PROCESS FOR PREPARING PYRIDINE DERIVATIVES

Abstract: Fused carbocyclic ring derivatives of pyridine which contain a nitrile or thioamide group on the carbocyclic ring e.g. 8-cyano or thiocarboxamido-5,6,7,8-tetrahydro-­ quinolines are prepared by a process in which a sodium, potassium, lithium or magnesium halide derivative of the pyridine compound is treated with a compound RaRbNCN wherein Ra and Rb are the same or different and represent alkyl, cycloalkyl, or aralkyl, or Ra and Rb are joined to form a heterocyclic ring with the nitrogen, and the product is treated with a proton source to obtain the nitrile which is optionally treated with a sulphurising agent to form the thioamide. The nitriles or thioamides may be isolated as their acid addition salts.

Description: The invention relates to a process for preparing pyridine derivatives which have value as anti-ulcer/ anti-secretory agents. UK Patent Specification 1,432,376 describes fused carbo cyciic ring derivatives of pyridine, for example S- cyano-5,6,7,B-tetrahydroquinolines and the corresponding thiosmides which are either anti-ulcer/anti-secretory agents or intermediates for such agents. Analogous nitriles and thioamides are described in UK Patent Specifications 1,495,993 and 1,458,148. Further examples of such nitriles and thioamides are given in UK Specifications 1,463,668; 1,463,669 and 1,471,371. These specifications describe various ways of making the nitriles and thioamides. However, it has been found that the previously described methods do not always give high yields of the desired end product. We have now found 2 new method for preparing the nitriles and thioamides which is often superior to the previous routes. According to the present invention there is provided a process for preparing compounds of Formula I EMI1.1 or acid addition salts thereof, wherein R1, R2, R3, R4 and R5 are the same or different and represent hydrogen, alkyl, cycloalkyl, alkyl, or aryl radicals, any of which radicals may be substituted or R1 and R2 taken together, or R2 and R3 taken together, form a 5,6, or 7 membered ring which may be saturated or unsaturated and 4 substituted or unsubstituted, R4 and R may also repres- ent alkoxy, n is 1,2 or 3 and X is CN or CSNHR characterised in that a compound of Formula II EMI2.1 wherein Tri, R2, R3, R4, R5 and n are as defined above, and M is lithium, sodium, potassium, or MgHal, where Hal is chlorine, bromine or iodine, is reacted with a compound of Formula RaRbNCS wherein Ra and Rb are the same or different and represent alkyl, cycloalkyl or aralkyl, or Ra and Rb may be joined to form a heterocyclic ring with the nitrogen atom to which they are attached and the product is treated with a proton source to obtain a nitrile of Formula I wherein X is CN and if desired the nitrile is treated with a sulphurising agent to obtain a thioamide of Formula I wherein X is CSNHR where R is hydrogen or lower alkyl and optionally the compound of Formula I is isolated as an acid addition salt. The starting compounds of Formula II may be prepared as discussed in any of the aforementicned prior UK Patent Specifications, or in UK Patent Specifications 1463665 and 1463666. The preferred method for introducing the metal ion M is as described in UK Patent 1463666 namely by reaction of a corresponding compound of Formula II whetein M is hydrogen with a metal alkyl MR6 wherein M is sodiom, potassion or lithium and R6 is alkyl, (e.g. n-butyl), aralkyl or aryl e.g. phenyl or mesityl (2,4,6trimethylphenyl) or with a metal amide MA wherein M is sodium, potassium or lithium and A is an amine radical, preferably a secondary amine. The metal amide may be formed in situ by reacting a metal compound MR6 as defined above with an amine R9R10 NH, wherein R9 and R10 have the same meanings as Ra and Rb, or R9 is hydrogen, preferably in a molar amount equal to that of the metal alkyl.The amine is preferably a secondary amine such as dialkylamine, e.g. diethylamine, di-isopropylamine, di-tbutylamine, di-n-decylamine, dicyclohexylamine, N-t-amyl N-t-butylamine, N-isopropyl-N-cyclohexylamine, N-t-butyl N-cyclohexylamine, N-t-butyl-a-methylbenzylamine or N(1 ethylcyclohexyl)-1,1,3,3,-tetramethylbutylamine or a cyclic amine e.g. piperidine, or an alkyl substituted piperidine 3.g. 2,2,6,6-tetremethylpipezidine. Preforrso amines are hindered amines soch as one in which R9 and R10 are selected from secondary or tertiary radicals or cycloalkyl radicals, especially when R3 is alkyl. When forming the starting compound of Formula II from a corresponding compound in which M is hydrogen the yield may be reduced by competing reactions when R1 or R3 contain exchangeable hydrogen atoms, e.g. when R1 or R3 are alkyl. In such cases a mixture may be formed with the desired compound of Formula II and one ,l which M is hydrogen and there is a metal substituent on R or R3. The reaction with RaRbNCN then produces as impurity 1 3 a cdmpound with the CN group in the radical R1 or R3. The mixture of desired product of Formula I and impurity may be separated by conventional methods, e.g. crystallisation, chromatography, distillation and so on. When competing metallations are liable to occur, it is possible to favour formation of compound II by appropriate choice of reaction conditions and/or reagents. For example when R3 is alkyl it has been found that formation of the compound of Formula II is favoured or exclusive when the starting compound wherein M is hydrogen is added to a solution ofa small excess of the metal alkyl or up to 2.5 molar equivalents of the metalamide, rather than the converse. When an alkyl group R is present in compound II it has been found that the reaction with compound RaRbNCN may still produce some of the "wrong" isomer. The amount of "wrong" isomer can be considerably reduced by adding compound II to a refluxing solution of RaRbNCN instead of the reverse of this procedure. Yields are even higher when metal amide (preferably a molar equivalent of metal amide) is present during the reaction with compound RaRbNCN. If the starting compound II is formed in situ using 2 molar equivalents of metal amide this provides the excess metal amide for use during the reaction with RaRbNCN. It has also been found that when the metalamide is of a hindered secondary amine,e.g.N-t-butyl-N-cyclohexyl- amine, formation of the desired isomer is favoured. The process of the invention is carried out by reacting compound II with RaRbNCN in a suitable solvent e.g. a hydrocarbon solvent such as benzene, toluene or xylene or an ether solvent e.g. ether, tetrahydrofuran or dioxan. The temperature may range from -70 C. to the reflux temperature of the solvent e.g. -200C.to 800C, A mixture of solvents may be used e.g. the compound II may be prepared in situ in a different solvent from that in which the reaction with RaRbNCN takes place e.g. hexane. The compound RaRbNCN may be added to a refluxing solution of compound II or vice versa but it is preferred to add compound II to refluxing RaRbNCN when R3 is lower alkyl in compound II. It is also preferable to keep the reaction time short e.g. up to 3 hours. When any of R1 22 R3, R4 R5, R6, Ra,Rb or R is an alkyl radical, a lower alkyl of 1-6 carbon atoms is preferred. This may be straight or branched chain e.g. methyl, ethyl, n-and iso propyl, n, s- and t-butyl, pentyl or hexyl. When any of.R1JR2,R3,R4,R5, Ra or Rb is a cycloalkyl radical this preferably has from 4 to 6 carbon atoms. When any of R1,R2,R3,R4,R5,R6, Ra or Rb is an aralkyl radical this is preferably aryl lower alkyl in which the lower alkyl portion has 1-6 carbon atoms and may be any of the radicals specified above for a lower alkyl radical. An aryl radical as used herein is preferably phenyl, which may be substituted e.g. by alkyl, alkoxy, fluorine, or trifluoromethyl. The alkyl and alkoxy radicals are preferably lower alkyl as discussed above or lower alkoxy in which the alkyl portion is as described above for a lower alkyl radical. Aralkyl radicals may be substituted on the aryl portion as discussed above for an aryl radical. Any of the alkyl radicals mentioned above may be substituted by alkoxy or trifluoromethyl. The reagent RaRbNCN is preferably dilsopropyl cyanamide but other examples are dimethyl cyaamide, diethyl cyanamide, ditert-butyl cyanamide, dicyclohexyl cyanamide, N-t-butyl N-cyclohexyl cyanamide, 1-cyano-piperidine or 1-cyano 2,2,6,6tetramethylpiperidine. Preferably Ra and Rb are chosen from secondary and tertiary alkyl radicals or cycloalkyl radicals. The product of reaction of RaRbNCN and Compound II is treated with a proton source such as water,e.g. in the form of an aqueous acid or other aqueous medium, an alkanol, e.g. of 1-6 carbon atoms, or ammonium chloride which can be added as a solid or in solution. The nitriles of Formula I may be used either as anti-ulcer/ anti-secretory agents or converted to the corresponding thioamides by treatment with a sulphurising agent e.g. by treat- ment with H2S(optionally in the presence of a lower alkylamine RNH2) or a thioamide R7CSNR2 wherein R7 is an alkyl group in a solvent such as pyridine, a lower alkanol, dioxane, dimethyl formamide, dimethyl sulphoxide, sulpholane. A base such as a trialkylamine may be present. Alternatively the sulphurising agent may be a dithio compound of formola (R8)2 PSSH wherein R8 is alkyl, aralkyl, aryl, alkoxy, aralkoxy or aryloxy which is used in the presence of a hydrogen halide. A thioamide of Formula I wherein X is CSNH2 may be con verted into a thioamide where X is CSNHR by treatment with -a lower alkylamine. The reaction may be carried out with or without an inert solvent, suitable solvents for the reaction with the dithio acid include chlorinated hydro carbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or hydrocarbons such as benzene and toluene. Particularly preferred dithio acids are diethyl dithiophosphate and diphenylphosphinodithioic acid. The nitriles or thioamides may be converted to acid add ition salts with inorganic acids e.g. hydrochloric, hydro bromic, sulphuric or nitric acids or organic acids e.g. citric, fumaric, maleic, or tartaric acids or organic sulphonic acids such as alkyl sulphonic acids e.g. methane sulphonic acid or aryl sulphonic acids e.g. p-toluene sulphonic acid. Preferably the compounds prepared according to the invention have Formula III EMI6.1 wherein R1, ,R2,R3,R4,R5 and X are as defined above. Especially preferred are those compounds obtained from a starting material of Formula IV EMI7.1 wherein M is as defined above. Example 1 5-@yeno-4-methyl-5,6,7,8-tetrahyoroquinoline A sclution of 4-methyl-5,6,7,8-tetrahydronuinoline (79. 5g, 0.5M) in tetrahydrofuren (300 ml) was aoded to a 1.6M solution of butyl lithium in bexane (344ml, 0.56m) maintained at O-C. After 10 min. the resulting red anIon solotion was adoed to a refluxing mixture of diisopropyl cyanamide (94.5g, 0.75 M) in tetrehydrofuren (300ml). The reaction mixture was cooled and poured on to iced water (500ml) neutralised wit 12M hydrochloric acid and the organis solvent removed under reduced pressure. The resioue was adjusted to pH 1 (12M HCl) and extracted witn Ethyl acetate (Zx500ml). The aqueous phase was adjusted to pH 10 (potassium carbonate) and extracted with dichloromethene (3X300ml). The final organic extrects were dried and the solvent removed. The residue was dissolved in methanol an treated with 2n excess of ethereal hydrogen chloride. Removal of the resulting crystals by Filtration gave the title compound as the hydrochloride (73g, 70 ) identical with authentio material. mp 253-5 C. round: 0,63.0, H,6.7; N,13.1, C 11H12N2.HCl reouires C,63.3 ; H, 6.3 ; N, 13.4 %. Example 2 6-Cyano-5,6,7,8-tetrahydroquinoline A solution of 5,6,7,8-tetrahydroquinoline (6,5ml, 50mM) in benzene (35ml) maintained below 100 was treated with 1.6M butyl lithium in hexane (31.25ml, 50mM). The resulting anion solution was heated to reflux then treated with a solution of diisopropyloyanamide (6.3g, 500mM) in benzene (15ml). After 15 min. the mixture was cooled and quenched with water (20ml). The organic phase was separated, driad and evaporated. Distillation of the residue gave the title compound 5,6g, 71%) Bp. 135-1400/2mm, identical with authentic material. Hyarochloride mp 185 C see Exemple 37 Ok catent 1,432,278, Examole 3 8-Cyano-5,6,7,8-tetrehydroquinoline A solution of 5-lithio-4,6,7,5-tetrahydrsquinoline (10mM) was generateo from 5,6,7,8-tetrehydroqcinoline (1.3ml), ether (6ml) and 1.6f1 butyl lithium i-n nexane (6.25 ml), then added to 2 soltion of diisopropylcyanamide (3.9g, 30mM) in ether (Eml) at O C. Work up of the reaction mixture after 15 minutes as described in Example 2 gave the title compound in 85% yield. Example 8-Cyano-3-methy-5,6,7,8-tetrahydroquinoline Following the procedure of Example 1 3-methyl-5,6,7,8- tatrahroroquinoline is treated with butyllithium in nexane and then the reaction mixture is added to a refiuxing solution of diisopropyl cyanamide in tetrahydrfuran. The reaction mixture is treated with water and the title compound isolated as the hydrochloride, after the manner of Example 1, mp 189 0C. Example 5 following the procedure of Example 1 but using alternative starting materials, the following compounds are prepared EMI10.1 <tb> <SEP> Starting <SEP> Material <SEP> RaRbNCN <SEP> Product <tb> a) <SEP> 2-Phenyl-5,6,7,8- <SEP> diisopropyl- <SEP> @-cyano-2-phenyl-5,6,7,8- <tb> <SEP> tetrahydroquinol- <SEP> cyanamide <SEP> tetranydroquinoline <tb> <SEP> ine <tb> b) <SEP> 2-t-Butyl-5,6,7,8- <SEP> diisopropyl- <SEP> 2-t-butyl-8-cyano-5,6,7,8 <tb> <SEP> tetrahydroquinol- <SEP> cyanamide <SEP> tetrahydroquinoline <tb> <SEP> ine <tb> c) <SEP> 2-Methyl-5,6,7,8- <SEP> dicyclohexyl <SEP> 8-cyano-2-methyl-5,6,7,8 <tb> <SEP> tetrahydroquinol- <SEP> cyanamide <SEP> tetrahydroquinoline <tb> <SEP> ine <tb> d) <SEP> sym-Octanydro- <SEP> di-t-butyl- <SEP> 4-cyano-sym-octahydro <tb> <SEP> acridine <SEP> cyanamide <SEP> acridine <tb> e) <SEP> 3,4-Dimethyl-5,6, <SEP> diisopropyl <SEP> 8-cyano-3,4-dimethyl <tb> <SEP> 7,8-tetrahycro- <SEP> cyanamide <SEP> 5,6,7,8-tetrahydro <tb> <SEP> quinoline <SEP> quinoline <tb> f) <SEP> 3,4-Dimethyl-5,6, <SEP> 1-cyano- <SEP> 8-cyano-3,5-dimethyl <tb> <SEP> 7,8-tetrahydro- <SEP> piperidine <SEP> 5,6,7,8-tetrahydro <tb> <SEP> quinoline <SEP> quinoline <tb> g) <SEP> 3,6-Dimethyl-5,6,7, <SEP> diethyl <SEP> 8-cyano-3,6-dimethyl <tb> <SEP> 8-tetrahydro- <SEP> cyanamide <SEP> 5,6,7,8-tetrahydro <tb> <SEP> quinoline <SEP> quinoline <tb> h) <SEP> 1,2,3,4,7,8,9,10- <SEP> diisopropyl <SEP> 4-cyano-1,2,3,4,7,8, <tb> <SEP> Octahydrophen- <SEP> cyanamide <SEP> 9,10-Octahydrophenanth <tb> <SEP> anthridine <SEP> ridine <tb> i) <SEP> 2,3,5,6,7,8- <SEP> dimethyl <SEP> 5-cyano-2,3,5,6,7,8 <tb> <SEP> Hexahydro-1-H- <SEP> cyanamide <SEP> hexahydro-1-H-cyclopenta <tb> <SEP> cyclopenta[b] <SEP> [b]quinoline <tb> <SEP> quinoline <tb> j) <SEP> 3-Methyl-cyclo- <SEP> N-t-butyl, <SEP> N- <SEP> 7-cyano-3-methyl <tb> <SEP> penteno[b] <SEP> cyclohexyl <SEP> cyclopenteno[b] <tb> <SEP> pyridine <SEP> cyanamide <SEP> pyridine <tb> Examole 6 3-methyl-3,6,7,8-tetrahydroquinoline-8-thiocarboxemide A) 8-Cyano-3-methyl-5,6,7,8-tetrahydroquinoline (8.8g,) 50mM) in dichloromethane (50ml) and diethyl dithiopnesphate (9.4ml, 50mM) were treated with HCl gas et reflux. After 2,9 hours reaction mixture was cooled to amoient tamp and ether (2SOml) added. The resulting precipitate was remove= by filtration, washed with ether and recrystallisad from ethenol to give the title compound as the hydrochloride (11.1g, 90%). mp 219 C identical with an authentic sample see Example 18 of U.K. Patent 1432378. B) The above reaction was repeated using dichlorcathane as solvent instead of dichloromethane. The reaction was complete in 1 hour giving the title compound as the hydrochloride in 95 yield. Example 7 4-methyl-5,6,7,8-tetrahydroquinolinoline-8-thiocarboxamide A mixture of 8-cyano-4-methyl-5,6,7,8-tetrahydroquinoline (739, 0.35M), diethyl dithiophcsphat (60ml, 0.36i9) and dichlornethane (350ml) was treated with HCl gas at reflux cver 4 hours. The mixture was ten cooled to ambient temperature, filtered and the product washed with d chloroethane, then recrystallised from methanol - ether to give the title compound as the hydrochloride (74.5g, 68%) mp 2130C identical with an authentic sample - see Example 1 of UK Patent 1463669. Example 8 Following the procedure of Example 6A the nitriles listed in Example 5 are converted to the corresponding thioamides: a) 2-Phenyl-5,6,7,B-tetrahydroquinoline-8-thiocarboxamide. b) 2-t-butyl-5,6,7,5-tetrahydroquinoline-8-thiocarboxamide. c) 2-methyl-5,6,7,8-tetrahydroqu noline-8-thiocarboxamide. d) sym-octahydroacridine-4-thiocarboxamide. 3) 3,4-dimcthyl-5,6,7,8-tetrahydroquinoline-8-thiocarbox amide. f) 3,5-dimethyl-5,6,7,8-tetrahydroquinoline-8-thiocarbox- amide. 9) 3,6-dimethyl-5,6,7,8-tetrahydroquinoline-8-thiocarbox amide. h) 1, 2,3,4,7,8,9,10-octahydrophenanthridine-4-thiocarbox- amide. i) 2,3,5,6,7,8-hexahydro-1-H-cyclopenta [b} quinoline-5 thiocarboxamide. j) 3-methyl-cyclopenteno [b]pyridine-7-thiocarboxamide Examole 9 5,6,7,8-Tetrahydroduinoline-8-thiocarboxamide A mixture of 8-cyano-5,6,7,8-tetrahydroquinoline (5.49, 34mM) dichloromethane (100 ml) and diethyl dithiophosphate (5.75 ml) was maintained at reflux and treated with hydrogen chloride gas. After 8 hours the mixture was cooled to ambient temperature and diluted with ether. The resulting precipitate was washed well with ether and recrystallised from methanol/ether to give the title compound as the hydrochloride (7.09 90%)mp 263 C. Examole 10 8-Cvano-4-methyl-5,67,8-tetrahydrosuinoline A solution of 1.55M butyl lithium in hexane (35.5 mi, 55 mM) maintained at Do to 5 C. under argon was treated successively with N-t-butylcyclohexylamine (4.65 g, 30 mM) and a solution of 4-methyl-5,6,7,8-tetrahydroquinoline (3.67 g, 25 mM) in tetrahydrofuran(10 ml). After 0.5 hours at about 5 C. a solution of di-isopropylcyanamide (3.5 9, 28 mM) was added in tetrahydrofuran (10 ml) and the mixture stirred further 0.5 hours at OOC. The mixture was quenched with water (50 ml), the aqueous layer extracted with toluene (50 ml), the combined organic phases dried and evaporated. Removal of t-butylcyclohexylamine under reduced pressure left an oil which contained (nmr analysis) 89% of the title compound and 11% 4-cyanomethyl-5,6,7,8-tetrahydroquinoline. Poure title compound was isolated by conversion to the hydrochloride in methanol as in Example 1. Examole 11 7-Cvanocyclosentenorbl-ovridine A solution of lithium dilsopropylamide [made ax 1.55M BuLi/hexane (64.5 ml, 0.1 M), diisopropylamine (14ml, 0.1M) tetrahydrofuran (30ml)] maintained at 0 C. under argon was treated with a solution of cyclopenter,o[b] pyridine (5.96 g,SOmM) in tetrahydrofuran (10ml). After 0.5 hours a solution of diisopropylocyanamide (7.0g, 55mM) in tetrahydrofuran (10ml) was added. After a further 0.5 hours the reaction mixture was quenched with water, extracted with toluene, the organic phase washed with water, dried and evaporated. The residus was dissolved in ether/ isopropanol and treated with an excess of ethereal hydrogen chloride. Removal of the resulting precipitate by filtration gave the title compound as the hydrochloride (5.6g)mp 1700C.(sublimes) Example 12 4-Cyeno-1,2.3,4,6,6,7,Boctahydroacridine A solution of lithium diisopropylamide [ex 1.55M BuLi/hexane (32.3ml, 50mM), diisopropylamine (3.5ml, 25mM), tetrahydrofuran (20ml)] maint ained at 0 C. und er an ergon atmosphere was treated with a solution of octahydroacridine (4.689,25mM) in the tetrahydrofuran (10ml). After 0.5 hours a solution of N-t-butyl-N-cyclohexylcyanamide (4.6g, 28mM) in tetrahydrofuran (10ml) was added and the mixture stirred overnight. The reaction was quenched with water, extracted with toluene and the organic phase washed with water, dried and evaporated. The residue, dissolved in ethyl acetate, was passed through a short silica column to yield the title compound. (3,8g) mp. 88-90 C.

Claims: CLAIMS 1. A process for preparing compounds of Formula EMI15.1 or acid addition salts thereof, wherein R1, R2, R3, R4 and R5 are the same or different and represent hydrogen, alkyl, cycloalkyl, aralkyl, or aryl radicals, any of which radicals may be substitoted or R1 and R2 teken together, or R2 and R3 taken together, form a 5, 6 or 7 membared ring which may be saturated or unsaturated and substituted or unsubstituted, R4 and R5 may also represent alkoxy, n is 1, 2 or 3 and X is CN cr CSNHR wherein R is hydrogen or lower alkyl cheracterised in that E compound of Formula II EMI15.2 wherein F?1, R2, R3 R4, R5 and n are as defined above, and @ is lithium, sodium, potassium, or MoHal, where Hal is chlorine, bromine or iodine, is reacted with a compound of formula RaRbNCN wherein Ra and Rb are the sam or different and represent alkyl, cyclo alkyl or aralkyl, or R2 and Rb may be joined to form a heterocyclic ring with the nitrogen and the product is treated with a proton source to obtain a nitrile of Formula I wherein X is CN and if desired the nitrile is treated with a sulphurising agent to obtain a thio amide of Formula I wherein X is CSNHR and optionally the compound of Formula I wherein X is CN or CSNHR is isolated as an acid addition salt. 2. A process as claimed in Claim 1, characterised in that the compound RaRbNCN is one in which Ra and Rb are chosen from secondary and tertiary alkyl radicals and cycloalkyl radicals. 3. A process as claimed in Claim 2, characterised in that the compound RaRbNCN is diisopropylcyanamide or N-t butyl-N-cyclohexylcyanamide. 4. A process as claimed in any one of the preceding claims, characterised in that the reaction of Compound II and RaRbNCN is carried out by adding Compound II to a solution of RaRbNCN, 5. A process as claimed in any one of Claims 1-3, charact erised in that the reaction of Compound II with RaRbNCN is carried out in the presence of a metal amide. 6. A process as claimed in Claim 5, characterised in that the metal amide has Formula MA wherein M is sodium. potassium, or lithium and A is a secondary amine radical -NR9R10 wherein R9 and R10 have the same meanings as Ra and Rb. 7. A process as claimed in Claim 6, characterised in that the compound RaRbNCN is diisopropylcyanamide and the secondary amine radical is N-t-butyl-N cyclohexylamino. 8. A process as claimed in any one of the preceding claims, characterised in that the proton source is water (which may be in the form of an aqueous acid or other aqueous medium), an alkanol of 1-6 carbon atoms, or ammonium chloride. 9. A process as claimed in any one of the preceding claims, characterised in that a nitrile is prepared and treated with a dithiocompound of formula (F?8 )2PSSH wherein F? 8 is alkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, in the presence of a hydrogen halide to obtain a thioamide of Formula I wherein X is CSNH2 and this is isolated as the free base or an acid addition salt thereof. 10. A process as claimed in any one of the preceding claims characterised in that the compound of Formula I which is prepared has the Formula (III) EMI17.1 wherein R1, R2 and R3 are the same or different and represent hydrogen or alkyl of 1 to 6 carbon atoms, R4 and R5 are the same or different and represent hydrogen, lower alkyl of 1 to 6 carbon atoms or lower alkoxy of 1 to 6 carbon atoms and X is CN or CSNH2, in which a compound of Formula III wherein X is M and fez is sodium potassium or lithium is reacted with the compound RaRbNCN, wherein Ra and Rb are as defined in Claim 1, and the product of Formula III is isolated as a free base or an acid addition salt. 11. A process as claimed in Claim 10, characterised in that the starting compound is one in which R1, R2, R4 and R are hydrogen and R3 is lower alkyl. 12. A process as claimed in Claim 12, characterised in that the compound prepared is one in which R3 is methyl. 13. A process as claimed in Claim 10, 11 or 12 chacter ised in that the starting compound of Formula III is prepared by adding a corresponding compound where X is hydrogen to solution of a small excess of a metal alkyl MR6 where R6 is alkyl or aryl and M is sodium, potassium or lithium or to a solution of up to 2.5 molar equivalents of a metal amide MA wherein M is sodium potassium or lithium and A is an amine radical.

Inventors: SHEPHERD, ROBIN GERALD
Applicants: JOHN WYETH & BROTHER LIMITED
Application year: 1981
Main classification: C07D215
IPC codes: C07D219, C07D215, C07D221