IE43314B1

IE43314B1 - 2-acylamino oxazoles

Info

Publication number: IE43314B1
Application number: IE1181/76A
Authority: IE
Original assignee: Lilly Industries Ltd
Priority date: 1975-06-07
Filing date: 1976-06-02
Publication date: 1981-01-28
Also published as: BG25516A3; BE842580A; SE7606227L; ZA763336B; AT345278B; JPS51146462A; NZ181026A; RO69114A; AR219281A1; CH598236A5; YU136976A; PH14307A; ES448591A1; HU174777B; IL49710A0; PT65183A; GB1552125A; DK243376A; FR2313372B1; NL7606177A

Abstract

Process for preparing 2-acylamino oxazoles useful in the treatment of immediate hypersensitivity conditions which process involves the nucleophilic displacement of the 2-substituent of an oxaxolyl intermediate by the anion -NR1COR2(-) derived from the salt ??R1COR2, where M represents a metal cation and NR1COR2 represents the acylamino moiety.

Description

This invention relates to a method of preparing certain novel oxasole derivatives substituted by a 2-acylamino group which possess pharmacological activity.

According to the present invention there is provided a method of preparing a novel oxazole derivative of the formula (X) : wherein R^ is alkyl, g alkenyl, θ alkoxyalkyl, g carboxyalky, Cj_6 haloalkyl, c3_£0 cycloalkyl, c3_-£0 cycloalkyl-Cj_6 alkyl, optionally substituted phenyl-C^ θ alkyl or optionally substituted phenyl-g alkenyl; and R is g alkyl, g haloalkyl, g alkenyl, cyeloalkyl^ C3 10cyC^°aRcir^-Cl-6 a^kyl, optionally substituted phenyl, optionally substituted phenyl-θ alkyl or optionally substituted phenyl-C^ θ alkenyl; 2 or R and R together form a lactam ring having 5 to 7 ring atoms; and wherein R3 and R4 are independently selected from hydrogen, formyl, carboxyl, hydroxy, hydroxyalkyl·, halogen, 4 alkyl, Cg cyeloalkyl, C3_(. acyloxyalkyl or an optionally substituted phenyl group; which method comprises reacting a salt of formula (II) : MNI^COR2 (II) 2 wherein M is a group IA or IIA metal and wherein R and R are as previously defined, with a 2-oxazolyl derivative of formula (III) ! (Ill) -24 3 314 where L is a leaving group and wherein R3 and i!' are as defined above.

The method of the invention is preferred for compounds of formula (I) wherein ii1 is C^_6 alkyl, C2_ft alkenyl, C2_6 alkonyalkyl, C-,_g cycloalkyl, G3-8 cycT°aTkyl-C^_g alkyl, optionally substituted phenyl-C^ g alkyl or optionally substituted phenyl-C2 alkenyl; R is C] alkyl, haloalkyl, Cg alkenyl, Cg g cycloalkyl, Cg g cycloalkyl-C^ g alkyl, optionally substituted phenyl, optionally substituted 1 2 phenyl-Cj g alkyl or optionally substituted phenyl-C3_6alkenyl, or R and R 3 4 together form a lactam ring having 5 or 6 ring atoms, and wherein R and R are independently hydrogen, 4 alkyl, hydroxyalkyl, Cg g cycloalkyl, Cg 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) R7 is alkyl, for instance n-butyl and n-propyl; (b) r’_ is C, 4 alkenyl; (c) R^ is phenyl-C^_2 alkyl; (d) R2 is phenyl; (e) R is 4 alkyl, for instance methyl, n-propyl and i-propyl; (f) R2 is Cg_3 cycloalkyl; ι ο (g) R and R taken together form a lactam ring having 5 carbon atoms; (h) one or both of tbe available positions in the oxazole nucleus is substituted by a methyl group; (i) one or hoth 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 1 2 preparation of the compound of formula (I) in which R is n-butyl, R is 'i 4 ^-propyl, R’ is methyl and R is hydrogen. -343314 The reaction between the salt of formula (II) and the 2-oxazolyl derivative of formula (III) can be accomplished using anhydrous conditions. Any suitable inert solvent may be utilised. Ethereal solvents such as diethyl ether, dioxan or tetrahydrofuran are particularly useful; however, solvents such as dimethylformamide, N-methylpyrrolidone or hexamethylphosphoric triamide may also be used. The reaction can normally be effected at temperatures between 0 and 110^0., preferably between 0 and 40°C,, most preferably at room temperature. At these temperatures the reaction will usually be complete after a time of from 1 to hours.

A preferred salt of formula (XI) is the lithium derivative which can be conveniently prepared by the reaction of butyl lithium with the 12 appropriate amide of formula HNR COR . This reaction should be carried out under an inert gas atmosphere such as nitrogen and preferably at low temperature, for example, less than -10°C. The presence of a chelating agent such as tetramethylethylene diamine has proved advantageous. Generation of 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 -SO^R, where R is C^ g alkyl, Cg_g eycloalkyl, benzyl or phenyl. The identity of suitable 1 groups will be appreciated by those skilled in the art once it is understood that the reaction of the invention proceeds via the (-) 1 2 nucleophilic displacement of the L group hy the anionic entity NR COR .

Derivatives of formula (III) may be obtained from 2-oxazolones or 2oxazole-thiones of formula : ,4 ,3 ,4 R S (IV) (V) -443314 Such canpounds are cither known (see for example, Berichte 89, 1748, (1956), Acta. Chem. Scan. 23 2879 (1969) and Bull. Soc. Chim. Belg. 70, 745 (1961)) or can be prepared frcm kncwn canpounds by conventional procedures.

If it is desired to prepare derivatives of formula (III) in which L is chlorine, brcmine or iodine, a compound of formula (IV) or (V) may be reacted with phosphorus pentachloride, phosphorus oxychloride, phosphorus pentabrcmide 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, brcmo or iodo derivative directly.

Canpounds of formula (III) in which L is -SOR or can be prepared frcm the corresponding alkylthio derivatives, i.e. where L is -SR, by treatment witli the appropriate amount of oxidising agent, pre15 ferably 3-chloroperbenzoic acid. 'Ihe derivatives may be prepared by alkylation of the corresponding thione of formula (V), preferably by generating the thiolate anion with sodium or sodium hydride. Compounds of formula (III), except for a snail number of exceptions (see, for instance, Berichte 92 1928 (1959), Chemical Abstracts 79 P126485m and 65 7159h) are novel.

Compounds of formula (I) have been shewn to be useful in the prophylactic and therapeutic treatment of inmediate hypersensitivity diseases including asthma and in the alleviation of status asthmaticus.

In certain cases the - 5 * 3 3 1 4 compounds have been found to be useful in diseases in which excessive amounts of prostaglandins are released 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 of formula (X) may be administered by the oral and rectal routes, topically, parenterally, e.g. by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example,containing from 1 to 10% byweight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support materia.l for making injection solutions. Advantageously for this purpose, compositions may be provided in dosage unit form, preferably each dosage unit 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 course, 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 preparations and Examples. Preparations 1 to 4 illustrate the preparation of various intermediates of formula (III) whereas Examples 1 to 127 illustrate the utilisation of these intermediates in the process of the invention. The -6433 14 abbreviations THF and fIMPA are used to denote tetrahydrofuran and hexamethylphosphoric triamide respectively. 3 314 PREPARATION 1 2-Chloro-5-phenyloxazole -Phenyl-2(3H)-oxazolethione (Acta» Ghent. Scand. 23 2879 (1969) ) (19.6 g, 0.11 m) and phosphorous oxychloride (70 ml) were stirred with cooling during the cautious addition of triethyiamine (12.4 g, 0.123 m). The mixture was then heated under reflux for 20 hours, excess reagents removed under reduced pressure and the residue distilled in vacuo to give the title product as a colourless oil which solidified on standing, b.p. 96-8°C/ 0.6 mm, m.p. 34°C.

PREPARATION 2 4,5-Pimethyl-2-methylthiooxazole 4,5-Dimethyl-2(3H)-oxazolethione [Bull. Soc. Ghim. Belg. 70, 745, (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 sulphate (40.0 g, 0.317 m). The mixture was stirred for 4 hours at room temperature and then wanned to 50°C, cooled, and the aqueous phase extracted with diethyl ether. Evaporation of the solvent and distillation of the residue under reduced pressure gave 33.85 g (817.) of the title product as a pale yellow oil, b.p. 82°C./13 nm. Analysis: Found: C: 50.39; H: 6.20; N: 10.03; 0: 11.30; S: 22.35% CgHgNOS requires: C: 50.32; H: 6;33; N: 9.78; 0: 11.17; S: 22.39% Similarly, there were prepared :4-Methyl-2-methylthiooxazole (Arch. Pharm. 301 (3) 186 (1968). 4- Ethyl-2-methylthiooxazole, b.p. 72°C. (airbath)/14 mm.

- Methyl-2-methylthiooxazole, b.p, 66°C, (airbath)/ll mm, 2-Methylthio-4-phenyloxazole, [zh. Ohshch. Khim. 33 1507 (1963)] 5-Ethyl~2-methylthiooxazole, b.p. 75°C. (airhath)/15 mm. •843314 2-Iithyi thiooxazole, [Phytopathology, 56 (8) 929 (1966)] 2-n-Butylthio-4-methyloxazole, b.p, 98°C./10 mm. 2-n-Hexylthio-4-methyloxazole, b.p. 124°C./10 ram. 2-Cyclohcxylthio-4-methyloxazole, b.p. 66°-68°/8 mm. 4-Methyl-2-plienylmethylthiooxazole, b.p. 114°/1 mm. 4,5~Diphenyl-2-phenylthiooxazole [Tetrahedron, Suppl. No. 8 Pt. 1,305 (1966)] was prepared by the literature method. ΡΚΕΡΑΡΛΤΙΟΜ 3 4-ΜΒΐ1ιγ1-2-Γ(ΐΰί1ινΐ3η1ρΙιϊηγ1οχ3ζο1ΰ , 4-Methyl~2-methylthiooxazole (6.06 g, 0.047 m) in dry chloroform (50 ml) was cooled to 0°C. with vigorous stirring and anhydrous sodium carbonate (6.06 g, 0.057 ib) added. 96% 3-Chlorope.rbenzoic acid (8.90 g, 0.0495 m) 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 mixture 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)76°C./0.1 mm.

Analysis; Pound: C: 41.54; H: 5.04; N: 9.89; 0: 22.24%, C5t!7NO2S requires: C: 41.36; H 4.86; N: 9.65; 0: 22.04¾ Similarly prepared were the following :4,5-Dimethyl-2-methylsulphinyloxazolG, b.p. (airbath)96°C./O.l mm. 4- Ethyl-2-inethylsulphinyloxazole, b.p. 82°C./0.1 ram.

- Ethyl~2-methylsulphinyloxazole, b.p. 85°C./0.i mm.

-Methyl-2-methylsulphinyloxazole, b.p. 79°C./0.1 mm. 2-Methylsulphinyl-4-phenyloxazole, m.p, 53°C. 2-Ethylsulpliinyloxazole, b.p. 68°C./O.l mm. -9/-3314 2-ri-BuLylsulpliinyl-4-inetliyloxazole, b.p. (airhath)82°C./0.1 mm. 2-nylk'xylsulpl)inyl-4-methyloxazolc, b.p. (airbath)90°C./0.1 mm. 2-Cycloln’xylsulpliinyl-4-metIiy]oxazole, b.p. (airbath) 100°C./0.1 mm. 4-Metliy] -2-phcnyliiie thy Isulphinyloxazole, m.p. 50°C. 4.5- I)i.pkcnyl-2-phenylsulphinyloxazole, m.p. 92°C.

PREPARATION 4 4.5- Dimethyl-2-Methylsulplionyloxazole 4,5-Dimethyl-2-methylthiooxazole (4.21 g, 0.029 m) in dry chloroform (15 ml) was cooled to 0°C. and anhydrous sodium carbonate (8.0 g, 0.0755 m) added. 88.57, 3-Chloroperbenzoic acid (11.5 g, 0.059 m) in dry chloroform wa then added over 45 minutes, and the mixture stirred for a further 45 minutes at 0°C. 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 recrystaliised from ethyl acetate/hexane as the title product, m.p. 42°C.

Similarly prepared were :4-Methyl-2-methylsulphonyloxazole; 4- Ethyl-2-methylsulphonyloxazole; - Ethyl-2-methylSuIphonyloxazole; -Methyl-2-methylsulphonyloxazole5 2-Metliylsulphonyl-4-plienyloxazole; 2-Ethylsulphonyloxazole; 2-n-Bu tylsulphony1-4-methyloxazole; 2-n-Hexylsulphonyl-4-methyloxazole; 2-Cyclohexylsulphonyl-4-methyloxazole; 4-Methyl-2-phenylmethylsulphonyloxazole; 4,5-Diphcnyl~2-phenylsulphonyloxazole. -10EXAMPLE 1 2-(N-biityl-2-methylprpp3nai3ido)-5-phenyloxaz(>le N-n-Butyl-isobutyramide (143 rag., 0,001 m) in dry tefcrahydrofuran (5 cc.) was cooled at -15°C. under nitrogen. Tetraraethylethylene diamine (0.116 g, 0.001 in) was added, followed by n-BuLi (0.75 cc, of an 8.87, W/V solution in hexane, 0.001 in) stirring was continued for 15 hours.

Gas evolution was apparent. 2-Chloro~5-phenyloxazole (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 tic. (b.p. 190°C. (air-bath temperature) /0.2 mmHg).

Analysis: C17H22N2°2 requires: C: 71.39; Hi 7.75; N: 9.797. found: C: 71.64; H: 7.59; N: 9.85% Infrared, nmr and tic confirmed the structure of the product.

EXAMPLE 2 2-(Ν-Βιιίγ1-2-ηιβί]Ίγ1ρΓθρ3ηα:η1όο)-4.5-Ρ1ρίΐΒη7ΐο;·ΐ3χο1{:.

N-n-Biityl-isobutyramide (2.06 g,0.0144 m) in dry THF (20 ml) was stirred at room temperature during the dropwise addition of a 1.445M solution of n_butyl lithium in hexane (10,0 ml., 0.01445 m). After the addition, the mixture was stirred for 5 minutes, and then 4,5-diphenyl-2-iodooxazole (Chemical Abstracts 65 7159h) (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) 200°C./0.1 mm. -114 3 314 Analysis; Found: C: 76.J0; H: 7.31; N: 7.62; 0: 8.92%C23H26N2°2 requires: C: 76.21; H: 7.23; N: 7.73; 0: 8.83% EXAMPLE 3 2-(H-Butylisobutyr amido)-oxazole N-n-Butyl-isobutyramide (4.93 g, 0.0344 m) in dry diethyl ether (25 ml) was stirred 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 mixture was stirred for 15 minutes at room temperature and then 2-ethylsulphinyloxazole (5.0 g, 0.0344 m) in dry diethyl ether (25 ml) was added rapidly. The mixture was stirred at room temperature for 3 hours and then hydrolysed with Water. The organic phase was washed several times with water, dried over magnesium sulphate and evaporated in vacuo to give a yellow oil. Distillation gave the title product as a colourless oil, b.p. (airbath) 120°C./0.5 mm.

Analysis: Found: C: 62.61; H: 8.74; N: 13.14; 0: 15.32% C11H18N2°2 requires: C: 62.83; H: 8.63; N; 13.32; 0: 15.22% EXAMPLE 4 2-(M-Ethyl-acetamido)-4,5-dimethyloxazole N-Ethyl-acetamide (10.0 g, 0.115 m) in dry butyl hexyl ether (50 ml) was stirred at room temperature under nitrogen during the dropwise addition of a 1.445 ·Μsolution of n-butyl lithium in hexane (79.6 ml, 0.115 m). Afte 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 butyl 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 colourless oil, b.p. 61-62°C/0.3 mm. -124 3 314 Analysis: Found: C: 56.21; H: 8.42; N: 16.41; 0: 18.92% C8!114N2°2 requires: C: 56.45; H: 8.29; ti: 16.46; 0: 18.80% EXAMPLE 5 2-(N-K Lhyl-acetamido )-4-tnethyloxazole N-Ethyl-acetamide (1.18 g, 0.0135 m) in dry dimethylformamide (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°C. and then 4-methyl-2-phenylmefchylsulphinyloxazole (3.0 g, 0.0135 m) was added. The mixture was stirred at 50°C. for 5 hours and then hydrolysed with water. The solvent was evaporated in vacuo and the residue extracted with diethyl ether. Golumn chromatography on silica using ether gave a pale yellow oil which gave the title product as a colourless oil on distillation, b.p. 50-51°C./0.05 ran. Analysis: Found: C: 53.92; H: 7.62; Ni 17.82; 0: 20.59% C7H12N2°2 re9uiress C: 53.83; Hi 7.74; N: 17.94; 0: 20.49% EXAMPLE 6 2-(N-Mc thyl-ace tamido)-4-me thyloxazole N-Methyl-acctamidc (1.02 g, 0.0140 tn) In HMPA (10 ml) was stirred at 50nC. under nitrogen during the portionwise addition of 507, potassium hydride/ oil dispersion (1.12 g, 0.0140 m). After the addition, the mixture was warmed to 100°C. and 2-ii-hexylsulphinyl-4-raethyloxazole (3.0 g, 0.0139 n>) in HMPA (10 ml) was added and the mixture stirred at 100°C. for 5 hours. The mixture was then hydrolysed with water, solvent removed in vacuo and the product isolated by column chromatography on silica using ether. Recrystallisation from diethyl ether/hexane at -20°C, gave the title product as colourless needles, m.p. 27-29°C. -1343314 EXAMPLE 7 2-(M-Butyl-phenylacetaniido)-4-methyloxazole N-Butyl-phenylacetaraide (1.80 g, 0.0094 m) in N-methyl pyrrolidone (10 ml) was stirred at 80°C, under nitrogen during the portionwise addition of a 507. sodium hydride/oil dispersion (0.75 g, 0.0094 m). After the addition, the mixture was warmed to 100°C. and 2-cyclohexylsulphinyl-4-methyloxazole (2.0 g, 0.0094 m) in dry N-methyl pyrrolidone (10 ml) was added. The mixture was stirred at 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. 126-130°C./0.2 mm. s.

Analysis! Found; C: 70.62; H: 7.60; N: 10.05; 0: 11.627.

C16H20N2°2 requites: Cs 70.56; Hi 7.40; Ni 10.29; 0i 11.757.

EXAMPLE 8 2-(Ν-3-Βυΐ7ΐ-ίΞθ1)πίγΓ3ίηίάο)-4-ιη£ίίψ1οχη2θΐ£ N-s-Butyl-isohutyramlde (2.30 g, 0.016 m) and tetramethylethylenediamine (1.87 g, 0.016 m) were stirred at 40°C. in sulpholane (20 ml) under nitrogen during the portionwise addition of a 507. potassium hydride/oil dispersion (1.29 g, 0.016 m). After the.addition, the mixture was warmed to 70°C. and 2-n-butylsulphinyl-4-methyloxazole (3.0 g, 0.016 m) in sulpholane (20 ml) was added. The mixture was stirred at 70°C. for 6 hours and then hydrolysed with water. Removal of the solvent in vacuo and column chromatography on silica using diethyl ether gave the title compound, which was a colourless oil after distillation in vacuo, b.p. 82°C./0.8 mm.

Analysis: Found: C: 64.04; H: 9.12; N: 12.54; 0: 14.347.

C12H20N2°2 requires: C: 64.26; H: 8.99; N: 12.49; 0: 14.277. -144 3 314 EXAMPLE 9 2-(N-s^-iiutyl-butyramido)-4-methyloxacoie N-s.-Butyl-butyraniide (0.99 g, 0.0069 m) in dry dioxan.(10 ml) was cooled to 10°C. under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 15 minutes at 10°C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry dioxan (10 ml) was added and tbe 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 tbe ether extract of the residue was chromatographed on silica using ether. The resulting compound (title product) was distilled iii vacuo as a colourless oil 0.95 g, b.p. 75-76°C./0.5 mm.

Analysis! Found: C: 64.02; H: 9.21; N: 12.25; 0: 14.317. i:i2H20N2°2 requires: C: 64.26; Π: 8.99; N: 12.49; 0: 14.277.

EXAMPLE 10 2-(N-n-iiiiLyl-2-methyIprcpanaiiiido)-4-methyl.oxazolc n-Cutyl-isobutyramide (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 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 20 minutes at -20°C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry THF (10 ml) was added rapidly and the mixture allowed to warm to 0°C. It was stirred at this temperature for 1¾ hours then allowed to warm to room temperature and stirred i'or 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 i.n vacuo to give the title compound as a colourless oil 1.21 g, (787.), b.p. (airbath) 7o°C. at 0.01 mm. -15A3314 Analysis: Found: C: 64.22; H: 8.76; N: 12.23; 0: 14.30% ;ΐ2ΙΓ20^2θ2 requires: C: 64.26; Hs 8.99; N: 12.49; 0: 14.27% EXAMPLES 11 to 127 Similarly prepared were :2-(N-butyl-pentanamido)-4-methyloxazole, b.p. 88-91°C./0.2 mm. 2-(N-butyl-hexanamido)-4-methyloxa2ole, b.p. 102°C./0.3 mm. 2-(N-butyl-2-etliylbutyratnido)-4-methyloxazole, b.p. 127°C./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. 46.5-48.5°C. -, 2-(N-hutyl-cycloheptanecarboxamido)-4-methyloxazole> b.p. 138-141°C./1 mm. 2-(N-butyl-3-phenylpropionamido)-4-metbyloxazole, b.p. 137-138°C./0.2 mm. 2-(N-butyl-2-chlorobenzamido)-4-methyloxazole, b.p. 130-131°C,/0.2 mm. 2-(N-butyl-3-chlorobenzamido)-4-methyloxazole, b.p. 145-147°C./0.4 mm. 2~(N-butyl-2-methoxybenzamido)-4-methyloxazole, b.p. 158-160°C./0.3 mm. 2-(N-butyl-4-methoxybenzamido)-4-methyloxazole, b.p. 162-163°C./1.O mm. 2-(N-butyl-4-toluamido)-4-methyloxazole, b.p. 139-140°C./0.7 mm, 2-(N-butyl-3-trIfluoromethylbenzamido)-4-methyloxazole, b.p. 114-115°C./0.3 mm 2-(N-butyl-4~nitrobenzamido)-4-methyloxazole, b.p, 178-18O°C./l.O mm. 2-(N-methyl-isobutyramido)-4-methyloxazole. b.p. 49-50°C./0.35 mm. 2-(N-ethyl-butyramido)-4-methyloxazole, b.p, 63-64°C./0,l mm. 2-(N-fisopropyl-acetamido)-4-methyloxazole, b.p. 75°C./3,O mm. 2-(N-isopropyl-propionamido)-4-methyloxazole, b.p. 65°G./0.5 mm, 2-(N-isopropyl-butYramido)-4-methyloxazole. b.p. 69°C./0.35 mm. 1- CN-isopropyl-isobutyramido^-methyloxazole, b.p. 60-62°C./0.4 mm. 2- (N-_s-butyl-acetamido)-4-methyloxazols, b.p. 64°C./0.6 mm. 2-(N-s-butyl-isobutyramido)-4-methyloxazole. b.p. 82°C./0.8 mm. 2-(N-hexyl-acetamido)-4-methyloxazole, b.p. 90-92°C,/0.08 mm. 2-(N-hexyl-isobutyramido)-4-methyloxazole, b.p. 106-109°C./1.0 mm. -164 3314 2-(N-benzyl-ace!amido)-!-methyloxazole, b.p. 119-120°C./0.3 ium. 2“(N-beiizyl-propionamido)-4-methyloxazole, b.p. 132-133°C./0.3 mm. 2-(N-beuz.yJ-buLyramido)-4-methyloxazole, b.p. 128°C./0.15 mm. 2-(N-propyl-pcfiraiia(iiido)-4-roethyloxazole, b.p. 83~84°C./0.2 torn. ϋ 2-(N-|> «methoxyethyljacetnmido)-4-methyloxazole, b.p. 84°C./0.6 rani. 2-(N-[2 -metlioxyethyl]propionamido)-4-methyloxazole, b.p. 88°C./0.4 mm. 2-(N-[2-n!ethoxyethyl]butyramido)“4-methyloxazole, b.p. 96°C./0.4 mm. 2-(N-[2-metlioxyethyl]-2-ethylbutyramido)-4-methyloxazole, b.p. 98OC./0.4 mm. 2-(N-|~2-methoxyetliyl1isobutyr amido)-4-me thy loxazole, b.p. 84-85°C./0.05 mm. 2-(N-allyl-acetamido)-4-methyloxazole, b.p.67°C./0.8 mm. 2-(N-allyl-propionamido)-4-metbyloxazole, b.p. 75°C./0.8 mm. 2-(N~allyl-benzamido)-4-methyloxazole, b.p. 119°C,/0.7 mm. 2~(N-allyl-butyramido)-4-methyloxazole, b.p. 76°C./0.6 mm. 2-(N~allyl-2-ethylbutyramido)-4-methyloxazole, b.p. 83°C,/0.65 mm. 2-(N-ethyl-propionamido)-4,5-dimethyloxazole, b.p,68-69°C./0.3 mm, 2-(N~cthyl-butyramido)-4,5-dimethyloxazole, b.p. 68-70°C./0.25 mn, 2-(N-e.tby l-isobutyramido)-4,5-dimetbyloxazole) b.p. 63-65°C./0.25 ram. 2-(N-buLyl-acettimido)-4,5-diraetliyloxazole, b.p. 89-91°(',,/1.0 mm. 2-(N-butyl-propi.onainido)-4,5-dimetliyloxazole, b.p. 86-88°C./0.4 mm. 2-(N~butyl-isobutyramido)-4-cyclohexyloxaaole, b.p. 165°C./0.4 mm.* 2-(N-butyl-isobutyramido)-4-butyloxazole, b.p. 140°C./0.5 mm.* 2-(N-butyl-acetamido)-5-acetoxymethyloxazole, b.p, 170°C./0.5 mm.* 5-isobutyroxymethyl-2-(N-butyl-isobutyramido)oxazole> b.p. 180°C,/0,5 mm,* 5-eyclohexyl-2-(N-butyl-isobutyramido Oxazole, b.p. 170°C./0.5 mm. 2-(N-cyclopentyl-valeramido)-4-methyloxazole, b.p. 102-104°C./0.2 mm. 2-(N-2'-rneth()xyeCiiylcyclopentnnecarboxa;:iido)-4-n>etliylo; 2-(N-2*~phenetliyl-acetaniido)-4-methyloxazole, b.p. 122°C./0.5 mm. 2-(N-allyl-isobutyram2do)-4-methyloxazole, b.p, 68°C./0.5 mm. 2”(N-i;-plienetliyl-butyramido)-4-methyloxazole, b.p. 133°C./0.7 mm. -171 3 314 2-(N-f)-plienethyl--isobutyraniif3o)-4-niel:hyloxazole, b.p. 128°C./0.65 mm. 4-isobutyroxymc tliyl-2-(N-bu tyl-isobu tyr amido )oxazole, b.p. 180°C./0.5 mm.* 2-(N-butyl-bonzamido)-4,5-dimetliyloxazole, b.p. 125-128°C./0.5 ran, 2-(N-butyl-valeramido)~4,5-dimethyloxazole, b.p. 1O2-1O5°C./O.5 mm. 2-(N-butyl-cyclobutanecarboxamido)-4,5-dimethyloxazole, b.p. 1O5-1O7°C./O.5 mm. 2-(N-butyl-butyramido)-4,5-dimethyloxazole, b.p. 95-98°C./0.5 mm. 2-(N-butyl-3-nitrobenzamido)-4-methyloxazole, b.p. 152-155°C./0.2 mm. 2-(N-[2-methyrbutyl]-butyr-araido)“4-methyloxazole, b.p, 87°C./0.5 mm, 2-(N-[2-methylbutyl]-propionamido)-4-metbyloxazole, b.p. 82-83°C»/O,5 mm. 2-(N-[2-methylbutyl]-isobutyramido)-4-methyloxazole, b.p. 83°C./0.5 mm. 2-(N-pentyl~benzamido)-4-methyloxazole, b.p. 130°C./0.7 mm. 2-(N-cyclohexyl-propionamido)-4-methyloxazole, b.p. 10l°C./0.5 mm. 2-(N-ethyl-hexanamido)-4-methyloxazole, b.p. 94-96°C./0.7 mm. 2-(N-butyI-cyclohexanecarboxamido)-4,5-dimethyloxazole, b.p. 122-126°C./0.5 mm. 2-(N-butyl-c.yclopentauecarboxamido)~4,5-dimethyloxazole, b.p. 112-116°C./0.5 mm 2-(N-cyclohoxyl-butyramido)-4-methyloxazole, b.p. 118°C./0.7 mm. 2-(N-butyl-3,4~dichlorobenzarnido)-4-methyloxazol.e, b.p. 162-165°C,/1.0 mm, 2-(N-pentyl-butyramido)-4-methyloxazole, b.p. 98°C./0.8 mm. 2-(N-benzyl-benzamido)-4-methyloxazole, m.p. 62°C. 2-(N-benzyl-valeramido)-4-methyloxazole, b.p. 134°C./0.7 mm. 4,5-Dimethyl~2-(N-methyl-acetamido)oxazole, m.p. 40-42°C. 2-(N-butyl-l-adamantanecarboxamido)-4-methyloxazole, b.p. 160°C./0.3 mm. 2-(N-athyl-2-ethylbutyramido)-4-m£thyloxazole, b.p. 71-2°C./0.3 mm. 2-(N-butyl-4-fluorobenzamido)-4-methyloxazole, b.p. 120-2°C./0.3 mm. 4-metliyl~2-(N-propyl-hexanarnido)oxazole, b.p, 96-8°C./0.4 mm. 4-methyl-2-[N-(l-ethylpropyl)-butanamido]oxazole, b.p, 58-6O°C./O,5 mm. 4-methyl-2-[N-(l-ethylpropyl)-pentanamidoJoxazole, b*p. 91°C./0.5 mm. 2-(N-pentyl-propanamido)-4-metbyloxazole, b.p.68°C./O.O5 mm. 2-(H-pentyl-isobutyramido)-4-methyloxazole, b.p. 86-7°C./0.4 mm. 2-(N-butyl-jsobutyramido)-4-roethylOxazoIe, b.p. 140°C./0.5 mm.* -1843314 .'-(N-lf;opropyl-pc;iit.'inainj.do)-4-tiicthyloxazole, b.p. 77°C./0.3 mm. 2~(N-buLyl-diciil.oroacetamido)-4-niethyloxazole, b.p, 112-4°C./0,8 mra. 2-(N-ji-clilorobenzyl-iaobutyraniido5-4-methyloxazole, b.p. 136°C./0.7 nun. 2-(N-hexyl-propanamido)-4-niethyloxazole, b.p. 1O6-8°C./1.O mm. 2-(N-butyl-chloroacetamido)-4-methyloxazole, b.p. 96-8°C./1.0 mm. 2-(N-butyl-+5obutyramido)-4-methyl-5-hydroxyoxazole f (-) 2-(N-but-2-yl-butanamido)-4-rnethyloxazole, b.p. 86-9°G./1.2 mm. (+) 2-(N-but-2-yl-butauaraido)-4-methyloxazole, b.p. 85-8°C./1.5 mm. 2-(N-butyl-N-isobutyrainido)-4-hydroxymethyloxazole, b.p. 185°C./0,3 mm.* 2-(N-cyclobexyl-isobutanamido)-4-methyloxazole, b.p. 108°C./0.8 mm. 2-(N-benzyl-hexanamido)-4-methyloxazole, b.p. 144°C,/0.6 mm. s 2-(N-butyl-4-chlorobutanamido)~4-methyloxazole, b.p. 124-8°C./1.2 mm. 2-(N-butyl-isobutyramido)-4-j}-chlorophenyloxazole, b.p. 2OO°C./O«5 mm,* 2-(N-butyl-isobutyramido)-5-methyloxazole, b.p. 100°C./0.I mm.* 1- (4-tnethyl-oxazol-2-yl)-2-oxo-hexahydro-lH-azepine, b.p. 130°C./0.1 mm,* 2- (N-cyclopentyl-ΐsobutyramido)-4-methyloxazole, m.p. 73°C.

D(-) 2-(N-butyl-2-methylbutanamido)-4-inethyloxazole, b.p, 88-92°C./0.6 mm. 1(+) 2-(N-butyi~2-methylbutanamido)-4-methyloxazole, b.p, 88-91°C./0.6 mm. 2-(N-butyl-2~methylbutanamido)-4-methyloxazole, b.p, 82-5°C./0,2 mm. 2-N-(butylisobutyramido)-5-phenyloxazole, b.p, 190°C./0.2 mm.* 2-(N-cinnamyl isobutyramido)-4-methyloxazole, b.p. 152-156°C./1.O rani. 2-[n-(4 -methylbenzyl)isobutyramidoj-4-methyloxazole, b.p. 120-4°G./0.3 mm. 2-[N-(3-methylbenzyl)_isobutyrtiinido]-4-methyloxazole, b.p. 118-122°C./0.3 mm, 2-(N-butyl-heptanamido)-4-methyloxazole, b.p. 106-8°C./0.05 mm. 2-(N-butyl-cyclopentylacetamido)-4-methyloxazole, b.p. 124-6°C./0.8 mm. 2-(N-cyclohexylrnethyl-isobutanamido)-4-methyloxazole, b.p, 122-4°C./0.8 turn. 2-rN-(4-mcthoxybenzyl)isobutyraniido l-4-methyloxazole, b.p. 145-8°C./0.4 mm. 2-(N-butyl-cinnamamido)-4-inethyloxazole, b.p. 200°C./0.2 mm. 2-[N-(3-carboxypropyl)octanamido]-4-methyloxazole, b.p. 200°C,/0.2 mm, . 2[N-(3-chloropropyl)pentanamido]-4-methyloxazole, b.p. 118-122°G./0.7 mm. -19<3314 2-|n-(3-chloropropyl)isobutyramido |-4-inethyloxazole, b.p. 99-102°C./0.5 nun. 2-(N~butyl-but-2-enaniido)-4-inethyloxazole, b.p. 15O°C./O.O2 mm. 2-(N-butyl-isobutyramido)-5-ethyloxazole, b.p. 70-72°C./0.2 mm. 2-(N-hutyl-trifluoroacetamido)-4-methyloxazole, b.p. 67-69°C./0.8 mm.

* Temperature recorded in an air-bath. t Boiling point not taken hut 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.

Claims

CLAIMS 4 3 3 1 1

I. A method o£ preparing an oxazole of formula (I) : NR l C0R 2 (I) R' V wherein R 3 is (] alkyl, & alkenyl, & alkoxyalkyl, C 2 _g carboxyalkyl, & haloalkyl, C 3_jq cycloalkyl, C^-lo c y c l° a lkyl-C^_ ( . alkyl, optionally substituted phenyl-C^ alkyl or optionally substituted phenyl-C 2 _ 6 alkenyl; and R is C^_g alkyl, haloalkyl, C 2 _ fi alkenyl, C 3-10 c Y cloalk y 1 > C 3-io c y cloa:Lk y 1-C i_6 a lkyl, optionally substituted phenyl, optionally substituted phenyl-C 1 _ & alkyl or optionally substituted phenyl-C 2 _ 6 alkenyl; or R and R together form a lactam ring having 5 to 7 ring atoms; and wherein R 3 and R 4 are independently selected from hydrogen, formyl, carboxyl, hydroxy, hydroxyalkyl, halogen, G^_ 4 alkyl, C 3-10 cycloalkyl, Cg acyloxyalkyl or an optionally substituted phenyl group; which method comprises reacting a salt of formula (XI) ί MNR 1 C0R 2 (II) 1 2 wherein M is a group IA or IIA metal and wherein R and R are as previously defined, with a 2-oxazolyl derivative of formula (III) : (III) -211 3 4 where L is a leaving group and wherein R and R are as defined above.
2. Λ method according to claim 1, wherein L is a chlorine, bromine or iodine atom or is a group of formula -SOR or SO^R where R is g alkyl, C g _ g cycloalkyl, benzyl or phenyl.
3. A method according to claim 1 or 2, wherein the reaction is effected under anhydrous conditions.
4. A method according to claim 1, wherein R^ is alkyl; 4 alkenyl; C 2 _ 4 alkoxyalkyl; C 2 4 carboxyalkyl; 4 alkyl substituted by a halogen atom; C g g cycloalkyl; C g g cycloalkyImethyl; benzyl optionally substituted by 2 halogen or g alkyl; phenethyl or cinnamyl; and R is g alkyl; alkyl substituted by 1, 2 or 3 halogen atoms; C 2 4 alkenyl; C g cycloalkyl; phenyl optionally substituted by 1 or 2 radicals selected from halogen, g alkyl, C^_ 3 alkoxy, nitro and trifluoromethyl; phenyl C^_ 2 alkyl or phenyl1 2 C 2 alkenyl; or R and R together form a lactam ring having 5 to 7 ring atoms 3 4 and wherein R and R are independently selected from hydrogen, hydroxy, 4 hydroxyalkyl, alkyl, C g g cycloalkyl, C g g acyloxyalkyl and phenyl optionally substituted by a halogen atom; which method comprises reacting under anhydrous conditions a salt of formula (II) 1 2 wherein M is a group IA metal and wherein R and R are as defined above, with a 2-oxazolyl derivative of formula (ill) : ,4 L (III) -2243314 3 4 wherein E and E are as defined above and wherein L is chlorine, bromine or iodine or is a group of formula -SOR or -SO..R, where R is C. o alkyl, C, „ Z 1Ο o cycloaikyl, benzyl or phenyl.
5. 5. A method according to any one of claims 1 to 4, wherein R^ is n-butyl, 2 3 4 t is .i-propyl, R is methyl and R is hydrogen.
6. An oxazole of formula (I) whenever prepared by a method according to my one of claims 1 to 5.
7. A method according to claim 1 substantially as hereinbefore described in any one of Examples 1 to 127.
8. A ccmpound of formula (I) whenever prepared by a method according to j.5 claim 7.