Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3P~
1 --
This is a divisional appli.cation of copending application
serial no. 449,711, filed March 15, 1984.
United States Patent Numbers 3,822,258 and
3,787,324 disclose, inter alia certain 4-hydroxy-3-
(~-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-
dioxides which are useful as antiinflammatory agents,
antipyretics and analgesics.
4-Hydroxy-N-[5-hydroxymethyl)-3.-isoxazolyl]-2-methyl,
2H-1,2-benzothiazine-3-carboxamide,l,l-dioxide, the
hum~n metabolite of the antiinflammatory drug,
- isoxicam, has been disclosed in P. E. Borondy, et al,
Pharmacologist, 23, 212 (1981~ and G. J. Yakatan,
Seminars in Arthritis and Rheumatism, 12, (2), suppl.
2, 154 (1982).
The present invention relates to 4-hydroxy-N-
[5-[(substituted hetero)methyl]-3-isoxazolyl~-2H-1,2-
benzothiazine-3-carboxamide, l,l-dioxide, i.e., novel
analogs of isoxicam where the 5 position of the
isoxazole ring contains a substituted heteromethyl
group having the following struFtural formula:
`0~ ~ Z ~R
wherein Rl is hydrogen or alkyl of 1 to 6 carbon
atoms; Z is 0, Sm where m is 0, 1, or 2, or NR3
where R3 is hydrogen or alkyl of 1 to 6 carbon
atoms, R2 is alkanoyl of 1 to 6 carbon atoms when
Z is 0, S or WR3, or -(CH2)nR where n is 1 to 10
and R is hydrogen or Ar in which Ar is
-(CH2)p ~ where p is 0 to 10 and X and Y
lti
-- 2
are independently hydrogen, halogen, alkyl of 1 to 6
carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon
atoms, lower alkylthio of 1 to 4 carbon atoms or
hydroxy, or R3R2 combine with N to form pyrrolidine,
piperidine, pipera7-ine, morpholine or thiomorpholine,
and pharmaceutically acceptable metal or amine salts
thereof.
Preferred compounds of the present invention are
those of formula 1 wherein Rl is hydrogen or methyl;
Z is 0 or Sm where m is 0, 1~ or 2, R2 is -(CH2)nR
where n is 1 to 10 and R is hydrogen or Ar in which
Ar is -(CH2)p ~ where p is 0 to 10 and X and
Y are independently hydrogen, halogen, alkyl of 1 to 6
carbon atoms, trifluoromethyl or alkoxy of 1 to 4
carbon atoms, and pharmaceutically acceptable metal or
amine salts thereof.
Also preferred are compounds of the formula 1
wherein Rl is hydrogen or methyl; Z is 0 or Sm
where m is 0, 1, or 2; R2 is -~CH2)nR where n is
1 to 10 and R is hydrogen, benzyl, or substituted
benzyl, and pharmaceutically acceptable metal or amine
salts thereof.
Particularly valuable are:
4-hydroxy-N-~5-(methoxymethyl)-3-isoxazolyl]-2-methyl-
2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide;
4-hydroxy-N-[5-[(~enzyloxy)methyl~-3-isoxazolyl~-2-
methyl-2H-1,2 benzothiazine-3-carboxamide l,1-dioxide;
4-hydroxy-N-~5-[(butylthio)methyl]-3-isoxazolyl]-2-
methyl-2H-1,2-benzothiazine-3-carboxa~ude l,l-dioxide
4-hydroxy-2-methyl-N-[5-[[[5-[~octyloxy)methyl]-3-
isoxazolyl]amino]methyl]-3-isoxazolyl]-2H-1,2-benzo-
thiazine-3-carboxamide, l,l-dioxide;
4-hydroxy-N-[5-[loctyloxy)methyl3-3-isoxazolyl]-2-
methyl-2H-1,2-benzothiazine-3carboxamide l,l-dioxide
N-~5-[(butylsulfonyl)methyl]-3-isoxazolyl~-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide;
4-hydroxy-N-[5-~octylthio)methyl]-3-isoxazolyl-2-
methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide;
4-hydroxy-2-methyl-N-[5-(octylsulfonyl)methyl]-3-
isoxa701yl]-2H-1,2-benzothiazine-3-carboxamide,
l,1-dioxide,
N-~5-t(heptylthio)methyl]-3-isoxazolyl]-4-hydroxy-
20 2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide,
N-[5-[(heptylsulfonyl)methyl]-3-isoxazolyl]-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,
l,1-dioxide;
N-[5-[(decylthio)methyl3-3-isoxazolyl]-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide;
N-[5-[(decylsulfonyl)methyl]-3-isoxazolyl]-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide;
N-~5-~(heptylsulfinyl)methyl~-3-isoxazolyl]-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide;
4-hydroxy-2-methyl N-[5-[(octylsulfinyl)methyl]-3-
isoxazolyl]-2H-1,2-benzothiazine-3-carbo~amide,
l,l-dioxide;
N-[5-t(decylsulfinyl~methyl]-3-isoxazolyl]-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide,
4-hydroxy-2-methyl-N-[S-[(nonylthio)methyl]~3-
isoxazolyl]-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide;
4-hydroxy-2-methyl-N-[5-~(nonylsulfonyl)methyl~-3-
isoxazolyl]-2_-1,2-benzothiazine-3-carboxamide,
l,l-dioxide;
N-[5-[(butylsulfinyl)methyl]-3-isoxazolyl]-4-hydroxy-
2-methyl-2H~1,2-benzothiazine-3-carboxamide, 1,1-
dioxide,
4-hydroxy-2-methyl-N-[5-[(nonylsulfinyl)methyl]-3-
isoxazolyl]-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide;
N-[5-[[[(3,4-dichlorophenyl?methyl]thio]methyl-3-
20 isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine~
3-carboxamide, 1,l-dioxide;
N-[5-t~[(3,4-dichlorophenyl)methyl3sulfonyl]methyl]-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide, l,l-dioxide,
N-[5-[[[(3,4-dichlorophenyl)methyl~sulfinyl]methyl]-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide, 1,l-dioxide;
N-[5-[[[(3,4-dimethoxyphenyl)methyl]thio]methyl~-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide, l,l-dioxide;
N-[5-[~[(3,4-dimethoxyphenyl)methyl]sulfonyl]methyl]-
3-isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide, l,l-dioxide, and
N-[5-[[t3,4-dihydroxyphenyl)methyl]thio~methyl]-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carboxamide, l,l-dioxide.
3 ~
The compounds of this invention are useful as
antiinflammatory agents, antipyretics, and anal~esics
in several mammalian species. When administered
ora~ly in rats at a dose of 20-200 mg/kg, they are
able to cause reduction in swelling of the paw induced
by injection into the foot pads of an irritant such as
carrageenin. Therapeutically or prophylactically
administered orally or intraperitoneally at a dose of
15-200 mg/kg, the compounds inhibit adjuvant induced
polyarthri~is in the rat. Intraperitoneal or oral
doses of 25-100 mg/kg are sufficient to inhibit yeast
induced hyperthermia in the rat. At intraperitoneal
or oral doses of 25-200 mg/kg they exhibit a
significant analgesic effect as determined by the
phenylquinone writhing procedure in mice.
Generally speaXing, these compounds are indicated
in conditions such as pain resulting from arthritis,
bursitis, and the like. A daily dosaae regimen of
about 0.5 grams to about 2 grams in several divided
doses is recommended for a mammal weighing about 70 kg
body weight to relieve the pain and swelling associ-
ated with these conditions. These compounds are
administered either orally or by injection.
In order to use these compounds, they are for-
mulated into dosage forms such as tablets or syrups
by blending with an inert pharmaceutical carrier such
as lactose or simple syrup by methods well known to
the pharmacist's art. For injectable dosage forms,
they are formulated with vehicles such as water,
peanut oil, sesame oil, and the like. In these dosage
forms, the active ingredlent is from about O.S grams
to 1 gram per dosage unit.
Accordingly, the present invention includes
a pharmaceutical composition for treating pain
resulting from inflammation such as arthritis or
bursitis comprisizlg an effective amount of a compound
of formula 1 in aclmixture with an inert pharmaceutical
carrier.
The present invention also provides for a method
of treating mammals suffering from pain resulting
from inflammation such as, arthritis or bursitis,
comprising administering to said mammal an effecti~e
amount of a compound of the formula 1 in the form
of a pharmaceutical composition.
According to the present invention, the above
compounds are prepared by a reaction scheme as follows:
OH
COOR4 H2N ~ ~2 - 1 + R40H
2 3 -
wherein Rl, R2, and Z are d~fined abo~e and R4 is
alXyl of 1 to 4 carbon atoms~ ~
Generally speaking, starting compound 2 is re-
fluxed with 3-amino-S-(substituted hetero)methyl
isoxazole (3) in an inert solvent such as xylene. In
a preferred embodiment of the present invention, the
reactants are refluxed in the presence of a molecular
sieve which promote the desired reaction by removing
the alcohol which is formed as a by-product. The use
of molecular sieves results in a more convenient and
practical process in that lengthy distillation to
remove the alcohol is no longer required. Typically
3~
the reaction is carried out in a Soxhlet apparatus
with the molecular sieves contained in the thimble.
Examples of the molecular sieves, which can be
used in this process, are commercially available
molecular sieves under the trade mark Linde type 4A
molecular sieve from Matheson Coleman & Bell Company.
The compounds of the formula 1 are capable of
existing in tautomeric forms which is illustrated by
the following equilibrium. Both forms are included
by the present invention.
OH O
~ R2
1~ '
O O
NH
la
The starting materials of formula 2 are known
compounds and are prepared in accordance with the
description in US Patent Numbers 3,960"356 and
3,501,466.
Starting compounds 3-amino-5-(substituted-hetero-
methyl)-isoxazoles are prepared as shown by the
following flow diagram:
COCl
H02C ~) (Me3Sl)2NH ~2~ COCl ClOC~
~C~l 2) NBS/GC14 ~O ~r H20 ~ CH2Br~Cl)
4 ~ 5 6
R ~ O ¦NaN 3
R OOC~ NaI R OOC ~ Br(C1) N30C~ Br(C1)
2 11 7
I ¦R OH
~HZR2tBase ~1~
R OOC R OCONH
~R2 ~ r(C1)
3 8
1) OH~3 B INaI
2) COC1.COC1
3) NaN3 ~
N30C ~ ~ ~ ~ R DCONH ~ I
4 10 9
~Ba(OH)2
H2N~
N~ O z~R2
- 9
The intermediate, 5-methyl-3-isoxazolecarboxylic
acid (4) is readily prepared in accordance with the
descriptio~ set forth in the United States Patent
Number 2,908,688 issued October 13, l9S9.
Accordingly the present invention encompasses the
novel intermediates illustrated in the above flow
diagram as well as the process for preparing the
intermediate of formula 3.
Preferred intermediates are compounds of the
formula
H2N~
` ~' Z ~R2
wherein Z and R2 are as defined for the compounds
of formula 1.
Also preferred intermediates are compounds of
the formula
R'OCONH ~
`--~ Z ~R2
wherein Z and R2 are as defined for the compounds
of formula 1 and R' is alkyl of 1 to 6 carbon atoms,
for example, methyl.
Compounds of formula 1 in accordance with the
present invention where Z is sulfinyl (i.e. S=O)
are prepared by oxidation of the corresponding thio-
compound (i.e. where Z is sulfur) with one equivalent
of hydrogen peroxide. Correspondingly, the sulfonyl
compounds (where Z is SO2) are prepared by
oxidation of the thio-compounds with two equivalents
of hydrogen peroxide.
Compounds of formula 1 where R2 is dihydroxy-
phenyl are conveniently prepared by reaction of boron
3~
-- 10
tribromide on the corresponding dimethoxyphenyl
compounds.
Thus the present invention fu~ther includes a
process for the preparation of a compound of the
formula 3 which comprises treating a compound of
formula lO, as defined above, with an alkaline earth
metal hydroxide, for example, calcium, strontium, and
especially barium hydroxide, at the reflux temperature
of the solvent such as an alcohol, e.g., ethanol.
The corresponding salts with metals or with
amines are prepared by treating the above compounds
of formula l with the desired base, e.g., sodium
alkoxide, potassium alkoxide, sodium hydroxide,
potassium hydroxide, calcium hydroxide, aluminum
hydroxide, pyrrolidine, arginine, N methylD-glucamine,
and the like by eonventional procedures.
The terms alkyl, alkoxy, alkylthio, and alkanoyl
used above have been designated by certain number of
carbon atoms and include whenever applicable straight
and branched chain hydrocarbons-as n-propyl, isopropyl,
n-butyl, sec-butyl, iso-butyl, t-butyl, and the like.
The following examples are illustrative of the
invention. All temperatures are in degrees centigrade
and melting points are not corrected.
EXAMPLE 1
4-Hydroxy-N-[5-(methoxymethyl)-3-isoxazolyl]-
2-methyl-2H-1,2-benzothiazine-3-carboxamide l,l-
ioxide
- A mixture of 0.52 g (4 mmole) of 5-tmet~oxY-
methyl)-3-isoxazolamine, 1.08 g ~4 mmole) of methyl 4-
hydroxy-2-methyl-2H-1,2~benzothiazine-3-carboxylate
l,l-dioxide, and lO0 ml of xylene is heated at reflux
for six hours in a soxhlet apparatus, the thimble of
which contains 20 g of Linde type 4A molecular sieve.
The reaction mixture is filtered to clarify it and is
allowed to stand at room temperature overnight when
A~ 3~
the product crystallize~ out. The product is
filtered, washed with methanol-ether mixture, and then
recrystallized from methanol to give 0.326 g of white
crystals, mp 218-223C dec.
EXAMPLE 2
The procedure described in Example 1 is repeated
to prepare the following 4-hydroxy-2-methyl-2H-1,2-
benzothiazine-3-carboxamides l,l~dioxides, starting
from methyl 4-hydroxy-2-methyl-2H-1,2 benzothiazine-3-
carboxylate l,l-dioxide and the appropriate 5-
substituted heteromethyl-3-isoxazolamines in each
case: -
4-Hydroxy-N-~5-~benzyloxy)methyl3-3-isoxazolyl]-2-
methyl-2H-1,2 benzothiazine-3-carboxamide l,l-dioxide,
mp 206-207.5C;
4-Hydroxy-N-[5-[(butylthio)methyl]-3-isoxazolyl]-2-
methyl-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide,
mp 155-156C;
4-Hydroxy-N-[5-[(octyloxy)methyl3-3-isoxazolyl]-2
methyl-2_-1,2-benzothiazine-3-carboxamide l,l-dioxide,
20 mp 152-154C;
4-hydroxy-N-~5-(octylthio)methyl]-3-isoxazolyl-2-
methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1
dioxide,mp 135-136C;
N-[5-[(heptylthio)methyl~-3-isoxazolyl]-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide, mp 132-133C;
N-[5-[(decylthio)methyl]-3-isoxazolyl]-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide, mp 127.5-128.5C;
4-hydroxy-2-methyl-N-[5-~(nonylthio)methyl]-3-
isoxazolyl]-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide, mp 129-130C;
N-[5-[[[(3,4-dichlorophenyl)methyl]thio]methyl-3
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
-3-carboxamide, l,l-dioxide, mp 188-189C;
N-~5-~[~(3,4-dimethoxyphenyl3methyl]thio3methyl]-3-
isoxazolyl3-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
-3-carboxamide, l,l-dioxide, mp 164-167C, and
4-hydroxy-2-methyl-N-[5-[[[5-[(octyloxy)methyl]-3-
isoxazolyl]amino]methyl]-3-isoxazolyl]-2H-1,2-benzo-
thiazine-3-carboxamide, l,l-dioxide;
EXAMPLE 2a
N-~5-[(decylsulfonyl)methyl]-3-isoxazolyl]-4-
hydroxy-2-methyl]-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide.
1.02 g (0.002 mole) of N-[5-[(decylthio)methyl]-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carboxamide, l,l-dioxide is suspended in 25 ml of
acetic acid and 2.23 g ~O.Q2 mole) of 30.5% hydrogen
peroxide in 5 ml of acetic acid is added. The mixture
is warmed on a steam bath for 30 minutes to obtain a
solution. The solution is evaporated to dryness and
the pinkish-white solid residue is recrystallized from
acetic acid-water mixture (10:3 v/v) to yield white
crystals of the tne title compound (650 mg), mp
150.5-153C.
EXAMPLE 2b
The procedure detailed in Example 2a is repeated
to prepare the following 4-hydroxy-2-methyl-2~-1,2-
benzothiazine-3-carboxamide, l,l-dioxides, starting
from the appropriate N-[5-[(alkyl or aralkylthio)-
methyl]-3-isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-
benzothiazine-3-carboxamide, 1,1-dioxides:
N-[5-[(butylsulfonyl)methyl3-3-isoxazolyl]-4-hydroxy-
30 2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
~4.~
- 13 -
dioxide, mp 196-1~9C.
4-hydroxy-2-methyl-N-~5-(octylsulfonyl)methyl]-3-
isoxazolyl3-2H-1,2-benzothiazine-3-~arboxamide,
I,l-dioxide, mp 145-148C.
N-[5-[(heptylsulfonyl)methyl]-3-isoxazolyl]-4-
hydroxy-2~methyl-2H-1,2-benzothiazine-3-carboxa~ide,
l,l-dioxide, mp 141-147C.
4-hydroxy-2-methyI N-~5-[(nonylsulfonyl)methyl~-3-
isoxazolyl~-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide, mp 150-151C.
N-[5-[[[(3,4-dichlorophenyl)methyl]sulfonyl]methyl]-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide, l,l-dioxide, mp 203-205C (dec.); and
N-[5-[[[(3,4-dimethoxyphenyl3methyl]sulfonyl]methyl]-
3-isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide, l,l-dioxide, mp 215-217C.
EXAMPLE 2c
N-[5-[nonylsulfinyl)methyl]-3-isoxazoly3-4-
hydroxy-2-methyl]-2H-1,2-benzothiazine-3-
carboxamide, l,l-dioxide.
.
0.987 g (2 mmol) of N-C5-[(nonylthio)methyl~-3-
isoxazolyl]-4-hydroxy-2-methyl]-2H-1,2-benzothiazine-
carboxamide, l,l-dioxide is dissolved in 50 ml of
acetic acid and 0.223 g (2 mmol) of 30.5~ hydrogen
peroxide, dissolved in 5 ml of acetic acid, is added
to the solution. The reaction mixture is allowed to
stand at room temperature for 18 hours and is then
evaporated to dryness on a rotary evaporator. The
solid residue is recrystallized from-diethyl ether to
yield off-white crystals of the title compound,
(0.65 g), mp 127-129C.
3~
- 14 -
EXAMPLE 2d
The procedure detailed in Example 2c is repeated
to prepare the following 4-hydroxy-2-methyl-2H-1,2-
benzothiazine-3-carboxamide, l,l-dioxides, starting
from the appropriate N-[5-[(alXyl or aralkylthio)-
methyl]-3-isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-
~enzothiazine-3-carboxamide, l,l-dioxides:
N-[5-[(heptylsulfinyl)methyl]-3-isoxazolyl]-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide, mp 134-136C.
4-hydroxy-2-methyl-~-[5-[~octylsulfinyl)methyl]-3-
isoxazolyl]-2H-1,2-benzothiazine-3-carboxamide,
l,l-dioxide, mp 130-132C.
N-[5-[(decylsulfinyl)methyl]-3-isoxazolyl~-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide, mp 121-123C.
~-[5-[(butylsulfinyl)methyl]-3-isoxazolyl~-4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-
dioxide, mp 186-188C.
N-[5-~[[(3,4-dichlorophenyl)methyl~sulfinyl]methyl]-3-
isoxazolyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
-3-carboxamide, l,l-dioxide, mp 196-200C.
Example 2e
4-Hydroxy-N-c5-[~(3,4-dihydroxyphenyl)methyl]thio]-
methyl-3-isoxazo_yl]-2-methyl-2H-1,2-benzothiazine-3-
carboxamide, l,l-dioxide
A solution of boron tribromide ( lM, 10 ml) in
methylene chloride is added to a cold (-70C) solution
of 4-hydroxy-N-[5-[[[3,4-dimethoxyphenyl)methyl]thio]-
methyl-3-isoxazolyl]-2-methyl-2H-1,2-benzothiazine-3-
carboxamide, l,l-dioxide (0.518 g; 1 m mol) over
5 minutes. The amber solution is kept cold for
30 minutes, then allowed to rise to room temperature
and let stand for 16 hours. The solution is chilled,
3~
decomposed with 25 ml of cold water and 25 ml of
methanol and evaporated to dryness. The residue is
redissolved in methanol and evaporated to dryness.
The process is repeated several times to give a tan
residue that is washed with water, and recrystallized
from isopropanol to give light tan solid (0.32g),
mp 210-213C (dec.).
EXAMPLE 3
5-(Bromomethyl)-3-isoxazolecarbonyl chloride and S-
(chloromethyl)-3-isoxazolecar~yl chlorlde:
36.8g (0.29 mole) of 5-methyl-3-isoxazole-
carboxylic acid is suspended in 250 ml of carbon
tetrachloride and then treated with 27.5 g (0.17 mole)
of hexamethyldisilazine. The mixture is heated to
reflux for one hour and the resulting yellow solution
is evaporated to dryness to give an oil. The tri-
methylsilyl ester is dissolved in 300 ml of fresh
carbon tetrachloride and is treated with 89 g
(0.5 mole) of N-bromosuccinimide and 2.0 g of benzoyl
peroxide. The reaction mixture is heated and illumin-
ated by a Cole-Parmer Dynalume high intensity lamp!
so that moderate reflux is maintained. After one hour
of reaction, the mixture is charged with an additional
10 g (0.056 mole) of N-bromosuccinimide and 0.5 g of
benzoyl peroxide, and maintained under reflux for an
additional 0.5 hour. The reaction mixture is cooled
and the succinimide is filtered off. The red filtrate
is evaporated to dryness and the residue is taken up
in THF containing 5 ml of 4N HCl. The solution is
heated on a steam bath for five minutes and then
3~
evaporated to a red oily solid which when triturated
with ether gives 30.6 g of crude bromo-acid. The
crude acid is dried under vacuum at roo~ temperature
for 15 hours over P20s.
The crude 5-(bromomethyl)-3-isoxazole-carboxylic
acid (18 g) is dissolved in 150 ml of dry THF and
36.38 g (0.28 mole~ of oxalyl chloride is added. The
reaction mixture is heat,d to reflux for two hours.
The solvent and excess oxalyl chloride is removed
under reduced pressure and the brown liquid is
distilled. The fraction ~6.27 g) boiling at
60-62C/0.1 mm is collected and used without further
purification. NMR and analysis indicates that it is
a mixture of 5-chloromethyl and 5-(bromomethyl)-3-
isoxazolecarbonyl chloride.
EXAMPLE 4
5-Bromomethyl-3-isoxazolecarboxylic acid:
The distilled 5-(bromomethyl)-3-isoxazole-
carbonyl chloride (lg) is dissolved in 2 ml of
acetone, cooled to 0C and 3 ml of water is added to
the solution. The solution is allowed to stand at
room temperature for one hour and then the solvent is
removed under reduced pressure giving 0.9 g of the
acid. It is dried over P20s for three days a~d has
mp 143-148C.
EXAMPLE 5
5-(Bromomethyl)-3-isoxazolecarbonyl azide and
5-(chloromethyl)-3-isoxazolecarbony~ azide:
A solution of 2.24 g (0.01 mole3 of distilled
acid chloride of Example 3 in 5 ml of acetone is
cooled in ice-water and a solution of 0.68 g
(0.0105 mole) of sodium azide in 2 ml of water is
- 17 -
added rapidly and allowed to ~tand for 15 minutesO
The solution is evaporated to dryness and ~he white
solid residue is washed with cold water and dried
under vacuum overnight over P20s. The acid azide
~1.82 g) is recrystallized from absslute ethanol as
white needles, mp 75-76.5C.
EXAMPLE 6
5-(Bromomethyl)-3-[(methoxycarbonyl)amino]isoxazole and
5-(chloromethyl)-3-~(methoxycarbonyl)amino]isoxaæole:
A solution of 1.16 9 (~ 5.0 mmole) of a mixture
of 5-(bromomethyl)-3-iso~azolecarbonyl azide and
5-(chloromethyl)-3-isoxazolecarbonyl azide of
Example 5 in 10 ml of methanol and 25 ml of p-dio~ane
is heated to reflux in an atmosphere of nitrogen for
six hours, and allowed to stand overnight at room
temperature. The reaction mixture is evaporated to
dryness to give 1.23 g of off-white solid which is
recrystallized from isopropyl ether, mp 140-143C~
EXAMPLE 7
5-(Iodomethyl)-3-[~methoxycarbonyl)amino]isoxazole:
A solution of 6 g (0.04 mole) of sodium iodide
in 50 ml of acetone is added to a solution o~ 6.5 g
(~ 0.027 mole) of a mixture of 5-(bromomethyl) and
5-(chioromethyl)-3-~(methoxycarbonyl)amino]isoxazole
in 25 ml of acetone. The reaction mixture is heated
to reflux for two hours and then allowed to stand at
room temperature overnight. The inorganic salts are
filtered off and the filtrate is evaporated to
dryness. The residue is washed thoroughly with water
and dried to give 7.2 g of yellowish tan solid. The
crude product is recrystallized from methanol to give
3.3 g of white crystals, mp lS4-156C dec.
3~
- 18 -
EX~MPLE 8
5-~(Benzyloxy)methyl]-3-isoxazolamine:
A 700 mg amount of 60% sodium-hydride in mineral
oil (0.42 g NaH = 0.0175 mole) is washed with dry
hexane, suspended in 5 ml of THF and then treated with
20 ml of benzyl alcohol. After the evolution f ~2
has ceased, the pale-yellow solution is warmed up to
~~ 70, and then treated with 3O5 g (0.0125 mole) of 5-
Iodomethyl-3-methoxycarbonyl aminoisoxazole in 60 ml
of benzyl alcohol. The reaction mlxture is warmed at
74C for one hour and then allowed to stand at room
temperature overnight. The reaction mixture is
acidified with 7 ml of lN HCl, and the excess benzyl
alcohol is distilled off. The crude 5-~(benzyloxy)-
methyl]-3-isoxazolamine (4.3 g) is isola~ed in the
usual way. The crude material is mixed with 40 ml
of ethanol, 40 ml of water, and 2.74 g (0.016 mole)
o~ barium hydroxide and refluxed under nitrogen for
1.5 hours. The reaction mixture is cooled, treated
with dry ice, and the barium carbonate is filtered
off. The filtrate is evapora-ted to dryness and
the product (0.64 g) is isolated by preparative layer
chromatography, mp 51-53C.
EXAMPLE 9
The procedure described in ~xample 8 is repeated
to prepare the following 5-[(substituted hetero)
methyl]-3-isoxazoleamines:
5-methoxymethyl-3-isoxazolamine, mp 49-52C;
5-~(butylthio)methyl]-3-isoxazolamine, oil;
5-~(octyloxy)methyl~-3-isoxazolamine, mp 50-52 DC;
5-t(Heptylthio)methyl~-3-isoxazolamine, mp 47-50C;
5-[(Octylthio)methyl]-3-izoxazolamine, mp 53.5-55C;
5-[(Nonylthio)methyl]-3-isoxazolamine, mp 63-66C;
5-[(Decylthio)methyl]-3 isoxazolamine, mp 63-66C;
- ] 9
5-C~[(3,4-Dichlorophe-lyl)methyl3thio~methyl~-3-
isoxazolamine, mp 89-91~C, and
5-[[[(3,4-Dimethoxyphenyl)methyl]thio3methyl~-3-
isoxazolamine, Dlp 83.5-;35.5C.
EX~MPLE 10
Methyl 5-(Bromomethyl)_-3-isoxazo_ecarboxylate and methyl
5-(chloromethyl)=3-isoxazolecarboxylate:
A solution of 49g (~ 0.22 mole) of crude 5-
bromo (chloro)methylisoxazole-3-carboxylic acid
chloride from Example 3 in 100 ml of ether is added
to 25 ml of methanol in an ice bath under N2. The
reaction mixture is allowed to reach room temperature
and then evaporated to dryness. The crude ester is
dissolved in ether, treated with anhydrous potassium
carbonate. The solvent is removed under reduced
pressure and the product is recrystallized from ether-
cyclohexane to give 24.4 g of off-white platelets,
mp 60-66C.
EXAMPLE 11
Methyl 5-(ioclomethyl)-3-isoxazolecarboxylate:
A solution of 0.45 g (3 mmoIe) of sodium iodide
in 5 ml of acetone is mixed with a solution of 0.5 g
(2.4 mmole) of methyl 5-bromo ~chloro) methyl 3
isoxazolecarboxylate. The mixture is warmed on a
steam bath for 30 minutes and the inorganic material
filtered off. The filtrate is evaporated to dryness
and the residue is washed with water and dried over
P20~ giving 0.58 g of the desired product, mp
91-95C.
EX~MPLE 12
Methyl 5-(methoxynethyl)-3-isoxazolecarboxylate:
A solution of 1.34 g (5 mmole) of methyl 5-
~iodomethyl)-3-isoxazolecarboxylate in 20 ml of
methanol--and 5 ml of THF is added to a solution of
3~
~ 20 -
methanol and 5 ml of THF is added to a solution of
sodium methoxide prepared from 0.15 g ~6.5 mmole)
sodium and 10 ml of methanol. The r-eaction mixture is
stirred at room temperature for four hours, heated to
reflux for 30 minutes, and then worXed up as usual
giving 0.65 g of product. q~e crude ester is
recrystallized from ether-cyclohexane mixture to give
0.33 g of off-white solid, mp 47.5-49C.
EXAMPLE 13
5-(Methoxymethyl)-3-isoxazolecarbonyl azide:
A 6.0 g (0.035 mole) amount of methyl 5-(methoxy-
methyl)-3-isoxazolecarboxylate is hydroly ed with
50 ml lN sodium hydroxide solution at 40 for five
minutes and then acidified with 4~ HCl and extracted
with chloroform as usual. The crude dry acid (4.0 g)
is converted to the acid chloride by treatment with
oxalyl chloride (7 ml) in THF (10 ml) at reflux
temperature for four hours. The solvent is removed
and the crude acid chloride is reacted with sodium
azide as described in Example 5, giving 4.65 g of
solid. The crude acid azide is recrystallized from
ether-n-hexane to give 2.8 g of off-white solid, mp
55-58C dec.
EXAMPLE 14
5-(Methoxymethyl)-3-[(methoxycarbonyl)amino~isoxazole:
A mixture of 2.5 g (0.0137 mole) of 5-(methoxy
methyl)-3-isoxazolecarbonyl azide, 15 ml of methanol
and 25 ml of p-dioxane is heated to reflux for
16 hours. The solvent is removed under reduced
pressure and the solid residue is triturated with
ether-cyclohexane giving an off-white solid,
mp 90-91C.
21 -
EX~MPLE 15
5-(Methoxymethyl)-3-isoxa olamine:
A mixture of 1.86 g (Q.01 mole) of 5-(methoxy-
methyl)-3-[(methoxycarbonyl)amino~isoxazole and 2~06 g
(0.012 mole) of Ba(OH)2 in 20 ml of ethanol and
20 ml of water is heated to reflux Xor one hour. Dry
ice is added lowering the_pH to 5 and the resulting
emulsion is evaporated to dryness. The residue is
extracted with boiling ether and the ether extract is
evaporated to dryness giving 1.1 g of colorless
liquid which crystallizes on standing. The amine
is recrystallized from ether-n-pentane as white
crystals, mp 49-52~C.
