Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
jl i
1 ll This inve~tion relates to a method of p~eparing certain novel oxa~oLe
- ~ derivatives subst:ituted by a 2-acylamino group ~hich possess pharmacological
activityO
¦ According to the present invention there is provided a method of
preparing a novel oxazole derivative of the formula (I) :
R3
...... ~ N~
: - R4 ~ o ~ (I)
` lO wherein Rl is Cl 10 alkyl, C2_6 alkenyl, C2_6 Y Y ~ 2-6
carboxyalky, Cl 6 haloalkyl~ C3 10 cycloalkyl, C3_10 cycloalkyl-Cl_6 alkyl~
. optionally subst.ituted phenyl-Cl 6 alkyl or optionally substituted phenyl-C2 6
alkenyl; and R is Cl 8 alkyl, Cl 6 haloalkyl, C2_6 alkenyl, C3_10 cycloalkyl7
C3 1Ocycloalkyl-Cl_6 alkyl~ optionally substituted phenyl, optionally
. 15 substituted phenyl-Cl_6 alkyl or optionally substituted phenyl-C2 6 alkenyl;
or Rl and R2 together form a lactam ring having 5 to 7 ring atoms; and
wherein R3 and R4 are independently selected from hydrogen, formyl, carboxyl,
hydroxy, Cl 4 hydroxyalkyl~ halogen~ Cl_4 alkyl, C3_10 cyclo~lkyl, C3_6
acyloxyalkyl or an optionally substituted phenyl group;
: 20 which method comprises reacting a salt of formula (II) :
1 2
MNR COR (II)
,.,,
:.: wherein M is a group IA or IIA metal and wherein R and R are as previously
defined, ~ith a 2-oxazolyl derivative of formula (III~ :
R4 / ~ o ~ (III)
.,
l 30 .
'
` I -2-
~..,
',' I
. . 1 ~
.- . .. : ~ .
Il !
~ he~e L is a leaving group and wherein R3 and R are as defined aboveO
: ~ The method of the invention is preferred for compounds of formula (I)
~; ~herein Rl is Cl_6 alkyl~ C2 6 alkenyl, C2 6 alkoxyalkyl~ C3 8 cycloalkyl,
C3 8 cycloalkyl-Cl 6 alkyl, optionally substituted phenyl-Cl 6
alkyl or optionally substituted phenyl-C2 6 alkenyl;
R is C1-6 alkYl~ Cl-6 halalkYl~ ~3 6 alkenyl, C3 8 Cycloalkyl, C3 8
: cycloalkyl-Cl 6 alkyl, optionally substituted phenyl, optionally substituted
phenyl-Cl 6 alkyl or optionally substituted phenyl-C3 6alkenyl~ or 21 and R
together Eorm a lactam ring having 5 or 6 ring atoms, and wherein R and R4
. 10 are independently hydrogen, Cl_4 alkyl, Cl_4 hydroxyalkyl, C3 8 cycloalkyl,
C3 6 acyloxyalkyl or an optionally substituted phenyl group~ .
: Preferred classes of compounds falling within the scope of the oxazoles
defined in formula (I) above are those having one or more of the following
. characteristics :
(a) Rl is C3 6 alkyl, for instance n-butyl and n-propyl;
. (b) Rl is C3 4 alkenyl;
~ (c) R is phenyl-Cl 2 alkyl;
.i (d) R2 is phenylj
~ (e) R is Cl 4 alkyl, for instance methyl, n-propyl and i-propyl;
.~ 20 (f) R2 is C3 5 cycloalkyl;
.~ (g) Rl and R2 taken together form a lactam ring having 5 carbon
. atoms;
(h) one or both of the available positions in the oxazole nucleus is
. substituted by a methyl group;
(i) one or both of the available positions in the oxazole nucleus
is substituted by a hydroxymethyl group;
~ (j) the oxazole nucleus~ not considering the acylamino group, is
.~ unsubstituted.
.;. The process of the invention is presently most preferred for the
preparation of the compound of formula (I) in which R is n-butyl, R is
~ i-propyl, R methyl and P is hydrogen.
l l
-
7~
~ '~ Tlle reaction between the salt of formula (II) and the ~-oxazolyl derivative
of Eormula (III) can be accomplished using anhydrous conditions. Any suitable I
inert solvent may be utilised. Ethereal solvents such as diethyl ether, dioxar~
or tetrahydrofu~an are particularly useful; however, solvents such as dirnethyll-
formamide, N-methylpyrrolidone or hexamethyLphosphoric tria~ide may also be
used. The reaction can normally be effected at temperatures between O and 110C.,
prelerably between O and 40C., most preferably at room temperature. At these
temperatures the reaction will usually be complete after a time of from 1 to
6 hours
A preferred salt of formula (II) is the lithium derivative which can be
conveniently prepared by the reaction of butyl lithium with the
appropriate amide of formula H~RlCOR2. This reaction should be carried
out under an inert gas atmosphere such as nitrogen and preferably at low
temperature~ for example~ less than -10C. The presence o~ a chelating
agent such as tetramethylethylene diamine has proved advantageous. Generation
oE the salt may be effected in situ, if desired, and proceeds with the
evolution of butane gas.
The leaving group L in the oxazolyl derivative of formula (III) is
preferably a chlorine, bromine or iodine atom, or is a group of formula
-SOR or -S02R, where R is Cl 8 alkyl, C3 8 cycloalkylg benzyl or phenyl. The
identity of suitable L groups will be appreciated by those skilled in the art
once it is understood that the reaction of the invention p~oceeds via the
nucleophilic displacement of the L group by the anionic entity ( )NRlCOR2.
Derivatives of formula (III) may be obtained from 2-oxazoloaes or 2-
oxa~ole-~hiol ~ of formu-~ ~IV)
~ ~ 5 ~V)
-4-
-j - . . . .
~, ' .
1 Jch compounds are either kno~n (see, for e~ample, Berichte 89, 1748, (1956),
,i Acta~ Chem. Scan 23 2879 (1969) and Bull. S~c. Chim. Bel~. 70, 745 (1961) )
j or can be prepared from kno~ compounds by conventional procedures.
If it is desired to prepare derivatives of formula (III) in which L
is chlorine, bromine or iodine, a compound of formula (IV) or (V) may be react~ d
with phosphorus pentachloride, phosphorus oxychlorlde, phosphorus
pentabromide or phosphorus triiodide, etc. (see, for example, Berichte, 92,
¦ 1928 (1959) ) in the presence of an acid acceptor such as triethylamine~ to
yield the corresponding chloro, bromo or iodo derivative directly~
l Compounds of formula (III) in which L is -SOR or -S02R can be prepared
¦ from the corresponding alkylthio derivatives, i.e. where L is -SR, by treatmen
¦ with the appropriate amount of oxidising agent, preferably 3-chloroperbenzoic ~
~ acid. The derivatives may be prepared by alkylation of the corresponding thiol e
; of formula (V), preferably by generating the thiolate anion with sodium or sod um
hydride.
Compounds of formula (III), except for a small number of exceptions (see,
for instance, Berichte 92 1928, (1959), Chemical Abstracts 79 P126485m and
65 7159h) are novel and are provided in a further aspect of the invention.
According to a further aspect of the invention there is provided a
compou d of formula (III)
¦ wherein R3 and R4 are as defined previou~ and where L is bromine or iodine
or is a group of formula -SOR or -S02R, where R is Cl 8 alkyl, C3 8 cyclo- ¦
alkyl, benzyl or phenyl; provided that when L is iodine, R3 and R4 cannot
both be phenyl.
` Compounds of formula (I) have been shown to be useful in the prophylactic
and therapeutic treatment of immediate hypersensitivity diseases including
; 30 ¦¦ asthma and in the alleviation of status asthmaticus. In certain cases the
_5_
'. ,;
'`' ' ,
compounds have been fou~d ~o be useful in diseases in which excessive arnounts
of prost~glandins are ~eleased and as a respiratory stimulant. The compounds
have low toxicity
The compounds produced according to the present invention may be
administered by various routes and for this purpose may be formulated in a
variety of forms~ Thus the compounds oE formula (I) ma~ be administered by
the oral and rectal routes9 topically9 parenterally, e.g. by injection and
by continuous or discontinuous intra-arterial infusion~ in the form of7 for
example, tablets, lozenges, sub-lingual tablets, sachets, cachets7 elixirs,
suspensions~ aerosols~ ointments~ for example~containing from 1 to 10~/o by
weigh-t of the actlve compound in a suitable base~ soft and hard gelatin cap-
sules, suppositories, injection solutions and suspensions in physiologically
acceptable media, and sterile packaged powders adsorbed onto a support materia]
for making injection solutions. Advantageously for this purpose~ compositions
may be provided in dosage unit form, preferably each dosage Ullit containing
! from 5 to 500 mg (from 5.0 to 50 mg. in the case of parenteral administration
from 5.0 to 50 mg. in the case of inhalation and from 25 to 500 mg~ in the
case of oral or rectal administration) of a compound of formula (I~. Dosages
of from 0.5 to 300 mg/kg per day~ preferably 0.5 to 20 mg/kg of active
ingredient may be administered although it will~ of cour9e, readily be
understood that the amount of the compound or compounds of formula (I)
actually to be administered will be determined by a physician~ in the light
of all the relevant circumstances including the condition to be treated,
the choice of compound to be administered and the choice of route of
administration and therefore the above preferred dosage range is not intended
to limit the scope of the present invention in any way~
The invention will now be further illustrated with references to the
following Examples. Examples 1 to 4 illustrate the preparation of various
intermedia~es of formula (III) whereas Examples 5 to 131 illustrate the
utilisation these intermedi~tes in the process of the invention. The
-6-
,~,
;
. ~ .
:` - . . . . . .
'" ' ' : ' ' ,':' '~'
:Loa~3 ~V7
abbreviations "THF" and "I-lrilPA" are used to denote tetrahydroEuran and
¦ hexamethylphospl.loric tria~ide respectively.
~1 . ' ` .
1 EX~IPLE 1
. 2-Chloro-5-phenyloxazole
5-Phenyl-2(3H)-oxazolethione (Acta. Chem. Scand. 23 2879 (1969) )
j (19.6 ~, 0.11 m) and phosphorus oxychloride (70 ml) were stirred with
!~ cooling during the cautious addition of triethylamine (12.4 g~ 0.123 m)~
~ The mixture was then heated under reflux for 20 hours~ excess reagents
1, removed under reduced pressure and the residue distilled in ~acuo to glve
: I! the title product as a colourless oil which solidified on standing~ b~po
~¦ 96-8C/ 0.6 mm~ m.p. 34C.
EXAMPLE 2
4~5-D ~ hvI~iooxazole
4~5-Dimethyl-2(3H)-oxazolethione rBull. Soc. Chim. Belj~. 70~ 745~
L5 (1961) ] (37~5 g, 0.29 m) in 2N aqueous sodium hydroxide (150 ml) was
~ stirred at room temperature during the dropwise addition of dimethyl
Il sulphate (40.0 g~ 0.317 m). The mixture was stirred for 4 hours at room
i temperature and then warmed to 50C, cooled, and the aqueous phase
¦ extracted with diethyl ether. Evaporation of the solvent and distillation
' 0 ~~ of the residue under reduced pressure gave 33,85 g (81%) of the title
¦ product as a pale yellow oil~ b.p. 82C./13 mm.
Analysis: Found: C: 50.39; H: 6.20; N: 10.03; 0: 11.30; S: 22~35'
6 9 requires:C: 50D32; H: 6.33; N: 9.78; 0: 11.17; S: 22.39%
jl Similarly~ there were prepared :-
¦ 4-Methyl-2-methylthiooxazole (Arch. Pharm. 301 (3) 186 (1968).
4-Ethyl-2-methylthiooxa701e, b.p. 72C. (airbath)/14 mm.
' 5-Methyl-2 methylthiooxazole~ b.p. 66C. (airbath)/ll mm.
i!
2-Methylthio-4-phenyloxazole~ [2h. Obshch. Khim. 33 1S07 (1963)~
5-Ethyl-2-methylthiooxazole~ b.p. 75Co (airbath)/15 mm.
'` , j :
"',' ~~
~ 8-
...
' . ' ' . ' :
~ , , ' ' A
1 1 2-Ethylth-iooxazole, LPhytopatholo~, 56 (8) 929 (1966)~
2-n-Butylthio-4-methylox~zol~7 b.p. 98C~/lO mm.
¦ 2~n-Hexylthio-4-methy1oxazole, ~.p. 124 C./10 mm.
2-Cyclohexylthio-4-methyloxazole~ b.p. 66-68 /8 mm.
4-Methyl-2-phenylmethylthiooxazole, b p. 114/l mm.
; 4~5-Diphenyl-2-phenylthiooxazole [Tetrahedron~ Suppl. No. 8 Pt. 1,305 (1966)~
was prepared by the literature method.
EXAMPLE 3
4-Methyl-2-methylsulphinyloxazole
4-Methyl-2-methylthiooxazole (6.06 g, 0.047 m) in dry chloroform (50 ml)
was cooled to 0C. with ~igorous stirring and anhydrous sodium carbonate
(6.06 g, 0.057 m) added. 96% 3-Chloroperbenzoic acid (8.90 g, 0.0495 m)
i 15 in dry chloroform (100 ml) was then added dropwise over 45 minutes and
the mixture stirred for a further 45 minutes at 0 C. Solid sodium sulphite
(2.0 g) was added and the mixture allowed to warm to room temperature. The
rnixture was then filtered, the filtrate evaporated and the resulting oil was
distilled under vacuum to give the title compound as a colourless oil 6.48 g
(95%), b.p. (airbath)76C./0.1 mm.
Analysis: Found: C: 41.54; H: 5.04; N: 9089; 0: 22.24%
C5H7N02S requires:C: 41.36; H: 4.86; N: 9.65; 0: 22.04%
Similarly prepared were the following :-
4~5-Dimethyl-2-methylsulphinyloxazole~ b.p. (airbath)96C./0~1 mm.
4-Ethyl-2-methylsulphinyloxazole~ b.p. 82C./0.1 mm~
5-Ethyl-2-methylsulphinyloxazole, b.p. 85 C./0.1 mm.
5-Methyl-2-methylsulphinyloxazole~ b.p. 79C./0.1 mm,
2-Methylsulphinyl-4-phenyloxazole, m.p. 53C.
2-Ethylsulphinyloxazole9 b.p. 68C./0.1 mm.
2-n~ButylsulphinyL-4-methyloxazole, b.p. (airbath)82C./0~1 mm.
2-_-He~ylsulphinyl-4-methyloxazole~ b.p. (airbath)90 C./0.1 mm.
2-Cyclohex~lsulphinyl-4-met}lyloxa2Ole, b.p. (airbath) 100 C./0.1 mm.
4-Methyl-2-phenylmethylsulphinyloxazole~ m.p. 50C.
4,5-Diphenyl-2-phenylsuphinyloxazole, m.p. 92C.
:,
':,
EXAMPLE 4
_ _
; 4,5-Dimethyl-2-Methylsulphonyloxazole
4~5-Dimethyl-2-methylthiooxazole (4.21 g, 0.029 m) in dry chloroform
(15 ml) was cooled to 0C. and anhydrous sodium carbonate (8.0 g, 0.0755 m)
added. 88.5% 3-Chloroperbenzoic acid (11.5 g, 0.059 m) in dry chloroform was
then added over 45 minutes~ and the mixture stirred for a fur-ther 45 minutes
at 0C. Solid sodium sulphite (5 g) was then added and the mixture allowed
to warm to room temperature, The mixture was then filtered and the filtrate
evaporated, the residue being chromatographed on silica using diethyl ether.
The resulting solid was recrystallised from ethyl acetate/hexane as the
title product, m.p. 42C. -~
Similarly prepared were :-
4-Methyl-2-methylsulphonyloxazole;
4-Ethyl-2-methylsulphonyloxazole;
5-Ethyl-2-methylsulphonyloxazole;
5-Methyl-2-methylsulphonyloxazole;
` 25 2-Methylsulphonyl-4~phenyloxazole;
; 2-Ethylsulphonyloxazole;
` 2-n-Butylsulphonyl-4-methyloxazole;
2-n-Hexylsulphonyl-4-methyloxazole;
I 2-Cyclohexylsulphonyl-4-methyloxazole;
4-Methyl-2-phenylmethylsulphonyloxazole;
~ 4,5-Diphenyl-2-phenylsulphonyloxazole.
~1 -10-
' li
`. 1 . : . .
EXAMPLE 5
il 2-(N-b~ltyl-2-methylpropanamido)-5-phenyloxazole
.' I
~ n-Butyl-isobutyramide (143 mg., 0.001 m) in dry tetrahydrofuran (5 cc.)
_ _
was cooled at -15C. under nitrogen. Tetramethylethylene diamine (0.116 g,
0.001 m) was added~ followed by n-BuLi (0.75 cc~ of an 8D8% W/V solution in
hexane, 0.001 m) stirring was continued for 1~ hours.
Gas evolution was apparent.
2-Chloro-5-phenyloxa~ole (0.18 g, 0.001 m) in dry THF (1 cc) was then
added slowly and the solution allowed to come to room temperature. Stirring
was maintained for a further 2 hours and then the product was isolated in
ether as a pale yellow oil, 0.22 g. Chromatography gave the title compound
` which was shown to be homogeneous by tlc. tb.p. 190C. (alr-bath temperature)
/0.2 mmHg).
Analysis: C17H22N~02 requires: C: 71.39; ~: 7.75; N: 9.79%
15found: C: 71.64; ~I: 7.59; N: 9.85%
Infrared, nmr and tlc confirmed the structure of the product.
EXAMPLE 6
202-(N- ~ henyloxazole.
n-Butyl-~sobutyramide(2.06 g~0.0144 m) in dry THF (20 ml) was stirred
at room temperature during the dropwise addition of a 1.445 M solution of n-
butyl lithium in hexane (lO.0 ml., 0.01445 m). After the addition~ the
mix~ure ~as stirred for 5 minutes, and then 4,5-diphenyl-2-iodooxa~ole
(Chemical Abstracts 65 7159~) (5.0 g, 0.0144 m) in dry THF (20 ml) was
added dropwise. The mixture was stirred for 6 hours at room temperature
~ and then hydrolysed with water. The solvent was removed in vacuo and the
; residue extracted with diethyl ether.
Distillation gave the title product as a coLourless oil~ b.p. (airbath)
~ 200C./0.1
-11-
... . I
.~ l I
.
' '~
3`7(~
1 l ~nalysis: Found: C: 76.10; H: 7031; N: 7.62; 0: 8.92%
Il C23H26N22 requires: C: 76.~ 7.23; N: 7.73; 0: 8.83%
E~AM~LE 7
2-(N-ButyLisobutyramido)-oxazole
n-Butyl- _ butyramide (4.93 g~ 0.0344 m) in dry diethyl ether (25 ml)
was stir~ed at room temperature under nitrogen during the dropwise addition
of a 1.445 M solution of n-butyl lithium (23.8 ml, 0.0344 m). The micture
was stirred for 15 minutes at room temperature and then 2-ethylsulphinyl-
oxazole (5.0 g, 0.0344 m) in dry diethyl e-ther (25 ml) was added rapid`ly~
The mixture was stirred at room temperature for 3 hours and then hydrolysed
with water. The organic phase was washed several times with water~ drîed
over magnesium sulphate and evaporated in vacuo to give a yellow oil.
DistiLlation gave the title product as a colourless oilg b.p. (airbath)
120C.~005 mm.
Analysis: Found: C: 62.61; ~: 8.74; N: 13.14; 0: 15.32%
Cll~ll8 2 2 requires: C: 62.83; ~l: 8.63; N: 13.32; 0: 15.22%
; EXAMPLE 8
2-(N-Ethyl-ac tamido)-4,5-dimethyloxazole
N-Ethyl-acetamide (10.0 g~ 0.115 m) in dry butyl hexyl ether(50 ml~
2S was stirred at room temperature under nitrogen during the dropwise addition
of a 1.445 ~M solution of n-butyl lithium in hexane (79.6 ml, 0.115 m), After
the addition~ the mixture was stirred for 15 minutes and then a solution of
4~5-dimethyl-2-methylsulphonyloxazole (20.0 g~ 0.114 m) in dry b~ltyl hexyl
ether (50 ml) was added dropwise. The mixture was stirred for 2 hours at
room temperature. Isolation of the product and distillation gave a colour~
less oil, b.p. 61-62 C/0.3 mm,
-12-
~1,
~nalysis: Found: C: 56.21; E-l: 8.42; N: 16~41; 0: 18.92%
C8H14N22 requireso C~ 56.45; ~1: 8.29; N: 16~46; 0- 18.80%
EXAMPLE 9
~-(N-Ethyl-acetamido)-4-methyloxazole
N-Ethyl-acetamide (1.18 g~ 0.0135 m) in dry dimethylEormamide (10 ml)
was stirred at room temperature under nitrogen during the portionwise
addition of 50% sodium hydride~oil dispersion (0.65 g, 0.0135 m). After the
addition~ the mixture was warmed to 50 CO and then 4-methyl-2-phenylmethyl-
sulphinyloxazole (3.0 g, 0.0135 m) was added. The mixture was stirred~ at
50C. for 5 hours and then hydrolysed with water. The solvent was
evaporated in vacuo and the residue extracted with diethyl ether. Column
chromatography on silica using ether gave a pale yellow oil which gave the
i 15 tltle product as a coLourless oil on distillation~ b~po 50-51C./0.05 mm.
Analysis:Found: C: 53.92; H: 7.62; N: 17.82; 0: 20.59%
C7H12N22requires: C: 53.83; H: 7,74; N: 17.94; 0: 20.49%
''''
.,,.,
EXAMPLE 10
2-(N-Methyl-acetamido)-4-methyloxazole
N-Methyl-acetamide (1.02 g~ 0.0140 m) in HMPA (10 ml) was stirred at
50C. under nitrogen during the portionwise addition o.E 50% potassium hydride/
oil dispersion (1.12 g~ 0.0140 m). After the addition~ the mixture was warmec
to 100C. and 2-n-hexylsulphinyl-4-methyloxazole (3.0 g, 0.0139 m) in HMPA
(10 ml) was added and the mixture stirred at 100C. for 5 hours. The mixture
was then hydrolysed with water~ solvent removed in vacuo and the product isol-
ated by column chromatography on silica using ether. Recrystallisation from
diethyl ether/hexane at -20C. gave the title product as colourless needles~
` 30 m.pO 27-29C.
-13-
,'''1. ~
';7~
EXA~!PLF. 1 1
2-(N-Butyl-phenylacetamido)-4-methyloXazole
~ N-Butyl-phenylacetaMide (1.80 g, 0.0094 m) in N-methyl pyrrolidone (10 ml)
¦Iwas stirred at 80C. under nitrogen during the portionwise addition of a
150% sodium hydride/oil dispersion (0.75 g~ 0.0094 m). After the addition, the
mixture ~as warmed to 100C. and 2-cyclohexylsulphinyl-4-methyloxaæole (2.0 g,
0.0094 m~ in dry N-methyl pyrrolidone (10 ml) was added. The mixture was
stirred ak 100 C. for 5 hours and then hydrolysed with water~ The solvent
was removed in vacuo and the product isolated by column chromatography on
silica using ether. Distillation gave the title product as a colourless
oil. b.p. 126-130C./0.2 mm.
Analysis: Found: C: 70.62; H: 7.60; N: 10.05; 0: 11.62%
C16~120N22 requires: C 70.56; H: 7.40; N: 10.29; 0: 11.75%
EXAMPLE 12
2-(N-s-Butyl-isobutyramido)-4-methyloxazole
: __ , _ _
N-s-Butyl-l butyramide (2.30 g, 0.016 m) and tetramethylethylenediamine
~1.87 g~ 0.016 m) were stirred at 40C. ln sulpholane (20 ml) under nitrogen
during the port~onwise addition of a 50% potassium hydride/oil dispersion
(1.29 g, 0~016 m). After the addition~ the mixture was warmed to 70C. and
2-n-butylsulphinyl-4-methyloxazole (3.0 g, 0.016 m~ in sulpholane ~20 ml~ was
added. The mix~ure was stirred at 70C. for 6 hours and then hydrolysed with
wate~. Removal of the solvent in vacuo and column chromatography on silica
using diekhyl ether gave the title compound, which was a colourless oil after
il distillation in vacuo~ b.p. 82C./0.8 mm.
Analysis: Found: C: 64.04; H: 9.12; N: 12.54; 0: 14.34%
C12H20N22 requires: C: 64.26; H: 8.99; N: 12.49; 0: 14.27%
` 30
-14-
1 ~ ~X~MPL~ 13
~2-(N-s-Butyl-butyramido)-4-methyloxa~ole
N-s-Butyl-butyramide (0~99 g~ 0.0069 m) in dry dioxan~lO ml) was cooled
~ to 10C. under nitrogen during the dropwise addition of a 1.445 M solùtion of
n~butyl lithium (4.S ml, 0,0069 m). The mixture was stirred for 15 minutes
at 10C. and then 4-methyl-2-methylsulphinyloxazole (l.0 g, 0.0068 m) in dry
dioxan (10 ml) was added and the mixture allowed to warm to room temperature.
It was stirred for 3 hours and then hydrolysed with water. The solvent was
removed in vacuo and the ether extract oE the residue was chromatographed on
silica using ether. The resulting compound (title product) was distilled
i~ vacuo as a colourless oil 0.95 g, b.p, 75 76C./0.5 mm.
Analysis: Found: C: 64.02; H: 9.21; N: 12.25; 0: 14~31%
12 20 2 2 requires: C: 64.26; H: 8.99; N: 12.49; 0: 14.27
EXAMPLE 14
2-(N-n-Bu~yl-2-methyl~opanamido~-4-methyLoxazole
n-Butyl- _ butyramide (0.99 g, 0.0069 m~ in dry THF (10 ml) was cooled
to -20 C. under nitrogen during the dropwise addition of a 1.445 ~ solution
of n-butyl lithium (4.8 ml~ 0.0069 m). The mixture was stirred for 20 minu~es
at -20 C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g~ 0.0068 m) in dry
THF ~L0 ml) was added rapidly and the mixture allowed to warm to 0C. It was
stlrred at this temperature for 1~ hours then allowed to warm to room
temperature and stirred for a further ~ hour. The mixture was hydrolysed
with water and the solvent was evaporated under reduced pressure. The residue
was extracted with diethyl ether and the extract was evaporated~ The resulting
oil was chromatographed on silica using ether/hexane. The compound was
distilled in vacuo to give the title compound as a colourless oil 1.21 g,
(78~/.), b.p. (~ rbath) 70C. at 0.0l mm.
~15-
, 1
.. . I
7(~7
Analysis: Found: C: 64.22; iI: 8.76; N: 12.23; 0 14.30%
I~ 20N2Z r~quires: C: 6~l.26; li: 8.99; N: 12,49; 0: I4.277
S EYA~IPLES 15 to 131
Similarly prepared were :-
2-(N-butyl-pentanamido)-4-methyloxazole, b.p. 88-91C /0.2 mm.
~: 2-(N-bu~yl-hexanamido)-4-methyloxazole, bop. 102C./0.3 mm
2-(N-butyl-2-ethylbutyramido)-4-methyloxazole, b.p. 127C./2.5 mm.
2-(N-butyl-cyclopropanecarboxamido)-4-methyloxazole, b.p. 97-100 C./0.5 mm.
2-(N-butyl-cyclohexanecarboxamido)-4-methyloxazole, m.p. 46.5-4805C. ~
2-(N-butyl-cycloheptanecarboxamido)-4-methyloxazole~ b.p. 138-141C.~l mm.
2-(N-butyl-3-phenylpropionanido)-4-methyloxazole, b.p. 137-138 C./0.2 mm.
2-(N-butyl-2-chlorobenzamido)-4-methyloxazole~ b.p~ 130-131C./0.2 mm.
2-(N-butyl-3-chlorobenzamido)-4-methyloxazole, b.p. 145-147C./0.4 mm.
2-(N-butyl-2~methoxybenzamido)-4-methyloxazole, b.p. 158-160 C./0.8 mm,
2-(N-butyl-4-methoxybenzamido)-4-methyloxazole, b.p. 162-163C.~l.0 mm.
2-(N-butyl-4-toluamido)-4-methyloxazole, b.p. 139-140C./0.7 mm.
2-~N-butyl-3-tri~luoromethylbenzamido)-4-methyloxazole~ b.p. 114-115C./0.3 mmO¦2-(N-butyl-4-nitroben3amido)-4-methyloxazole~ b.p. 178-180C./l.0 mm.
2-(N-methyl-i butyramido)-4-methyloxazole~ b.p. 49-50C./0.35 mm.
i 2-(N-ethyl-butyramido)-4-methyloxazole, b.p. 63-64C./0.1 mm.
2-(N-isopropyl-acetamido)-4-methyloxazole~ b.p. 75C./3.0 mm.
2-(N-isopropyl-propionamido)-4-methyloxazole, b.p. 65C./0.5 mm.
2-(N-isopropyl-butyramido)-4-methyloxazole, b,p. 69C./0.35 mm.
2-(N-isopropyl- _ butyramido)-4-methyloxazole, b.p. 60-62C./0.4 mm.
2-(N-s-butyl-acetamido)-4-methyloxazole~ b.p. 64C./0.6 mm.
2-(N-s-butyl- _ butyramido)-4-methyloxa~ole, b.p. 82C./0.8 mm.
2-(N-hexyl-acetamido)-4-methyloxazole, b.p. 90-92C,/0.08 mm~
2-(N-hexyl- _ butyramido)-4-methyloxazole, b.p. 106-109C./l.0 mm
,., I
~1 -16-
.; 1',
: il
.; .
. .
~ .
~4~ ~ ~
2-(N-benzyl-acetamido)-4-methyloxazole~ b.p~ 119-120C./0.3 mm
j2-(N-benzyl-propionamido)-4-methyloxazole~ b.p. 132-133C./0.3 rnm.
2-(N-benæyl-butyramido)-4-methyloxazole~ b.p. 128C./0.15 mm.
2-(N-propyl-pentanamido)-4-methyloxazole9 b.p. 83-84C./0.2 mm.
2-(N-[2-methoxyethyl~acetamido)-4-methyloxazole, b.p. 84 C./0.6 mm.
2-(N-[2-methoxyethyl~propionamido)-4-methyloxazole~ b.p~ 88CC./0.4 mm.
2-(N-[2-metho~yethyl~butyramido)-4-methyloxazole~ b.p. 96C./004 mm.
¦2-(N-[2-methoxyPthyl]-2-ethylbutyramido)-4-methyloxazole~ b.p. 98C./0.4 mm.
2-(N-[2-methoxyethyl] _ butyramido)-4-methyloxazole, b.p. 84-85 C./0.05 mm
2-(N-allyl-acetamido)-4-methyloxazole~ b.p.67C./0.8 mm.
2-(N-allyl-propionamido)-4-methyloxazole, b.p. 75C./0.8 mm.
2-(N-allyl benzamido)-4-methyloxazole, b.p. 119C./0.7 mm.
~-(N-allyl-butyramido)-4-methyloxazole, b.p. 76C./0.6 mm.
2-(N-allyl-2-ethylbutyramido)-4-methyloxazole, b.p. 83C./0.65 mm.
2-(N-ethyl-propionamido)-~5-dimethyloxazole~ b.p.68-69 C./0.3 mm.
2-(N-ethyl-butyramido)-4,5-dimethyloxazole, b.p. 68-70 C./0.25 mm.
; 2-~N-ethyl- _ butyramido)-4,5-dimethyloxazole, b.p. 63-65 C./0025 mm.2-(N-butyl-acetamido)-4,5-dimethyloxazole, b.p. 89-91C./l.0 ~m.
2-(N-butyl-propionamido)-4,5-dimethyloxazole, b.p. 86-88C./0.4 mm.
2-(N-butyl-l butyramido)-4-cyclohexyloxazole~ b.p. 165C./0.4 mm.
2-(N-butyl- _ butyramido)-~-butyloxazole, b.p. 140C./0.5 mm.*
2-(N-butyl~acetamido)-5-acetoxymethyloxazole~ b.p 170C./0.5 mm.-:;
5-isobutyroxymethyl-2-(N-butyl- _ butyramido)oxazole, b.p. 180 C.~0.5 mm.*
5-cyclohexyl-2-{N-butyl- _ butyramido)oxazole, b.p. 170C./0.5 mm.
2-(N-cyclopentyl-valeramido)-4-methyloxazole, b.p. 102-104 C./0.2 mm.
2-(N-2~-methoxyethylcyclopentanecarboxamido)-4-methyloxazole~ b.p. 117C./l.0 m l.
2-(N-2'-phenethyl-propionamido)-4-methyloxazole, b.p. 126 C.~0.6 mm.
2-(N-2~-phenethyl-acetamido)-4-methyloxazole, b.p. 122C./0.5 mm.
2-(N-allyl- _ butyramido)-4-methyloxazole, b.p. 68 C.~0.5 mm.
¦ Z-(N-3-phenet~yl-butyrAmido)-4-methyloxazoLe~ b.p. 133C./0.7 mm.
-17-
.
2-(N-~-pllenethyl- _ butyramido)-4-methyloxazole~ b.p. 128 C./0.65 mm.
~'4- _ butyroxyme~hyl-2-(N~butyl- _ butyramido)oxazole~ b.p. 180C./0.5 mm.:~
¦2-(N-butyl-benzamido)-4~5-dimethyloxazole~ b.p. 125-128 C./~5 mm
2-(N-butyl-valeramido)-4,5-dimethyloxazole, b.p. 102-105C,/0.5 mm,
; 5 2-(N-butyl-cyclobutanecarboxamido)-4~5-dimethyloxazolea b.p 105-107C./0.5 mm.
2-(N-butyl-butyramido)-4,5-dimethyloxazole, b.p. 95-98G./0.5 mm.
2-(N-butyl-3-nitrobenzamido)-4-methyloxazole, b.p. 152-155C./0.2 mm.
2-(N-[2-methylbutyl~-butyramido)-4-methyloxazole, b.p. 87 C./0.5 mm.
2-(N-[2-methylbutyl~-propionamido)-4-methyloxazole~ b.p. 82-83C./0.5 mm.
2 ~N-[2 methylbutyl~- _ butyramido)-4-methyloxazole, b.p. 83C./0.5 mm.
2-(N-pentyl-benzamido)-4-methyloxazole, b.p. 130C./0.7 mm,
2-(N-cyclohexyl-propionamido)-4-methyloxazole, b.p. 101 C./0.5 mm.
- 2-(N-ethyl-hexanamido)-4-methyloxazole~ b.p. 94-96C./0.7 mm,
lS 2-(N-butyl-cyclohexanecarboxamido)-4,5-dimethyloxazole, b.p. 122-126C./0.5 mm.
2-(N-butyl cyclopentanecarboxamido)-4,5-dimethyloxazole, b,p. 112-116C./0.5 mm
l 2-(N-oyclohexyl-butyramido)-4-methyloxazole~ b.p. 118C./0.7 mm.
; 2-(N-butyl-3~4-dichlorobenzamido)-4-methyloxazole~ bop~ 162-165C./l.0 mm.
2-~N-pentyl-butyramido)-4-methyloxazole, b.p. 98C./0.8 mm.
2-(N-benzyl-benæamido)-4-methyloxazole~ m.p. 62C.
2-~N-benzyl-valeramido)-4-methyloxazole, b.p~ 134C./0.7 mm.
4~5-Dimethyl-2-(N-methyl-acetamido)oxazole~ m.p. 40-42C.
2-(N-butyl-l-adamantanecarboxamido)-4-methyloxazole~ b.p. 160C./0.3 mm.
~` 2-(N~ethyl-2-ethylbutyramido)-4-methyloxazole~ b.p, 71-2C./0.3 mm.
2-(N-butyl 4-fluorobenzamido)-4-methyloxazole9 b.p. 120-2 C./0.3 mm.
4-methyl-2-(N-propyl-hexanamido)oxazole~ b.p. 96-~C./0.4 mm.
4-methyl-2-[N-(l-ethylpropyl)-butanamido~oxazole~ b.p. 58-60 C./0~5 mm.
4-methyl-2-~N-(l-ethylpropyl)-pentamido~oxazole, b.p. 91C./0.5 mmt
2-(N-pentyl-propanamido)-4-methyloxazole~ b.p.68C./0.05 m~.
2-(N-pentyl- _ butyramido)-4-methyloxazole~ b.p. 86-7C./0~4 mm.
~` 30 2-(N-~utyl-i butyramido)-4-ethyloxazole~ b.p. 140 Co/0.5 mm.:~
' '
,. I
~ l -18-
11 I
': .
; 2-(N~isopropyl-pentanaMido)-4-methyloxazole~ b.p. 77C./0.3 ~n.
I 2-(N-butyl dichloroacetamido)-4-methyloxazole, b.p. 112-4C./0.8 mm.
; 2-(N-~-chlorobenzyl- _ butyramido)-4~methyloxazoleg b.p. 136C./0.7 m~n.
2-(N-hexyl-propanamido)-4-methyloxazole, b.p. 106-8C./l.0 mm.
!2-(N-butyl-chloroacetamido)-4-methyloxazole, b.p. 96-8C./l.0 mm.
2-(N-butyl-l butyramido)-4-methyl-5-hydroxyoxazole t
(-) 2-(N-but-2-yl-butanamido)-4-methyloxazole, b.p. 86-9C./1.2 Tnm,
(+) 2-(N-but-2-yl-butanamido)-4-methyloxazole, b.p. 85-8C./1.5 mm.
2-(N-butyl-N- _ butyramido)-4-hydroxymethyloxazole, b.p. 185 C./0.3 mm.-~
, 10 2-(N-cyclohexyl- _ butanamido)-4-methyloxazole, b.p. 108C./0.8 mm.
2-(N-benzyl-hexanamido)-4-methyloxazole, b.p. 144C./0.6 mTn.
2-(N-butyl-4-chlorobutanamido)-4-methyloxazole, b.p. 124-8C./1.2 mm.
2-(N-butyl-l butyramido)-4-~-chlorophenyloxazole, b.p. 200 C./005 Tnm.*
2-(N-butyl-_ obutyramido)-5-methyloxazole~ b.p. 100C./0.1 mm.~
1-(4-methyl-oxazol 2-yl)-2-oxo-hexahydro-lH-azepine~ b.p. 130C./0.1 mm.*
2-(N-cyclopentyl- _ butyramido)-4-methyloxazole, m.p. 73C.
D(-) 2-(N-butyl-2-methylbutanamido)-4-methyloxazole, b.p. 88-92C./0.6 mm.
L(+) 2-(N-butyl-2-tnethylbutanamido)-4-methyloxazole, b.p. 88-91 C./0.6 Tnm.
2-(N-butyl-2-methylbutanamido)-4-methyloxazole~ b.p. 82-5C./002 nLmO
2-N-(butyll butyramido)-5-phenyloxazole~ b.p. 190C./0.2 Tnm.*
2-(N-cinnamyl i butyramido)-4-methyloxazole~ b.p. 152-156C./l.0 mm.
; 2-[N-~4-methylbenzyl) _ butyramido~-4-methyloxazole~ b.p. 120-4C./0.3 ~n.
2-[N-t3-methylbenzyl) _ butyramido~-4-methyloxazole, b.p. 118-122C./003 nlm.
2-(N-butyl-heptanamido)-4-methyloxazole, b.p. 106-~C./0.05 mm.
2-(N-butyl-cyclopentylacetamido)-4-methyloxazole, b.p. 124-6C./0.8 n~n.
2-(N-cyclohexylmethyl- _ butanamido)-4-methyloxazole, b.p. 122-4C./0.8 mm.
2-[N-(4-methoxybenzyl) _ butyramido~-4-methyloxazole~ b.p. 145-8 C./0.4 mm.
2-(N-butyl-cinnamamido)-4-methyloxaæole, b.p. 200 Co/0~2 mTn~
¦2-[N-(3-carbox~propyl)octanamido~-4-methyloxazole, b.p. 200 C./0.2 mm.
;:30 2-[N-(3-chloropropyl)pentanamido~-4-methyloxazole, b7p. 118-122 C~/0.7 mm.
~' l
~ l
I -19-
1 12-[N-(3 chloropropyl) _ob~tyramido~-4-methyloxazole~ b.p. 99-1~2C./0.5 mln
2-(N-butyl-but-2-enamido)-4-methyloxazole~ b.p. 150 C./0.02 mm.
2-(N-butyl-l butyramido)-5-ethyloxazole, b.p~ 70-72C./0.2 mm.
2-(N-butyl-trifluoroacetamido)-4-methyloxazole~ b.p. 67-69C./0.8 mm.
~ Temperature recorded in an air-bath.
t Boiling point not taken but mass-spectral data in accord with
structure.
-.-
Microanalysis (C,H,N) for each of the compounds listed in Examples 15 to 131
was (within the limits of experimental error) equal to the expected theoret-
ical result. In addition~ infra-red~ ultra-violet and proton magnetic
resonance spectra were consistent with the assigned structures.
All pressures measured in mm. of mercury.
