according to claim 1. 8. In the general formula (2), Ar represents (a) 4
Phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-phenyl which may be substituted with not more than ^three substituents (R ³ , R ⁴ , R ⁵ , R ⁶ ) Naphthyl group,
1-anthranyl group, 2-anthrenyl group, 9-anthrenyl group, 1-indenyl group, 2-indenyl group, 3-indenyl group, 4-indenyl group, 5-indenyl group, 6-indenyl group, 7-indenyl group, Pyrrole-2-yl group, pyrrole-3
-Yl, indol-2-yl, indol-3-yl, indol-4-yl, indole-5-yl, indole-6-yl, indole-7-yl, benzofuran-2- Yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran
-6-yl group, benzofuran-7-yl group, benzimidazole-2-yl group, benzimidazole-4-yl group, benzimidazole-5-yl group, benzothiazol-2-yl group, benzothiazol-4- Yl group, benzothiazole-5
-An yl group, a benzothiazol-6-yl group or a benzothiazol-7-yl group, or (b) optionally substituted with up to ^three substituents (R ³ , R ⁴ , R ⁵ ) A furyl group, a 3-furyl group, a 2-thienyl group, or a 3-thienyl group, or (c) a 2-thiazolyl group which may be substituted with up to two substituents (R ³ , R ⁴ ); Thiazolyl group,
Or a 5-thiazolyl group (where R ³ , R ⁴ , R ⁵ ,
R ⁶ is the same or different and has a linear or branched alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 1 to 7 carbon atoms,
C1-C7 alkoxyalkyl group, C1-C10
An aminoalkyl group, a halogenated alkyl group having 1 to 7 carbon atoms, an alkoxy group having 1 to 7 carbon atoms, an aromatic oxy group having 6 to 12 carbon atoms, an alkylamino group having 1 to 7 carbon atoms, 7, a cyclic alkylamino group having 7 carbon atoms, an aromatic amino group having 6 to 12 carbon atoms, an alkylsulfonylamino group having 1 to 7 carbon atoms, an aromatic sulfonylamino group having 6 to 12 carbon atoms,
Indicates a nitro group or a halogen atom. Where Ar is
In the case of a phenyl group, it is not an alkoxy group having 1 to 6 carbon atoms. A) a racemic or optically active oxazoline represented by the general formula (2): 9. In the general formula (2), Ar is (a) a phenyl group, 1-naphthyl group which may be substituted by not more than 4 substituents (R ³ , R ⁴ , R ⁵ , R ⁶ ) , A 2-naphthyl group,
1-anthranyl group, 2-anthranyl group, 9-anthranyl group, or (b) three or less substituents (R ³ , R ⁴ ,
R ⁵ ) optionally substituted 2-furyl, 3-furyl, 2-thienyl or 3-thienyl (where R ⁵ )
³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above. A) a racemic or optically active oxazoline represented by the general formula (2): 10. A racemic or optically active oxazoline represented by the general formula (2) according to claim 7, 8 or 9 wherein the ring is opened and deprotected. (Wherein, Ar has the same meaning as described above).