THIAZOLE DERIVATIVES AND PRODUCTION THEREOF

DERIVES DU THIAZOLE ET PRODUCTION DUDIT DERIVE

English Abstract

A B S T R A C T

Thiazole derivatives represented by the general formula:
Image

wherein A is oxygen, sulfur, imino or NR3; R3 is alkyl, alkenyl,
alkynyl, cycloalkylalkyl or aralkyl; R1 is hydrogen, alkyl,
alkenyl, alkynyl, cycloalkylalkyl or aralkyl; R2 is hydroxy,
ester residue or OM; M is alkali metal, one-equivalent of alkaline
earth metal, cupric or aluminium cation; n is an integer of 0 or 1
and the thiazole ring may have one or two substituents selected
from alkyl or halogen and the benzene ring may have one or two
substituents selected from halogen, alkyl, alkoxy or trifluoro-
methyl synthesized by condensation with halogenothiazole or
carboxylation being useful as anti-inflammatory, anti-rheumatic,
analgesic or anti-lipemia agents.

Claims

THE EMBODIMENTS OF AN INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing thiazole derivatives of the
general formula:

Image

wherein A is oxygen, sulfur, imino or NR3; R3 is C1-5 alkyl,
C2-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkylalkyl or aralkyl;
R1 is hydrogen, C1-5 alkyl, C2-5 alkenyl, C3-5 alkynyl, C3-6
cycloalkylalkyl or aralkyl; R2 is hydroxy, ester residue or OM;
M is alkali metal, one-equivalent of alkaline earth metal,
cupric or aluminium cation; n is an integer of 0 or 1 and the
thiazole ring may have one or two substituents selected from
C1-5 alkyl or halogen and the benzene ring may have one or two
substituents selected from halogen, C1-5 alkyl, C1-5 alkoxy or
trifluoromethyl, which comprises one or more of the following
steps:
(A) subjecting to condensation a compound represented by the
general formula [IIa] or [IIb]:

Image Image
[IIa] [IIb]
wherein hal is chlorine, bromine or iodine and Z is a group
which can be converted to -COOH or Image by hydrolysis;
wherein R1 has the same significance designated above and the
thiazole ring may have one or two substituents designated above
with a phenyl compounds represented by the general formula
[IIIa] or [IIIb], respectively:

27





Image
Image
[IIIa] [IIIb]
wherein A and Z each has the same significance designated above
and the benzene ring may have one or two substituents designated
above
and further subjecting to hydrolysis, if necessary; or
(B) (i) subjecting to cyanation a compounds represented by
the general formula [IV]:


Image
[IV]
wherein hal, A and n each has the same significance designated
above and the thiazole ring and benzene ring may have substitu-
ents designated above; and
(B) (ii) then hydrolysis with or without esterification to
obtain a compounds represented by the general formula [VI]:

Image
[VI]
wherein W is hydroxy or an ester residue; A and n each has the
same significance designated above and the benzene ring and
thiazole ring may have substituents designated above; or
(B) (iii) condensation with halogenohydrocarbon before or
after step (B) (ii), if necessary, to obtain a compound rep-
resented by the general formula [I']:

28





Image
[I']
wherein R'1 is C1-5 alkyl, C2-5 alkenyl, C3-5 alkynyl, C3-6
cycloalkylalkyl or aralkyl, A and W each has the same signif-
icance designated above and the benzene ring and the thiazole
ring may have substituents designated above; and
(c) further treating the prepared compounds to prepare corres-
ponding pharmaceutically acceptable salts thereof, if necessary.

2. A process according to claim 1, wherein the condensation
with a phenyl compound is effected at a temperature ranging
from about 20°C to about 200°C in the presence of base.

3. A process according to claim 1, wherein the condensation
with a phenyl compound is effected in the presence of copper
powder or cupric oxide.

4. A process according to claim 1, wherein the cyanation
is effected at a temperature ranging from about 50°C to about
200°C when n=0; or about 0°C to about 100°C when n=1.

5. A process according to claim 1, wherein the condensation
with halogenohydrocarbon can be effected with aromatic sulfonic
acid ester instead of halogenohydrocarbon.

6. A process according to claim 1, wherein the condensation

29





with halogenohydrocarbon can be effected in the presence of
condensing agent.

7. A process according to claim 1, wherein the condensation
with halogenohydrocarbon is effected at a temperature ranging
from about -70°C to about 200°C.

8. A process of claim 1, wherein step A, compounds of formula
[IIb] are condensed with compounds of formula [IIIb].

9. A process of claim 1, wherein step A, compounds of form-
ula [IIa] are condensed with compounds of formula [IIIa].

10. A process of claim 1, wherein step A, compounds of form-
ulas [IIa] or [IIb] are condensed respectively with compounds
of formulas [IIIa] or [IIIb] wherein Z is converted to -COOH;
or in steps B (i) and B (ii) n is 0.

11. A process of claim 1, wherein step A, compounds of formulas
[IIa] or [IIb] are condensed respectively with compounds of
formulas [IIIa] or [IIIb] for which Z is converted to Image;
or step B (iii) is used to prepare compounds of formula [I'].

12. A process of claim 1, for preparing 2-[4-(2-thiazolyloxy)-
phenyl] propionic acid and its salts, wherein step A, formula
[IIIa], A is oxygen and Z is a propionate ester at the 4-
position; followed by hydrolysis.

13. A process of claim 1 for preparing 2-[4-(2-thiazolyloxy)-
phenyl] propionic acid and its salts, wherein for step B (iii),








n=1, A is oxygen and the (CH2)-hal group is at the 4-position
on the benzene ring in formula [IV] and R? is -CH3 and W is
hydroxy in formula [I'].

14. A process of claim 1 for preparing 2-(2-phenoxy-4-methyl-
5-thiazolyl) propionic acid and its salts, wherein step A, is
a propionate ester at the 5-position and the thiazole ring is
substituted at the 4-position with a methyl group and in
formula [IIIb] A is oxygen; followed by hydrolysis.

15. A process of claim 1 for preparing 2-(2-phenoxy-4-methyl-
5-thiazolyl) propionic acid and its salts, wherein for step B
(iii) n=1, and W is hydroxy in formula [I'], A is oxygen, the
thiazole ring is substituted at the 4-position with a methyl
group, and the (CH2)-hal group is at the 5-position on the
thiazole ring in formula [IV] and R? is -CH3.

16. A process of claim 1 for preparing 2-[4-(2-thiazolyloxy)
-phenyl] acetic acid and its salts, wherein step A, formula
[IIIa] A is oxygen and Z is an acetate ester at the 4-position
followed by hydrolysis.

17. A process of claim 1 for preparing 2-[4-(2-thiazolyloxy)-
phenyl] acetic acid and its salts, wherein for step B (ii) n=1,
A is oxygen and the (CH2)-hal group is at the 4-position on
the benzene ring in formula [IV] and W is hydroxy in formula
[VI].

18. A process of claim 1 for preparing 2-[4-(N-methyl-N-
thiazol-2-ylamino)phenyl] acetic acid and its salts, wherein


31





step A, formula [IIIa] A is methylimino and Z is an acetate
ester at the 4-position followed by hydrolysis.

19. A process of claim 1 for preparing 2-[4-(N-methyl-N-
thiazol-2-ylamino)phenyl] acetic acid and its salts, wherein
for step B (ii), n=1, A is methylimino and the (CH2)-hal
group is at the 4-position on the benzene ring in formula
[IV] and W is hydroxy in formula [VI].

20. A process of claim 1 for preparing 3-[4-(N-methyl-N-
thiazol-2-ylamino)phenyl] propionic acid and its salts, wherein
step A, formula [IIIa] A is methylimino and Z is a propionate
ester at the 4-position followed by hydrolysis.

21. A process of claim 1 for preparing 3-[4-(N-methyl-N-
thiazol-2-ylamino)phenyl] propionic acid and its salts, wherein
for step B (iii), n=1 A is methylimino and the (CH2)-hal
group is at the 4-position on the benzene ringe in formula
[IV] and R? is -CH3 and W is hydroxy in formula [I'].

22. A process of claim 1 for preparing 2-[4-(4-methyl-2-
thiazolyloxy)phenyl] propionic acid and its salts, wherein
step A, formula [IIIa] A is oxygen, Z is a propionate ester
at the 4-position and the thiazole ring is substituted at the
4-position with a methyl group; followed by hydrolysis.

23. A process of claim 1 for preparing 2-[4-(4-methyl-2-
thiazolyloxy)phenyl] propionic acid and its salts, wherein
for step B (iii), n=1, A is oxygen, the (CH2)-hal group is
at the 4-position on the benzene ring and the thiazole ring


32





is substituted at the 4-position with a methyl group in
formula [IV] and R' is -CH3 and W is hydroxy in formula [I'].

24. A process of claim 1 for preparing 2-[2-chloro-4-(2-
thiazolyloxy)phenyl] propionic acid and its salts, wherein
step A, formula [IIIa] A is oxygen, Z is a propionate ester
at the 4-position and the benzene ring is substituted at the
3 position with a chloro group; followed by hydrolysis.

25. A process of claim 1 for preparing 2-[2-chloro-4-(2-
thiazolyloxy)phenyl] propionic acid and its salts, wherein
for step B (iii), n=1, A is oxygen, the (CH2)-hal group is
at the 4-position on the benzene ring and the benzene ring
is substituted at the 3-position with a chloro group in
formula [IV] and R? is -CH3 and W is hydroxy in formula [I'].

26. A process of claim 1 for preparing 2-[3-chloro-4-(2-
thiazolyloxy)phenyl] propionic acid and its salts wherein
step A formula [IIIa] A is oxygen, Z is a propionate ester
at the 4-position and the benzene ringe is substituted at
the 2-position with a chloro group; followed by hydrolysis.

27. A process of claim 1 for preparing 2-[3-chloro-4-(2-
thiazolyloxy)phenyl] propionic acid and its salts, wherein
the step B (iii), n=1, A is oxygen, the (CH2) -hal group is
at the 4-position on the benzene ring and the benzene ring
is substituted at the 2-position with a chloro group, and
R? is -CH3 and W is hydroxy in formula [I'].

28. A process of claim 1 for preparing 2-[2-methyl-4-(2-

33




thiazolyloxy)phenyl] propionic acid and its salts, wherein
step A, formula [IIIa], A is oxygen, Z is a propionate ester
at the 4-position and the benzene ring is substituted at the
3-position with a methyl group; followed by hydrolysis.

29. A process of claim 1 for preparing 2-[2-methyl-4-(2-
thiazolyloxy)phenyl] propionic acid and its salts, wherein
for step B (iii), n=1, A is oxygen, the (CH2)-hal group is
at the 4-position on the benzene ring and the benzene ring
is substituted at the 3-position with a methyl group in
formula [IV] and R? is -CH3 and W is hydroxy in formula [I'].

30. A process of claim 1 for preparing 2-(2-phenoxy-5-
thiazolyl)propionic acid and its salts, wherein step A,
formula [IIb], Z is a propionate ester at the 5-position and
in formula [IIIb] A is oxygen; followed by hydroylsis.

31. A process of claim 1 for preparing 2-(2-phenoxy-5-
thiazolyl) propionic acid and its salts, wherein for step B
(iii), n=1, A is oxygen, and the (CH2)-hal group is at the
5-position on the thiazole ring in formula [IV], and R? is
-CH3 and W is hydroxy in formula [I'].

32. A process of claim 1 for preparing 2-(2-(N-methyl-
anilino)-4-thiazolyl] propionic acid and its salts, wherein
step A, formula [IIb], Z is a propionate ester at the 4-
position and in formula [IIIb] A is -NH-; followed by hyd-
rolysis.


34




33. A process of claim for preparing 2-[2-(N-methyl-anilino)-
4-thiazolyl] propionic acid and its salts, wherein for step
B (iii), n=1, A is -NH-, and the (CH2)-hal group is at the
4-position on the thiazole ring in formula [IV], and R? is
-CH3 and W is hydroxy in formula [I'].

34. A compound represented by the general formula:

Image

wherein A is oxygen, sulfur, imino or NR3; R3 is C1-5 alkyl,
C2-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkylalkyl or aralkyl;
R1 is hydrogen, C1-5 alkyl, C1-5 alkenyl, C3-5 alkynyl, C3-6
cycloalkylalkyl or aralkyl; R2 is hydroxy, ester residue or
OM; M is alkali metal, one-equivalent of alkaline earth metal,
cupric or aluminum cation; n is an integer of 0 or 1 and the
thiazole ring may have one or two substituents selected from
C1-5 alkyl or halogen and the benzene ring may have one or two
substituents selected from halogen, C1-5 alkyl, C1-5 alkoxy or
trifluoromethyl when prepared by the process of claim 1.

35. A compound represented by the general formula:

Image

wherein A is oxygen sulfur, imino or NR3; R3 is C1-5 alkyl,
C2-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkylalkyl or aralkyl;
R1 is hydrogen, C1-5 alkyl C1-5 alkenyl, C3-5 alkynyl,







-36-
C3-6 cycloalkylalkyl or aralkyl; R2 is hydroxy, ester res-
idue or OM; M is alkali metal, one-equivalent of alkaline
each metal cupric or aluminum cation; n is an integer of
0 or 1 and the thiazole ring may have one or two substit-
uents selected from C1-5 alkyl, or halogen and the benzene
ring may have one or two substituents selected from halogen,
C1-5 alkyl, C1-5 alkoxy or trifluoromethyl when prepared
by the process of claim 8.

36. A compound represented by the general formula:
Image

wherein A is oxygen, sulfur, imino or NR3; R3 is C1-5 alkyl,
C2-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkylalkyl or aralkyl;
R1 is hydrogen, C1-5 alkyl, C1-5 alkenyl, C3-5 alkynyl,
C3-6 cycloalkylalkyl or aralkyl; R2 is hydroxy, ester
residue or OM; M is alkali metal, one-equivalent of alkaline
earth metal cupric or aluminium cation; n is an integer of
0 or 1 and the thiazole ring may have one or two substituents
selected from C1-5 alkyl or halogen and the benzene ring
may have one or two substituents selected from halogen,
C1-5 alkyl, C1-5 alkoxy or trifluoromethyl when prepared by
the process of claim 9.

37. A compound represented by the general formula:

Image





wherein A is oxygen, sulfer, iminio or NR3; R3 is C1-5 alkyl,
C2-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkylalkyl or aralkyl;
R2 is hydroxy, ester residue or OM; M is alkali metal, one-
equivalent of alkaline earth metal cupric or aluminum cation
and the thiazole ring may have one or two substitutents
selected from C1-5 alkyl or halogen and the benzene ring
may have one or two substituents selected from halogen, C1-5
alkyl, C1-5 alkoxy or trifluoromethyl when prepared by the
process of claim 10.

38. A compound represented by the general formula:

Image


wherein A is oxygen, sulfur, imino or NR3; R3 is C1-5 alkyl,
C2-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkylalkyl or aralkyl;
R1 is hydrogen, C1-5 alkyl, C1-5 alkenyl, C3-5 alkynyl,
C3-6 cycloalkylalkyl or aralkyl; R2 is hydroxy, ester
residue or OM: M is alkali metal, one-equivalent of alkaline
earth metal cupric or aluminum cation and the thiazole ring
may have one or two substituents selected from C1-5 alkyl or
halogen and the benzene ring may have one or two substituents
selected from halogen, C1-5 alkyl, C1-5 alkoxy or trifluoro-
methyl when prepared by the process of claim 11.

39. A compound according to claim 34, namely 2-[4-(2-thia-
zolyloxy)-phenyl] propionic acid and its alkali metal,
alkaline earth metal, cupric or aluminium salts when prepared
by the process of claim 12 or 13.


37




40. A compound according to claim 34, namely 2-(2-phenoxy-
4-methyl-5-thiazolyl) propionic acid and its alkali metal,
alkaline earth metal, cupric or aluminium salts, when
prepared by the process of claim 14 or 15.

41. A compound according to claim 34, namely 2-[4-(2-thia-
zolyloxy)-phenyl] acetic acid and its alkali metal, alkaline
metal, cupric or aluminium salts when prepared by the process
of claim 16 or 17.

42. A compound according to claim 34, namely 2-[4-(N-methyl-
N-thiazol-2-ylamino)phenyl] acetic acid and its alkali metal,
alkaline earth metal, cupric or aluminium salts, when prepared
by the process of claim 18 or 19.

43. A compound according to claim 34, namely 3-[4-(N-methyl-
N-thiazol-2-ylamino)phenyl] propionic acid and its alkali
metal, alkaline earth metal, cupric or aluminium salts,
when prepared by the process of claim 20 or 21.

44. A compound according to claim 34, namely 2-[4-(4-methyl-
2-thiazolyloxy)phenyl] propionic acid and its alkali metal,
alkaline earth metal, cupric or aluminium salts, when
prepared by the proces of claim 22 or 23.

45. A compound according to claim 34, namely 2-[2-chloro-
4-(2-thiazolyloxy)phenyl] propionic acid and its alkali
metal, alkaline earth metal, cupric or aluminium salts,
when prepared by the process of claim 24 or 25.


38





46. A compound according to claim 34, namely 2-[3-chloro
4-(2-thiazolyloxy)phenyl] propionic acid and its alkali
metal, alkaline earth metal, cupric or aluminium salts,
when prepared by the process of claim 26 or 27.
47. A compound according to claim 34, namely 2-[2-methyl-
4-(2-thiazolyloxy)phenyl] propionic acid and its alkali
metal, alkaline earth metal, cupric or aluminium salts,
when prepared by the process of claim 28 or 29.
48. A compound according to claim 34, namely 2-(2-phenoxy-
5-thiazolyl)propionic acid and its alkali metal, alkaline
earth metal, cupric or aluminium salts, when prepared by
the process of claim 30 or 31.
49. A compound according to claim 34 namely 2-[2-(N-methyl-
anilino)-4-thiazolyl] propionic acid and its alkali metal,
alkaline earth metal, cupric or aluminium salts, when pre-
pared by the process of claim 32 or 33.

39

Description

1051~6

Thi~ invention relates to novel thiazol~ derlvatives and
the ~alts. Further~ lt r~late~ to proce~es for their preparation.
The sa~d thiazole derivative~ and th~ir pharmacoutically
accoptable salt~ and the corresponding esters are represented by
the general for~ula:



~S ~
A ~ - CH -COR2

I
I ~ ~ t~
~ J
~herein A i8 oxyg~n, sulfur, imino, or NR3, R3 i8 alkyl, alkenyl,
alkynyl, cycloalkylalkyl or aralkyl: ~ is hydrogen, alkyl, al-
k~nyl, alkynyl, cycloalkylalkyl or aralkyl; ~ i8 hydroxy, ester
reqidue or OM: M i8 alkali metal, one-equivalent of alkaline
earth metal, cupric or aluminium cation: n i8 an integer of O or 1
and the thiazole ring may have one or two substituentR selected
from alkyl or halogen and the benzene ring may have one or two ~ub-
~tituents selected from halogen, alkyl, alkoxy or trifluoromethyl.
Alkyl, a~ u~ed herein, refer~ to both straight and branched chain
Cl_5 alkyl~ including ~ethyl, ethyl, propyl, i-propyl, butyl,
i-butyl, t-butyl, pentyl, i-pentyl and the like. Alkenyl refers
to C2 5 ~lkenyl group including vinyl, allyl, methallyl, 1-
pentenyl, 2-i~opentenyl and the like. Alkynyl refer~ to C3_5
alkynyl group including l-propynyl, 2-propynyl, l-butynyl, 2~
pentynyl and the like. Cycloalkylalkyl r~fers to alkyl ~ubstituted
by C3_6 cycloalkyl including cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl. Arylalkyl refQrs to benzyl, phenethyl and the like.
Ester re~idue i8~ for exa~ple, Cl_5 alkoxy (e.g. methoxy, eShoxy,
propoxy, i-propoxy, butoxy, t-burooy~ aralkyloxy (e.g. phenoxy,

tolyloxy, naphthloxy), cycloalkyloxy (e.g. cyclopentyl-



10~19(~6
oxy, cyclohexyloxy, cycloheptyloxy~, anilino, N-Cl 5 alkylanllino
t~-g- N-methylanilino, N-othylanilino, N-propylanllino, N-butyl-
anilino) and the like. Halogen include~ chlorlne, fluorine, bro-
mine and iodine. Alkali metal refer8 to sodium, pota~8ium and
lithium. Al~aline earth metal refers to calcium, magnesium and
barium. ~he8e 8ignificance~ are applied to the de~cription bolow.
In the above general for~ula [I~ )n CR2 may 8ub8titute
either the thiazole ring~or the benzene ring. The said thiazole
derivative8 of the formula [I~are novel and have excellent anti-
inflammatory, anti-rheumatic and analge~ic activite~ a8 well a~
nn~ltlip~mia activitie~. They ara useful in the treatment of
inflammatory or lipemia di8ease8 in mammals.
Accordingly, a ba8ic object Of thi~ invention i8 to provide
novel thiazole derivatives of the formula ~I~ . Another ob~ect
lS of the invention i8 to provide thiazole derivative8 and their
pharmaceutically acceptable 8alt8 8howing anti-inflammatory, anti-
rheumatic, analge8ic and anti-lipemia activities. A further
ob~ect of the ~nvention i8 to provide proce~s for preparlng the
novel thiazole derivative~.
As illu8trative of the ob~ective compound~ [I~ ar~:
2-phenoxy-4-thiazolecarboxylic acid,
2-phenoxy-5-thiazolecarboxylic acid,
2-phenoxy-5-methyl-4-thiazolocarboxylic acid,
2-phenoxy-4-methyl-S-thiazolecarboxylic acid,
2-(4-chlorophenoxy)-4-thiazolecarboxylic acid,
2-(4-chlorophenoxy)-5-thiazolecarboxylic acid,
2-(4-chlorophenoxy)-5-methyl-4-thiazolecarboxylic acid,
2-(4-chlorophenoxy)-4-methyl-5-thiazolecarboxylic acid,
2-(4-methylphenoxy)-4-methyl-5-thiazolecarboxylic acid,
2-(3-trifluoromethylphenoxy)-4-methyl-5-thiazolecarboxylic acid,


10~906
2-(2,3-dimethylphenoxy)-4-methyl-5-thia~olecarboxylic acid,
2-phenylthio-5-methyl-4-thiazolecarbGxylic acid,
2-phenylthio-4-methyl~5-thiazolecarboxylic acid,
2-(2-phenoxy-4-thiazolyl)acetic acid,
2-(2-phenoxy-4-methyl-5-thiazolyl)acetic acid,
2-(2-phenylthio-4-thiazolyl)acetic acid,
2-(2-phenylthio-4-methyl-5-thiazolyl)acetic acid,
2-(2-anilino-4-thiazolyl)acetic acid,
2-[2-(N-methylanilino)-4-thiazolyl]acetic acid,
2-[2-(N-methylanilino)-5-thiazolyl]acetic acid,
2-[2-(N-methylanilino)-4-methyl-5-thiazolyl]acetic acid,
2-[2-(N-allylanilino)-4-thiazolyl]acetic acid,
2-[2-(N-allylanilino)-5-thiazolyl]acetic acid,
2-[2-(N-allylanilino)-4-methyl-5-thiazolyl]acetic acid,
2-[2-(N-cyclopropylmethylanilino)-4-thiazolyl]acetic acid,
2-[2-(N-benzylanilino)-4-thiazolyl]acetic acid,
2-(2-phenoxy-4-thiazolyl)propionic a~id,
2-(2-phenoxy-5-thiazolyl)propionic acid,
2-(2-phenoxy-5-methyl-4-thiazolyl)propionic acid,
2-(2-phenoxy-4-methyl-5-thiazolyl)propionic acid,
2-[2-(4-chlorphenoxy)-4-thiazolyl]propionic acid,
2-[2-(4-chlorophenoxy)-5-thiazolyl]propionic acid,
2-[2-(4-chlorophenoxy)-5-methyl-4-thiazolyl]propioni:c acid,
2-[2-(4-chlorophenoxy)`4-methyl-5-thiazolyl]propionic acid,
2-[2-(4-methylphenoxy)-4-methyl-5-thiazolyl]propionic acid, ~ :
2-[2-~3-trifluoromethylphenoxy)-4-methyl-5-thiazolyl]propionic .
acidr
2-[2-(2,3-dimethylphenoxy)-4-methyl-5-thiazolyl]propionic acid,
2-(2-2phenylthio-4-methyl-5-thiazolyl)propionic acid,
2-(2-anilino-4-methyl-5-thiazolyl)propionic acid,

1051~06
~-[2-(3-trifluoromethylanilino)-4-rnethyl-5-thiazolyl~propionic
acid,
2-[2-(N-methylanilino)-4-thiazolyl]propionic acid,
2-[2-(N-methylanilino)-5-thiazolyl]propionic acid,
2-[2-(N-methylanilino)-4-methyl-5-thiazolyl]propionic acid,
2-[2-(N-cyclopropylmethylanilino)-4-thiazolyl]propionic acid,
2-[2-(N-cyclopropylmethylanilino)-4-methyl-5-thiazolyl]propionic
acid,
2-[2-(N-allylanilino)-4-thiazolyl]propionic acid,
2-[2-(N-allylanilino)-5-thiazolyl]propionic acid,
2-[2-(N-allylanilino)-4-methyl-5-thiazolyl]propionic acid,
2-[2-(N-benzylanilino)-4-thiazolyl]propionic acid,
4-(2-thiazolyloxy)benzoic acid,
3-fluoro-4-(2-thiazolyloxy)benzoic acid,
2-chloro-3-methyl-4-(2-thiazolyloxy)benzoic acid,
2-[4-(2-thiazolyloxy)phenyl]acetic acid,
2-[4-(N-thiazol-2-ylamino)phenyl]acetic acid,
2-[4-(N-methyl-N-thiazol-2-ylamino)phenyl]acetic acid,
2-[4-(N-allyl-N-thiazol-2-ylamino)phenyl]acetic acid,
2-[3-(2-thiazolyloxy)phenyl]propionic acid,
2-[4-(2-thiazolyloxy)phenyl]propionic acid,
2-[4-(2-thiazolyloxy)phenyl]propionic acid,
2-[3-fluoro-4-(2-thiazolyloxy)phenyl]propionic acid,
2-[2-chloro-3-methyl-4-(2-thiazolyloxy)phenyl]propionic acid,
2-[2-methyl-4-(2-thiazolyloxy)-5-chlorophenyl]propionic acid,
2-[4-(4-methyl-2-thiazolyloxy)phenyl]propionic acid,
2-[4-(4,5-dimethyl-2-thiazolyloxy)phenyl]propionic acid,
2-[2-chloro-4-(2-thiazolyloxy)phenyl]propionic acid,
2-[3-chloro-4-(2-thiazolyloxy)phenyl]propionic acid,
2-[2-methyl-4-(thiazolyloxy)phenyl]propionic acid,

-
l~S~90~;
1 2-[3-methyl-4-(2-thiazolyloxy)phenyl]propionic acid,
2-[3-methoxy-4-(2-thiazolyloxy)phenyl]propionic acid,
2-[4-(N-methyl-N-thiazol-2-ylamino)phenyl]propionic acid,
2-[4-(N-allyl-N-thiazol-2-ylamino)phenyl]propionic acid,
4-[4-(2-thiazolyloxy)phenyl]butyric acid,
2-[4-(2-thiazolyloxy)phenyl]-4-pentenic acid,
2-[4-(2-thiazolyloxy)phenyl]-4-pentynic acid,
2-[4-(2-thiazolyloxy)phenyl]-3 cyclopropylpropionic acid,
2-[4~(2-thiazolyloxy)phenyl]-4-methyl-4-pentenic acid,
2-[4-(2-thiazolyloxy)phenyl]-3-phenylpropionic acid,
and corresponding esters and the salts.
The compounds of the present invention can be prepared by
various methods. Some of the preferred methods are presented
below:
15 A. Preparation by Condensation
The objective thiazole derivatives [I] can be prepared by
condensation of halogenothiazole with phenyl compound as follows:


~ ~ hal + HA~ ~ ~ A ~


[IIa] [IIIa] [Ia] ~;


hal + ~ ~S ~ ~



[IIb] [IIIb] [Ib]



25 wherein A has the same significance designated above; hal repre--
sents chlorine, bromine or iodine; Z represents a groups which
can be converted to -COOH or 11 by hydrolysis; Rl has the
- CHCOOH
same significance designated above and the thiazole ringe may have

one or two substituents selected from alkyl or halogen and the
-- 5 --
E

lOS1906
b enzene ring may b~ substituted by one or two groups selected from
halogen, alkyl, alkoxy or trifluoromethyl.
The objective compound [I] can be prepared by condensation
of halogenothiazole derivative [IIa] with phenyl compound [IIIa]
(scheme (a)) or that of halogenothiazole derivative [IIb] with
phenyl compound [IIIb] (scheme (b)). Z of compound [IIIa] and
[lIb] is a group which can be converted to -COOH or ~CHCOOH b


hydrolysis. There are exemplified corresponding nitrile, amide
or esters. The starting compound [IIa] or [IIb] can be prepared
by the method described on pages 539-541 and 545-547 of "Hetero-
cyclic Compound, Vol 5" by Elderfield.
The reaction represented by either scheme (a) or (b) can be
executed in the same condition. The compound [IIa] or [IIb] is
condensed with the compound [IIIa] or [IIIb] in the presence of
base. Generally, the reaction may be executed at a temperature
ranging from about 20C to about 200C, namely from at room
temperature to the boiling point of the solvents, if employed,
in the presence of base. The base to be used are, for example,
alkali metal hydroxides (e.g. sodium hydroxide, potassium
hydroxide), alkali metal carbonates (e.g. sodium carbonate,
potassium carbonate), alkali metal hydrogen carbonates (e.g.
sodium hydrogen carbonate, potassium hydrogen carbonate), alkali
metal acetates (e.g. sodium acetate, potassium acetate). Metal
catalyst (e.g. cupper powder, cupric oxide) can be employed to
accelerate the reaction, when phenol derivatives are used as
starting compound [IIIa] or [IIIb]. Further, the reaction may
be practised without base if basic starting material such as
anilino derivative is used. The reaction solvent is not necess-
arily required, but may be selected from inert solvents, for
example, aromatic hydrocarbons (e.g. benzene, toluene, xylene,

~5~9~6
p~ridin~), aliphatic hydrocarbons (e.g. pentane, ~ ane, he~ane),
a1cohols (e.q. me~hanol, ethanol, propanol), dimet~,yl~ulfoxide,
dimeth~Lformamide, dimethvlacetoamide and the like. They can be
employed solelv or as a mixture in considera~ion of the solubility
S of the starting compounds as well as other reaction conditions
employed. The reaction may be effected without ot~er solvent
by use of an excess of liquid starting compound. The product can
be subjected to hydrolysis, if necessary. The hydrolysis can be
executed by the usual method used to hydrolyze nitriles, amides
or esters to the corresponding carboxylic acids. Namely, the
product is hydrolyzed with acids (e.g. hydrochloric acid, sulfuric
acid, hydrobromic acid, acetic acid) or bases (e.g. sodium hydro-
xide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium hydrogen carbonate, potassium hydrogen carbonate) in water
or other organic solvent containing water. The reaction can be
practised at room temperature or under heating.
B. Preparation by carboxvlation
Another method to give the objective compound [I~ may be
illustrated by the following scheme:-




:, - - , :

. , :
''' ' '~'

105~906
~'
A ( 2)n
1 (1)

[IV] ~


A ~ (CH2) -CN
l l n
~ J [v] ~ n=l (5)

I (2) ~


A l ~ (C~ -COW l ~i
n ¦ -CHCN

[VI] ~ [VII]
n=l (3)
~ ,

~ Ri 1 (6)
A - HCOW
~ ~ 1 Tl
\ (4) A ~ -CHCOOH

~ J [Ic']

wherein A, hal and n each has the same significance designated
above R' is Cl 5 alkyl, C2 5 alkenyl, C3_5 alkynyl, C3_6 y
alkylalkyl or aralkyl; W is hydroxy or ester residue and the
thiazole ring and the benzene ring may have substituents designa-
ted above.

105190~;
The present method starts with cyanation of halogeno
(methyl) compound [IV]. The cyanation (Process 1) may be executed
in a usual manner with cyanating agent (e.g. cuprous cyanide, sod-
ium cyanide, potassium cyanide, benzyltrimethylammonium cyanide)
in an inert solvent (e.g. pyridine, dimethylformamide, dimethylsul-
foxide, l-methyl-2-pyrrolidone, water, methanol, ethanol) under
heating. The reaction temperature may range from about 50C to
about 200C, preferably about 100C to about 200C (n=0) or from
about 0C to about 100C, preferably about 30C to about 80C
~cc~ r~eG/
(n=l). The reaction may be accc~atcd by the addition of sodium
iodide or iodine-potassium iodide. Thus obtained cyano(methyl)
compound [V] is subjected to hydrolysis and esterification, if
desired, (Process 2) to give compound [VI] or to condensation
with halogenohydrocarbon (Process 5) to give compound [VII]. The
hydrolysis (Process 2) can be effected in the same manner as
described in the above method A; the hydrolysis may be executed
with acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic
acid, acetic acid) or bases (e.g. sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen
carbonate, potassium hydrogen carbonate) in water or inert
organic solvent containing water. The reaction can be executed
at ~oom temperature or under heating. Hydrolysis effected com-
paratively in the mild condition gives the carbamoyl(methyl) com-
pound (compound [VI] of which W is amino), which can be used to
the following Process 3. Alcoholysis or aminolysis effected in
suitable aliphatic or aromatic alcohol or anilide may afford car-
boxylic acid derivatives, the corresponding estersandanllides. By
the method hydrolysis and esterification can be effected simultan-
eously. Usual manners for ester ficationalso canbe employedafter




'

1051~0~
1 hydrolysis. These esterifications give desired esters of compound
[VI] of which W is, for example, alkoxy (e.g. methoxy, ethoxy,
propoxy, butoxy), aralkyloxy (e.g. benzyloxy, phenetyloxy),
aryloxy (e.g. phenoxy, tolyloxy, naphthyloxy), cycloalkyloxy (e.g.
cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), anilino, N-
alkylanilino (e.g. N-methylanilino, N-ethylanilino) and the like.
The condensation of compound [VI] with halogenohydrocarbon
(Process 3) is effected in the presence or not of condensing
agent in a suitable medium. The halogenohydrocarbon to be used is
L0 iodide, bromide or chloride of alkane (e.g. methane, ethane, pro-
pane, i-propane, butane, pentane, i-pentane), alkene (e.g. ethene,
propene, butene, i-butene, pentene) and alkynes (e.g. propyne,
butyne-l, pentyne-2), cycloalkylalkane (e.g. cyclopropylmethane,
cyclopropylethane, cyclobutylmethane, cyclopentylethane, cyclo-
hexylmethane), arylalkane (e.g. toluene, methylnaphthalene).
There are exemplified as condensing agent alkali metals (e.g.
sodium, potassium), alkali metal alkoxide (e.g. sodium methoxide,
sodium ethoxide, potassium ethoxide), magnesium alkoxide (e.g.
magnesium ethoxide), alkali metal amide (e.g. sodium amide,
potassium amide), alkylamino alkali metal (e.g. diisopropylamino
lithium), butyl lithium, phenyl lithium, sodium hydride, triphenyl-
methyl sodium and the like. Reaction solvent is selected from
alcohols (e.g. ethanol, propanol, i-propanol, butanol), ethers
(e.g. ether, dioxane, tetrahydrofurane, 1,2-dimethoxyethane,
ethyleneglycol dizlkyl ether, diglyme), benzenes (e.g. benzene,
toluene, xylene), hexamethylphosphoric triamide, dimethyl forma-
mide, dimethylsulfoxide, liquid ammonia and the like. They are
used solely or as a mixture. The reaction may be effected at a
temperature ranging from about -70C to about 200C.
Aromatic sulfonic acid ester (e.g. alkyl benzenesulfGnate,
DJ` -10-


1,~,05~06


alkyl p-toluenesulfonate) are also available instead of halogeno-
hydrocarbon in the same conditions as halogenohydrocarbon is used.
The method of Process 3 can be completely employed to con-
densation of compound [VII] with halogenohydrocarbon (Process 5)

to give compound [Ic'].
Yield of the present processes can be increased by pro-
tecting the methylene of cyanomethyl group of compound [V] or
-CH2COW group of compound [VI] with diethylcarbonate before con-
densation with halogenohydrocarbon. The protection of amino group
with ethyl chlorocarbonate, if the starting compound is anilino
derivative, also provides higher yield. Processes 4 and 6 each is
consist of hydrolysis. The hydrolysis may be executed in the
same manner as described above for Process 2.
Thus obtained compound [Ia], [Ib], [Ic] or [Ic'] can be
converted to the salts in conventional manner in accordance with
requirement for separation, purification, formulation and so on.
The above product is treated with base to give alkali metal salts
(e.g. sodium salt, potassium salt, lithium salt), alkaline earth

metal salts (e.g. calcium salt, magnesium salt, barium salt)~ or
other salts (e.g. cupric salt, aluminium salt).
Besides, some of compound [I] are an optically active
compound and may be resolved into d-isomer and l-isomer. The opti-
cal resolution can be executed in a conventional manner and both
isomers can be used solely or as a mixture depending on the

therapeutical requirement. ~ ~ -
Thus obtained compound [I] including the non-toxic salts
is useful as medicament having anti-inflammatory, analgesic and
anti-lipemia activities. The compound [I] is useful in the treat-

ment of various rheumatic diseases, inflammations or pains
and lipemia solely or in combination with a solid or liquid
'~ ~ ~ - 11 -



.,

105~906
pharmaceutical carrier. Practical examples of suitable pharmaceu-
tical preparations of compound tI~ are tablets, capsules, pills,
granules, powders, suppositories, or injectable solutions.
The following examples are given solely for the purpose of
lllustration and not to be construed as limitation of the present
lnvent lon .
Example 1
A mixture of 2-chlorothiazole (5.0 g), ethyl 2-(4-hydroxy-
phenyl)propionate (8.1 g), potassium carbonate powder (8.65 g)
10 and dimethylformamide (80 ml) is stirred at 150-155C for 2.5
hours. The solvent is distilled out under reduced pressure. To
the residue is added water and extracted with ether. The extract
is washed with lO~o aqueous solution of sodium hydroxide and water
and dried. The ether is evaporated. The residue is subjected to
chromatography using silica gel and eluted with 50% benzene-
hexane, benzene and 10% ether-benzene to yield ethyl 2- [4-(2- .
thiazolyloxy)phenyl~propionate (5.8 g). IR yCCa 4 1740, 1240,
700 cm 1.
The product is dissolved in a mixture of 200~ aqueous solution
of potassium hydroxide (30 ml) and 95% ethanol (30 ml). The
solution is kept at room temperature for 30 minutes. The solvent
is evaporated. The residue is acidified with hydrochloric acid
after addition of water, and extracted with ether. The extract
is washed with water and dried over magnesium sulfate. The sol-
vent is distilled out. The residue is recrystallized from ether-
hexane to give 2-[4-(2-thiazolyloxy)phenyllpropionic acid (4.8 g).
IR ~Nujo 2520, 1715 cm Anal- C~lcd- for C12H113NS C~ 57-81
H, 4.45: N, 5.62; S, 12.86 Found: C, 57.72; H, 4.50; N, 5.69;
S, 12.70.
The product (5.0 g) is dissolved in an aqueous solution
12

lOS~906
(30 ml) of sodium hydroxide (0.82 g). To the solution washed
with ether is added an aqueous solution (5 ml) of calcium chlorid~
2 hydrate (1.6 g) to form precipitates. The precipitates washed
with water gives calcium 2-[4-(2-thiazolyloxy)phenyl~propionate
(5.5 g) melting at 143 - 145C.
IR~ aj 3400~ 1570 cm Anal. Calcd. for (C12H10O3N5)2-
Ca.2H20 : C, 50.33; H, 4.22: N, 4.89; Ca, 7.00 Found: C, 50.07;
H, 4.37; N, 4.91; Ca, 7.18.



A mixture of 2-chlorothiazole (2.0 g), ethyl 4-hydroxy-
benzoate (2.8 g), potassium carbonate powder (3.5 g) and dimethyl-
formamide (30 ml) is stirred at 135 - 140 C for 6 hours. The
reaction mixture is treated in the same manner as in Example 1.
From the eluate of 30% ether-benzene, ethyl 4-~2-thiozolyloxy)-
benzoate (1.16 g) is obtained. IR ~ 4 1730, 1280 cm
The product is hydrolyzed in the same manner as in Example 1
and recrystallized from ethanol to give 4-(2-thiazolyloxy)benzoic ;~
acid (1.00 g) melting at 162 - 163 C. IR~ maj 1680, 1240 cm
Anal. Calcd. for C12HllO3NS: C, 54.29; H, 3.19; N, 6.33; S, 14.49.
Found: C, 54.48; H, 3.13: N, 6.34: S, 14.24.
Example 3
A suspension of 2-bromothiazole (8.3 g), ethyl 3-fluoro-4-
hydroxybenzoate (7.7 g), potassium carbonate powder (8.7 g) and
cupric oxide (1 g) in pyridine (100 ml) is stirred at 160 C for
24 hours. The reaction mixture is filtered and the precipitate
is washed with benzene. The filtrate and benzene washings are
combined. The solvent is distilled out. The residue is dissolved
in benzene. The benzene solution is washed with lO~o aqueous
solution of sodium hydroxide and water successively, dried over
potassium carbonate and the solvent is evaporated. The residue

13

1~519~
i s sub jected to chromatograph~ using silica yel, F-~m benzene
and 2% ether-benzene eluates ethyl 3-fluoro-4-(2-thiazoluloxy)-
benzoate (2.2 g) is obtained.
The product is dissolved in a mixture (22 ml) of 20~ aqueous
solution of potassium hydroxide and ethanol (1:1). rhe solution
is kept at room temperature for 1 hour. The solvent is distilled
out. To the residue is added water. The solution is adjusted to
pH4 with hydrochloric acid and then extracted with ether. The
extract is washed with water and dried over magnesium sulfate.
The solvent is evaporated yielding 3-fluoro-4-t2-thiazolyloxy)-
benzoic acid (1.7 g) melting at 129-132C. Recrystallization
from ether gives crystals melting at 133-134C. Anal. calcd. for
C12H6O3NSF : C, 50.21; H, 2.53; N, 5.86; S, 13.40; ~, 7.94
Found: C, 50.44; H, 2.66; N, 5.71; S, 13.73; F, 7.62.
Examples 4-21
Treatments in the same manner as in Example 1 give the com-
pounds illustrated by the following formula:



~HCOOH
2 ~ 1 ~ ~ 1





10S~906

No 1 2 A Yl 2 mP(C)
4 H H O H H 4 H150-151
H H NH H H 4 H195-196
6 H H N-CH H H 4 H202-204
7 H H N-CH -CH=CH H H 4 H139-140
8 H H O H H 4 CH388-89
3 3 H H 4 CH3122-124
10CH3 ~ O H H 4 CH387-88
11 H H S H H 4 CH385-87
12 H H N-CH H H 4 CH3123-124
13 H H 3-CCH3 H 4 CH3Ca.H20 175(d)
14 H H 0 3-CH3 H 4 CH393~94
15 H H O 2-CH3 H 4 CH3120-121
16 H H o 2-Cl H 4 CH386-87
17 H H 0 3-Cl H 4 CH3115-116
18 H H 0 3-F H 4 CH3107-108
19 H H 0 2-C13-CH3 4 CH3147-148
20 H H 0 2-CH5-C1 4 CH130-131
21 H HN-CH -CH=CH HH 4 CH3118-119

Note: Figures in column Yl and Y2 represent the position where
substituent is present; for example 3-CH3 in colymn Yl means that
methyl group substitutes at 3 position of benzene ring.
*: The position of the benzene ring substituted by -A-thiazole
moiety.
Ca: Calcium salt
H20:hydrate
d: decomposition
The above significances are used in the followinq examples.
Example 22
Ethyl 2-bromo-5-thiazolecarboxylate (iO g), phenol (4.38 g)
" ~ 15

10~1906
~nd potassium carbonate powder (11.7 g) are suspend~d in dime~hyl-
formamide (S0 ml) and the suspension is stirred for 3 hours at
80C. The reaction mixture is filtered and the residue is washed
with benzene. The filtrate and washings are combined and the sol-

vent is distilled out under reduced pressure. The residue isdissolved in benzene, washed with water and a dilute aqueous
solution of sodium hydroxide, and dried over potassium carbonate.
The solution is subjected to chromatography using alumina eluted
with benzene. The solvent is evaporated yielding ethyl 2-phenoxy-

5-thiazolecarboxylate (10.2 g) boiling at 127-128C at 1 mmHg.
To a solution of the product in ethanol (30 ml) is added an
aqueous solution (3.5 ml) of sodium hydroxide (6 g). The solution
is kept at room temperature for 2 hours. The solvent is distilled
out and water is added to the residue. The solution is washed with
ether and adjusted to pH 3 with hydrochloric acid. Resultant
crystals are filtered, washed, dried and recrystallized from
acetone to give 2-phenoxy-5-thiazolecarboxylic acid (8.56 g)
melting at 172-173C. IR max 2400, 1840, 1710 cm Anal.
Calcd. for CloH7O3NS: C, 54.29; H, 3.19; N, 6-33; S, 14-49
Found: C, 54.32; H, 3.12; N, 6.25; S, 14.48.
Examples 23-34
Treatments in the same manner as in Example 22 give the
compounds illustrated by the following general formula:



Y2 ~ ~2~ ~ OOR

1051906

No 1 2 X R (o~) mp ( C)

23 H H 3 2 5 Pl~5 227-228(d)
242-CH3 3 mp 65-66 H17~3-180
253-CH H 0 " ~ bPl 120 H145-146
264-CH H 0 ~ " Pl H211-212
274-Cl H 04-CH3 C2H5 bPl 140 H219-220
28 H H S " ~ bpl 160-161 H187-188
294-Cl H 0 H " mp 66-67 H 210-211
30 H H 0 H " bpo 3133-135 H 177-178
314-Cl H 05-CH3 CH3 mp 82-82.5 H 158-159
32 H H 3 2 5 Pl H 92- 94
334-Cl H 0 H " mp 92-93 H214-215
34 H H S H " mp 84-85 H226-227
-

Example 35
A mixture of ethyl 2-bromo-4-thiazolylacetate (2.5 g) and N-
ethylaniline (2.1 g) is stirred at 150-155 C for 30 minutes. The
resultant solution is treated in the same manner as in Example 22
to give ethyl 2-(N-methylanilino)-4-thiazolylacetate (2.5 g).
The product is hydrolyzed in the same manner as in Example 22 and
recrystallized from ethyl acetate-hexane to give 2-(I~-methyl-
~ anilino)-4-thiazolylacetic acid (1.5 g) melting at 99-100 C
(decomp.). IR~ mai -2500, -1970, 1730 cm Anal. calcd. for
C12H1202N2S: C, 58.06; H, 4.87; N, 11.29; S, 12.89 Found:
C, 57.94; H, 4.90; N, 11.17; S, 12.62.
xamples 36-48
Treatments in the same manner as in Example 22 or 34 give
the compounds illustrated by the following general formula:
17

It~ 6 / ~ -


2 3 ~ 2 ~ X



_

No 1 2 A X R mp (C)
36 H H O H H Ca.l/2H20 120-122
37 H H S H H 112-113
38 H H NH H H 1/4CH3COCH3 140(d)
39 H H N-cH2-cH=cH2 H H Ca.2H2O 113-115
40 H 2 3 5 H H Ca.2H20 133-136(d)
41 H H N-CH -C H H H Ca.l/2H20 140-145(d)
42 H H 0 H CH3 Ca.2 1/2 H20 142(d)
43 H H CH3 CH3 Ca.2 1/2 H20 142(d)
44 4-Cl H o H CH3 Ca.2 1/2 H20 133-135
45 4-Cl H CH3 CH3 Ca.2 1/2 H20 134-136(d)
46 H HN-cH2-cH=cH2 H CH3 Ca.2H20 173-178(d)
47 H 2 3 5 H CH3 Ca.3H20 180-183
48 H HN-CH -C H H CH3 Ca.H20 120-125(d)

Note: C3H5 means cyclopropyl.
Examples 49-66
Treatments in the same manner as in Example 22 or 34 give
the compounds illustrated by the following general formula:



2 C A,-~ ~ CHCOOH


~

1051906


No 1 2 A X R mp(C)
49 H ~ c~3 H Ca.2 1/2H20 124(d)
50 H H S CH3 H 195-196
51 H H N-CH3 H H 186-187
52 H H N-CH3 CH3 H Ca.2H20 181(d)
53 H H N-CH -CH=CH H H 119-120
54 H H N-CH2-CH-CH2 CH3 H 116-117
55 H H 0 H CH3 Ca.l 1/2H20 169-170(d)
10 56 H H CH3 CH3 111.5-112.5
57 4-Cl H 0 H CH3 Ca.H20 145(d)
58 4-Cl H CH3 CH3 Ca.2 1/2H20 133(d)
59 4-CH3 H CH3 CH3 Ca.2 1/2H20 146(d)
3-CF3 H CH3 CH3 Ca.l 1/2 H20 106(d)
15 61 2-CH3 3-CH3 CH3 CH3 142-143
62 H H S CH3 CH3 128-130
63 H H NH CH3 CH3 1/2C2H50H 145(d)
64 3-CF3 H NH CH3 CH3 1/4cH3cocH3 195(d)
H H N-CH2-C3H5 CH3 CH3 120-121
20 66 H H N-CH -CH=CH H CH3 134-135
67 H H N-CH2-CH=CH2 CH3 CH3 106-107
~ = .. _ .. _ _ _ _ . . . . _ _
Note: C3H5 means cyclopropyl.

Example 68
A mixture of 2-(2-methyl-3-chloro-4-bromophenoxy)thiazole
(19.75 g), anhydrous dimethylformamide (70 ml) and cuprous cyanide
(12.2 g) is refluxed at 180 C for 2 hours and 45 minutes. To the
reaction mixture cooled to 65-70 C is added an aqueous solution
(50 ml) of sodium cyanide (7.7 g) and benzene (100 ml). The
30 solution is stirred at 60-70 C for 20 minutes. The benzene layer
19

10519(~6
is separated and the mother li~uor is extracted with benzene. The
benzene layer and the extract are combined, washed with 10~/o
aqueous solution of sodium cyanide and water and dried over sodium
sulfate. The solvent is evaporated yielding oily residue. The
residue is subjected to chromatography using silica gel. From
benzene eluate 2-(2-methyl-3-chloro-4-cyanophenoxy)thiazole (14 g)
is obtained. Recrystallization from 95% ethanol and benzene-
hexane gives crystals melting at 104-105 C. IR ~CC 4 2240, 700 cm.
The product is dissolved in a mixture of 20~/o aqueous solution
(57 ml) of potassium hydroxide and ethanol (57 ml) and the solu-
tion is refluxed for 7 hours. The solvent is distilled out. To
the residue is added water. The solution is acidified with hydro-
chloric acid. Oily precipitate formed is dissolved in an aqueous
solution of sodium hydrogen carbonate. The solution is washed
with dichloromethane ,acidified with hydrochloric acid and extrac-

ted with ether. The extract is washed with water and dried over
magnesium sulfate. The solvent is evaporated yielding 2-chloro-
3-methyl-4-(2-thiazolyloxy)benzoic acid (8.5 g). Recrystalliza-
tion from ethanol gives crystals melting at 150-152 C.
20 IR ~ ai 1695 cm . Anal. calcd. for CllH8O3NSCl : C,
48.98; H, 2.93; N, 5.19: S, 11.89: Cl, 13.15 Found: C, 49.09;
H, 3.00: N, 5.30: S, 11.94: Cl, 12.91.
The product is dissolved in ethereal solution of diazomethane.
The solvent is evaporated. The residue is dissolved in benzene.
The solution is washed with 10% aqueous solution of sodium hydrox-

ide and water, and dried over potassium carbonate. The solvent
is evaporated yielding methyl 2-chloro-3-methyl-4-(2-thiazolyloxy)-
benzoate (10.0 g).
Example 69
To a solution of 2-phenoxy-4-methyl-S-chloromethylthiazole



lOS~9V~;
(1.08 g) in anhydrous dimethylformamide (6 ml) are added sodium
cyanide (340 mg) and sodium iodide (60 mg). The mixture is
stirred at 50-55 C for 1 hour. The dimethylformamide is evaporated
under reduced pressure. The residue is extracted with ether after
addition of water. The extract is washed with water, dried over
magnesium sulfate and the solvent is evaporated yielding oily
residue. The residue is subjected to a column chromatography
using silica gel to give 2-phenoxy-4-methyl-5-cyanomethylthiazole
(800 mg) from the eluates of benzene and 5% ether-benzene.
B.P.o 1 148-155 C. IR ~ 4 1240, 1220, 2230 cm . NMR ~CDCl
-2.7 (Aromatic, 5H), 6.3 (s, 2H), 7.8 (s, 3H).
The above product (1.5 g) dissolved in a mixture of 2~/o
aqueous solution of potassium hydroxide and 95% ethanol (15 ml)
is refluxed for 2 hours with stirring. The solvent is distilled
out under reduced pressure. The residue is dissolved in water,
acidified with hydrochloric acid to form oily precipitate. The
precipitate is collected and dissolved in an aqueous solution of
sodium hydrogen carbonate. The solution is washed with chloro-
form, treated with active carbon, acidified with hydrochloric
acid, and extracted with ether. The extract is washed with water
and dried over magnesium sulfate. The solvent is evaporated
yielding 2-phenoxy-4-methyl-5-thiazolylacetic acid (1.20 g)
melting at 112-116 C. Yield is 74%. Recrystallization from
ether-hexane gives crystals melting at 120-121 C.
Example 70
(1) To a solution of diisopropylamine (430 mg) of tetra-
hydrofuran (8 ml) is added a solution (2.96 ml) of butyllithium-
hexane at below 0 C in nitrogen atmosphere. A solution of 2-
phenoxy-4-methyl-5-thiazolylacetic acid (450 mg) in anhydrous
tetrahydrofuran (4 ml) is dropwise added to the above mixture at
21

lOSl9V6
helow 0 C with stirring. To the resultant yellow transparent
solution is added hexamethylphosphoric triamide (0.77 ml) at
3-5 C and the mixture i~ stirred at 3-5 C for 15 minutes. After
addition of methyl iodide (1.3 g) at 0C, the mixture i8 stirred
for 4 hours at room temperature. The reaction mixture acidified
by dropwise addition of 10% hydrochloric acid, is extracted with
ether. The extract washed with water is extracted with an aqueous
solution of sodium hydrogen carbonate. After washed with ether,
the extract is acidified with hydrochloric acid and again extrac-

ted with ether. The ethereal extract is washed with water anddried over magnesium sulfate. The solvent is evaporated yielding
2-(2-phenoxy-4-methyl-5-thiazolyl)propionic acid (464 mg). Yield
is 9~%. Recrystallization from ether-hexane gives crystals
melting at 109-110C.
(2) A solution of 2-phenoxy-4-methyl-5-cyanomethylthiazole
(5.6 g) in anhydrous ethanol (56 ml) is saturated with dry hydro-
gen chloride. After stirring for 30 minutes, the ethanol and the
hydrogen chloride are evaporated. After addition of some pieces
of ice, the residue is made alkaline with sodium hydrogen carbonate
and extracted with ether. The extract is washed with an aqueous
solution of sodium hydrogen carbonate and water, and dried over
magnesium sulfate. The solvent is evaporated yielding oily resi-
due (6.7 g). Distillation under reduced pressure gives ethyl 2-
phenoxy-4-methyl-5-thiazolylacetate (6.57 g) boiling at 138-140 C

under 0.1 mmHg. Yield is 97 %. IR ~CC14 1745, 685 cm
max

NMR ~ CDCl -2~7 (Aromatic, 5H), 5.8 (q, 2H), 8.75 (t, 3H), 4.4
(s, 2H), 7.8 (s, 3H)o
The product (6.5 g) is dissolved in diethyl carbonate (22 ml)
and heated at 85-90 C with stirring. To the solution is dropwise
added an ethanol solution of sodium ethoxide, prepared from sodium

22

~05~906
(600 mg) and ethanol (13 ml), for 2 hours and the mixture is
stirred further for 2 hours. The diethyl carbonate is distilled
out. The residue is acidified with hydrochloric acid and extrac-
ted with ether. The extract is washed with water, dried over
magnesium sulfate and the solvent is evaporated yielding oily
residue (8.4 g). column chromatography using silica gel gives
diethyl 2-(2-phenoxy-4-methyl-5-thiazolyl)malonate (7.4 g) from
eluates of benzene and 5% ethanol-benzene. IR ~CC 4 1760, 1745
~ CDC13 2.7 (Aromatic, 5H), 5 2 (s lH)
10 8.75 (t, 3H), 7.7 (s, 3H).
To a solution of the product (7.4 g) in isopropanol (15 ml)
is dropwise added a solution of sodium isopropanol, prepared from
sodium (536 mg) and isopropanol (30 ml), at room temperature with
stirring. After 10 minutes methyl iodide (5 g) is dropwise added
15 at 75-80C. After another 10 minutes methyl iodide (10 mg) is
added and the mixture is kept to react for 1 hour. The solvent
is distilled out under reduced pressure. The residue is extracted
with ether after addition of water. The extract is washed with
dilute hydrochloric acid and water, and dried over magnesium
sulfate. The ether is evaporated yielding oily residue. Column
chromatography using silica gel gives diethyl ~2-methyl-2-(2-
phenoxy-4-methyl-5-thiazolyl)~malonate (6.73 g) melting at 65-67 C
from eluates of benzene and 5% ether-benzene. Yield is 8P/o.
Washing with hexane gives crystals melting at 73-73.5 C.
25 IR ~max4 1740, 685 cm N ~ cDcl 2.7 (Aromatic, 5H), 5.8
(q, 4H), 8.7 (t, 6H), 7.8 (s, 3H), 8.2 (s, 3H).
The product (5.9 g) is added to a mixture of 200/o aqueous
solution of potassium hydroxide and 95% ethanol (59 ml) and
refluxed for 20 minutes with stirring. The ethanol is distilled
out. The residue is acidified with hydrochloric acid to form a
23

~os~9o~
syrupy precipitate. It is ~issolve~ in an aqueous solution of
sodium hydrogen carbonate by heating. The solution is washed
with methylene chloride, treated with active carbon, acidified
with hydrochloric acid and then extracted with ether. The extract
is washed with water and dried over magnesium sulfate. The ether
is distilled out. The residue is treated with active carbon to
give 2-(2-phenoxy-4-methyl-5-thiazolyl)propionic acid (4.2 g).
Yield is 98%. Recrystallization from ether-hexane gives crystals
melting at 110-111C.
(3) To a solution of 2-phenoxy-4-methyl-5-cyanomethylthia-
zole (460 mg) in diethyl carbonate (3.4 ml) is dropwise added a
solution of sodium ethoxide in ethanol at 85-90 C with stirring
for 4 hours under reduced pressure. After the mixture is kept
for 1 hour, the diethyl carbonate is distilled out under reduced
pressure. The residue is acidified with hydrochloric acid and
extracted with ether. The solvent is evaporated yielding oily
residue (620 mg). By chromatography using silica gel eluted with
ethyl acetate:benzene(l:9), 2-cyano-2-(2-phenoxy-4-methylthiazolyl)-
acetate (385 mg) is obtained. Yield is 63%. IR ~max4 1760,
1240, 685 cm NMR~ CDCl 2.7 (Aromatic, 5H), 5.1 (s, lH), 5.7
(q, 2H), 8.7 ~t, 3H), 7.7 (s, 3H).
To a solution of the product (168 mg) in isopropanol (3 ml)
are dropwise added at room temperature an isopropanol solution
(2 ml) of sodium isopropaxide, prepared from sodium (14 mg), and
then methyl iodide (129 mg). The mixture is heated at 75-80 C
for 10 minutes and refluxed for further 30 minutes after another
addition of methyl iodide (129 mg). The solvent is distilled out.
The residue is acidified with hydrochloric acid and extracted
with ether. The solvent is evaporated yielding oily residue
(155 mg). ChromatOgraphy eluted with ethyl acetate-benzPne-
24

1051~V6
1 chloroform (1:1:3) gives ethyl 2-cyano-2-methyl-2-(2-phenoxy-4-
methyl-5-thiazolyl) acetate (104 mg.) IR max 1755, 1240, 685 cm
The product is dissolved in a mixture of 20~ aqueous solution
(2 ml) of potassium hydroxide and 95~ ethanol (2 ml). The solu-
tion is refluxed for 1.5 hours. The ethanol is evaporated. The
residue is acidified with hydrochloric acid and extracted with
ether. The ether is evaporated yielding 2-(2-phenoxy-4-methyl-5
thiazolyl)propionic acid (83 mg~. Recrystallization from ether-
hexane gives crystals melting at 110-112C.
The product is treated with calcium chloride in the same
manner as in Example 1 gives calcium 2 - (2-phenoxy-4-methyl-5-
Nujol
thiazolyl)propionate 2 1/2 hydrate. IR max 3680, 3380 cm

Anal. Calcd. for (C13H12O3NS2) Ca. 2 1/2H2O C, 51-23; H, 4-80;

N, 4.60 Found: C, 51.46; H, 4.69; N, 4.53.

Examples 71-79

Treatments in the same manner as in Example 70 give the

compounds illustrated by the following general formula:




~ CIH3
X

:
Ex. X Position of O
Propionic Acid Moiety mp( C)



71 H 4 Ca.2H2O 145-147
72 H 5 198-200

73 CH3 5 141-142



R



~S ~ O ~ CHCOOH


~ - 25 -
,~_, . . .

lOS~90~;
Ex . R mp ( C )
No . _ _ _
2 5 115-116
CH -CH=CH Ca.H20 134(d)
5 76 CH=C--CH 99-100
77 CH -C H 85-86
78 CH-CCH3=CH2 111-112
79 CH -C H 121-122

Note: C3H5 means cyclopropyl.




26