ALKYLTHIOALKYL-ISOXANZOLES AND -ISOXAZOLINES

ALKYLTHIOALKYL-ISOXAZOLES ET -ISOXAZOLINES

English Abstract

CONL-42
ALKYLTHIOALKYL-ISOXAZOLES AND
-ISOXAZOLINES
Abstract of the Disclosure
Compounds of the formula 1
<IMG> 1
in which the dotted line represents an optional
double bond, R1 is lower alkyl, COOH, COO(lower
alkyl), CONH2, CON(lower alkyl)2, CN, CH2OH,
CH2OSO2(lower alkyl), CH2O(lower alkyl), or
CH2S(lower alkyl), R2 is H, H2, or lower alkyl, R3
is H or S(lower alkyl), R4 and R5 are the same or
different and each is H, lower alkyl, S(lower alkyl),
COOH, or COO(lower alkyl), and the sulfoxides and sul-
fones of the above compounds as well as their
pharmaceutically acceptable salts. The compounds
possess anti-inflammatory, analgesic, and anti-pyretic
properties, and methods for their preparation and
use are also disclosed.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows.
1. A process for preparing compounds of the
formula 1
<IMG> 1
in which the dotted line represents an optional
double bond, R1 is lower alkyl, COOH, COO(lower
alkyl), CONH2, CON(lower alkyl)2, CN, CH2OH,
CH2OSO2(lower alkyl), CH2O(lower alkyl), CH2S(lower alkyl),
CH2SO(lower alkyl), or CH2SO2(lower alkyl), with the
proviso that R1 may only be lower alkyl when R3 contains a
sulfoxide or sulfone group or when R4 or R5 are other than
hydrogen or lower alkyl, R2 is H, H2, or lower alkyl with
the proviso that R2 is H2 when the double bond is absent
in which case there is an additional hydrogen atom at C5,
R3 is H, S(lower alkyl), SO(lower alkyl), or SO2(lower alkyl)
with the proviso that R3 is H only when R1 is CH2S(lower
alkyl), CH2SO(lower alkyl), or CH2SO2(lower alkyl) and that
only one of R1 or R3 must contain an S(lower alkyl),
SO(lower alkyl), or SO2(lower alkyl) group, R4 and R5 are
the same or different and each is H, lower alkyl, S(lower
alkyl), SO(lower alkyl), SO2(lower alkyl), COOH, or
COO(lower alkyl) with the proviso that only one of Rl, R4,
and R5 may be COOH or COO(lower alkyl), which comprises
(i) treating a 3-(lower alkyl)-5-methylthio(lower alkyl)-
isoxazole with substentially one or two molar equivalents
69

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of an organic peracid and isolating the corresponding
compounds of formula 1 in which the dotted line represent
a double bond, R1 is lower alkyl, R2 is hydrogen, R3 is
SO(lower alkyl) or SO2(lower alkyl), respectively, and R4
and R5 are both hydrogen, or
(ii) treating a 3-(lower alkyl)-5-methylthio(lower alkyl)-
isoxazole with n-butyllithium followed by a di(lower alkyl)-
disulfide and isolating the corresponding thioacetal of
formula 1 in which the dotted line represents a double bond,
R1 is lower alkyl, R2 is hydrogen, R3 and R4 are both
S(lower alkyl) and R5 is hydrogen, or
(iil) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 and R are both S(lower alkyl) and
R5 is hydrogen with substantially one, two, three or four
molar equivalents of an organic peracid and isolating,
respectively,
the corresponding compound of formula 1 in which the dotted
line, R1, R2, R4, and R5 are as defined above and R3 is
SO(lower alkyl), or
the corresponding compound of formula 1 in which the dotted
line, R1, R2, and R5 are as defined in the first instance
of section (iii) and both R3 and R4 are SO(lower alkyl),
o r
the corresponding compound of formula 1 in which the dotted
line, R1, R2, and R5 are as defined in the first instance
of section (iii), R3 is SO2(lower alkyl), and R4 is
SO(lower alkyl), or
the corresponding compound of formula 1 in which the dotted
line, R1, R2, and R5 are as defined in the first instance

CONL-42
of section (iii) and both R3 and R4 are SO2(lower alkyl),
or
(iv) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 is SO2(lower alkyl), and R4 and R5 are
both hydrogen with n-butyllithium followed by a di(lower
alkyl)disulfide and isolating the corresponding compound
of formula 1 in which R1, R2, R3, and R5 are as defined
Immediately above and R4 is S(lower alkyl), or
(v) treating a thioacetal of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 and R4 are both S(lower alkyl), and
R5 is hydrogen with n-butyllithium followed by a di(lower
alkyl)disulfide and isolating the corresponding ortho-thio-
ester of formula 1 in which R1 and R2 are as defined imme-
diately above and R3, R4, and R5 are all S(lower alkyl),
or
(vi) treating a 3-(lower alkyl)-5-methylthio(lower
alkyl)isoxazole with n-butyllithium followed by a lower
alkyl halide and isolating the corresponding compound of
formula 1 in which the dotted line represents a double
bond, R1 is lower alkyl, R2 is hydrogen, R3 is S(lower
alkyl), R4 is lower alkyl, and R5 is hydrogen, or
(vii) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower
alkyl, R2 is hydrogen, R3 is S(lower alkyl),
R4 is lower alkyl, and R5 is hydrogen with n-butyllithium
71

CONL-42
followed by a lower alkyl halide and isolating the corres-
ponding compound of formula 1 in which R1, R2, R3, and R4
are as defined immediately above and R5 is lower alkyl,
or
(viii) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 is S(lower alkyl), R4 is lower alkyl,
and R5 is hydrogen with substantially one or two molar
equivalents of an organic peracid and isolating, respectively,
the corresponding compound of formula 1 in which the dotted line, R1,
R2, R4 and R5 are as defined immediately above and R3 is SO(lower alkyl)
or the corresponding compound of formula 1 in which the dotted line,
R1, R2, R4 and R5 are as defined immediately above and R3 is SO2(lower
alkyl), or
(ix) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 is S(lower alkyl), and R4 and R5 are
both lower alkyl with substentially one or two molar equi-
valents of an organic peracid and isolating, respectively,
the corresponding compound of formula 1 in which the dotted
line, R1, R2, R4 and R5 are as defined immediately above
and R3 is SO(lower alkyl), or
the corresponding compound of formula 1 in which the dotted
line, R1, R2, R4 and R5 are as defined immediately above and
R3 is SO2(lower alkyl), or
(x) treating a 3-(lower alkyl)-5-methylthiotlower
alkyl)isoxazole with n-butyllithium followed by carbon
dioxide and isolating the corresponding compound of
formula 1 in which the dotted line represents a double
72

CONL-42
bond, R1 is lower alkyl, R2 is hydrogen, R3 is S(lower
alkyl), R4 is COOH, and R5 is hydrogen, or
(xi) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 and R4 are both S(lower alkyl), and
R5 is hydrogen with n-butyllithium followed by carbon
dioxide and isolating the corresponding compound of
formula 1 in which the dotted line, R1, R2, R3 and R4
are as defined immediately above and R5 is COOH, or
(xii) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 is S(lower alkyl), R4 is COOH or
S(lower alkyl), and R5 is hydrogen or COOH with a diazo-
(lower alkane) or treating the lithium salts of the
above acids with a lower alkyl halide, and isolating the
corresponding compound of Formula 1 in which the dotted
lines, R1, R2, and R3 are as defined immediately above,
R4 is COO(lower alkyl) or S(lower alkyl), respectively,
and R5 is hydrogen or COO(lower alkyl), respectively, or
(xiii) treating a compound of formula 1 in which the
dotted line represent a double bond, R1 is lower alkyl,
R2 is hydrogen, R3 is S(lower alkyl), R4 is COO(lower
alkyl) or S(lower alkyl), and R5 is hydrogen or COO(lo-
wer alkyl) with substantially one, two, three or four
molar equivalents of an organic peracid and isolating,
respectively, the corresponding compound of formula 1
in which the dotted line, R1, and R2 are as defined
immediately above, and
73

CONL-42
R3 is SO(lower alkyl), R4 is COO(lower alkyl)
and R5 is hydrogen, or
R3 is SO2(lower alkyl), R4 is COO(lower alkyl)
and R5 is hydrogen, or
R3 and R are both SO(lower alkyl) and R5 is
COO(lower alkyl), or
R3 is SO2(lower alkyl), R4 is SO(lower alkyl)
and R5 is COO(lower alkyl), or
R3 and R4 are both SO2(lower alkyl) and R5 is
COO(lower alkyl), or
(xiv) treating a lower alkyl chloroximinoacetate with
an organic base and a propargyl halide to obtain the
corresponding lower alkyl 5-halomethylisoxazole-3-carboxy-
late, treating said last-named compound wlth an alkali
metal lower alkyl mercaptan and isolating the correspon-
ding compound of formula 1 in which the dotted line re-
presents a double bond, R1 is COO(lower alkyl), R2 is
hydrogen, R3 is S(lower alkyl), and R4 and R5 are both
hydrogen, or
(xv) treating said last-named compound with substan-
tially one or two molar equivalents of an organic peracid
and isolating the corresponding compound of formula 1 in
which R1, R2, R4 and R5 are as defined immediately above
and R3 is SO(lower alkyl) or SO2(lower alkyl), respec-
tively, or
(xvi) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is COO(lower
alkyl), R2 is hydrogen, R3 is S(lower alkyl) or SO2(lo-
wer alkyl), and R4 and R5 are both hydrogen with a strong
74

CONL-42
mineral acid and isolating the corresponding compound
of formula 1 in which R1 is COOH, R3 is S(lower alkyl)
or SO2(lower alkyl), respectively, and R2, R4, and R5
are all hydrogen, or
(xvii) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is
COO(lower alkyl), R3 is S(lower alkyl) and R2, R4, and R5
are all hydrogen with a di(lower alkyl)amine and isolating
the corresponding compound of formula 1 in which R1 is
CON(lower alkyl)2, and R2, R3, R4 and R5 are as defined
immediately above, or
(xviii) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is COO(lower alkyl),
R3 is S(lower alkyl), and R2, R4, and R5 are all hydrogen
with ammonia and isolating the corresponding compound of
formula 1 in which R1 is CONH2 and R2, R3, R4, and R5 are
as defined immediately above, or
(xix) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is CONH2, R3 is
S(lower alkyl), and R2, R4, and R5 are all hydrogen with
n-butyllithium followed by a lower alkyl halide and iso-
lating the corresponding compound of formula 1 in which R1,
R2, R3 and R5 are as defined immediately above and R is
lower alkyl, or
(xx) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is CONH2, R3 is
S(lower alkyl), and R2, R4 and R5 are all hydrogen with a

CONL-42
dehydrating agent and isolating the corresponding compound
of formula 1 in which R1 is CN and R2, R3, R4, and R5 are
as defined immediately above, or
(xxi) treating a compound of formula 1 in which the
dotted line represents a double bond, R1 is COO(lower alkyl),
R3 is S(lower alkyl) and R2, R4 and R5 are all hydrogen
with an alkali metal aluminium hydride and isolating the
corresponding compound of formula 1 in which R1 is CH2OH,
and R2, R3, R4, and R5 are as defined immediately above,
or
(xxii) treating said last-named compound with a lower
alkyl sulfonyl halide and isolating the corresponding
compound of formula 1 in which R1 is CH2OSO2(lower alkyl)
and R2, R3, R4, and R5 are as defined immediately above,
or
(xxiii) treating said last-named compound with an alkali
metal lower alkoxide and isolating the corresponding com-
pound of formula 1 in which R1 is CH2O(lower alkyl) and
R2, R3, R4, and R5 are as defined immediately above, or
(xxiv) treating a lower alkyl chloroximinoacetate with
an organic base and an allyl(lower alkyl)sulfide and
isolating the corresponding compound of formula 1 in which
the dotted line is regarded as being absent to indicate a
single bond C4-C5, R1 is COO(lower alkyl), R2 is H2, R3 is
S(lower alkyl), and R4 and R5 are both hydrogen, or
(xxv) treating said last-named compound with substantial-
76

CONL-42
ly one or two molar equivalents of an organic peracid
and isolating the corresponding compound of formula 1
in which the dotted line, R1, R2, R4, and R5 are as defi-
ned immediately above and R3 is SO(lower alkyl) or SO2-
(lower alkyl), respectively, or
(xxvi) treating a compound of formula 1 in which the
dotted line is regarded as being absent to indicate a
single bond C4-C5, R1 is COO(lower alkyl), R2 is H2, R3
is S(1ower alkyl) and R4 and R5 are both hydrogen with a
strong mineral acid and isolating the corresponding com-
pound of formula 1 in which R1 is COOH and the dotted line,
R2, R3, R4, and R5 are as defined immediately above, or
(xxvii) treating a compound of formula 1 in which the
dotted line is regarded as being absent to indicate a
single bond C4-C5, R1 is COO(lower alkyl), R2 is H2, R3
is S(lower alkyl), and R4 and R5 are both hydrogen with
ammonium hydroxide and isolating the corresponding com-
pound of formula 1 in which R1 is CONH2 and the dotted
line,R2, R3, R4, and R5 are as defined immediately above,
or
(xxviii) treating said last-named compound with a dehydra-
ting agent and isolating the corresponding compound of
formula I in which R1 is CN and the dotted line, R2, R3,
R4, and R5 are as defined immediately above, or
(xxix) treating a compound of formula 1 in which the
dotted line is regarded as being absent to indicate a
single bond C4-C5, R1 is COOH, CONH2, or CN, R2 is H2,
77

CONL-42
R3 is S(lower alkyl), and R4 and R5 are both hydrogen with
substantially one or two molar equivalents of an organic
peracid and isolating the corresponding compounds of
formula 1 in which R3 is SO(lower alkyl) or SO2(lower
alkyl), respectively, and R1, R2, R4, and R5 are as defi-
ned immediately above, or
(xxx) treating a 3-(lower alkyl)pentane-2,4-dione with
hydroxylamine to obtain the corresponding compound of
formula 1 in which the dotted line represents a double
bond, R1 is methyl, R2 is lower alkyl, and R3, R4, and
R5 are all hydrogen; treating said last-named compound with
n-butyllithium follwed by a di(lower alkyl)disulfide and
isolating the corresponding compound of formula I in which
the dotted line represents a double bond. R1 is CH2S(lower
alkyl), R2 is lower alkyl, and R3, R4 and R5 are all hydro-
gen, and the corresponding compound of formula 1 in which
the dotted line represents a double bond, R1 is methyl,
R2 is lower alkyl, R3 is S(lower alkyl), and R4 and R5 are
both hydrogen, or
(xxxi) treating each of said last-named compounds of
formula 1 with substantially one or two molar equivalents
of an organic peracid and isolating, respectively, the
corresponding compounds of formula 1 in which the dotted
line is as defined above, R1 is CH2SO(lower alkyl) or
CH2SO2(lower alkyl), R2 is lower alkyl, and R3, R4, and
R5 are all hydrogen, and the corresponding compound of
formula 1 in which the dotted line is as defined above,
R1 is methyl, R2 is lower alkyl, R3 is SO(lower alkyl ) or
SO2(lower alkyl), and R4 and R5 are both hydrogen, or
78

CONL-42
(xxxii) treating a compound of formula 1 in which the
dotted line represents a bouble bond, R1 is methyl,
R2 is lower alkyl, R3 is S(lower alkyl), and R4 and R5
are both hydrogen with n-butyllithium followed by a
di(lower alkyl)disulfide, and isolating the corresponding
compound of formula 1 in which R1, R2, R3, and R5 are as
defined immediately above and R4 is S(lower alkyl).
79

2. A process as claimed in Claim 1 in which R1 is
selected from CH3, COOEt, COOH, CON(CH3)2, CONH2, CN, CH2OH,
CH2OSO2CH3, CH2OCH3, CH2SCH3, CH2SOCH3, and CH2SO2CH3; R2 is
selected from H, H2, and CH3; R3 is selected from SCH3,
SOCH3, SO2CH3, and H; R4 is selected from H, SCH3, SOCH3,
SO2CH3, CH3, COOH, and COOCH3; and R5 is selected from H,
SCH3, CH3, COOH, and COOCH3.
3. A process as claimed in Claim 1 in which the
organic peracid is m-chloroperbenzoic acid.
4. A process as claimed in Claim 1 in which the
di(lower alkyl)disulfide is dimethyldisulfide.
5. A process as claimed in Claim 1 in which the
organic base is triethylamine.
6. A process as claimed in Claim 1 in which the
lower alkyl chloroximinoacetate is ethyl chloroximinoacetate.
7. A process as claimed in Claim 1 in which the 3-
(lower alkyl)pentane-2,4-dione is 3-methylpentane-2,4-dione.
8. A compound of the formula 1
<IMG>
in which the dotted line represents an optional double bond,
R1 is lower alkyl, COOH, COO(lower alkyl), CONH2, CON(lower
alkyl)2, CN, CH2OH, CH2OSO2(lower alkyl), CH2O(lower alkyl),
CH2S(lower alkyl), CH2SO(lower alkyl), or CH2SO2(lower alkyl),
with the proviso that R1 may only be lower alkyl when R3
contains a sulfoxide or sulfone group or when R4 or R5 are

other than hydrogen or lower alkyl, R2 is H, H2, or lower
alkyl with the proviso that R2 is H2 when the double bond is
absent in which case there is an additional hydrogen atom at
C5, R3 is H, S(lower alkyl), SO(lower alkyl), or SO2(lower
alkyl) with the proviso that R3 is H only when R1 is
CH2S(lower alkyl), CH2SO(lower alkyl), or CH2SO2(lower alkyl)
and that only one of R1 or R3 must contain an S(lower alkyl),
SO(lower alkyl), or SO2(lower alkyl) group, R4 and R5 are the
same or different and each is H, lower alkyl, S(lower alkyl),
SO(lower alkyl), SO2(lower alkyl), COOH, or COO(lower alkyl)
with the proviso that only one of R1, R4, and R5 may be COOH
or COO(lower alkyl),
when prepared by the process of Claim 1 or by an obvious
chemical equivalent thereof.
9. A compound of the formula 1 in which R1 is
selected from CH3, COOEt, COOH, CON(CH3)2, CONH2, CN, CH2OH,
CH2OSO2CH3, CH2OCH3, CH2SCH3, CH2SOCH3, and CH2SO2CH3; R2 is
selected from H, H2, and CH3; R3 is selected from SCH3,
SOCH3, SO2CH3, and H; R4 is selected from H, SCH3, SOCH3,
SO2CH3, CH3, COOH, and COOCH3; and R5 is selected from H,
SCH3, CH3, COOH, and COOCH3; with the provisos that R1 may
only be CH3 when R3 contains a sulfoxide or sulfone group or
when R4 or R5 are other than hydrogen or CH3; that R2 is H2
when the double bond is absent in which case there is an
additional hydrogen atom at C5; that R3 is H only when R1 is
CH2SCH3, CH2SOCH3, or CH2SO2CH3; that only one of R1 or R3
must contain an SCH3, SOCH3, or SO2CH3 group; and that only
one of R1, R4, or R5 may be COOH or COOCH3; when prepared by
the process of Claims 1 or 2 or by an obvious chemical
equivalent thereof.
81

10. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-methylthiomethylisoxazole
in a solvent selected from aliphatic hydrocarbons and cyclic
ethers at -20°C to -95°C with substantially one molar equiva-
lent of n-butyllithium, adding the resulting mixture to a
solution containing substantially one molar equivalent of
dimethyldisulfide, and isolating 3-methyl-5-di(methylthio)-
methylisoxazole.
11. 3-Methyl-5-di(methylthio)methylisoxazole, when
prepared by the process of Claim 10 or by an obvious chemical
equivalent thereof.
12. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-di(methylthio)methyl-
isoxazole in a solvent selected from aliphatic hydrocarbons
and cyclic ethers at -20°C to -95°C with substantially one
molar equivalent of n-butyllithium, adding the resulting
mixture to a solution containing substantially one molar
equivalent of dimethyldisulfide, and isolating 3-methyl-5-
tri(methylthio)methylisoxazole.
13. 3-Methyl-5-tri(methylthio)methylisoxazole, when
prepared by the process of Claim 12 or by an obvious chemical
equivalent thereof.
14. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-methylthiomethylisoxazole
in a halogenated hydrocarbon solvent at a temperature within
the range of from -10°C to 10°C with substantially one molar
equivalent of m-chloroperbenzoic acid, and isolating (3-
methyl-5-isoxazolylmethyl)methylsulfoxide.
82

15. (3-Methyl-5-isoxazolylmethyl)methylsulfoxide,
when prepared by the process of Claim 14 or by an obvious
chemical equivalent thereof.
16. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-methylthiomethylisoxazole
in a halogenated hydrocarbon solvent at a temperature within
the range of from -10°C to 10°C with substantially two molar
equivalents of m-chloroperbenzoic acid, and isolating (3-
methyl-5-isoxazolylmethyl)methylsulfone.
17. (3-Methyl-5-isoxazolylmethyl)methylsulfone,
when prepared by the process of Claim 16 or by an obvious
chemical equivalent thereof.
18. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-.alpha.-(methylthio)ethylisox-
azole in a halogenated hydrocarbon solvent at a temperature
within the range of from -10°C to 10°C with substantially one
molar equivalent of m-chloroperbenzoic acid, and isolating
(3-methyl-5-isoxazolyl-.alpha.-ethyl)methylsulfoxide.
19. (3-Methyl-5-isoxazolyl-.alpha.-ethyl)methylsulfoxide,
when prepared by the process of Claim 18 or by an obvious
chemical equivalent thereof.
20. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-.alpha.-(methylthio)ethylisox-
azole in a halogenated hydrocarbon solvent at a temperature
within the range of from -10°C to 10°C with substantially two
molar equivalents of m-chloroperbenzoic acid, and isolating
(3-methyl-5-isoxazolyl-.alpha.-ethyl)methylsulfone.
83

21. (3-Methyl-5-isoxazolyl-.alpha.-ethyl)methylsulfone,
when prepared by the process of Claim 20 or by an obvious
chemical equivalent thereof.
22. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-.alpha.,.alpha.-di(methyl)methylthio-
methylisoxazole in a halogenated hydrocarbon solvent at a
temperature within the range of from -10°C to 10°C with
substantially one molar equivalent of m-chloroperbenzoic
acid, and isolating (3-methyl-5-isoxazolyl-.alpha.,.alpha.-dimethyl-
methyl)methylsulfoxide.
23. (3-Methyl-5-isoxazolyl-.alpha.,.alpha.-dimethylmethyl)-
methylsulfoxide, when prepared by the process of Claim 22 or
by an obvious chemical equivalent thereof.
24. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-.alpha.,.alpha.-di(methyl)methylthio-
methylisoxazole in a halogenated hydrocarbon solvent at a
temperature within the range of from -10°C to 10°C with
substantially two molar equivalents of m-chloroperbenzoic
acid, and isolating (3-methyl-5-isoxazolyl-.alpha.,.alpha.-dimethyl-
methyl)methylsulfone.
25. (3-Methyl-5-isoxazolyl-.alpha.,.alpha.-dimethylmethyl)-
methylsulfone, when prepared by the process of Claim 24 or
by an obvious chemical equivalent thereof.
26. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-di(methylthio)methylisox-
azole in a halogenated hydrocarbon solvent at a temperature
within the range of from -10°C to 10°C with substantially one
molar equivalent of m-chloroperbenzoic acid, and isolating
3-methyl-5-.alpha.-(methylsulfoxide)methylthiomethylisoxazole.
84

27. 3-Methyl-5-.alpha.-(methylsulfoxide)methylthiomethyl-
isoxazole, when prepared by the process of Claim 26 or by an
obvious chemical equivalent thereof.
28. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-di(methylthio)methyl-
isoxazole in an inert solvent at a temperature within the
range of from -10°C to 10°C with substantially two molar
equivalents of m-chloroperbenzoic acid, and isolating 3-
methyl-5-.alpha.,.alpha.-di(methylsulfoxide)methylisoxazole.
29. 3-Methyl-5-.alpha.,.alpha.-di(methylsulfoxide)methyl-
isoxazole, when prepared by the process of Claim 28 or by
an obvious chemical equivalent thereof.
30. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-di(methylthio)methyl-
isoxazole in an inert solvent at a temperature within the
range of from -10°C to 10°C with substantially three molar
equivalents of m-chloroperbenzoic acid, and isolating 3-
methyl-5-.alpha.-(methylsulfone)-.alpha.-(methylsulfoxide)methylisoxazole.
31. 3-Methyl-5-.alpha.-(methylsulfone)-.alpha.-(methyl-
sulfoxide)methylisoxazole, when prepared by the process
of Claim 30 or by an obvious chemical equivalent thereof.
32. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-di(methylthio)methyl-
isoxazole in an inert solvent at a temperature within the
range of from -10°C to 10°C with substantially four molar
equivalents of m-chloroperbenzoic acid, and isolating 3-
methyl-5-di(methylsulfone)methylisoxazole.

33. 3-Methyl-5-di(methylsulfone)methylisoxazole,
when prepared by the process of Claim 32 or by an obvious
chemical equivalent thereof.
34. A process as claimed in Claim 1 which comprises
agitating a suspension of 3-methyl-5-methylsulfonemethyl-
isoxazole in a cyclic ether with a substantially equimolar
amount of n-butyllithium dissolved in the same solvent at a
temperature within the range of from -20°C to -95°C, adding a
substantially equimolar amount of dimethyldisulfide dissolved
in the same solvent, and isolating 3-methyl-5-.alpha.-(methyl-
sulfone)methylthiomethylisoxazole.
35. 3-Methyl-5-.alpha.-(methylsulfone)methylthiomethyl-
isoxazole, when prepared by the process of Claim 34 or by an
obvious chemical equivalent thereof.
36. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-methylthiomethylisoxazole
in a cyclic ether with a substantially equimolar amount of
n-butyllithium dissolved in the same solvent at a temperature
within the range of from -65°C to -95°C, contacting the
reaction mixture with a large molar excess of carbon dioxide,
and isolating 3-methylisoxazole-5-.alpha.-(methylthio)acetic acid.
37. 3-Methylisoxazole-5-.alpha.-(methylthio)acetic acid,
when prepared by the process of Claim 36 or by an obvious
chemical equivalent thereof.
38. A process as claimed in Claim 1 which comprises
agitating a mixture of the lithium salt of 3-methylisoxazole-
5-.alpha.-(methylthio)acetic acid with a substantially equimolar
amount of methyl iodide in dimethylformamide at ambient
temperature, and isolating methyl 3-methylisoxazole-5-.alpha.-
86

(methylthio)acetate.
39. Methyl 3-methylisoxazole-5-.alpha.-(methylthio)-
acetate, when prepared by the process of Claim 38 or by an
obvious chemical equivalent thereof.
40. A process as claimed in Claim 1 which comprises
contacting 3-methylisoxazole-5-.alpha.-(methylthio)acetic acid with
diazomethane, and isolating methyl 3-methylisoxazole-5-.alpha.-
(methylthio)acetate.
41. Methyl 3-methylisoxazole-5-.alpha.-(methylthio)-
acetate, when prepared by the process of Claim 40 or by an
obvious chemical equivalent thereof.
42. A process as claimed in Claim 1 which comprises
agitating a solution of methyl 3-methylisoxazole-5-.alpha.-methyl-
thio)acetate in an inert solvent at a temperature within the
range of from -10°C to 10°C with substantially one molar
equivalent of m-chloroperbenzoic acid, and isolating methyl
3-methylisoxazole-5-.alpha.-(methylsulfoxide)acetate.
43. Methyl 3-methylisoxazole-5-.alpha.-(methylsulfoxide)-
acetate, when prepared by the process of Claim 42 or by an
obvious chemical equivalent thereof.
44. A process as claimed in Claim 1 which comprises
agitating a solution of methyl 3-methylisoxazole-5-.alpha.-(methyl-
thio)acetate in an inert solvent at a temperature within the
range of from -10°C to 10°C with substantially two molar
equivalents of m-chloroperbenzoic acid, and isolating methyl
3-methylisoxazole-5-.alpha.-(methylsulfone)acetate.
87

45. Methyl 3-methylisoxazole-5-.alpha.-(methylsulfone)-
acetate, when prepared by the process of Claim 44 or by an
obvious chemical equivalent thereof.
46. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methyl-5-di(methylthio)methyl-
isoxazole in a cyclic ether with a substantially equimolar
amount of n-butyllithium dissolved in the same solvent at a
temperature within the range of from -65°C to -95°C, con-
tacting the reaction mixture with a large molar excess of
carbon dioxide, and isolating 3-methylisoxazole-5-.alpha.,.alpha.-
di(methylthio)acetic acid.
47. 3-Methylisoxazole-5-.alpha.,.alpha.-di(methylthio)acetic
acid, when prepared by the process of Claim 46 or by an
obvious chemical equivalent thereof.
48. A process as claimed in Claim 1 which comprises
agitating a mixture of the lithium salt of 3-methylisoxazole-
5-.alpha.,.alpha.-di (methylthio)acetic acid with a substantially equi-
molar amount of methyl iodide in dimethylformamide at ambient
temperature, and isolating methyl 3-methylisoxazole-5-.alpha.,.alpha.-
di(methylthio)acetate.
49. Methyl 3-methylisoxazole-5-.alpha.,.alpha.-di(methylthio)-
acetate, when prepared by the process of Claim 48 or by an
obvious chemical equivalent thereof.
50. A process as claimed in Claim 1 which comprises
contacting 3-methylisoxazole-5-.alpha.,.alpha.-di(methylthio)acetic acid
with diazomethane, and isolating methyl 3-methylisoxazole-5-
.alpha.,.alpha.-di(methylthio)acetate.
88

51. Methyl 3-methylisoxazole-5-.alpha.,.alpha.-di(methylthio)-
acetate, when prepared by the process of Claim 50 or by an
obvious chemical equivalent thereof.
52. A process as claimed in Claim 1 which comprises
adding a substantially equimolar amount of triethylamine
dissolved in ether to a substantially equimolar mixture of
ethyl chloroximinoacetate and propargyl bromide in toluene
and agitating at ambient temperature to obtain ethyl 5-
bromomethylisoxazole-3-carboxylate; adding said last-named
compound to a solution in ether or a cyclic ether containing
a substantially equimolar amount of the lithio salt of methyl
mercaptan at a temperature within the range of from 0°C to
ambient temperature, agitating the mixture thus obtained, and
isolating ethyl 5-methylthiomethylisoxazole-3-carboxylate.
53. Ethyl 5-methylthiomethylisoxazole-3-carboxylate,
when prepared by the process of Claim 52 or by an obvious
chemical equivalent thereof.
54. A process as claimed in Claim 1 which comprises
agitating a solution of ethyl 5-methylthiomethylisoxazole-3-
carboxylate in an inert solvent with substantially one molar
equivalent of m-chloroperbenzoic acid, and isolating ethyl
5-(methylsulfoxide)methylisoxazole-3-carboxylate.
55. Ethyl 5-(methylsulfoxide)methylisoxazole-3-
carboxylate, when prepared by the process of Claim 54 or by
an obvious chemical equivalent thereof.
56. A process as claimed in Claim 1 which comprises
agitating a solution of ethyl 5-methylthiomethylisoxazole-3-
carboxylate in an inert solvent with substantially two molar
equivalents of m-chloroperbenzoic acid, and isolating ethyl
89

5-(methylsulfone)methylisoxazole-3-carboxylate.
57. Ethyl 5-(methylsulfone)methylisoxazole-3-
carboxylate, when prepared by the process of Claim 56 or by
an obvious chemical equivalent thereof.
58. A process as claimed in Claim 1 which comprises
agitating ethyl 5-methylthiomethylisoxazole-3-carboxylate
with a molar excess of concentrated hydrochloric acid at
ambient temperature, and isolating 5-methylthiomethyl-
isoxazole-3-carboxylic acid.
59. 5-Methylthiomethylisoxazole-3-carboxylic acid,
when prepared by the process of Claim 58 or by an obvious
chemical equivalent thereof.
60. A process as claimed in Claim 1 which comprises
agitating ethyl 5-(methylsulfone)methylisoxazole-3-carbox-
ylate with a molar excess of concentrated hydrochloric acid
at ambient temperature, and isolating 5-(methylsulfone)-
methylisoxazoie-3-carboxylic acid.
61. 5-(Methylsulfone)methylisoxazole-3-carboxylic
acid, when prepared by the process of Claim 60 or by an
obvious chemical equivalent thereof.
62. A process as claimed in Claim 1 which comprises
agitating ethyl 5-methylthiomethylisoxazole-3-carboxylate
with a molar excess of concentrated ammonia at ambient
temperature, and isolating 5-methylthiomethylisoxazole-3-
carboxamide.
63. 5-Methylthiomethylisoxazole-3-carboxamide, when
prepared by the process of Claim 62 or by an obvious chemical
equivalent thereof.

64. A process as claimed in Claim 1 which comprises
adding a molar excess of dimethylamine to a solution of ethyl
5-methylthiomethylisoxazole-3-carboxylate in ether, keeping
the resulting mixture in a closed pressure vessel for several
weeks, and isolating 5-methylthiomethylisoxazole-3-dimethyl-
carboxamide.
65. 5-Methylthiomethylisoxazole-3-dimethylcarbox-
amide, when prepared by the process of Claim 64 or by an
obvious chemical equivalent thereof.
66. A process as claimed in Claim 1 which comprises
agitating and heating at 80°C to 150°C a mixture of 5-
methylthiomethylisoxazole-3-carboxamide and 2 - 10 molar
equivalents of phosphorus pentoxide in an aromatic hydro-
carbon solvent for 5 - 12 hours, and isolating 3-cyano-5-
methylthiomethylisoxazole.
67. 3-Cyano-5-methylthiomethylisoxazole, when
prepared by the process of Claim 66 or by an obvious chemical
equivalent thereof.
68. A process as claimed in Claim 1 which comprises
agitating a solution of 5-methylthiomethylisoxazole-3-
carboxamide in a cyclic ether with substantially two molar
equivalents of n-butyllithium at a temperature within the
range of from -50°C to -100°C, adding substantially two molar
equivalents of methyl iodide with continued agitation at the
same temperature as above, and isolating 5-.alpha.-(methylthio)-
ethylisoxazole-3-carboxamide.
69. 5-.alpha.-(Methylthio)ethylisoxazole-3-carboxamide,
when prepared by the process of Claim 68 or by an obvious
chemical equivalent thereof.
91

70. A process as claimed in Claim 1 which comprises
agitating a mixture of ethyl 5-methylthiomethylisoxazole-3-
carboxylate and substantially 1.0 to 1.2 molar equivalents of
lithium aluminium hydride at a temperature within the range
of from -10°C to 10°C in a cyclic ether, and isolating 3-
hydroxymethyl-5-methylthiomethylisoxazole.
71. 3-Hydroxymethyl-5-methylthiomethylisoxazole,
when prepared by the process of Claim 70 or by an obvious
chemical equivalent thereof.
72. A process as claimed in Claim 1 which comprises
adding 1.0 - 1.1 molar equivalents of mesyl chloride to a
mixture of 3-hydroxymethyl-5-methylthiomethylisoxazole and
1 - 2 molar equivalents of triethylamine in a halogenated
hydrocarbon solvent at a temperature within the range of from
-10°C to 0°C, agitating the resulting mixture within the same
temperature range, and isolating 3-mesyloxymethyl-5-methyl-
thiomethylisoxazole.
73. 3-Mesyloxymethyl-5-methylthiomethylisoxazole,
when prepared by the process of Claim 72 or by an obvious
chemical equivalent thereof.
74. A process as claimed in Claim 1 which comprises
adding a solution of 3-mesyloxymethyl-5-methylthiomethyl-
isoxazole in a cyclic ether to a solution of substantially
1.5 molar equivalents of sodium methoxide in methanol at a
temperature within the range of from -10°C to 0°C, agitating
the resulting mixture within the same temperature range, and
isolating 3-methoxymethyl-5-methylthiomethylisoxazole.
92

75. 3-Methoxymethyl-5-methylthiomethylisoxazole,
when prepared by the process of Claim 74 or by an obvious
chemical equivalent thereof.
76. A process as claimed in Claim 1 which comprises
adding 1.1 - 1.4 molar equivalents of triethylamine to a
mixture of ethyl chloroximinoacetate and 1.1 - 1.4 molar
equivalents of allyl methyl sulfide in ether at substantially
0°C, agitating the resulting mixture at substantially 0°C,
and isolatiny ethyl 5-methylthiomethylisoxazoline-3-carbox-
ylate.
77. Ethyl 5-methylthiomethylisoxazoline-3-carbox-
ylate, when prepared by the process of Claim 76 or by an
obvious chemical equivalent thereof.
78. A process as claimed in Claim 1 which comprises
agitating a solution of ethyl 5-methylthiomethylisoxazoline-
3-carboxylate in a halogenated hydrocarhon solvent at a
temperature within the range of from -10°C to 10°C with
substantially one molar equivalent of m-chloroperbenzoic
acid, and isolating ethyl 5-(methylsulfoxide)methylisox-
azoline-3-carboxylate.
79. Ethyl 5-(methylsulfoxide)methylisoxazoline-3-
carboxylate, when prepared by the process of Claim 78 or by
an obvious chemical equivalent thereof.
80. A process as claimed in Claim 1 which comprises
agitating a solution of ethyl 5-methylthiomethylisoxazoline-
3-carboxylate in a halogenated hydrocarbon solvent at a
temperature within the range of from -10°C to 10°C with
substantially two molar equivalents of m-chloroperbenzoic
acid, and isolating ethyl 5-(methylsulfone)methylisoxazoline-
93

3-carboxylate.
81. Ethyl 5-(methylsulfone)methylisoxazoline-3-
carboxylate, when prepared by the process of Claim 80 or by
an obvious chemical equivalent thereof.
82. A process as claimed in Claim 1 which comprises
agitating ethyl 5-methylthiomethylisoxazoline-3-carboxylate
with a molar excess of concentrated hydrochloric acid at
ambient temperature, and isolating 5-methylthiomethylisox-
azoline-3-carboxylic acid.
83. 5-Methylthiomethylisoxazoline-3-carboxylic
acid, when prepared by the process of Claim 82 or by an
obvious chemical equivalent thereof.
84. A process as claimed in Claim 1 which comprises
agitating ethyl 5-methylthiomethylisoxazoline-3-carboxylate
with a molar excess of concentrated ammonium hydroxide at
ambient temperature, and isolating 5-methylthiomethylisox-
azoline-3-carboxamide.
85. 5-Methylthiomethylisoxazoline-3-carboxamide,
when prepared by the process of Claim 84 or by an obvious
chemical equivalent thereof.
86. A process as claimed in Claim 1 which comprises
agitating and heating at 80°C to 150°C a mixture of 5-
methylthiomethylisoxazoline-3-carboxamide and 2 - 10 molar
equivalents of phosphorus pentoxide in an aromatic hydro-
carbon solvent for 3 - 10 hours, and isolating 3-cyano-5-
methylthiomethylisoxazoline.
94

87. 3-Cyano-5-methylthiomethylisoxazoline, when
prepared by the process of Claim 86 or by an obvious chemical
equivalent thereof.
88. A process as claimed in Claim 1 which comprises
agitating a solution of 3,4,5-trimethylisoxazole in a cyclic
ether with substantially one molar equivalent of n-butyl-
lithium at a temperature within the range of from -50°C to
-95°C, adding the resulting solution within the same tempera-
ture range to a solution containing substantially one molar
equivalent of dimethyldisulfide in a cyclic ether with con-
tinued agitation at ambient temperature to obtain a mixture
of 3-methylthiomethyl-4,5-dimethylisoxazole and 3,4-dimethyl-
5-methylthiomethylisoxazole, and separating said last-named
mixture.
89. 3-Methylthiomethyl-4,5-dimethylisoxazole, when
prepared by the process of Claim 88 or by an obvious chemical
equivalent thereof.
90. 3,4-Dimethyl-5-methylthiomethylisoxazole, when
prepared by the process of Claim 88 or by an obvious chemical
equivalent thereof.
91. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methylthiomethyl-4,5-dimethylisox-
azole in a halogenated hydrocarbon solvent at a temperature
within the range of from -10°C to 10°C with substantially one
molar equivalent of m-chloroperbenzoic acid, and isolating
3-(methylsulfoxide)methyl-4,5-dimethylisoxazole.
92. 3-(Methylsulfoxide)methyl-4,5-dimethylisox-
azole, when prepared by the process of Claim 91 or by an
obvious chemical equivalent thereof.

93. A process as claimed in Claim 1 which comprises
agitating a solution of 3-methylthiomethyl-4,5-dimethylisox-
azole in a halogenated hydrocarbon solvent at a temperature
within the range of from -10°C to 10°C with substantially two
molar equivalents of m-chloroperbenzoic acid, and isolating
3-(methylsulfone)methyl-4,5-dimethylisoxazole.
94. 3-(Methylsulfone)methyl-4,5-dimethylisoxazole,
when prepared by the process of Claim 93 or by an obvious
chemical equivalent thereof.
95. A process as claimed in Claim 1 which comprises
agitating a solution of 3,4-dimethyl-5-methylthiomethylisox-
azole in a halogenated hydrocarbon solvent at a temperature
within the range of from -10°C to 10°C with substantially one
molar equivalent of m-chloroperbenzoic acid, and isolating
3,4-dimethyl-5-(methylsulfoxide)methylisoxazole.
96. 3,4-Dimethyl-5-(methylsulfoxide)methylisox-
azole, when prepared by the process of Claim 95 or by an
obvious chemical equivalent thereof.
97. A process as claimed in Claim 1 which comprises
agitating a solution of 3,4-dimethyl-5-methylthiomethyl-
isoxazole in a cyclic ether with substantially one molar
equivalent of n-butyllithium at a temperature within the
range of from -50°C to -95°C, adding the resulting solution
within the same temperature range to a solution containing
substantially one molar equivalent of dimethyldisulfide in a
cyclic ether with continued agitation at ambient temperature,
and isolating 5-di(methylthio)methyl-3,4-dimethylisoxazole.
96

98. 5-Di(methylthio)methyl-3,4-dimethylisoxazole,
when prepared by the process of Claim 97 or by an obvious
chemical equivalent thereof.
97

Description

~13483'7
CoNL-42
The present invention relates to alkylthioalkyl-
isoxazoles and -isoxazolines of the formula 1
R > ~ R
C - R4
\R5
in which the dotted line represents an optional
double bond, Rl is lower alkyl, COOH, COO(lower
alkyl), CONH2, CON(lower alkyl)2, CN, CH20H,
CH20SO2(10wer alkyl), CH~O(lower alkyl), CH2S(lower alkyl),
CH2SO(lower alkyl), or CH2SO2(10wer alkyl), with the
proviso that Rl may only be lower alkyl when R3 contains a
sulfo~ide or sulfone group or when R4 or R5 are other than
hydrogen or lower alkyl, R2 is H, H2, or lower alkyl with
the.proviso that R2 jS H2 when the double bond is absent
` in which case there is an additional hydrogen atom at C5,
R3 is H, S(lower alkyl), SO(lower alkyl), or so2(10wer alkyl)
with the proviso that R3 is H only when Rl is CH2S(lower
alkyl), CH2SO(lower alkyl), or CH250z(lower alkyl) and that
only one of R1 or R3 must contain an S(lower alkyl), : :
SO(lower alkyl), or 502(10wer alkyl) group, R4 and R5 are
the same or different and each is H, lower alkyl,.S(lower
alkyl), SO(lower alkyl), SO2(10wer alkyl), COOH, or
COO(lower alkyl) with the proviso that only one of Rl, R4,
and R5 may be COOH or COO(lower alkyl). The term "lower
alkyl" denotes the presence of 1-4 carbcn atoms in a
straight or branched chain. Thi 5 invention also relates
to processes for the preparation of the compounds of
formula 1, to geometrical and optical isomers thereof,
and to their pharmaceutically acceptable salts.
- 1 -
: . :
,~ ,

CONL-42
~1348~7
The compounds of this invention have anti inflammatory,
analgesic, and anti-pyretic properties and low orders
of toxicity.
Back round of the Invention
Although thioethers and thioacetals are generally
well known, no such compounds seem to be known
in the isoxazoline field and only three such
derivatives of isoxazole seem to have been
described to date, viz., 3-methyl-5-methylthio-
methylisoxazole (3), its 3-phenyl analog, and
3,5-dimethyl-4-methylthiomethylTsoxazole, see
Bravo et al., J. Het. Chem. 14, 37(1977). There
appears to be no mention in the literature
of sulfoxide or sulfone derivatives in the
isoxazole series.
Summary Description of the In'vent'i'on
-
The isoxazoles of formula 1 in which the dotted
line represents a double bond, R is lower alkyl
e.g. methyl, R2 is hydrogen, R3 is a sulfoxide
such as SO(lower alkyl) e~g. SOCH3 or a sulfone
such as SO2(10wer aikyl), e-g- S02CH3, and R
and R5 are both hydrogen are conveniently
prepared by treating a 3-(lower alkyl)-5-methyl-
thio(lower alkyl)isoxazole, e.g. 3-methyl-5-
methylthiomethylfsoxazole 3 described by Bravo

CoNL-42
~134B;37
et al. cited above with a suitable organtc peracid, e.g.
m-chloroperbenzoic acid. When one molar equivalent
of the peracid is used the corresponding sulfoxide
4A is obtained, and when two molar equivalents
of the peracid are used the corresponding sulfone
_ is obtained. The latter compound may in turn
be lithiated by treatment with n-butyllithium
and then reacted with one molar equivalent of
a ditlower alkyl)disu~fidé, e.g. dimethyldi-
sulfide, to obtain the corresponding compound of
formula 1 in which the dotted line, R1, and
R2 are as defined above, R3 is S02(1ower alkyl)
e.g. S02CH3, R is S(lower alkyl) e.g. SCH3,
and R5 is hydrogen, i.e. the compound of formula
7. It should be noted that it is not possible
to prepare such compounds of formula 7 by
oxidation of the corresponding compounds of
formula 5 discussed below.
The isoxazoles of formula 1 in which the dotted line
represents a double bond, R is lower alkyl, e.g. -
methyl~ R2 jS hydrogen, and R3 and R are both
S(lower alkyl), e.g. SCH3, and R5 is hydrogen
are conveniently prepared by treating a 3-(lower alkyl)-
5-methylthio(lower alkyl)isoxazole e.g. 3-methyl-
5-methylthiomethylisoxazole of formula 3 with
n-butyllithium followed by treatment w7th a
dl(lower alkyl)disulfide e.g. dimethyldisulfide,
~ .
~ . .
.

CoNL-42
~48;~7
to obtain the corresponding thioacetal of formula
5, i.e. the compound of formula 1 in which the
dotted line, R1, R2, R3, R4 and R5 are as defined
above, e.g. 3-methyl-5-di(methylthio)methylisoxazole.
To obtain the isoxazoles of formula 1 in which the
dotted line, R and R2 are as defined above and
R3, R and R are S~lower alkyl), e.g. SCH3, a
compound of formula 5 as described above is treated
successively with n-butyllithium and a di(lower alkyl)-
disulfide in the manner described above and the
10corresponding tri(lower alkylthio)methylisoxazole
of formula 8, e.g. the ortho-thioester 3-methyl-
5-tri(methylthio)methylisoxazole is isolated.
The oxidation of the compounds of formula 5 may
b ~carried out in several distinct steps, depen-
difng upon stoichiometry and reaction conditions.
Thus, when it is desired to convert only one of
the -S(lower alkyl) groups R3 or R to the corres-
ponding sulfoxide, a compound of formula 5 as
~ dcfined above, e.g. 3-methyl-5-di(methylthio)methyl-
isoxazole is treated with one molar equivalent of an
organic peracid, e.g. m-chloroperbenzoic acid, to
obtain the corresponding compound of formula 1
in which the dotted line, R , and R are as
defined above, R3 is SO(lower alkyl), R is
S(lower alkyl), and R5 is hydrogen, i.e. the
corresponding compound of formula 6A, e.g.
.

113~837 CoNL-42
3-methyl-5a(methylsulfoxide)methylthiomethyl-
isoxazole, as well as an isomer of said compound
having a different m.p. and a different nmr
spectrum.
Similarly, when it is desired to convert both
S(lower alkyl) groups R3 and R to the corres-
ponding sulfoxides, a compound of formula 5 is
treated with two molar equivalents of an organic
peracid, e.g. m-chloroperbenzoic acid, to obtain
the corresponding compound of formula 1 in
which the dotted line, R , and R are as defined
above, R3 and R are both SO(lower alkyl), and
R5 is hydrogen, i.e. the corresponding compound
of formula 6B, e.g. 3-methyl-5-,-di(methyl-
sulfoxide)methylisoxazole, as a mixture of
isomers.
Again similarly, where it is desired to convert
one of the S(lower alkyl) yroupS R3 and R4
:~:'.,
to the corresponding sulfone and the other to the
corresponding sulfoxide, a compound of formula 5
is treated with three molar equivalents of an
organic peracid, e.g. m-chloroperbenzoic acid,
to obtain the corresponding compound of formula 1
in which the dotted line, R , and R are as
defined above, R3 is S02(1Ower alkyl), R4 is
SO(lower alkyl), and R5 is hydrogen, i.e. the
corresponding compound of formula 6C, e.g~

~34837 CONL-42
3-methyl-5-a-(methylsulfone)-a-(methylsulfcxide)-
methylisoxazole as a mixture of isomers.
Again similarly, when it is desired to convert
both Stlower alkyl) groups R3 and R to the
corresponding sulfones, a compound of formula 5
is treated with four or a little more than four
molar equivalents of an organic peracid, e.g.
m-chloroperbenzoic acid, to obtain the corres-
ponding compound of formula 1 in which the
dotted line, R, and R are as defined above,
R3 and R4 are both SO2(10wer alkyl), and R5 is
hydrogen, i.e. the corresponding compound of
formula 6D, e.g. 3-methyl-5-dl(methylsulfone)-
methyltsoxazole.
It should be noted that a chiral centre is
created in a number of the above procedures,
e.g. ;n those leading to the compounds of
formulae 6A, 6C, and 7, so that those compounds
; exist in the forms of pairs of opti al isomers.
Moreover, as the sulfur in the sulfoxide groups
is not planar isomerism around that centre is
also possible, e,g. in the compounds of formulae
6A, 6B, and 6C.
The isoxazoles of formula 1 in which the dotted
line, R, and R are as defined above, R3 is
S(lower alkyl) e.g. SCH3, R4 is lower alkyl, e.g.
methyl, and R is hydrogen or lower alkyl, e.g.
. ~ . ~ . . '
: ~ '' -''' ' .

1134837 CONL 42
methyl, and their respective sulfoxides and sul-
fones are also conveniently prepared from a
3-(lower alkyl)-5-mçthylthio(lower alkyl)isoxazole
of formula 3, e.g. from the known 3-methyl-5-
methylthiomethylisoxazole described by Bravo
et al. cit~d above, as follows.
A compound of formula 3 is treated with
n-butyllithium and the lithio derivative thus
obtained is reacted with a lower alkyl halide,
e.g. methyl iodide, to obtain the corresponding
0
compound of formula 9, i.e. the compound of
formula 1, in which the dotted line, R , R , and
R3 are as defined above, R4 is lower alkyl, e.g.
methyl, and R5 is hydrogen. Said last-named
compound is again subjected to the above sequence
of reactions, viz. lithiation with n-butyllithium
followed by reaction with a lower alkyl halide,
e.g. methyl iodide, to obtain the corresponding
compound of formula 10, i.e. the compound of
formula 1 in which the dotted line, R , R , R3
4 5
and R are as defined immediately above and R
is lower alkyl, e.g. methyl.
Both of the compounds of formulae 9 and 10 described
above are then treated with an organic peracid,
e.g. m-chloroperbenzoic acid in the manner des-
cribed above; when using one molar equivalent
of the peracid the corresponding sulfoxides
: , .
' ' " -',

1134837 CoNL-42
are obtained, and when using two molar equiva-
lents the corresponding sulfones are obta'ined.
Thus, when using a compound of formula 9 as
starting material the corresponding sulfoxide
of formula 11A or the corresponding sulfone of
formula llB is obtained, and when using a com-
pound of formula 10 as starting material the
- corresponding sulfoxide of formula 12A or the
corresponding sulfone of formula 12B is obtained.
Thc isoxazoles of formula 1 in which thc dottcd
line represents a double bond, R is lower alkyl~
e.g. methyl, R is hydrogen, R3 is S(lower alkyl),
R is hydrogen or S(lower alkyl), and R5 is
COOH or COO(lower alkyl) and their respectlve
sulfoxides and sulfones are conveniently
prepared'by treating a 3-(lower alkyl)-5-methyl-
thio(lower alkyl)isoxazole, e.g. the known
3-methyl-5-methylthiomethylisoxazole 3 or a
3-(lower alkyl)-5-di(S~lower alkyl)methylisoxazole
5, e.g. 3-methyl-5-di(methylthio)methylisoxazole,
with'n-butyllithium to obtain the corresponding
lithio derivative, and reacting the latter with
carbon dioxide to obtain the corresponding acid
of formula 13, i.e. the compound of formùla 1
in which the dotted line represents a double
bond, R is lower alkyl~ R is hydrogen, R3 is
S(lower alkyl), R4 is hydrogen, and R5 is COOH,

~134837 c o N L - 4 2
e.g. 3-methyl-5-a-(rrlethylthio)acetic acid,
or the corresponding acid of formula 16, i.e.
the compound of formula 1 in which the dotted
line, R1, R2, R3, and R5 are as defined imrned-
iately above and R4 is S(lower alkyl), e.g.
3-methyl-5-a~a-di(methylthio)acetic acid, respectively.
Esterification of said acids of forrnulae
13 or 16, e.g. by treatment of the lithium
salt of the acid with a lower alkyl halide
or by treatment of the acid with a diazo(lower alkane)
gives the corresponding lower alkyl esters 14
or 16A, i.e. the compound of formula 1 in
which the dotted line, R , R and R3 are as
defined immedlately above, R4 is H or S(lower
alkyl), respectively, and R5 is COO(lower alkyl),
e.g. COOCH3.
Said lower alkyl esters of formulae 14 or 16A
may then be treated with one to four molar
equivalents of an organic peracid, e.g.
m-chloroperbenzoic acid, to obtain the
corresponding sulfoxides and/or sulfones in the
manner described above. For example, treatment
of an ester of formula 14 with one molar
equivalent of the organic peracid gives the
corresponding sulfoxide 15A, i.e. the compound
of formula 1 Tn which the dotted line, R , and
R are as defined above, R3 is SO(lower alkyl),
R4 is hydrogen, and R5 is COO(lower alkyl~i
,

~134~7 CONL-42
when two molar equivalents of the organic peracid
are used there is obtained the corresponding
sulfone 15B, i.e. the compound of formula 1 in
which the dotted line, R and R are as defined
immediately abové, R3 is SO2(10wer alkyl), R4 is
hydrogen, and R5 is COO(lower alkyl).
The isoxazoles of formula 1 in which the dotted
line represents a double bond, R is COOH,
COO(lower alkyl), CONH2, CON(lower alkyl)2,
CN~ CH20H, CH20502(10wer alkyl), or CH20(10wer
alkyl), R is hydrogen, R3 is S(lower alkyl),
R is hydrogen or lower alkyl, and R5 is hydrogen,
as well as their respe~tive sulfoxides and
s~lfones, are convenlently prepared as follows.
The nitr71e oxide prepared In situ by treating
a lower alkyl chloroximinoacetate of fo-rmula
17 (see G.S; Skinner, J. Am. Chem. Soc. '-
46, 73~(1g24)) with an organic base, e.g. a
tri(lower alkyl)amine is reacted with a propargyl
halide, e.g. propargyl bromlde 18 to obtain
- the corresponding lower alkyl 5-halomethyl-
isoxazole-3-carboxylate 19, i.e. the compound
of formula 1 in which the dotted line represents
a double bond, R1 ;5 COO(lower alkyl), R is
hydrogen, R3 is halogen, and R4 and R5 are
both hydrogen, e.g. ethyl 5-bromomethylisoxazole-
3-carboxylate. Said last-named compound is
-- ~O ~

1 ~ ~ ~ CONL-42
treated with the lithio derivative of a lower
alkyl mercaptan, e.y. methylmercaptan, pre-
pared by treating saTd mercaptan with n-butyl-
lithium in a solvent such as an ether or
cyclic ether, e.g. tetrahydrofuran, to obtain
the corresponding iower alkyl 5-(lower alkylthio)-
methylisoxazole-3-carboxylate 20, i.e. the
compound of formula 1 in which the dotted line
represents a double bond, R is COO(lower alkyl),
R2 ;5 hydrogen, R3 is S(lower alkyl), and R
and R5 are both hydrogen, e.g. ethyl 5-methyl-
thiomethylisoxazole-3-carboxylate.
Sald last-named compound is capable of a number
of transformations.
Thus, treatment of said compound of formula 20
with one or two molar equivalents of an organic
peracid, e.g. m-chloroperbenzoic acid, gives
the correspond;ng sulfoxide 25A or the
corresponding sulfone 25B, respectively, i,e.
the compounds of formula 1 in which the dotted
line, R1, R , R4, and R5 are as defined immed-
iately above and R3 is SO(lower alkyl~ or
S02(1Ower alkyl), respectively.
Treatment of said compound of formula 2Q with a
strong mineral acid, e.g. concentrated hydro-
chloric acid, hydrolyzes the ester group to
obtain the corresponding free acid of formula

1~3483'7 c o N . - 4 2
21, i.e. the compound of formula 1 in which the
dotted line, R2, R3, R , and R5 are as defined
immediately above and R Ts COOH, e.g. 5-methyl-
thiomethylisoxazole-3-carboxylic acid. Similarly,
acid hydrolysis of the sulfone 25B gives the
sulfone of the corresponding free acid 21A,
i.e. the compound of formula 1 in which the
dotted line represents a double bond, R2, R4,
and R5 are all hydrogen, R3 is SO2(10wer alkyl),
and Rl is COOH, e.g. 5-(methylsulfone)methyl-
isoxazole-3-carboxylic acid.
Treatment of said compound of formula 20 with a
dl(lower alkyl)amlne, e.g. dimethylamine,
transforms the COO(lower alkyl~ group lnto the
corresponding di(lower alkyl)carboxamidQ group
to give the corresponding compound of formula
22, i.e. the compound of formula 1 in which the
dotted line represents a double bond, R , R ,
and R5 are all hydrogen, R3 is S(lower alkyl~,
and R is CON(lower alkyl)2, e.g. 5-methylthio-
methylisoxazole-3-dimethylcarboxamide.
Similarly, treatment of said compound of formula
20 with ammonia transforms the COO(lower alkyl)
group into the carboxamido group to obtain the
corresponding compound of formula 23, i.e. the
compound of formula 1 in which the dotted line
represents a double bond, R2, R , and R5 are all
~ 12

113~E137 c o N L - 4 2
hydrogen, R3 is S(lower alkyl), and R is CONH2,
e.g. 5-methylthiomethyliSoxazole-3-carboxamide
Said last-named compound of formula _ is
treated with a dehydrating agent, preferably
phosphorus pentoxide, to obtain the corresponding
3-cyano compound of formula 24, i.e. the
compound of formula 1 in which the dotted line,
R , R3, R , and R5 are as defined immediately
above and R is CN, e.g. 3-cyano-5-methylthio-
1 methylisoxazole.
Alternatively, said compound of formula 23 istreated with n-butyllithTum followed by
treatment wlth a lower alkyl halide, to obtain
the corresponding compound of formula 29, i.e~
the compound of formula 1 in which the dotted
line represents a double bond, R1 is CONH2, R2
and R5 are both hydrogen, R3 is S(lower alkyl),
and R is lower alkyl, e.g. 5-~(methylthio)-
ethylisoxazole-3-carboxamide.
Treatment of the compound of formula 20 with an
alkali metal aluminium hydride, e.g. Iithium
aluminium hydride reduces the COO(lower alkyl)
group to the CH20H group, to obtain the
corresponding compound of formula 26, i.e.
the compound of formula 1 in which the dotted
line represents a double bond, R , R , and R5
are all hydrogen, R3 ls S(lower alkyl)~ and R
- 13

~ W ~ CONL-42
is CH20H, e.g. 3-hydroxymethyl-5-methylthio-
methylisoxazole.
Treatrnent of said compound of formula 26 with a
lower alkyl sulfonyl halide, e.g. mesyl chloride,
transforms the CH20H group into the corresponding
CH20SO2(10wer alkyl) group to obtain the
corresponding compound of formula 27, i.e. the
compound of formula 1 in which the dotted line,
R2, R3, R4, and R5 are as defined in the preceding
paragraph and R is CH20S02(1ower alkyl), e.g.
3-mesyloxymethyl-5-methylthiomethylisoxazole.
Treatment of said compound of formula 27 with an
alkall metal lower alkoxlde, e.g. sodium methoxlde,
transform~ the CH20S02(1ower alkyl) group into
the corresponding CH20(10wer alkyl) group to
obtain the corresponding compound of formula 28,
i.e. the compound of formula 1 in which the
dotted line, R2, R3, R4, and R5 are as defined
in the precedlng paragraph and R1 is CH20(10wer
alkyl), e.g. 3-methoxymethyl-5-methylthiometh'yl-
isoxazole.
The isoxazolines of formula 1 in ~hich the dotted
ltne is regarded as being absent to i:ndicate
the presence of a single bond C4_C5, R1 is COOH,
COO(lower alkyl~, CONH2, or CN~ R is hydrogen (H2),
R3 is S(lower alkyl), R4 and R5 are both hydrogen,
and the sulfoxides and sulfones of sa;d isoxazolines
~- 14 -~

~134837
CoNL-42
are conveniently prepared as follows.
The nitrile oxide prepared (n situ by treating
a lower alkyl chloroximinoacetate of formula
17 with an organic base, e.g. a tri(lower alkyl)-
amine is reacted wTth an allyl(lower alkyl)-
sulfide of formula 30, e-g- allylmethylsulfide,
to obtain the corresponding isoxazoline of
formula 31, i.e. the compound of formula 1 in
which the dotted line is regarded as being absent,
Rl ;5 COO(lower alkyl), R is hydrogen, R3 is
S(lower alkyl), and R4 and R5 are both hydrogen,
e.g. ethyl 5-methylthiomethylisoxazoline-3
carboxylate, which is also capable of a
number of transformations, as follows.
Treatment of a compound of formula 31 with one
or two molar equivalents of an organic peracid
gives the corresponding sulfoxide 32A or the
corresponding sulfone 32B, respectively, i.e~
the isoxazol;nes of formula 1 in which the dotted
line, R1, R2, R4, and R5 are as defined in the
pre~eding paragraph and R3 is SQ(lower alkyl~
or S02(1Ower alkyl), respectively, e~g. the
compounds ethyl 5-(methylsulfoxide)methyl
isoxazoline-3-carboxylate 32A or ethyl 5-(methyl-
sulfone)methylisoxazoline-3-carboxylate 32B,
respectlvely.
Treatment of a compound of formula 31 w7th a

1134~7 CoNL-42
strong mineral acid, e.g. concentrated hydro-
chloric acid, hydrolyzes the ester group R
to obtaTn the corresponding free acid 33, i.e.
the isoxazolines of formula 1 in which the
dotted line, R2, R4, and R5 are as defined
in the preceding paragraph, R3 is S(lower
alkyl), and R is COOH, e.g. 5 methylthio-
methylisoxazoline-3-carboxylic acid.
Treatment of a compound of formula 31 with
ammonium hydroxide converts the ester group in
R to the carboxamido group, to obtain the
corresponding compound of formula 34, i.e.
an isoxazoline of formula 1 in which the
dotted line, R2, R3, R4, and R5 are as defined
In the preceding paragraph and R is CONH2,
e.g. 5-methylthiomethylisoxazoline-3-carboxamide.
Treatment of said last-named compound of
formula 34 with a dehydrating agent, e.g. phos-
phorus pentoxide, converts the carboxam;de group
in R1 to the cyano group, to obtain the
corresponding compound of formula 35, i.e. an
isoxazoline of formula 1 in wh;ch the dotted
line, R , R3, R and R5 are as defined in the
precedTng paragraph and R1 is CN, e.g. 3-cyano-
5-methylth;omethylisoxazoline.
The isoxazolines of formulae 33, 34, and 35
are conveniently converted to t~etr respectiye
- 16

li34837 CoNL-42
sulfoxides or sulfones by treatment wîth one or
two molar equivalents, respectively, of an
organic peracid, e.g. m-chloroperbenzoic acid.
The isoxazoles of formula 1 in which the dotted
line represents a double bond, Rl is methyl or
CH2S(iower al~yl)~ R2 jS lower alkyl, R3 i5
hydrogen or S(lower alkyl) wi)th the proviso that
R3 is hydrogen only when Rl is CH2S(lower alkyl),
and R4 and R5 are both hydrogen are conveniently
prepared as follows.
Acetylacetone substituted on the 3-carbon atom
with a lower alkyl group, e.g. 3-methylpentane-2,4-
dione 37 as prepared by the method described în
Org. Syntheses~ 42, 75 (1962), is treated with
hydroxylamine to obtain the corresponding 3,5-
dimethyl-4-(lower alkyl)isoxazole 38, e.g. 3,4,5-
trimethylisoxazole. Said last named compound is
treated with n-butyllithium and the resulting lithio
derivative ;s réacted with a di(lower alkyl)disulfide,
~,
e.g. dimethyldisulfide, to obtain a mixture of the
corresponding 3-(lower alkyl)thiomethyl-4-(10wer
alkyl)-5-methylisoxazole 39, i.e. the compound of
formula 1 in which R is CH2S(lower alkyl), R is
lower alkyl, and R3, R , and R5 are all hydrogen, and
3-methyl-4-(lower alkyl)-5-methylthio(lower alkyl)
isoxazole 40, T.e. the compound of formula 1 in
which R is methyl, R2 is lower alkyl, R3 is
~ ~7
- , ~

1134837
S(lower alkyl), and R4 and R5 are both hydrogen, e.g. a
mixture of 3-methylthiomethyl-4,5-dimethylisoxazole, and
3,4-dimethyl-5-methylthiomethylisoxazole, which may be
separated, e.g. by chromatography.
Treatment of said compounds with one or two molar equivalents
of an organic peracid, e.g. _-chloroperbenzoic acid, gives
the corresponding sulfoxides or sulfones, respectively.
Thus~ treatment of the compound 39 with one molar equivalent
of an organic peracid in the manner described above gives the
corresponding sulfoxide 41A, i.e. the compound of formula 1
in which Rl is CH2SO(lower alkyl), R2 is lower alkyl, and
R3, R4, and R5 are all hydrogen, e.g. 3-(methylsulfoxide)-
methyl-4,5-dimethylisoxazole; treatment with two molar
equivalents of an organic peracid gives the corresponding
sulfone 41~, i.e. the compound of formula 1 in which Rl is
CH2SO2(lower alkyl), R is lower alkyl, and R , R , and R
are all hydrogen, i.e. 3-~methylsulfone)methyl-4,5-dimethyl-
isoxazole; similarly, treatment of the compound of formula 40
with one molar equivalent of an organic peracid gives the '
corresponding sulfoxide 42, i.e. the compound of formula 1
in which Rl is methyl, R2 is lower alkyl, R3 is SO(lower
alkyl), and R4 and R5 are both hydrogen, e.g. 3,4-dimethyl-5-
(methylsulfoxide)methylisoxazole.
- 18 -

CoNL-42
~134~37
A second lower alkylithio group may also be intro-
duces on the same carbon atom which carries the above
substttuent in the same manner as described earlier
in this Application. For example, treatment of a
compound of formula 40 with n-butyllithium followed
by treatment of the resulting lithio derivative with
a di(lower alkyl)disulfide, e.g. dimethyldisulfide,
gives the corresponding thioacetal 43, i.e. the
compound of formula 1 in which Rl is methyl, R is
lower alkyl, R3 and R4 are both S(lower alkyl), and
R5 is hydrogen, e.g. 3,4-dimethyl-5-di(methylthio)~
metbylisoxazole.
Detailed D'escr'i'p'ti'on''of't'he'lnvent'ion
More speciflcaly, the starting materials for the
preparation of the above compounds are either known
or commercially available, or they may be conveniently
~~ prepared from known materials by procedures which are
known per se. Thus, 3-methyl-5-methylthiomethyl-'
isoxazole (3) is conveniently prepared according to the
method'~ Bravo et al, cited above; the lower alkyl
choroximinoacetates are prepared according to the
method of Skinner cited above, and propargyl halides
such as the bromide are commercially available; allyl
methyl sulfide is commercially available; and the 3-
~lower ~alky'3`)pentane-2,4-diones are prepared
according to Org.Syntheses 42, 75 (1962) cited above.

CONL-42
~13~837
The oxidation of the S(lower alkyl) groups in the
isoxazo1es and isoxazolines to the corresponding
sulfoxides or sulfones is advantageously carried
out with an organic peracid, preferably m-chloro-
perbenzoic acid in an inert solvent, preferably
a hallo~enate~d hydrocarbon solvent such as
methylene chloride, chloroform, carbon tetrachlor-
ide, or ethylene dichloride, at a temperature within
the range of -10C to lûC, preferably at about
0C, followed by gradual warming to ambient
temperature. The by-product m-chlorobenzoic
acid usually crystallizes and is re~oved by
filtration, the filtrate is washed with bisulfite
to remove any unreacted peracid and evaporated
to yield the desired sulfoxide or sulfone- The
nature of the final product depends upon stoichio-
metry: when one molar equivalent of the peracid
is used the sulfoxides, and when two molar equiv-
alents are used the sulfones are generally obtained.
A convenient method for introducing S(lower alkyl)
groupsinto the lower alkyl, e.g. methyl, side
chains of the isoxazoles of this invention com-
prises lithiation followed by reaction of the
resulting lithio compound with a di~lower alkyl)
disulfide. Lithiation is preferably carried out
with n-butyllithium in an inert solvent such as an
aliphatic hydrocarbon, e.g. hexane, or a cyclic
ether, e.g. tetrahydrofuran, in an atmosphere of nitrogen,
and at temperatures within the range of -20C to -95C, pre-
ferably at about -30C to -75C, for one to several hours,
2Q -

CoNL-42
~34837
preferably for 1-2 hours. The resul~ing solution of
the lithio compound is added to a solution of the
respective di(lower alkyl)disulfide, e.g. dimethyl-
disulfide, in a cyclic ether such as tetrahydrofuran,
previously cooled to the same low temperature range as-above,
the mixture is stirred for 1-2 hours at the same low
temperature as above and then at ambient temperature
for 8-24 hours, preferably for about 16 hours.
Evaporation of the solvent gives the desired product
containing at least one S(lower alkyl) group On a
given reactive carbon atom, with the corresponding
thioacetal containing two S(lower alkyl) groups on the
~amecarbon atom sometimes being obtained as a minor
by-product. However, if it is desired to obtain such a
thioacetal, e.g. compound 5, it is preferred to use as
starting materials an isoxazole of formula 1 in which
R1 in lower alkyl, R2 is hydrogen, R3 is S(iower
alkyl) and R4 and R5 are both hydrogen, to lithiate
said last-named compound and to react the respective
lithio derivative with a di~lower alkyl)disulfide in
the same manner as described above, to obtain the
corresponding thioacetal, e.g. compound 5. The
same procedure may be repeated again under the same
conditions to obtain the corresponding ortho-thioester
having three S(lower alkyl) groups on the same
carbon atcm, e.g. compound 8.
When oxidi~ing an isoxazole-thioacetal obtained as
described above to the corresponding sulfoxide or
sulfone it is obviously not possible to direct the
- 21 -
,
:

CONL-42
li3483~
oxidation in such a manner as to obtain the correspond-
ing compound in which one of the S(lower alkyl) groups
is oxidized to the correspondTng sulfone hav7ng an
502(10wer alkyl) groups while the other S(lower alkyl)
group remains unchanged. If it is des~red to obtain
such compounds of formula 1 in which e.g. R1 and R2
are as defined immediately above,R3 is SO2(10wer alkyl)
and R4 is S(lower alkyl) with R5 as hydrogen, it is
preferred to use as starting material an isoxazole of
formula 1 in which Rl and R2 are a defined immediately
above, R3 is 502(10wer alkyl) and R4 and R5 are both
hydrogen, and to react said starting material
successively with n-butyllithlum and with the appro-
prlate di(lower alkyl)dlsulflde in the manner and
under the condltlons descrlbed above, to obtain the
desired compound. For example, when starting with
the sulfone of compound 4 there is obtained
compound 7.
~;~
Alkylation of the compounds of formula 1 in which
R1 jS lower alkyl, R2 jS hydrogen, R3 is S(lower
alkyl) and R4 and R5 are both hydrogen takes place on
the same carbon atom which carries the S~lower alkyl)
group and is advantageously carried out by treating the
starting material with n-butyllithium in an atmosphere
of nitrogen and at the same low temperature range as
described above. The reaction is preferably carried
out in an inert so1vent such as a cyclic ether, e.g.
tetrahydrofuran, and the resulting solution of the
lithio derivative is added to a solution of the
- 22 -

C O N L - 4 2
~1348~7
appropriate lower alkyl halide in the same solvent
as above, maintaining the mixture for 10-60 minutes,
preferably for about 30 minutes,within the above low
temperature range and then for 0.5-2 hours, preferably
for about one hour, at ambient temperature. Evapor-
ation of the major part of the solvent, taking up the
residual mixture in a water-immiscible solvent such as
a halogenated;' hydrocarbon, e.g. methylene chloride,
washing with water, drying, and evaporating the
solvent yields the corresponding isoxazole of formula 1
in which R1 and R are as defined immediately above,
R3 is S(lower alkyl), R4 is lower alkyl, and R5 is
hydrogen, e.g. compound 9. The above reaction may be
repeated with said last-named compound as starting
materlal, to obtain the corresponding isoxazole of '
formula 1 in which R1 and R2 are as defined immediately
above, R3 Is S(lower alkyl), and R4 and R5 are both the
same or different lower alkyl groups, e.g. compound 10.
The S(lower alkyl) group in the above compounds may
be oxidized with an organic peracid in the manner
- described above, io obtain the corresponding sulfoxides
or sulfones. e.g. compounds 11A and 11B, or 12A and 12B.
.
The lithiation with n-butyllithi'um followed by
reaction with carbon dioxide may also be used to
introduce a carboxylic acid group into the isoxazoles
of formula l in which R1 ;5 lower alkyl, R2 jS
hydrogen, R3 is S(lower alkyl), R4 is hydrogen or
S(lower alkyl), and R is hydrogen. Lithiation
- 23 -

CONL-42
113~837
of the above compounds takes again place on the
same carbon atom which carries the S(lower alkyl)
groups and is carried out in the same manner and
under the same conditions as described above. The
resulting solution of the lithio derivative is
contacted with a large molar excess of carbon dioxide,
preferably by pouring theabove solution onto crushed
dry ice and allowing the resulting mixture to come
to ambient temperature. Evaporation of the solvent
and washing of the residue with ether gives the
lithium salt of the corresponding acid from which the
free acid is obtained by careful acidification,
e.g. compounds 13 or 16.
The lithlum salts obtalned as described above may
conveniently be used as starting materials for preparing
the corresponding lower alkyl esters of the acids,
by treating said lithium salts with a lower alkyl
halide in a suitable solvent, e.g. dimethylformamide,
at ambient temperature for 1-2 hours, dilution with
ether, washing with water, and evaporation of the
solvent followed, if desired, by purification,
e.g. by chromatography. Thus, when methyl iodide ts
used as the alkyl halide, the corresponding methyl
esters are obtained, e.g. compounds 14 or 16A. Some
of the lower alkyl esters may also be obtained by
treatment of the free acid with an appropriate diazo
(lower alkane~, e.g. diazomethane, which has been used
to prepare e.g. the methyl ester 16A.
: '

CoNL-42
~13~3i7
Treatment of the lower alkyl esters obtained as
described above with an organic perac;dj~prefer~rb~y
m-chloroperbenzoic acid, in the sarne manner and under
-
the same conditions as described above, gives the
corresponding sulfoxides and sulfomes, e.g. compounds
15A and 15B, respectively.
The isoxazoles of formula 1 in which R1is COO(lower
alkyl) e.g. COOEt , R2 ;5 hydrogen, R3 is S(lower''
alkyl) and R4 and R5 are both hydrogen are convén;ently
prepared by adding a solution af an organic base in
an inert solvent to an ice-cold mixture of ethyl
chloroximinoacetate 17 and a propargyl halide, prefer-
ably propargyl bromide 18, in an inert
solvent. The preferred organic base is a tri(lower
alkyl)amine such as triethylamine, and the preferred
solvent therefor is diethyl ether; the preferred
solvent for the above mixture is a mixture of an
aromatic hydrocarbon such as toluene with ether.
The three components may be used in substantially
equimolar amounts, but it is preferable touse approx-
imately 1.1 molar equivalents of triethylamine and
of propargyl bromide per mole of ethyl chloroximino-
acetate. After allowing the initial exothermic
reaction to subside the mixture is stirred at
ambient temperature for 30-120 minutes, preferably
for about 60 minutes~ filtered to remove tri-
ethylamine hydrochloride and the latter washed with
ether. Evaporation of the combined filtrates and
- 25 -

CoNL-42
~134B37
washings followed by distillation of the residual
oil gives ethyl 5-bro~omethylisoxazole-3-carboxylate
19. Replacement of the bromine in said last-named
compound by an S(lower a1kyl) group is conveniently
carried out by adding said compound 19 to 1.0-l.1
molar equivalents of an ice-cold solution of LiS(lower
alkyl), e.g. LiSCH3 in an ether or cyclic ether, pre-
ferably in tetrahydrofuran, previously prepared from
n-butyllithium and a lower alkyl mercaptan, e.g. methyl
mercaptan. Stirring the resulting mixture at ambient
temperature for 2-lO hours, preferably for about 4
hours, evaporation of the solvent, taking up in ether,
washing with water, drying, evaporating of the ether
and purifying the residue, e.g. by distillation,
gives the corresponding isoxazole of formula 1 in
whtch R1 is COO(lower alkyl~, R2 is hydrogen, R3 is
S(lower alkyl), and R4 and R5 are both hydrogen,
e.g. ethyl 5-methylthiomethylisoxazole-3-carboxylate
20.
Treatment of said last-named compound 20 with one
or two molar equivalents of m-chloroperbenzoic
acid in the manner described above gives the correspond-
ing sulfoxide, e.g. ethyl 5-(methylsulfoxide)
methylisoxazole-3-carboxylate 25A and the corresponding
sulfone e.g. ethyl 5-(methylsulfone`)methylisoxazole-
3-carboxylate 25S.
Hydrolysls of the ester groups COO(lower alkyl) in
said compound 20 is advantageously effected by
- 26 -

CoNL-42
1~34837
stirring said compound 20 with 10-20 molar equi-
valents, preferably with about 15 molar equivalent
of concentrated hydrochloric acid at ambient
temperature ~or l-24 hours, preferably for about 16
hours. Cooling in an ice bath and separation of the
crystals gives the the corresponding free acid,
e.g 5-methylthiomethylisoxazole-3-carboxylic
acid 21. The corresponding sulfone is conveniently
prepared by treating ethyl-5-(methylsulfone)methyl-
isoxazole-3-carboxylate 25B with concentrated hydro-
chloric acid in the manner described above, to
obtain 5-(methylsulfone)methylisoxazole-3-carboxylic
acid 21A.
The transformation of the ester group COO~lower
alkyl) in said compound 20 to the ditlower alkyl)car-
boxamide group CON(lower alkyl)2 or to the carboxamide
group CONH2 is easily accomplished by treating said
compound 20 at ambient temperature with 2-10
molar equivalents of a di(lower alkyl)amine, e.g.
with 5-molar equivalents of dimethylamine in ether
solution in a closed vessel for several weeks, pre-
ferably for about 4 weeks; evaporation of the solvent
and purification of the residue, e.g. by chromatography,
gives 5-methylthiomethylisoxazole-3-dimethylcarbox-
amide 22. Similarly, when stirring a mixture of
compound 20 with 5-10 parts per weight of concentrated
ammonia at ambient temperature for several hours,
addtng water, cooling in ice, and filtering, there is
- 27 -

CONL-42
~3~837
obtained 3-methylthiomethylisoxazole-3-carboxamide 23.
The conversion of the carboxamide group in said
last-named compound 23 to the cyano group is con-
veniently effected by treatment with a dehydrating
agent, e.g. with 2-10 molar equivalents, preferably
with about 5 molar equivalents of phosphorus pentoxide
in an inert solvent such as an aromatic hydro-
carbon,e.g. toluene, at 80-150c, preferably at
about 120c or at the reflux temperature of the
'O mixture, for 5-12 hours, preferably for about 8 hours.
Separation of the gummy solids and washing them with a
halogenated hydrocarbon, e.g. chloroform, and
evaporation of the combined liquid phase and
washings glves 3-cyano-5-methylthiomethylisoxazole
24 which may be purified, e.g. by distillation.
Alternatively, 5-methylthiomethylisoxazole-3-car-
boxamide 23 may also be alkylated on the same carbon
atom which carries the methylthio group, by treating
said compound 23 with 2.0-2.2 molar equivalents of
n-butylithium in solution in an ether or a cyclic
ether, preferably in tetrahydrofuran, at -50C to
-100C, preferably at -65C to -80C, in an atmo-
sphere of nitrogen for 1-3 hours, preferably for about
1,5 hours. A solution of 2.0-2.2 molar equivalents
of the approprTate lower alkyl haltde, e.g. methyl
Todide, tn the same solvent as above is added and
the mixture is stirred at -65C to -80C for 1-5
,,~ - 28 -

CoNL-42
837
hours, p.referably for about.2 hours, and allowed
to come to ambient temperature. Evaporation of the
solvent, taking up in a water-immiscibl.e inert solvent
such as ethyl acetate, washing with water, drying,
and evaporating the solvent gives the correspondingly
alkylated compound, e.g. 5-a(methylthio)ethylisoxazole
-3-carboxamide 29.
The transformation of the COO(lower alkyl) group
in compound 20 to the CH20H group and to other groups
related thereto is advantageously carried out by
treating a solution of compound 20.in an ether or
cyclic ether, preferab1y tn tetrahydrofuran, at
~10 C to 10C, preferably at about 0C, wlth l.0 -
1.2 molar equTvalents of lithium aluminium hydride
for 1-5 hours, preferably for about 2.5 hours.
Additton of methanol, saturated ammonium chloride,
and ether,separatton of the soltds and washtng them with
ether, washtng the combtned ftltrates and wash.tngs
wtth bftne, drytng,~and evaporattng the solvents
gtves 3-hydroxymethyl-5-methylthtomethyltsoxazole
26 whtch may be purtfted, e.g. by dtstt.llatton.
The hydroxymethyl group tn satd compound 26 ts
conventently esterifted wtth methanesulfontc actd
by trcattng a solution of compound 26 tn a halo-
genated hydrocarbon solvent, e.g. methylene
chlortde at -10C to 0C, preferably at about
~5 C, with l.0 - l.l molar equtvalents of mesyl

CoNL-42
~'13~B37
chloride in the presence of 1-2 molar equivalents,
preferably about 1.5 molar equivalents, of an
organic base such as triethylamine, for 1-3 hours,
preferably for about 2 hours. Washing with water,
dilute hydrochloric acid, sodium bicarbonate, and
water followed by drying and evaporating the sol-
vent-gives 3-mesyloxymethyl-5-methylthiomethyl-
isoxazole 27.
The corresponding isoxazoles in which the hydro-
xymethyl group is etherified with a lower alkyl,
e.g. methyl, are advantageously obtained by
treattng said last-named compound 27 in solution
In a lower alkanol, e.g. methanol, w;th the
appropriate alkali metal lower alkoxide, e.g.
with about 1.5 molar equivalents of sodium
methoxide at -10C to 0C, preferably at about
-5C to 0C,for 2 - 10 hours, preferably for
about 5 hours. Evaporation of the solvent,
taking up in a water- immiscible solvent such as
a halogenated hydrocarbon, e.g. methylene
chloride, washing, drying, and evaporating the
solvent gives 3-methoxymethyl-5-methylthiomethyl-
isoxazole 28 which may be purified, e.g. by
distillation.
The isoxazolines of this invention, i.e. the
compounds of formula 1 in which the dotted line
is regarded as being absent to indicate a single
bond C4-C5, R1 is COO(lower alkyl), R2 jS
- 30 -

CoNL-42
1~3~837
hydrogen, R3 is S(lower alkyl), and R4 and R5
are both hydrogen are conveniently prepared by
treating ethyl chloroximinoacetate 17 in ether
solution with 1,1 - 1.4 molar equivalents,
preferably with about 1.2 molar equivalents of
both an organic base such as triethylamine and
of allyl methyl sulfide 30, at about 0C for
2-8 hours, preferably for about 4.5 hours. Removal
of the hydrochloride salt of the base, i.e of
triethylamine hydrochloride, followed by washing
with water and dilute hydrochloric acid, drying,
and evaporating the solvent gives ethyl 5-methylthio-
methylisoxazoline-3-carboxylate 31 which may be
purlfled, e.g. by distillation.
Said last-named compound 31 may be transformed to
thecorresponding sulfoxide and the corresponding
sulfone by treatment with one or two molar
equivalents, respectively, of an organic peracid such as
m-chloroperbenzoic acid, in the same manner and
under the same conditions as described above
for a number of isoxazole derivatives, to
obtain ethyl 5-(methylsulfoxide )methlyisoxazoline-
3-carboxylate 32A and ethyl 5-(methylsulfanç~-
methylisoxazoline-3-carboxylate 32B, respectively.
The hydrolysis of the COO(lower alkyl) group
in said compound 31 to the COOH group is
advantageously effected by agitating said

CONL-42
~13~
compound 31 with concentrated hydrochloric acid
at ambient temperature for 8-24 hours, preferably
for about 16 hours, followed by extraction
with a water-immiscible solvent such as ethyl
acetate, washing, drying, and evaporating the
extracts, to obtain S-methylthiomethylisoxazoline-
3-carboxylic acid 33 which may be purified,
e.g. by crystallization.
The transformat;on of the COO(lower alkyl)
group in compound 31 to the carboxamido group
is conveniently carried out by stirring a
suspension of 31 in concentrated ammonia for
12-24 hours, preferably for about 20 hours, at
ambient temperature; addition of ice-water and
coolTng in ice gives the corresponding carbox-
amide , i.e. 5-methylthiomethylisoxazoline-
3-carboxamide 34.
The carboxamido group of said last-named
compound is easily converted into the cyano
groups by heating a solution of compound 34
in an aromatic hydrocarbon such as toluene with
a dehydrating agent, e.g. with 2-10 molar equi-
valents, preferably with about 5 molar equiv-
alents, of phorphorus pentoxide for 3-10 hours,
preferably for about 6.5 hours, at 80~C-150C, preferably
at about 120C or at the reflux temperature
of the mixture. Separation of the gummy by-
products and washing them with chloroform, fol-
- 32 -
-
',' ,'

CoNL-42
~3~837
lowed by evaporation of the combined liquid
phase and washings gives 3-cyano-5-methylthio-
methylisoxazoline 35 which may be purified,
e.g. by distillation.
Treatment of the compounds 33, 34, and 35 with one
or two molar equivalents of m- chloroperbenzoic
acid in the manner and under the conditions
described above gives, respectively, the cor
responding sulfoxides or sulfones of the above
compounds.
The isoxazoles of formula 1 in which R1 jS
methyl, R2 jS lower alkyl, and R3,R and R5
are all hydrogen are readily prepared by treat-
ing a 3-(lower alkyl)pentane-2,4-dione, e.g.
3-methylpentane-2,4-dione 37, prepared from
acetylacetone 36 by the method described in Org.
Syntheses 42,75 cited above, in aqueous solution
with one molar equivalent of hydroxylamine
hydrochloride at temperatures within the range
of 15C-40C, for 12-24 hours, preferably for
about 16 hours. Extraction with a water-
immiscible solvent such as a halogenated hydrocar-
bon, e.g. methylene chloride, drying, and evap-
orating the solvent gives 3,4,5-trimethyl-
isoxazole 38 which may be purified, e.g. by
distillation.
- 33 -

113~337
Lithiation of the above compound 38 takes place on both
methyl groups in the 3- and the 5-position so that a mixture
of the 3- and the 5-methyll.ithio derivatives is obtained when
su.bstantially one molax equivalent of _-butyllithium is used.
The lithiation reaction is carried out in the same manner as
described above, at -50C to -95C, preferably at -65C to
-70C, in an ether or cyclic ether such as tetrahydrofuran as
solvent, and in an atmosphere of nitrogen for 1-5 hours,
preferably for about 2-3 hours. The mixture of 3- and 5-
methyllithio derivatives is then contacted with substantiallyone molar equivalent of dimethyldisulfide in the same solvent
as above, first for about one hour at -65C to -70C and then
at ambient temperature for 12-24 hours, preferably for about
16 hours. Evaporation of the solvent, taking up the residue
in water, extraction with ether, washing and drying of the
ether extracts followed by evaporation and distillation of
the residue gives a mixture of the 3- and the 5-methylthio-
methyl derivatives which is separated, e.g. by chromatography,
to give 3-methylthiomethyl-4,5-dimethylisoxazole 39 and 3,4-
dimethyl-5-methylthiomethylisoxazole 40.
- 34 -
:

CONL-42
~134~7
Lithiation of said last-named compound 40 in
the same manner as described above takes place
exclusively on the same carbon atom which carries
the SCH3 group, and subsequent treatment with
dimethyldisulfide in the same manner as described
above gives the thioacetal 5-di(methylthio)methyl-
3,4-dimethylisoxazole 43 after working up as
above.
Treatment of the above compounds 39 and 40 with
one or two molar equivalents of m-chloroperbenzoic
acid in the same manner and under the same
conditions as described above gives the correspon-
ding sulfoxides and sulfones, respeetively. Thus,
treatment of compound 39.with one molar
equivalent of m-chloroperbenzoic acid gives
3-(methylsulfoxide)methyl-4,5-dimethylisoxazole
41A and treatment with two molar equivalents
gives 3-(methylsulfone)methyl-4,5-dimethyl-
isoxazole:41B. Similarly, treatment of compound
40 with one molar equivalent of m-chloroperbenzoic
acid gives 3,4-dimethyl-5-(methylsulfoxide)-
methylisoxazole 42.
- 35 ~

1'134837 CoNL-42
The compounds of formula 1 have anti-inflammatory,
analgesic, and anti-pyretic properties and have
a low order of toxicity. The anti-inflammatory
properties are demonstrated in a mod;fication of
the test using the carrageenin-induced paw edema
described by Winter et al., Proc.Soc.Exp.Biol.Med.
111, 544 (1962) and in the cotton pellet granuloma
test described by Winder et al., J. Pharmacol. Exp.
Therap. 138, 405 (1962), both in the rat. The
analgesic activities are demonstrated in a
modification of the phenylquinone-induced muscular
writhing test in mice described by Siegmund et al.,
Proc.Soc.Exp.Biol. 95, 729 (1957). The anti-pyretic
propertles are demonstrated in rats in the yeast-
lnduced fever test described by Sophia et ai.,
Journal of Pharm.Sciences 64, 1321-1324 (1975).
Acute toxicities are determined in rats and in mice
and the LD50's are calculated according to the
method of Litchfield and Wilcoxon, J.Pharmacol.Exp.
Therap. 96, 99 (1949).
The low order of toxicity found for the compounds
of this invention of formula 1 and the very high
therapeutic indices which may be calculated for~someo~ those
~ 36 ~

113~837
CoNL-42
compounds as LD50/anti-inflammatory ED50 are o.f particular
advantage when consi.dering that anti-inflammatory
drugs have to be administered repeatedly over pro-
longed periods of time.
When one of the compounds of formula 1 is employed
as an anti-inflammatory, analgesic, and/or anti- -
pyretic agent in warm-blooded animals, e.g. in
rats, it may be used alone or in combination with
pharmaceutically acceptable carriers, the proportion
of which is determined by the solubility and chemical
nature of the compound, chosen route of adminis-
tration and standard biological practice. For
example, an antl-lnflammatory, analgesic, and/or
antTpyretically effective amount of the compound
may be administered orally in solid form containing
such excipients as starch, sugar, certain types
of clay and the like . Similarly, such an amount
may also be administered orally in the form
of soluti~ons or suspensions, or the compound may
be injected parenteral1y. For parenteral administra-
tion the compound may be used in the form of a
sterile solution or suspension containing other
solutes or suspending agents, for example enough
saline or glucose to make the solution isotonic,
bile salts, acacia, gelatin, sorbitan monoleate,
Tween 80 (registered trademark) or polysorbate 80
(oleate esters of sorbitol and its anhydrides
copolymerized with ethylene oxide), and the like.
~ 37 ~
`': . ' -

1~34~337
C O N L _ L~ 2
The dosage of the present compounds of formula
1 will vary with the form of administration
and the particular compound chosen. Furthermore,
it will vary with the particular host under
treatment. Generally, treatment is initiated with
small dosages substantially less than the optimum
dose of the compound. Thereafter, the dosage is
increased by small increments until the optimum
effect under the circumstances is reached. In
general, the compounds of this invention are most
desirably administered at a concentration level
that will generally afford anti-inflammatory,
analgesically, and/or anti-pyretically effective
results without causlng any harmful or deleterious
side effects and preferably at a level that is in
a range of from about 1.0 mg to about 250 mg per
kilo per day, although as aforementioned variations
will occur. However, a dosage level that is in
the range of from about 10 mg to about 100 mg per
kilo per day is most desirably employed in order to
achieve effective results;
The anti-inflammatory, analgesic, and anti-pyretic
activities of the compounds of this invention are
well within the range of those of a number of well
known anti-inflammatory drugs.
.
- 38 -
., ~.,' '. ~ ''' '" ' . ' ' '

CoNL-42
~3~83'7
Some of those compounds are particularly
distinguished by remarkable anti-inflam-
matory and analgesic activities and by low
orders of toxicity, a combination of pro-
perties which give favourable therapeutic
I indices and which make those compounds esp-
ecially advantageous for long-term admini-
stration as anti-inflammatory drugs.
The following Table 1 shows the structures
of the compounds of formula 1 which have
been prepared (the presence of the optional
double bond is indicated in the appro-
prTate column of Table l by a double line
and tts absence by a single line ) and
the results obtained with those compounds in
the tests for anti-inflammatory, analgesic
and anti-pyretic activities described above,
as well as their respective LD50's. The
results obtained in the above tests with
certain well known anti-inflammatory drugs
are given at the end of Table 1 for purposes
of comparison. The mode of formation for -
some key compounds is also indicated.
~ 39 ~

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- 40 -

837
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~L~3~1837
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.....

CoNL-42
i~3~83~
The following Examples will illustrate this invention.
Example 1. 3-Methyl-5-methylthiomethylisoxazole~3
n-Butyllithium (625 ml of a 1.6M soln,in n-hexane,1 mole)
was added slowly to a stirred. cold (dry ice-acetone bath)
solution of 3,5-dimethylisoxazole (97 9., 1.0 mole)
in tetrahydrofuran(THF) (900 ml) in a nitrogen atmosphere,
maintaining the temperature below -65C. The reaction
mixture was stirred an additional hour at -70C and
the cold solution then blown over slowly by nitrogen
into a stirred, cold (-70C) solution of dimethyldisulfide
(110 ml., d-1.046, 115 9., 1.2 mole) in THF (900 ml)
maintaining the temperature below -65C. Stirred for
1 hr. at -70C and stirred at ambient temperature under
nitrogen over nlght. Concentrated the reaction mixture under
vacuum, added water (300 mi) and extracted with ether (3 x 300 ml).
The combined ether extracts were dried (MgS04), f;ltered,
; and concentrated to give 145 9. of-the title compound,
b.p. 50 52/0.1 mm wit~h an nmr (CDC13) spéctrum ~ 6.1
; (s, lH, C4-H),~3.7 (s, 2H, C -CH2), 2.15 and 2.28 (ss,
6H,-C3-CW3 and~SCH3), consistent withi~he assigned
structure.
There was also obtained 9 9. of the thioacetal, 5, b.p
90 - 95,~0.1 mm, white fluffy solid from hexane, m.p.
40 - 41C
Example 2. 3-Methyl-5-Di(methylthio)-methyl7soxazole~5
By repeating the reaction exactly as described in
Example 1 using as startTng material 28.6 9 (0.2 mole)
of 3-methyl-5-methylthiomethylisoxazole, obtained as
- 44 -
,

CONL~42
~3~837
described in Example l, there was obtained 35.3 9. of
crude title compound, which on distillation b.p. 112/
1.5 mm gave 28.3 9 (75%) of an oil whTch slowly crystal-
lized. Crystallization from hexane gave 25.9 9 (69%)
fluffy white crystals, m.p. 40--41 C. The nmr (CDC13)
spectrum: ~ 5.89 (s, 1H, C4-H), 4.72 (s, 1H, C5-CH),
2 05 ( 3H C -CH3), 1.95 (s~ 6H~ -SCH3)~ is
sistent with the assigned structure.
Example 3. 3-Methyl-5-Tri(methylthio)methylisoxazole~ 8
The reaction was repeated as described in Example 1
uslng as starting material 3-methyl-5-dl(methylthio)-
methylisoxazole prepared as described in Example 2.
There was thus obtained the title product, b.p. 101-
110/0.4 mm; nmr (CDC13) spectrum ~6.2 (s, lH, C4-H),
2-3 (s, 3H, C3-CH3), 2.15 (s, 9H, SCH3).
When dimethyldisulfide was added to the 17thio derivative
of 3,5-dimethylisoxazole ("normal" addition rather than
the "reverse" addition described in Example 1), a
mixture of the thioether 3, the thioacetal 5 , and the
ortho-thioester 8, with considerable amounts of 5 and 8 was
obtained, the compounds being separated by fractional
distillation. The relative amounts of 5 or 8 could
be considerably increased by reacting 3,5-dimethyl-
isoxazole, 2, sequentially with n-butyllithium (1
equivalent) and then dimethyldisulfide (1 equivalent),
and repeating this sequence once more to give 5, or
twice more to give 8.
. .
- 4$ -

CONL-42
~3~Eil37
Example 4. 3-Methyl-5-~(methylthio)ethylisoxazole, ~
n -Butyllithium (17 ml of a 2.l mo1ar soln, 0.036 mole) was
added slowly to a stirred cold (-70C) solution of
3-methyl-5-methylthiomethylisoxazole, 3, (5 g., 0.035
mole) in THF (50 ml) in a nitrogen atmosphere at such
a rate as to keep the temperature below -65~C. After
1 hr at this temperature the cold reaction mixt~re
was blown over by nitrogen into a stirred, cold (-70C)
solution of methyl iodide (7 ml, 0.049 mole) in THF
(20 ml) also under a nitrogen atmosphere. After ~ hr
at this temperature and 1 hr at ambient temperature the
reaction mixture was concentrated, taken up in methylene
chlorlde, washed with water and drled (MgS04). The
filtered solution was concentrated and distilled whén
4.7 g (85%) of the title compound b.p. 95/12 mm was
obtained as a clear liquid, nmr (CDC13) ~6.12 (s, 1H,
C4-H), 4.o8 (q, 1H, C5-CH), 2.3 and 2.1 (ss, 6H, C3-
CH3,-SC_3), 1.65 (d, 3H, C5-CHCH3).
'`'~'
Example 5. 3-Methyl-5-~,~di(methyl)methylthlome~hylisoxazole, 10
By repeating the reaction of Example 4 on the product
from Example 4, an 80% yield of the title compound was
obtained as a clear liquid b.p. 70 /1 mm, nmr (CDC13)
spectrum: ~6.o (s, 1H, C4-H), 2.23 (s, 3H, SCH3) ,
2-0 (s, 3H, C3-CH3), 1.65 (s, 6H, C5C(CH3)2).
Example 6. (3-Methyl-5-isoxazolymethyl)methyl sulfoxide, 4A
A solution of 3-methyl-5-methylthiomethylisoxazole, 3,
- 46 -
, , ~ . . . .. . .

CONL-42
37
(7.15 9., 50 mmole) in methylene chloride (50 ml) was cooled
to 0, and a solution of m-chloroperbenzoic acid (85%,
10 9., 50 mmole) in methylene chloride (10 ml) was
added slowly maintaining the temperature at 0C. After
~ hr stirring at 0 the ice bath was removed and the
mixture stirred an additional hour at ambient temperature.
The reaction mixture was cooled to 0C and the crystal-
lized m-chlorobenzoic acid filtered off and discarded.
The filtrate was concentrated to dryness. The resulting
oily crystals were stirred with ether at 0C. Most
of the title compound dissolved initially but soon
crystallized as a white solid, m.p. 58-60C, yield
6.1 9 (75%), nmr (CDC13) ~6.2 (s, lH, C4-H), 4.o8
' 5 -2)~ 2.58 (s, 3H, -SOCH3), 2.3 (s 3H C CH )
Example 7. (3-Methyl-5-isoxazolylmethyl)methylsulfone, 4R
A solution of m-chloroperbenzoic acid (85%, 66 9., 0.33
mole) in methylene chloride (100 ml) was added slowly
to a stirred, ice-cold solution of 3-methyl-5-methylthio-
methylisoxazole, 3, (21.5 9., 0.15 mole) in methylene
chloride t200 ml), maintatning the temperature at oC-
After the addition was complete the reaction mixture
was allowed to warm to room temperature and stirred
at this temperature for 17 hrs. The reaction mixture
was cooled in an ice-salt bath and the crystallized
m-chlorobenzoic acid (46.4 9) removed by filtration.
~he filtrate was washed with aqueous 5% sodium
bTsulfite (2 x), saturated aqueous sodium bicarbonate
~ 47 ~

CoNL-42
113~83'7
(2 x), brine (2 x), dried (MgS04), filtered and con-
centrated, when 29.6 9. of a white solid was obtained.
The material was stirred well with ether, cooled to
0C overn;ght, fTltered, washed well with cold ether,
and dried to give 25 9 (95%) of the title compound as
a white solid, m.p. 103-105c; (recrys~t. from CH2C12), nmr
(CDCi3) spectum ~6.4 (s, 1H, C4-H), 4.5 (s, 2H, C5-CH3),
3.00 (sbr, 3H, S02CH3), 2.35 (s, 3H, C3-CH3).
'
i~xample 8. (3-Methy ! -5-isoxazolyl-~-ethyl)methyl~ ___A_
A so1ution~of ~-chloroperbenzoic acid (85%, 109;, 50 mmole)
1 0
In methyle'ne chloride (100.m'1) was added slowly'to a
stirred ice-'cold~solution of'3-methy'1-5-~(rnethyle.hio)-
ethylisoxazole ~,(9.45 9., 60 mmoles) in rnethylene
chloride (100 ml), while maintaining the temperature at 0C.
Stirred at 0C for ~ hour'and then at ambient temperature for l hr.
Cooled in an ice-salt bath, fi'l~ered and d'iscarded the precipi-
tated m-chlorobenzoic acid. Concentrated the filtrate''and dis-
solved the residue in ether and washed with saturated sodium
bicarbonate,'water, and brine. The organic layer on~concentration
:
gave 2.1.9 of a semi-solid which was found to consist of starting
material, title compound, and m-chlorobenzoic acid.
.
The combined aqueous layers were extracted with
chloroform (3 x), and the combined organic layers
dried (MgS04), filtered and concentrated to give
the title compound (8.6 9., 83%) as an oil, b.p.
123-125/0 1 mm (careful distillation) nmr (CD513)
spectrum, ~6.19 (s, 1H, C4'-H), 4.12 (q, lH, C5-CH-CH3),
- 48 -

CONL-42
~3~837
2.49 (s, 3H, SOCH3), 2.3 (s 3H, C3-CH3), 1-72 (q, 1H,
C -CH-CH )
Example 9. (3-Methyl-5-isoxazolyl(~ -ethyl`methylsulfone, llR
A solution of m-chloroperbenzoic acid (85~, 74 9., G.372
mole) in methylene chloride (600 ml), was added slowly
to a stirred, cooled (0C) solution of 3-methyl-5-~-
(methylthio)ethylisoxazole 9,(29~15 9.~ 0.186 mole)
in methylene chloride (250 ml). After ~ hr stirring
at 0, the reaction mixture was stirred-overnight at
ambient temperature. The reaction mixture was cooled
in an ice bath and the crystalllzed m-chlorobenzoic actd
(60 9) removed by filtration. The filtrate was washed
with aqueous 5~ sodium bisulfite (2 x), sat. aqueous
bicarbonate (2 x), brine (2 x), dried (MgS04), filtered
and concentrated, when 33.2 9 (94~) of the title
compound was obtained as a white powder. It was washed
wtth ether and dried, giving 29.1 9 of solid m.p. 77-78,
nmr (CDC13) spectrum~ ~6.3 (s, 1H, C4-H), 4.45 (q, 1H,
C5-CHCH3), 2.87 (s, 3H, S02CH3), 2.29 (s, 3H, C3-CH3),
1-75 (d, 3H, C5CH-cH3).
Example 10, (3-Methyl-5-isoxazolyl-~-dimethylmethyl)methylsulfoxide,12A
,
;~ Using the same procedure as in Example 8 and starting
.. .
from 3-methyl-5~ -di(methyl)methylthiomethylisoxazole,
10~ the title compound was obtained in 80~ yield as
a pale yel low o7 I which decomposed on distillation,
nmr (CDCl3) spectrum ~6.15 (s, 1H, C4-H), 2.27 and 2.20
- ~ (ss, 6H, SCH3 and C3-CH3), 1.60 (s, 6H, C5-c(cH3)2)-
- 49 -

CoNL-42
~13~837
Example 11. (3-Methyl-5-isoxazolyl-~,~-dimethylmethyl)methylsulfone,1~B
Using the same procedure as in Example 9 and starting
from 3-methyl-5-~,~-dt(methyl)methylthiomethylisoxazole,
10, the title compound was obtained in 90~ yield, nmr
(CDC13) spectrum, ~6.25 (s, IH, C4-H), 2.79 (s, 3H,
S02CH3), 2.25 (s, 3H, C3-CH3), 1.80 (s, 6H, C5-C(CH3)2).
Example 12. 3-Methyl-5-~(methylsulfoxide)methylthiomethylisoxazole, hA
A solution of m-chloroperbenzoic acid (85~, 28.5 9.,
1 0
0.15 mole) in methylene chloride (300 ml) was added
slowly to a stirred, cold (-5~) solution of 3-methyl-
5-di(methylthlo)methylisoxazole 5, t28.3 9., 0.15 mole)
in methylene chlorlde (lO0 ml), maintalning the temp-
erature below 0C. The reaction mixture was stirred
overnight at ambient temperature and then cooled in an
ice bath. The precipitated m-chlorobenzoic acid (14.3
9., m.p. 154-155C) was removed by filtration and discarded.
The filtrate was stirred with saturated aqueous
sodium bicarbonate (125 ml) for ~ hr (twice). The
combined saturated bicarbonate solutions were extracted
with chloroform (3 x). The total combined organic layers
were washed with brine (2 x 125 ml), dried (M9504), and
concentrated, when 30.3 9 (98.5%) of a light yellow
oil, which crystallized on standing, was obtained.
This material was stirred well with cold ether and the
resulting white powder filtered and washed well with
ether leaving 21.3 9 of material m.p. 64 - 97C. This
mater;al was recrystall7zed from hot ethyl acetate
.
- 50 -

CONL-42
113~837
(ca. 50 mls) and the resulting material, 14.3 9
washed well with ethyl acetate (3 x 25 ml) giving
8.3 9 (27%) of the title compound as white
crystals, m.p. 104 - 106~; nmr (CDC13) spectrum,
( , , 4 H), 4-85 (s, 1H, C5-CH), 2.51 (5~ 3H,
SOCH3), 2-4 (s, 3H, SCH3), 2-35 (s, lH, C3-CH3).
The combined ether and ethyl acetate filtrates from
above were concentrated to give 22 9 of material.
Chromatography over silica gel using ethyl acetate
as eluant gave 4.1 9. of starting material, and 4.9
9 (16%) of a white solid, which was washed with cold
ether to give 4.4 g of material, m.p. 65 - 70.
The nmr spectrum of this material showed that it was
not the same as the compound m.p. 104 - 106, although
it did contain 20% of this material. The major com-
ponent ismQ5t ~ikely an isomer. nmr (CDC13) spectrum:
~6-3 (s, lH, C4-H3), 5.0 (s, lH, C5-CH), 2.62 (s, 3H,
SOCH3), 2.43 (s, 3H, SCH3), 2.39 (s, 3H, C3-CH3).
. . .
Examp!e 13.-_3-Methyl-5a,a di(methylsulfoxi'de)methylisoxazole, 6B
A solution of m-chloroperbenzoTc acid (90%~ 19 9.1 1QQ
mmole) in ethyl acetate (100 ml), was added slowly
to a stirred cold (-5) solution of 3-methyl-5-
di(methylthio)-methylisoxazole 5 ~9.45 9., 50 mmole)
in ethyl acetate (100 ml), keeping the temperature
below 0. The mixture was stirred overn7ght at ambient
temperature and the resulting white precipitate
filtered, washed with ethyl acetate and ether and
- 51 -
: .

C O N L - 4 2
113~837
dried to give 3.3 9. (29.9%) of a white powder,
m.p. 131 - 132C, whose nmr (DMSOd6) spectrum in-
dicated a mixture of isomers of the title compound,
with nmr (DMSOd6): ~2.30 (s with sL) C3-CH3,
2.65 (s) and 2.77 (s) two SOCH3; 5.81 (s), 6.02
(s) C5-H, 6.62 (d) C4-H.
The combined filtrates were stirred with solid potassium
carbonate for 2 hrs and the white solid filtered
off and discarded. The filtrate on concentration
1û gave 23.2~ g. of a pale yellow solid. This solid was
washed with cold ether (leaving 6.2 g. of white solid)
and cold ethyl acetate, providing 4.8 9 (43.4~6) of
a whlte powder, m.p. 105 - 110C. Chromatography
over silica gel using ethyl acetate as eluant gave
2.6 9 of a white powder, m.p. 109-111& whose nmr
(DMSOd6) spectrum indicated a mixture of isomers
of the title compound, with the nmr spectrum
-~ similar to the above but with changes in the relative
intensites of the signals.
Example 14. 3-Methyl-5-CL-(methylsulfone)-ol-(methylsulfoxide)
methylisoxazole C
A solution of in-ehloroperbenzoic acid (57 9., 0.3
`~ mole) in ethyl ac~tate (175 ml) was added slowly to
a stirred, cold (-5) solution of 3-methyl-5-di(methyl-
thio)methylisoxazole, 5 (18.9 g., 0.1 mole) in
ethyl acetate (100 ml), maintaining the temperature
of the reaction below C ~ The reaction mixture
- 52 -

CoNL-42
~13~837
was stirred at ambient temperature overnight and the
white precipitate recovered by filtration and washing
with ether. It weighed 7.3 9., m.p. 99 - 100C
and its nmr spectrum showed it was mainly the title
compound (mixture of isomers) with some disulfone
and m-chlorobenzoic acid. The ethyl acetate filtrate
was concentrated a~nd the resulting white residue
washed well with cold ether (to remove most of the
m-chlorobenzoic acid). There was thus obtained
13.7 9. of white powder whose nmr spectrum showed
it to be the title compound (mixture of isomers) as
the main product, along with the disulfone 6D and
disulfoxide 6B as minor by-products.
Chromatography of the two fractions separately on
silica gel using ethyl acetate as eluant effected
separation of the components. In:the case of the
ethyl acetate insoluble fraction, 5.4 9. and the
ethyl acetate soluble fraction 8.5 9. of the t7tle
compound was obtained as an isomer mixture, m.p.
2Q 94 - 95&. The nmr spectrum was consistent with the
; assigned structure but indicated a mixture of two
isomers to be present~
Example 15. 3-Methyl_5-di(methylsulfone)methylisoxazole,
A solution of m-chloroperbenzoic acid (85%, 41.7
9., 210 mmoles) in ethyl acetate (200 ml) was added
slowly to a stirred, cold (-5) solution of
3-methyl-5-di(methylthio)methylisoxazole 5, (9.45 9.,
- 53 ~
: , -

CoNL-42
1~3~837
50 mmole) in ethyl acetate (150 ml), keeping the
temperature below 5C. The reaction mixture was
stirred at ambient temperature overnight and the
white preicpitate filtered, washed with ethyl
acetate and dried to give 6.2 g. The solid was
washed well with cold ether to give 5.3 9 (41.9%) of
the title compound, m.p. 164 - 166C.
The ethyl acetate filtrate was washed will with
aqueous sodium bicarbonate, then brine, dried
(MgS04) and concentrated. The resulting white
solid was washed well with cold ether to give another
5.4 9 (42~) of the title compound, m.p. 166 - 168Ç,
nmr (DMS0-d6) spectrum: ~7.31 (s, lH, C5-CH),
6-75 (s, 1H, C4-~!), 3.35 (s, 6H. S02CH3), 2.3
(s, 3H, C3-CH3).
Example 16. 3-Methyl-5~ (methylsulfone)methylthiomethylisoxazole,
n-Butyllithium (70 ml of 1.6 molar, 0.11 mole) was
added slowly under nitrogen to a stirred, cold
t-30 C) slurry of 3-methyl-5-methylsulfonemethyl-
, .
isoxazole 4, (17.5 9., 0.1 mole), in THF (300 ml),
at such a rate as to maintain the temperature
below -20C. The reaction m;xture was stirred at
-30 to -40 for an additional 2 hrs, then cooled to
l -70 and a solution of dimethyldisulfide (10.6 9.,
lOml, 0.113 mole) in THF (20 ml) added all at once.
The slurry was stirred 2 hrs at -70~C and then at ambient
temperature overnight. The mixture was concentrated,
.
!
~ 54 ~
.

837
shaken with brine (100 ml) and extracted with ether ~4 x).
The combined ether extracts were dried and concentrated to
give 15.3 y (69~) of residue. The residue was crystallized
from methylene chloride-ether ~6.5 g), and then ethyl acetate
(4.2 g) to give the title compound as a white solid, m.p.
98 - 100 C, nmr (CDC13) spectrum: ~6.48 (s, lH, C4-H), 5.12
(s, lH, C5-CH), 3.13 (s, 3H, SO2CH3), 2.5 (s, 3H, SCH3), 2.32
( ' ' 3 -3)
EXAMæLE 17
3-Methylisoxazole-5-a-(methylthio)acetic Acid 13, Methyl
Ester thereof 14, Sulfoxide 15A and Sulfone 15B thereof, and
3-Methylisoxazole-5-a,a-di(methylthio)acetic Acid 16 and
Methyl Ester théreof 16A.
_-Butyllithium (110 ml. of 2.1 molar solution in hexane, 0.21
mole) was added slowly to a stirred, cold (-75C) solution of
crude 3-methyl-5-methylthiomethylisoxazole, 3 (30 g. 0.21
mole) in THF (250 ml) in a nitrogen atmosphere, maintaining
the temperature below -65C. Stirring was continued 1 hr at
this temperature and the reaction mixture poured on to a
large excess of crushed dry ice and stirred until the
reaction mixture reached room temperature. The solvent was
removed under reduced pressure and the solid residue slurry
washed with ether and dried under vacuum at 50C to give
40.5 g. (100%) of the lithium salt of the acid 13 as a light
yellow powder; nmr (D2O) spectrum ~6.5(s, lH, C4-H), 4.72
(s, DOH), 4.88 (s, lH, C5-CH), 2.45 (s, 3H, SCH3), 2.28
(s, 3H, C3-CH3). The free acid 13 could be obtained

CoNL-42
113~837
by acidification of this lithium salt.
The lithium salt (38.5 9., 0.2 mole), methyl iodide
(31.29., 0.22 mole) in dimethylformamide (200 ml)
was stirred at room temperature for 1~ hr and the
clear solution diluted with ether and the resulting
mixture washed with water (3 x), saturated brine,
dried and concentrated to give the methyl ester
(28.8 9., 72%?, as a red-brown oil. The product was
purified by graded elution chromatography over
silica gel using hexane-acetone as eluant. There
was thus obtained 12.8 9. of the methyl ester 14,
nmr (CDC13) spectrum, ~6.3 (s, lH, C4-H), 4.7 (s, 1H,
C5-CH), 3-82 (s, 3H, C00CH3), 2.35 (s, 3H, SCH3),
2.22 (s, 3H, C3-CH3).
From the same column there was obatined 3 9. of
methyl 3-methyl-5-~, ~di(methylthio)acetate, 16A,
nmr (CDC13), spectrum, ~6.22 (s, lH, C4-H), 3.72
~s, 3H, COOCH3), 2.3 and 2.1 (ss, 6H, SCH3), 1.85
(s, 3H, S3-CH3), formed ~from the 3-methyl-5-
a,~-di(methylthio)methylisoxazole, 5, present as
an impurity in the starting material 3.
The acid 16, was obtained by lithiation of 3-methyl-
; 5-di(methylthio)methylisoxazole 5, followed by
reaction with carbon dioxide, as described above.
The free acid 16 m.p. 110 - 113& dec. (benzene)
nmr (acetone d6), spectrum,~ 8.5(sbr, 1H, COOH),
.
56 -
''

CONL-42
~13~837
6.48 (s, lH,C4-H), 2.31 (s, 3H, C3-CH3), 2-1
(s, 6H, SCH3). Treatment of this acid with dia-
zomethane gave the same methyl ester 16A described
above.
The sulfoxide 15A, 98% yield, colourless oil, nmr
(CDC13) spectrum, 6.6 (d, 1H, C4-H), 5.18 (d, 1H,
C5-CH), 3.98 (s, 3H, COOCH), 2.62 (d, 3H, SOCH3),
2-35 (s, 3H, C3-CH3) a~d'the sulfone,g7% yield,
m.p. 97 - 99C, nmr (CDC13) spectrum, ~6.55 (s,
1H, C4-H),5.3 (s, 1H, C5-CH), 3.9 (s, 3H, COOCH3),
2 H3), 2-35 (s, 3H, C -CH )
obtained by oxidation of the sulfide 14, using
one and two equlvalents of m-chloroperbenzoic acid,
respecttvely, in the manner described above.
Example 18. Ethyl 5-Methylthiomethylisoxazole-3-carboxylate,
`~ 2Q, and Sulfoxjde ~5A and Sulfone 2~B thereof.
_ _
A solution of triethylamine (38.3 ml, 27,8 9., 0.275
; mole) in ether (20 ml) was added slowly to a stirred, cooled (ice bath) solution of ethyl chloroximino-
,
acetate (34.9 9., 0.25 mole) and propargyl bromide
(80% in toluene, 40.9 9., 0.275 mole) in ether (250 ml).
There was a mild exothermic reaction and triethyl-
amine hydrochoride separated as silky white crystals.
Stirred the reaction mixture at ambient temperature
for 1 hr, filtered and washed the solid with ether.
The total filtrate was washed with brine (3 x 200 ml),
dried and concentrated to give an bil with crystals.
~ 57 ~

CONL-42
~3~837
Added dry ether and filtered off the crystals. The
filtrate was evaporated and the resulting oil
distilled under reduced pressure to give 26.1 9
of ethyl 5-bromomethylisoxazole-3-carbxylate 19
(skin irritant) , b.p. 97 ~ lO0 ~0.25 mm, nmr (CDC13)
spectrum, ~6.7 (s, 1H, C4-H), 4.45 (sq, 4H, C5-CH2CH3),
1-4 (t, 3H, CH2CH3).
n-Butyllithium (45 ml of 2.45 molar~ 0.11 mole) and
methylmercaptan (gas) were simultaneously added to
cooled (ice-bath), stirred THF. After 45 mins the
clear solution was allowed to reach room temperature
when a white solid separated. The stlrred mixture
was cooled to 0 and the ethyl 5-bromomethylisoxazole-
3-carboxylate 19, (23.4 9., 0.1 mole) was added.
There was an eXothermic (0 to 5C) reaction. The mixture
was stirred at room temperature for 4 hrs and con-
centrated to give 18.7 g of an oil. Distil'iation
gave 13.7 g (68%) of the title compound 20, colourless
oi1, b.p. 97 -~100/0.05 mm,nmr (CDC13) spectrum,
~6-6 (s, lH, C4-H), 4.4.(q, 2H, CH2CH3), 3-8 (s, 2H,
C5-CH2), 2.12 (s, 3H, SCH3), 1.37 (t, 3H, CH2CH3).
The sulfoxide, 25A, 75%, oil, nmr (DMSOd6) spectrum,
~6-9 (s~ 1H,C4-H), 4-48 (sq, 4H, C5-CH2, CH2CH3),
2-67 (s, 3H, SOCH3~, 1.4 (t, 3H, CH2CH3) and the
sulfone, 25B, 89~, m.p. 99 - 101C, nmr (DMSOd6)
spectrum, ~7.07 (s, lH, C4-H), 5.12 (s,2H, C5-CH2),
4-45 (q, 2H, CH2CH3), 3-22 (s, 3H, S02CH3), 1-4
(t, 3H, CH2CH3), were obtained by oxidaton of 20
- 58 -
:,

CoNL-42
~3~83'7
with one or two equivalents of m-chloroperbenzoic
acid in the manner described above.
Example 19. 5-Methylthiomethylisoxazole-3-carboxylic acid,
21 and its Sulfone ~lA
The ethyl ester 20 (2.019.,0.01 mole) was stirred
with concentrated hydrochloric acid (15 ml). After
1 hr at room temperature a clear solution resulted.
Left overnight at room temperature then cooled in
an ice-bath, filtered the resulting white crystals,
washed witIl ice water and dried, to obtain 0.90 9
(63.4~) of the title compound 21, m.p. 119 - 122C,
with an infrared spectrum consistent with that
expected.
In a similar manner ethyl 5-(methylsulfone)methylis-
oxazole-3-carboxylate was hydrolyzed by concentrated
hydrochloric acid to the corresponding free acid
21A, m.p. 183 - 186C with an infrared spectrum
consistent with the assigned structure.
Example 2~. 5-Methylthiomethylisoxazole-3-carboxamide, 2~ and
5-Methylth10methylisoxazoie-3-dimeth~lca~boxa~ide
-- . .
The ethyl ester, 20 (2.01 9., 10 mmole~ was stirred
with concentrated ammonia (15 ml) at room temper-
ature. A clear solution resulted and in a short
while white crystals separated. Added ice water
(20 ml), cooled in an ice bath, filtered, washed
with ice water and dried when 1.63 9 (94.7~) of
~ 59 ~
:
- ~ ,

CoNL-42
~3~837
the title compound 23, m.p. 141 - 143 C, was obtained
with an infrared spectrum consistent with the
assigned structure.
The dimethylamide 22 was obtained (99%) as a colour-
less oil, nmr (CDC13) spectrum, ~6.42 (s, lH, C4-H),
3-75 (s, 2H, C5 CH2), 3.25 and 3.1 (ss, 6H, NCH3),
2.12 (s, 3H, SSH3) by leaving a solution of the
ethyl ester 20 (2.01 9., 0.1 mole), dimethylamine
(2.25 9., 3.30 ml., 0.5 mole), and ether (50 ml)
in a closed pressure vessel at room temperature for
one month and purifying by chromatography over silica
using acetone-ether as eluant.
Example 21. 3-Cyano-5-methylthiomethylisoxazole, 74
A mixture of 5-methylthiomethylisoxazole-3-carbox-
amide, 23 (1.72 9., 10 mmoles) and phosphorus pentoxide
(7.0 9., 50 mmole) Tn toluene (40 ml) was stirred
and heated in an oil bath at 120C for 8 hrs. The
supernatane liquid was decanted from the gum and0
the gum washed wlth chloroform (3 x). The com-
bined organic layers were concentrated to an oil,
1.54 9., which on disti11ation gave the title
compound as a clear liquid, b.p. 68 - 71 /0.25 mm,
1.14 9 (74%). The infrared spectrum and nmr spectrum
were consistent with the assigned structure. The
nmr (CDC13) spectrum ~6.68 (s, lH, C4-H), 3.90
(s, 2H, C5-CH2), 2.2C (s, 3H, SCH3).
- 60 -

CoNL-42
:113/~837
Example 22. 5-~(Methylthio)ethylisoxazole-3-carboxamide 29
n-Butyllithium (13.2 ml of 1.6 molar, .021 mole)
was added slowly to a cooled (-78) stirred sol-
ution of 5-methylthiomethylisoxazole-3-carboxamide
23 (1.72 9., .01 mole) in THF (40 ml) in a ni-
trogen atmosphere, maintaining the temperature
below -65C. The white solid dissolved to a
yellow solution. After stirring 1.5 hrs at -74C,
a solution of methyl iodide (3.12 9., 0.022 mole)
in THF (20 ml) was added over 15 mins. Stirred
for 2 hrs at 70 then allowed to warm to room
temperature. The reaction mixture was concentrated,
taken up tn ethyl acetate, washed wlth brTne, drled
(MgS04), and concentrated to give 1.07 g (57.5%)
of the title compound as a white solid, nmr (CDCl3)
spectrum, ~7.3 (br, 2H, NH2), 6.68 (s, lH, C4-H),
4.10 (q, lH, C5-CHCH3), 2.12 (s, 3H, SCH3), 1.7
(d, 3H, C5-CHCH3).
Example 23. 3-Hydroxymethyl-5-methylthiomethylisoxazole 2h
A solution of ethyl-5-methylthiomethylisoxazole-
3-carboxylate, 20 (40.2 g., 0.2 mole-) In THF
(lO0 ml) was added to a stirred, cooled (ice-bath)
suspension of lithium aluminum hydride (9.60 g.,
0.24 mole) in THF (150 ml) over a l hr period and
the mixture stirred for 1.5 hr more at 0 C when
a tlc showed complete reaction. Methanol (17 ml)
was added dropwise, followed by saturated ammonium
- 61 -

CONL-42
1134837
chloride (30 ml) and ether (lOO ml), and the
resulting mixture was filtered through Celite
(reg. trademark). The residue was washed with
ether and methylene chloride. The combined ~
trates were washed with brine (3 x), dried (MgS04)
and concentrated to give 29,8 9 of residue. Dis-
tillation gave 21.21 g (66.7%) of the title
- compound as a colourless oil, b.p. 116 -118/
0.25 mm, nmr (CDCl3) spectrum, ~6.22 (s, 1H, C4-H),
4.70 (5, 2H, C3-CH2), 3.83 (sbr, 1H, OH), 2.72
(s, 2H, C5-CH2), 2.18 (s, 3H, SCH3).
Example 24. 3-Mesyloxyme_hyl-5-m_thylthiomethylisoxazole ~Z, and
3-Methoxymethyl-5-methylthiomethylisoxazole 28.
Trlethylamine (5.3 ml, 3.78 9, 0.0375 mole) was
added to a stirred, cold (-5C) solution of the
alcohol 26 (3.98 g., 0.025 mole) in methylene
chloride (25 ml). Mesyl chloride ( 3.15 9., 0.0275
mole) was then added dropwise. Within 30 mins the
temperature rose from -5 to O~C. Stirred for 2
~`~ 20 hrs, then washed at 0C sequentially with water,
5% HC1, sat. sodium bicarbonate,then water, dr7ed
(MgS04) and concentrated when 5.76 9. of the title
compound 27 was obtained as a mobile brown oil
`~ whose ~lc and nmr spectrum were consistent for the
mesylate.
Sodium (o.36 9) was dissolved in methanol and the
resulting solution cooled to -5 C. A solution of
the mesylate 27 (3.31 9., 15 mmoles) in THF (4 ml)
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CoNL-42
11;~4837
was added, and the mixture stirred at 0C for 5
hrs. Concentrated to dryness, extracted with
methylene ch!oride, washed with brine (3 x), dried
(MgS04) and concentrated, when 2.47 9 oF an oil was
obtained. On distillati~n 1.8 9 (69.5%) of the
title compound 28 was obtained, b.p. 70 - 72/
0.1 mm, nmr (CDC13) spect`rum, ~6.22 (s, 1H, C4-H),
4-47 (s, 2H, C3-CH2), 3-72 (s, 2H, C5-CH2), 3-37
(s, 3H, OCH3), 2.12 (s, 3H, SCH3).
Example 25. Ethyl 5-~ethylthiomethylisoxazoline-3-carboxylate ~1
and Sulfoxide 32A and Sulfone 32~ thereof.
Triethylamine (55.5 9., 76.6 ml., 0.55 mole) was
added slowly (over 4 hrs) to a cold (Ice-bath)
stirred solution of ethyl chloroximinoacetate
(69.8 9., o.46 mole), and allyl methyl sulfide
(48.5 9., 0.55 mole) in ether (500 ml). The
reaction mixture was stirred an additional half hour
at 0C and the precipitated triethylamine hydrochloride
removed by filtration.. The ether filtrate was
washed sequentially at 0C with brine, 5~ HC1, and
brine, dried and concentrated to give 89.5 9
(95.7%) of a colourless oil. Distillation gave
75.18 9 (80.5~) of the title compound 31 as a
~; colourless oil, b.p. 114 - 116 /0.2 mm; t~e nmr (CDC13)
spectrum was consistent with the assigned structure
and showed that the product was a mixture of the
two isomers, isomeric at C5.
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.
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CONL-42
~13~837
The sulfoxide, 32A, colourless oil (79.5%), and
sulfone, 32B liquid (71.5%), were prepared by oxi-
dation of the sulfide, 31, using one and two
equivalents of m-chloroperbenzoic acid, respect-
ively. The nmr spectra were consistent with the
structures~and indicated that mixtures~of the
C5-isomers were present.
Example 26. 5-Methylthiomethylisoxazoline-3-carboxylic Acid,
The ethyl ester 31 (15.24 9., 0.075 molé) was stirred
with concentrated hydrochloric acid (lOO ml) over-
night and the reactlon mixture extracted w.ith
ethyl acetate (3 x). T.he c~mb~ined layers were
dried (MgS04), flltered and concentrated and the
resulting crude acid (12.76 9) crystallized from
ether to give 6.97 9 (53.2%) of the title compound,
m.p. 93 - 96C, with an infrared spectrum (1700 cm 1)
~ consistent with this structure.
-~ 20 Example 27. 5-Methylthiomethylisoxazoline-3-carboxamide ~4
The ethyl ester 31 (15.24 9., 0.075 mole) was
stirred with concentrated ammonium hydroxide (112 ml)
for 20 hrs, ice water (150 ml) was added and the
mixture cooied. The resulting crystallized amide
was collected by filtration. After washing with ice
water and drying 9.33 9. (71.4~) of the title
compound was obtained, m.p. i34 - 136C, with an
tr spectrum consistent with the assigned structure.
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CONL-42
, .
~3~837
Example 28. 3-Cyano-5-methylthiomethylisoxazoline, ~S
A mixture of the amide 34 (1.74 9., 10 mmoles),
P205 (7.0 9., 50 mmoles), and toluene (50 ml),
was stirred well and heated under reflux in an
oil bath at 120C for 6.5 hrs. Decanted the
liquid and washed the residue with chloroform
(3 x). The combined organic layers were concentrated
- and the residue (0.65 9) distilled to give o.6 9
(38.5%) of the title compound as a colourless
liquid, b.p. 82/0.05 mm, with nmr (CDC13) and ir
spectra consistent with the assigned structure and
indicating a mixture of C5-isomers.
Example 29. 3,4,5-Trimethyliso~azole ~
Hydroxylamine hydrochloride (88.4 9., 1.272 moles)
was added portionwise to a stirred solution of
3-methylpentane-2,4-dione 37 (Org. Syn., Vol.42,
p.75; 145 9., 1.272 moles) in water (900 ml), at
such a rate as to maintain the temperature below
40 C. The reaction mixture was stirred at ambient
temperature overnight by which time an oily layer
~ .
had separated at the top. This layer was separated,
and the aqueous layer extracted with methylene
chloride (4 x). The combined extracts were dried
(MgS04), filtered and cOncentrated when 145.7 9 of an
oil resulted. Distillation using a glass helices
packed column gave 54.4 9 of the title compound
b.p. 165 - 167C, nmr tCDC13) spectrum,~ 2.2, 2.12,
1.85 (sss, C3, 4 and 5 -CH3).
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.

CONL-42
1~34837
Example 30. 3-Methylthiomethyl-4,5-dimethylisoxazole, ~9,
3, -Dimethyl-5-methylthiomethylisoxazole, 40
and their Sulfoxides ~ and 41A and Sulfone _41R
n-Butyllithium (97 ml of 1.6M in hexane, 0.155
mole) was added slowly to a stirred, cold (-70C)
solution of 3,4,5-trimethylisoxazole (16.5 9.,
0.15 mole) in THF (150 ml) in a nitrogen atmo-
sphere, maintaining the temperature below -65C.
The reaction mixture was stirred an additional
2 hrs at -75C, and then blown over slowly, using
nitrogen, into a stirred, cold (-70 C) solution
of dimethyldisulfide (15.1 9., 0.16 mole) in
THF (150 ml ) under nitrogen. The reaction
mlxture was stirred overnight at ambient
temperature under a nitrogen atmosphere, and the
solvent removed using a rotary evaporator. The
yellow solid residue wa~ dissolved in water and
extracted with ether. The ether layer was
extracted with brine, dried (MgS04) and con-
centrated when 23.5 9. of an oil resulted. Dis-
tillation gave 16 9. of material , the nmr spectrum
of which indicated a mixture of compounds.
Graded elution chromatography over silica using
hexane-ethyl acetate, gave 3.15 9 (crude), 2.7 9
(distilled) of 3-methylthiomethyl-4,5-dimethyl-
isoxazole 39p b.p. 57 - 58 /0.2 mm, nmr (CDC13)
spectrum, ~3.68 (s, 2H, C3-CH2), 2.36 (s, 3H,
SCH3), 2.06 and 1.98 (ss, 6H, C4 5-CH3) followed
by a mixture of 39 and 40, followed by 10 9.
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113~837
(crude), 9.5 g., (distilled) of 3,4-dimethyl-5-methylthio-
methylisoxazole 40, b.p. 66 - 68/0.4 mm, nmr (CDC13)
spectrum, ~3.73 (s, 2H, C5-C 2), 2.27, 2.18 and 1.98
(sss, 9H, C3 4-CH3 and SCH3).
Oxidation of 40 with _-chloroperbenzoic acid provided the
sulfoxide 42 (90%), m.p. 96 - 97C, nmr (CDC13) spectrum,
~4.1 (s, 2H, C5-CH2~, 2.6 (s, 3H, SOCH3), 2.25 and 2.05
(ss, 3H, 3H, C3 4-CH3), and oxidation as above of 39 gave
the sulfoxide, 41A (88.6%), m.p. 101 - 103C, nmr (CDC13)
spectrum ~4.0 (d, 2H, C3-CH2), 2.58 (s, 3H, SOCH3), 2.30
and 1.95 (ss, 3H, 3H, C4 5-CH3) and the sulfone, 41B,
(77.6%), m.p. 146 - 147C, nmr (DMSOd6) spectrum ~4.62
(s, 2H, C3-CH2), 3.08 (s, 3H, SO2CH3), 2.35 and 1.93
(g5, 3H, 3H, C3 4-C~3).
EXAMPLE 31
5-Di(methylthio)methyl-3,4-dimethylisoxazole, 43
n-Butyllithium (6.5 ml. of 1.6 molar, lQ.5 mmole) was added
slowly to a stirred, cold (-70C) solution of 3,4-dimethyl-5-
methylthiomethylisoxazole 40, (1.57 g., 10 mmole) in THF
(15 ml) in a nitrogen atmosphere. After stirring for 2 hrs at
-65, the reaction mixture was blown slowly, using nitrogen,
into a stirred, cold (-70&) solution of dimethyl disulfide
(1.04 g., 11 mmole) in THF (10 ml) in a nitrogen atmosphere.
Stirred at ambient temperature overnight in a nitrogen
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CoNL-42
113~837
atmosphere and concentrated. The residue was shaken
with water and ether. The ether layer was washed
with brine, dried and concentrated to give 1.8 9
(90~) of the title compound as a light yellow oil,
b.p. 105J0.1 mm, nmr (CDC13) spectrum, ~4.9 (s, 1H,
C5-CH), 2.22 (s, 9H), and 2.0 (s, 3H)
(SCH3 and C3,4 _3
- 68 -
., ~