IL45890A - 2,5-or 2,6-disubstituted benzoxazole derivatives and their preparation - Google Patents

Description

45890/2 n viti n nan ID 11-6, 2 i«-5,2 ^iTttoatersa rmVin Sovel 2,5-or 2 , 6-disubsti ut ed ¾enzoxazol© de;r£vatives aaad their preparation LILLY IUDUS RIIIS LXKITBD This invention relates* to heterocyclic chemical compounds .and more particularly to certain novel derivatives of benzoxazole which are pharmacologically active and/or which may be used as chemical intermediates in preparing compounds possessing pharmacological activity.

The scope of the invention also extends to processes for preparing th« compounds of the invention.

According to the present invention there are provided novel benzoxazole derivatives of the formula: wherein the group -CR R R is in the 5- or 6- position of the benzoxazole nucleus, ^ is a phenyl group optionally substituted in any available position by one or more halogen, C^g alkyl, or C^g alkoxy, R is one of the groups : where R5 and R6 are independently alkyl and R1 and R are independently hydrogen or alkyl; or R3 is a cyano group, or carboxf£?Pa salt thereof or an alkoxycarbonyl group, R1 is hydrogen, halogen or alkyl, and R2 is halogen, hydroxy, alkoxy, alkanoyloxy, - - !fie present invention -Is'o provid n a process fcv "c ri,K- the foreeoing compou ds of formula I which compri: GS cUsi g a compound of the fo mla:- wherein - , . V.' and Z arc respectively the g o s R , R and R- or, independently, m¾y be groups which are respectively convertible to the groups P.1, R~ an '\\J , and either X is hydrogen or the group R^' CO- and Y is H2H- or X is hydrogen and Y is 'the group OG-KII- or lV' CH=N-, the cyclisation being carried out, in the case where X is hydrogen and Y is ^2^~' in ^~ie Proaence °'jF a cyclising agent capable of donating the required group Rf and thereafter where one or more of the groups Y,V In carrying cat the foregoing cyclisation using a compound of formula II in which X is hydrogen and Y is I^N-, it will be appreciated that, if one or more of the groups 7, V/ and Z are also capable of react ing with the cyclising agent used, -the reaction ay produce a mixture of products rather than the desired compound of formula I alone. Although tie undesired products could be separated from the reaction mixture, it is obA-iously desirable to use a compound of formula II in which V, V and Z are groups which are incapable' of reaction with the cyclising agent. Thus, for example, in the case where Z is a group convertible to R , Z is preferably hydrogen or of v halogen and where ?> is one/the groups encompassed by ^, it is pi"eferably a cyanp , group or an esterified carboxy, esterified hydroxymethyl, carbamoyl " . or salnfied carbo x grou .

The cyclisation of a compound of formula II· in which X is hydrogen and Y is K&r CO-FH- or in which X is p' 00- and Y is HgN- niay be carried cut under the influence of heat and/or under acidic conditions, for example in the presence of- hydrochloric, acid or polyp osphoric acid. In the case A where* i\ is hydrogen and Y is Rr CH--- - , cyclisation is easily accomplished by treatment with an oxidising agent such ac lead tetra-acetate or nickel peroxide.

W en a compound of formula II in which X is hydrogen and Y is H li- is used, cyclisation is normally accompli she by mixing the eyelising agent with the compound of formula usually in a suitable solven ..which mav.be water- or an . organic solvent such as pyridine,, at room temperature or below followed by the application of heat to complete the reaction. Examples of suitable cyclising agents which may be used are compounds of the formulae R COOH, (R r COj R4 COOl, R4 C0HH2, R4 C0iiHNH2, R4 CF, R4 C(OR7)=NH and R4 CC1=KR7 where R7 is C,_4 alkyl. above, when As stated /one or more of the groups V, W and Z are not 1 2 "5 the groups R , R and R respectively, completion of the cyclisation step must be followed by conversion to the 1 2 "5 desired groups R , R and/or R . As is well known in the art, many different types of groups may be converted to the 1 2 3 R , R and R functions in the desired compounds of this invention. However, it is preferred for the purposes of tl present invention that, where Z is not the group R , it is hydrogen or halogen. When Z is hydrogen, the compound resulting from he cyclisat on reaction may be halogenated in conventional manner, for example usi g chlorine, sulphuryljchloi'idc , bromine or -'bromosuccini ide, preferably in the presence of a suitable solvent such as carbon tetrachloride, to produce the corresponding compound in wbicl Z is halogen. This compound , or the. same compound obtained reacted with an alkali metal cyanide in a suitable 'diluent or solvent, usually under he' influence of beat, to produc compound of formula 1 in which R is Cft.

The latter compound, or the same compound obtained directly from the above cyclisation reaction, may then be treated in a number of wa s to achieve its conversion to another compound of formula I.. For example, the nitrile may then be -reacted with ammonium azide, which is preferably formed in situ in the reaction medium, to xjroduce a compound of the present invention wherein R is a tetrazolyl group..

Alternatively the nitrile may be reacted with an appropriate alcohol under acidic conditions to produce a compound of formula. I in which R is an esterified carboxy group.

Alternatively, the nitrile can be hydrclysed, for example using sulphuric acid, to produce a compound of formula I in which R · is a carbamoyl/ group. Hydrolysis of the nitrile , or the last mentioned carbamoyl, with a strong base or an acid such as concentrated hydrochloric acid results in the formation of a compound of formula I in which R is a carboxy group. This compound may be reacted with ethanolamine or an alkyl or hydrox alk l derivative thereof to produce a compound of the invention in which R is an cxaaolinyl or substituted oxaaolinyl group.

An acid of formula I may be salified by treatment with ai appropriate base such as an ammonium, alkylam onium, aralkylammonium, aluminium, alkali metal or alkaline earth metal hydroxide and of course a salt of formula I may readily be converted to the free acid by treatment with an acid such ε hydrochloric or sulphuric acid. An acid of formula I or a salt thereof may be converted to an este3? by treatment with course be hydrolysed to the corresponding acid of formula I by treatment with a suitable hydrolytic agent such as an inorganic base or acid.

A resultant compound./ of formula I in which R^" 2 and/or R is hydrogen may be alkylated to produce the corresponding compound of formula I in which and/or 2 R is C, , alkyl. The alkylation may be carried out 1— by interaction of an alkali metal derivative of the appropriate benzoxazole derivative with an alkyl halide such as, for example, methyl or ethyl iodide.

Compounds of formula I in which R^ is hydrogen 2 or halogen and R is halogen may, for example, be prepared by reaction of the corresponding compounds in 1 2 which R and R both represent hydrogen with an appropriate halogenating agent, for example N-bromo^-succinimide. Compounds of formula I in which R^" is 2 hydrogen and R is halogen may thereafter, for example, be reacted with an alcohol to produce the corresponding 2 compound in which R is alkoxy or may be hydrolysed to the corresponding hydroxy compound. Compounds of 2 formula I in which R is alkylamino may, for example, be prepared from the corresponding compound of formula I 2 3 in which R is hydrogen, when R is, for example, a cyano group, by reaction with the corresponding amine. The hydroxy and amino derivatives may subsequently be acylated In a situation where it may prove difficult by the above route to produce a compound of formula I in which 4 1 2 3 both the group R and the group -CR R R have the desired 4 meanings, a compound of formula I in which group R is not the desired group may be prepared, the oxazole ring in the and Y is Η_Ν-, for example by cleavage with concentrated , „ hydrochloric acid at a temperature of around 150oC. , and the resultant compound of formula II is re-cyclised in the presence of a cyclising agent which will donate 4 the required group R .

Compounds of formula I in which is hydrogen or 2 C^_g alkyl, R is halogen, hydroxy, or ¾1^¾ηοΥΐ°χΥ and R3 is a cyano group, carboxy group or a salt thereof or an alkoxycarbonyl group, are useful intermediates not only in the preparation of pharmaceutically active compounds of formula I as defined herein but also in the preparation of the 2-phenyl benzoxazole derivatives described and claimed in Belgian Patent Specification No. 799,790. that It will be understood/the scope of the invention extends not only to an overall process for preparing the novel compounds of the invention as described hereinbefore but also to the individual synthetic steps as herein described,—and combinations—of two .ox more_ of__s.uch synthetic steps.

Compounds for formula I have been shown to have low toxicity and to possess analgesic, antipyretic and/or anti-inflammatory activity; or as stated above have been found useful as intermediates in the preparation of such compounds .

The foregoing activities have been demonstrated in tests carried out in animals usually at doses of from 0.1 to 250 mg/kg. In the treatment of humans, the dose administered may be, for example, between 0.1 and 25 mg./kg but, of course, doses outside this range may be used at the discretion of the physician treating the patent. for this purpose they will normally be formulated into ^ pharmaceutical compositions comprising the active ingredient in association with at least one pharmaceutically acceptable carrier therefor. Such compositions will normally consist of the active ingredient mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by a carrier in the form of a capsule, sachet, cachet or other container. The carrier may be a solid, semi-solid or liquid material-. hich, serves as - _^ a vehicle, excipient, coating agent, or medium for the active ingredient. Some examples of the carriers which may be used are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, methylcellulose , polyoxyethylene sorbitan monolaurate, methyl- or propyl- hydroxybenzoate , ethyl cellulose acetate phthalate, low viscosity acetyl-cellulose acetate, paraffin wax, mineral wax, vegetable wax, vegetable gum, silicone rubbers such as liquid poly-dimethylsiloxane rubber, plasticised or unplasticised polyvinyl chloride, plasticised polyethylene terephthalate , modified collagen, cross- linked hydrophilic polyether gel, cross-linked polyvinyl alcohol or cross-linked partially hydrolysed polyvinyl acetate.

Advantageously the compositions are formulated in a dosage unit form containing from 1 to 1000 mg. (preferably 25 to 500 mg.) of the active ingredient. Examples of suitable dosage unit forms are tablets, hard or soft gelatin capsules, microcapsules and suppositories as well as drug dispensing systems comprising the active ingredient contained in a flexible, imperforate polymeric material through which the term "dosage unit form" as used herein means a physically discrete unit containing the active ingredient, generally in admixture with and/or enclosed by a pharmaceutical carrier, the quantity of active ingredient being such that one or more units are normally required for "a single therapeutic administration.

In addition to the active ingredient of formula I, the compositions may also contain one or more pharmacologically active ingredients, for example, acetyl-salicyclic acid and salts thereof, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and indomethacin.

The compositions will of course be adapted to the particular route of administration. Thus, for oral administration, tablets, pills, capsules, solutions or suspensions may be used; for parenteral administration, sterile injection solutions or suspensions may be used; for rectal administration, suppositories may be used; and for topical administration, creams, lotions or ointments may be used. Any οί' the foregoing composi ions may, of course, be formulate c in delayed or sustained release form in a manner well known in the art.

Examples of the novel benzoxazole derivatives of the present invention are as follows : - 2~ -Chlorophenyl-5~/j ' -( 5"~tetrazolyl)ethyl/benzoxazole; 2»j2-Chlorophenyl-5-ZT,-(4" , ,,~dimethyl~2,,-oxazolin-2,,-yl)- ethyl/benzoxazo 1e ; Ethyl 2-bromo~2~(jj-chloroplienyl~5-benzox:azolyl )acetate ; Ethyl 2 , 2~dib'romo-2- (j2-chlorophenyl-5-benzoxazolyl )acetate Methyl 2-methox37"--2~(_p-chlorophenyl~5-benzoxazolyl) acetate ; 2-Methylamino-2-( 2-O-chlorophenyl~5~benzoxazolyl ) "* propionitrile; 2-Methylamino-2- ( 2-_p_~chlorophenyl-5~bensoxazolyl)"" propionic- acid; 2-( N-Acetyl-^-methylamin()-2-( 2-p~chlorophenyl-5-benzoxazole)"" propionic acid; 2-Hydroxy-2-( 2-p-chiorophenyl-5-benzo azoly1) propionic acid# and the corresponding 6-benzoxazolyl compounds,, C. il our nyl .

EXAMPLE 2 -ChlorophenyL-5-[l*-( ",4"-dimethyL-2"-oxazolin-2"-yl)ethyl-] benzoxazole A solution of 2»( 2' -£-chlorophenyl-5 ' -benzoxazolyl) propionitrile (prepared as described in Example l) (28.3 g; 0.1 mole) in concentrated hydrochloric acid (220 ml.) was re.fluxed for 2.5 hours. The mixture was poured into ice/water (1 litre). The precipitated 2-(2'-£-chlorophenyl-5' benzoxazolyl) ropionic acid was filtered off and washed with water. The dry acid weighed 25 g.

Analysis: C, 63.68; H, 4.00; N, 4.64; Found: C, 63.50; H, 4.16; N, 4.72.

A mixture of 2-( 2' -j>-chlorophenyl-5' -benzoxazolyl) ropionic acid (3.5 gm. ) , 2-amino-2-methylpropanol (1.3 ml.) and xylene (70 ml.) was heated using a Dean and Stark apparatus to collect the water formed. Afte 24 hours, the solution was evaporated to dryness and the residue was crystallised from toluene to yield the title compound.

Similarly prepared were: (b) 2-phenyl-5-[l,-(4",4"-dimethyl-2"-oxazolin-2"-yl)ethyl]benzoxazole. (c) 2-(2,4-dichlorophenyl)-5-[ll-(4",4"-dimethyl-2"-oxazolin-2"-yl) ethyl]benzoxazole. (d) 2-£-fluorophenyl-5-[l,-(4",4"-dimethyl-2"-oxazolin-2"-yl)ethyl] benzoxazole. (e) 2-£-methylphenyl-5-[l'-(4",4"-dimethyl-2"-oxazolin-2"-yl)ethyl] benzoxazole. (f) 2-£-methoxyphenyl-5-[l,-(4",4"-dimethyl-2"-oxazolin-2"-yl)ethyl] benzoxazole.

The compounds in Examples (b) to (f) above were characterised by a combination of thin-layer chromatography and C,H,N microanalysis. im (2.4 g.), m.p. 81-82°C.

Analysis: C -,Η QBrClN03 Calculated: C, 51.73; H, 3.31; N, 3.54; Br, 20,25 Found: C, 51.45; H, 3.29; N, 3.50; Br, 20.46 Similarly prepar^ and characterised were: (b) Ethyl 2-bromo-2-(phenyl-5-benzoxazolyl)acetate. (c) Ethyl 2-bromo-2-(_p_-fluorophenyl-5-benzoxazolyl)acetate. (d) Ethyl 2-bromo-2-( 2, 4-dichlorophenyl-5-benzoxazolyl) acetate, (e) Ethyl 2-bromo-2-(£-methoxyphenyl-5-benzoxazolyl)acetate. (f) Ethyl 2-bromo-2-(£-methylphenyl-5-benzoxazolyl) acetate EXAMPLE 4 (a) Ethyl 2, 2-dibromo-2-( p-chlorophenyl-5-benzoxazolyl) acetate The bromo compound (3.16 g.) from Example 3 was suspended together with N-bromosuccinimide (2.86 g.) and a-azoisobutyronitrile (approx. 20 mg.) in dry carbon tetrachloride (4.5 ml.) and refluxed under U.V. light for 66 hours. After cooling to room temperature and filtering to remove undissolved solids, the carbon tetrachloride solution was evaporated to leave a gum which solidified. The MR spectrum of the solid showed that it was the required product.

Similarly prepared and characterised were: (b) Ethyl 2, 2-dibromo-2-(phenyl-5-benzoxazolyl)acetate. (c) Ethyl 2, 2-dibromo-2-(_p_-fluorophenyl-5~benzoxazolyl)acetate. (d) Ethyl 2, 2-dibromo-2-(2,4-dichlorophenyl-5-benzoxazolyl)acetate. (e) Ethyl 2, 2-dibromo-2-(_p_-methoxyphenyl-5-benzoxazolyl)acetate. (f) Ethyl 2, 2-dibromo-2-(jv-methylphenyl-5-benzoxazolyl) acetate EXAMPLE 5 (a) Methyl 2-methoxy-2-(p-chlorophenyl-5-benzoxazolyl) acetate Sodium (0.23 g.) was dissolved in dry methanol (60 ml.) and this solution added to ethyl 2~bromo-2-(.£-chlorophenyl-5~benzoxazolyl) acetate 2.8 .). The resultin solution was stirred for 68 hours at room The oil was stirred in water (50 ml.) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting suspension was extracted with ether (3 x 75 ml.). The extracts were combined and washed with saturated sodium bisulphite solution (3 x 25 ml.). After drying (N^SO^), the ether solution was evaporated to leave a gummy solid (2.15 g.). 1 Gram was purified by chromatography to yield a waxy solid (0.4 g.), which was subsequently recrystallised from carbon tetrachloride and 40-60° petroleum ether. The resulting solid was the required product, m.p. 100-105°C.

Similarly prepared and characterised by C, H and N microanalysis were: (b) Methyl 2-methoxy-2-(phenyl-5-benzoxazolyl)acetate (c) Methyl 2-ethoxy-2-(j -fluorophenyl-5-benzoxazolyl) acetate (d) Methyl 2-methoxy-2-( 2, -dichlorophenyl-5-benzoxazolyl)acetate (e) Methyl 2-methoxy-2-(p_-methoxyphenyl-5-benzoxazolyl) acetate (f) Methyl 2-methoxy-2-(p_-methylphenyl-5-benzoxazolyl)acetate EXAMPLE 6 ( a) 2-Methylamino-2-( 2-p-chlorophenyl-5-benzoxazolyl)propionitrile 2-(2l"£-Chlorophenyl-5-benzoxazolyl)propionitrile (5 g.) and a 337» solution of methylamine in ethanol (50 ml.) under reflux for 24 hours gave the expected methylamino compound as an oil. The structure of this product was confirmed by thin- layer chromatography.

The following nitrxles were similarly prepared and characterised by thin-layer chromatography. (b) 2-Methylamino-2-( 2-£-fluorophenyl-5-benzoxazolyl) ropionitrile. ( c) 2-Methylamino-2-( 2-phenyl-5-benzoxazolyl) propionitrile ( d) 2-Methylamino-2-[2-( 2, -dichlorophenyl) -5-benzoxazolyl]propionitrile EXAMPLE 7 (a) 2-Hethylamirib-2-( 2- p-chloropheny1-5-benzoxazolyl) ropionic acid The nitrile of Example 6 (a) (2.0 g.) and concentrated hydrochloric acid (20 ml.) were heated under reflux for 3 hours. The cooled solution was treated with 50% NaOH solution until the pH was 5. This yielded the expected acid which was pure by thin layer chromatography.

Similarly, the following acids were prepared by hydrolysis of the nitriles formed in Examples 6(b) to (d) and characterised by thin-layer chromatography. (b) 2-Kethylamino- 2-( 2-£-fluorophenyl-5-benzoxazolyl) pro ionic acid. (c) 2-Methylamino-2-( 2-phenyl-5-benzoxazolyl) propionic acid. (d) 2-Methylamino-2-[2-( 2, -dichlorophenyl) -5-benzoxazolyl]propionic acid.

EXAMPLE 8 (a) 2—( N-Acetyl-N-me thyla ino-2)-(2-p-chlorophenyl-5-benzoxazolyl) propionic aci The acid (1 g.) of Example 7(a) and acetic anhydride (10 ml.) were heated under reflux for 1 hour and the excess of anhydride was evaporated off under reduced pressure. Recrystallisation of the solid from ethanol gave the required N-acetyl compound. Thin-layer chromatography was in agreement with the expected structure.

Similarly, the following N-acylated compounds were prepared and characterised by C, H and N microanalysis: (b) 2-(N-acetyl-N-methylamino)-2-( 2-£-fluorophen l-5-benzoxazolyl) propionic acid. (c) 2-(N-acetyl-N-methylaminc)-2-( 2-phenyl-5-benzoxazolyl)propionic acid. (d) 2-(N-acetyl-N-nethylaming-2-[2-( 2,4-dichlorophenyl)-5-benzoxazolyl] propionic acid.

EXAMPLE 9 (a) 2-Hydroxy-2-( 2- -chlorophen 1-5-benzoxazolyl) acetic acid Reaction of ethyl 2-bromo-2(jp_-chlorophenyl-5-benzoxazolyl)acetate with sodium hydroxide solution gave the expected hydroxy-acid. Formation Similarly, the following 2-hydroxy compounds were prepared and characterised: (b) 2-hydroxy-2-( 2-j>-fluorophenyl-5-benzoxazolyl) acetic acid. (c) 2-hydroxy-2-( 2-£=chlorophenyl-5-benzoxazolyl)propionic acid (d) 2-hydroxy-2-[2-(2,4-dichlorophenyl)-5-benzoxazolyl]propionic acid (e) 2-hydroxy-2-( 2-phenyl-5-benzoxazolyl) propionic acid. (f) 2-hydroxy-2-( 2-phenyl-5-benzoxazolyl)acetic acid. (g) 2-hydroxy-2-[2-( 2,4-dichlorophenyl)-5-benzoxazolyl]propionic acid.

EXAMPLE 10 (a) 2-p-chlorophenyl-6-benzoxazolylcarboxaldehyde cyanohydrin A suspension of N-bromosuccinimide (40 g.) in a solution of 2-£-chlorophenyl-6-methylbenzoxazole (50 g.) in carbon tetrachloride (65 ml.) was heated under reflux in the presence of O.V. radiation, for 2 hours. The solution was filtered and evaporated to dryness. The residue was crystallised from carbon tetrachloride to give 2- -chlorophenyl-6-benxozazolyl^thyl bromide A mixture of this compound (65 g.), hexamine (20 g.), acetic acid (250 ml.) and water (250 ml.) was heated under reflux for 3 hours.

Concentrated hydrochloric acid (250 ml.) was added and reflixing continued for 1 hour. After cooling, the solid was filtered off and recrystallised to give 2-£-chlorophenyl-6-benzoxazolylcarboxaldehyde, m.pt. 153°C.

Analysis: Found: C, 65.6; H, 3.2; N, 5.6; CI, 14.0.

C1 HgClN02 requires: C, 65.3; H 3.1; N, 5.4; CI, 13.87.

A saturated solution of sodium metabisulphite in water (27.5 ml.) was steadily added to a stirred suspension of 2-£-chlorophenyl-6-benzoxazolylcarboxaldehyde (25 g.) in a solution of sodium cyanide (5 g.) in water (200 ml). After stirring for three hours the solid was filtered off and recrystallised from ethyl" acetate to yield 2-£-chlorophenyl-6-benzoxazolylcarboxaldehyde cyanohydrin, m.p. 178 C.

Analysis: Found; C, 63.3; H, 3.4; N, 9.6; CI, 12.7.

Similarly, the following cyanohydrins were prepared and characterised by C, H, N microanalysis: (b) 2-£-fluorophenyl-6-benzoxazolylcarboxaldehyde cyanohydrin. (c) 2-_p_-chlorophenyl-5-benzoxazolylcarboxaldehyde cyanohydrin. (d) 2-phenyl-5-benzoxazolylcarboxaldehyde cyanohydrin. (e) 2-( 2,4-dichlorophenyl)-5-benzoxazolylcarboxaldehyde cyanohydrin.

EXAMPLE 11 (a) 2-p-Chlorophenyl-6-benzoxazolylglycolic acid A solution of 2-£-chlorophenyl-6-benzoxazolylcarboxaldehyde cyanohydrin (20 g.) in concentrated hydrochloric acid (200 ml.) was heated on a steam bath for 1 hour. The solid produced on dilution with water was crystallised from acetic acid to give 2-£-chlorophenyl-6-benzoxazolylglycolic acid, m.p. 222-4 C.

Analysis: Found; C, 59.6; H, 3.6; N, 4.7; CI, 12.0 C15H10C1 04 requires, C, 59.3; H, 3.3; N, 4.6; CI, 11.77.

The cyanohydrins of Examples 10(b) to (e) were similarly hydrolysed to yield: (b) 2-jp_-fluorophenyl-6-benzoxazolylgycolic acid. (c) 2-£-chlorophenyl-5-benzoxazolylglycolic acid. (d) 2-phenyl-5-benzoxazolylglycolic acid. (e) 2-(2,4-dichlorophenyl)-5-benzoxazolylglycolic acid.

C,H,N Microanalysis carried out on the above acids was in full agreement with their expected structures.

EXAMPLE 12 (a) Methyl-2-p-chlorophenyl-a -methoxy-6-benzoxazolylacetate A mixture of 2-£-chlorophenyl-6-benzoxazolylglycolic acid (4.4 g.), silver oxide (6.6g.) and methanol (60 ml.) was stirred for sixteen hours. The solution was filtered and evaporated to dryness. The residue was crystallised from carbon tetrachloride to yield methyl 2rp_-chlorophenyl-oc-methox -6-benzoxazol lacetate m. . 131-.2°C.

Analysis: Found, C, 61.3; H, 4.5; N, 4.1, CI, 10.8.

C17H14C1K0 requires C, 61.5; H, 4.3; N, 4.2; CI, 10.77.

Similarly prepared (and characterised by microanalysis) were the following (X-methoxy compounds: ( b) Methyl 2-£-chlorophcnyl-a-methoxy-5-benzoxazolylace ate. (c) Methyl 2-( 2, -dichlorophenyl) -a-methoxy-5-benzoxazolylacetate.

EXAMPLE 13 ( a) 2-p-chlorophenyl-a-me thoxy-6-henzoxazolylacetlc acid Methyl 2->p_-chlorophenyl-a-methoxy-6-benzoxazolyl-acetate (4.0 g.) was dissolved in dioxan (50 ml.) and a solution of sodium hydroxide (0.7g) in water was added. The solution was stirred for three hours then evaporated to dryness. The residue was stirred with dilute hydrochloric acid for thirty minutes. The solid was filtered off and recrystallised from water-ethanol to give 2-£-chlorophenyl-oc-methoxy-6-benzoxazolylacetic acid, m.pt. 164-6 C.

Analysis: Found, C, 60.3; H, 3.9; N, 4.6; CI, 11.0.

C16H12C1N04 recJuires» C» 60'55 H» 3·8' N> ' » C1» l' 2'l" Similarly, the esters of Examples 12(b) and (c) were hydrolysed to yield: (b) 2-j>-chlorophenyl-o:-methoxy-5-benzoxazolyl^acetic acid. (c) 2-( 2,4-dichlorophenyl)-cc-methoxy-5-benzoxazolyl^,acetic acid.

Thin-layer chromatography was in full agreement with the expected structures of the acids. 458902 EXAMPLE 14 o Acetoxy-2-p-chlorophenyl-5-benzoxazolylacetic acid A mixture of 2-£-chlorophenyl-5-benzoxazolylglycolic acid ( g.) and acetyl chloride (50 ml.) was heated under reflux for 24 hours. The residue on evaporation was crystallised to give pure oc-acetoxy-2-chlorophenyl-5-benzoxazol lacetic acid.

Claims (14)

1. CLAIMS 45890/3 1. A process of preparing ,a benzoxazole derivative of fonnula I: wherein the group -CR R R is in the 5- or 6- position of the benzoxazole nucleus, R is a phenyl group optionally substituted in any available position by one or more halogen, alkyl or 3 alkoxy, R is one of the groups where R and R are independently C1_6 alkyl, and R and R are independently hydrogen or is a cyano group, or carboxy group or a salt thereof, or an alkoxycarbonyl 1 2 group, R is hydrogen, halogen or C^_g alkyl, and R is halogen, hydroxy, C^_g alkoxy, C2-7 alkanoxyloxy , C^_g alkylamino, C^_-j alkanoylamino or N~(cj^_g alkyl) -N- (02_^ alkanoyl ) amino which process comprises cyclising a compound of the formula 45890/3 wherein V, W and Z are respectively the groups R , R and R or, independently, 1 2 3 may be groups which are. respectively convertible to the groups R , R and R ,^' 4 and either X is hydrogen or the group R CO- and Y is H^ - or X is hydrogen 4 4 ' . and Y is the group R CO-NH- or R . CH=N-, the cyclisation being carried out, in the case where X is hydrogen and Y is H^N-, in the presence of a cyclising agent capable of donating the required group R and thereafter where one or more of the groups Vr W and Z in the resultant compound are not the same 1 2 3 groups R , R and R , respectively, converting the said V, W and Z groups to 1 2 3 the groups R , R and R in conventional manrier. 1 2

2. A process according to claim 1, wherein V and W are R and R respectively. 3

3. A process according to claim 1 or 2, wherein Z is R .

4. A process according to claim 3, wherein R1 is hydrogen 2 or C1_6 alkyl, R is halogen, hydroxy or C2_? alkanoyloxy and 3 R is a cyano group or carboxy group or a salt thereof or an alkoxycarbonyl group.

5. A process according to any one of claims 1 to 4 wherein 4 R is phenyl or halophenyl.

6. A process for prep ring a compound of formula I substantially as hereinbefore described with reference to any one of the foregoing Examples. of formula τ in Claim χ

7. A 5- or 6- substituted benzoxazole/ hene er prepared by a process according to any of claims 1 to 6.

8. An intermediate useful for the preparation of biologically active 5- or 6- substituted benzoxazoles and characterised by the structure : wherein the group -CRW is in the 5- or 6- osition o 45890/3 position by one or more halogen, <^_6 alkyl, or C1_g alkoxy; R is a cyano group, carboxy group or a salt thereof,- or an alkoxycarbonyl group, R1 is hydrogen or C, g alkyl, and R2 is halogen, hydroxy or alkanoyloxy.

9.. An intermediate as claimed in claim 8, wherein R1 is hydrogen or methyl.

10. An intermediate as claimed in claim 8 or 9, wherein 4 R is phenyl or halophenyl.

11. A benzoxazole derivative of the formula wherein the group -CR½2R3 is in the 5- or 6- position of the benzoxazole nucleus, R is a phenyl group optionally substituted in any available position by one or more halogen, g alkyl, or g alkoxy, 3 . R is one of the groups : H where R5 and R are independently <^_6 alkyl and R and R 3 . are independently hydrogen or C-^g alkyl; or R xs a cyano group group, or carboxy /or a salt thereof or an alkoxycarbonyl group, R1 is hydrogen/ halogen or <^_6 alkyl, and R is halogen, hydroxy, C^g alkoxy, C2_? alkanoyloxy, Οχ_6 45890/2

12. A compound of formula I as claimed in Claim 11, 3 wherein R is a carboxylic acid group.

13. A compound of formula I as claimed in Olaim 11 or 12, 4 wherein R is phenyl or halo-substituted phenyl.

14. A compound of formula I substantially as hereinbefore described with reference to any one of the foregoing Examples. PC:mz