GB2088860A

GB2088860A - Process for preparing ring-fused pyridine derivatives

Info

Publication number: GB2088860A
Application number: GB8135212A
Authority: GB
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1980-12-09
Filing date: 1981-11-23
Publication date: 1982-06-16
Also published as: MX5982E; EP0054384B1; GB2088860B; EP0054384A1; DE3164471D1

Description

1 GB 2 088 860 A 1

SPECIFICATION Process for Preparing Pyridine Derivatives

The invention relates to a process for preparing pyridine derivatives which have value as anti ulcer-/anti-secretory agents.

UK Patent Specification 1,432,378 describes fused carbocyclic ring derivatives of pyridine, for 5 example 8-cyano-5,6,7,8-tetrahydroquinolines and the corresponding thioamides which are either anti-ulcer/anti-secretory agents or intermediates for such agents.

Analogous nitriles and thloamides 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 thloamides. 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 a 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 15 Formula I 4 R R2 t Hr R5 X H or acid addition salts thereof, wherein R', R', R', R' and R' are the same or different and represent hydrogen, alkyl, cycloalkyl, aralkyl, or aryl radicals, any of which radicals may be substituted or R' and R 2 taken together, or R' and R' taken together, form a 5, 6, or 7 membered ring which may be saturated or unsaturated and substituted or unsubstituted, R' and R 5 may also represent alkoxy, n is 1, 2 or 3 and X is M or CSHNR characterised in that a compound of Formula 11 4 R 3 R R 2 C H R5 N R M H (11) wherein W, R 2, R', R 4, R' 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 RaRbNCN wherein Ra 25 and Rb are the same or different and represent alky], 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 1 wherein X is M and if desired the nitrile is treated with a sulphurising agent to obtain a thioamide of Formula 1 wherein X is CSNHIR where R is hydrogen or lower alkyl and optionally the compound of Formula 1 is isolated as an acid addition salt. 30 The starting compounds of formula 11 may be prepared as discussed in any of the aforementioned prior UK Patent Specifications, or in UK Patent Specifications 1,463,665 and 1, 463,666. The preferred method for introducing the metal ion M is as described in UK Patent 1,463, 666 namely by reaction of a corresponding compound of Formula 11 wherein M is hydrogen with a metal alkyl MR1 wherein M is sodium, potassium or lithium and R' is alkyl, (e.g. n-butyl), aralkyl or aryl e.g. phenyl or mesityl (2,4,6- 35 tri methyl phenyl) 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 MR1 as defined above with an amine R'R"NH, wherein R' and R") have the same meanings as Ra and Rb, or R' is hydrogen, preferably in a molar amount equal to that of the metal alkyl. The amine is preferably a secondary amine such as a dialkylamine, e.g. diethylamine, di-isopropylamine, cl-tbutylamine, di-n-decylamine, dicyclohexylamine, N-t-a myi-N-t-butyla mine, N-isopropyi-N- cyclohexylamine, N-t-butyl-N cyclohexylamine, N-t-butyl-a-methylbenzyl a mine or N(1 -ethyl cycl ohexyl)- 1 ' 1,3,3 tetra methylbutyla mine or a cyclic amine e.g. piperidine, or an alkyl substituted piperidine e.g. 2,2,6,6 tetramethylpiperidine. Preferred amines are hindered amines such as one in which R9 and R10 are 45 selected from secondary or tertiary radicals or cycloalkyl radicals, especially when R 3 is alkyl.

When forming the starting compound of Formula 11 from a corresponding compound in which M is hydrogen the yield may be reduced by competing reactions when R' or R' contain exchangeable hydrogen atoms, e.g. when R' or R' are alkyl. In such cases a mixture may be formed with the desired compound of Formula 11 and one in which M is hydrogen and there is a metal substituent on R' or R'. 50 The reaction with RaRbNCN then produces as impurity a compound with the M group in the radical R' or R'. The mixture of desired product of Formula 1 and impurity may be separated by conventional methods, e.g. crystallisation, chromatography, distillation and so on. When competing metallations are 2 GB 2 088 860 A 2 liable to occur, it is possible to favour formation of compound 11 by appropriate choice of reaction conditions and/or reagents. For example when R' is alkyl it has been found that formation of the compound of Formula 11 is favoured or exclusive when the starting compound wherein M is hydrogen is added to a solution of a 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 11 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 11 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 11 is 10 formed in situ using 2 molar equivalents of metal amide this provides the excess metal amide for use during the reaction with RaRbNCM It has also been found that when the metal amide is of a hindered secondary amine, e. g. N-t-buty]-N-eyclohexylamine, formation of the desired isomer is favoured.

The process of the invention is carried out by reacting compound 11 with RaRbNCN in a suitable solvent e.g. a hydrogen solvent such as benzene, toluene or xylene or an ether solvent e.g. ether, tetrahydrofuran or dioxan. The temperature may range from -701C. to the reflux temperature of the solvent e.g. -20'C. to 801C. A mixture of solvents may be used e.g. the compound 11 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 11 or vice versa but it is preferred to add compound 11 to refluxing RaRbNCN when R' is lower alkyl in compound 11. It is also 20 preferable to keep the reaction time short e.g. up to 3 hours.

When any of R', R', R 3, R 4, R5, R 6, 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!so propyl, n, s- and t-butyl, pentyl or hexy].

When any of W, R 2, R 3, R 4, R', Ra or Rb is a cycloalkyl radical this preferably has from 4 to 6 25 carbon atoms.

When any of R', R', R3, R 4, R', R, 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, 30 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 prelerably diisopropyl cyanamide but other examples are dimethyl 35 cyanamide, diethyl cyanamide, ditert-butyl cyanamide, dicyclohexyl cyanamide, N-t-butyl-N-cyclohexyl cyanamide, 1 -cyano-piperidine or 1 -cyano 2,2,6,6-tetra methyl pipe ridi ne. Preferably Ra and Rb are chosen from secondary and tertiary alkyl radicals or cycloalkyl radicals. The product of reaction of RaRbNCN and Compound 11 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 40 which can be added as a solid or in solution.

The nitriles of Formula 1 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 treatment with H2S (optionally in the presence of a lower alkylamine RNH2) or a thioamide R'ICSNI-1, wherein R is an alkyl group in a solvent such as pyridine, a lower alkanol, dioxane, dimethyi formamide, dimethyl sulphoxide, 45 sulpholane. A base such as a trialkylamine may be present. Alternatively the sulphurising agent may be a dithio compound of formula (R'), PSSH wherein R' is alkyl, aralkyl, ary], alkoxy, aralkoxy or aryloxy which is used in the presence of a hydrogen halide. A thioamide of Formula 1 wherein X is CSM2 may be converted 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 50 acid include chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or hydrocarbons such as benzene and toluene. Particularly preferred dithio acids are diethyl dithiop hosph ate and diphenylphosphinodithioic acid.

The nitriles or thioamides may be converted to acid addition salts with inorganic acids e.g.

hydrochloric, hydrobromic, 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 111 p4 R3 R2 1 N R' X 1 (111) X Y -11 i 3 GB 2 088 860 A 3 wherein R', R 2, R', R', R' and X are as defined above.

Especially preferred are those compounds obtained from a starting material of Formula IV wherein M is as defined above.

C: ONj 1 F- c M OV) Example 1 8-Cyano-4-methyi-5,6,7,8-tetrahydroquinoline A solution of 4-methyi-5,6,7,8-tetrahydroquinoline (73.5 g, 0.5M) in tetrahydrofurar (300 mi) was added to a 1.6M solution of butyl lithium in hexane (344 m], 0.55M) maintained at OIC. After 10 min. the resulting red anion solution was added to a refluxing mixture of diisopropyl cyanamide (94.5 g, 0.75M) in tetrahydrofuran (300 m]). The reaction mixture was cooled and poured onto iced water (50010 mi) neutralised with 12M hydrochloric acid and the organic solvent removed under reduced pressure. The residue was adjusted to pH 1 (1 2M H131) and extracted with ethyl acetate (2x500 mi). The aqueous phase was adjusted to pH 10 (potassium carbonate) and extracted with dichloromethane (3 x 300 ml). The final organic extracts were dried and the solvent removed. The residue was dissolved in methanol and treated with an excess of ethereal hydrogen chloride. Removal of the resulting crystals 15 by filtration gave the title compound as the hydrochloride (73 g, 70%) identical with authentic material. mp 253-51C. Found: C, 63.0, H, 63; N, 13.1, C,,H,,N2. HCl requires C, 63.3; H, 6.3; N, 13.4%.

Example 2

8-Cyano-5.6,7,8-tetrahydroquinoline A solution of 5,6,7,8-tetrahydroquinoline (6.5 m], 50 mM) in benzene (35 mi) maintained below 20 10' was treated with 1.6 M butyl lithium in hexane (31.25 m], 50. The resulting anion solution was heated to reflux then treated with a solution of diisopropylcyanamide (6.3 g, 50 mM) in benzene (15 mi). After 15 min. the mixture was cooled and quenched with water (20 mi). The organic phase was separated, dried and evaporated. Distillation of the residue gave the title compound (5.6 g, 71 %) bp. 135-1401/2 mm, identical with authentic material. Hydrochloride mp 1185IC-see Example 37 UK Patent 1,432,378.

Example 3

8-Cyano-5.6,7,8-tetrahydroquinoline A solution of 8-lithio-5,6,7,8-tetrahydroquinoline (10 mM) was generated from 5,6,7,8tetrahydroquinoline (1.3 mi), ether (6 m]) and 1.6 M butyl lithium in hexane (6.25 mi), then added to a 30 solution of diisopropylcyanamide (3.9 g, 30 mM) in ether (6 mi) at OOC.

Work up of the reaction mixture after 15 minutes as described in Example 2 gave the title compound in 85% yield.

Example 4

8-Cyano-3-methy]-5,6,7,8-tetrahydroquinoline Following the procedure of Example 1,3-methyl-5,6,7,8-tetrahydroquinoline is treated with butyllithium in hexane and then the reaction mixture is added to a refluxing solution of diisopropyi cyanamide in tetra hydrofu ran. The reaction mixture is treated with water and the title compound isolated as the hydrochloride, after the manner of Example 1, mp 1 891C.

Example 5

Following the procedure of Example 1 but using alternative starting materials, the following compounds are prepared Starting Material RaRbNCN Product a) 2-Phenyl-5,6,7,8 tetrahydroquinoline b) 2-t-Butyl-5,6,7,8tetrahydroquinoline c) 2-Methyi-5,6,7,8- tetrahydroquinoline d) sym-Octahydro acridine diisopropylcyanamide diisopropylcyanamide dicyclohexyl cyanamide di-t-butylcyanamide 8-cyano-2-phenyl-5,6,7,8tetrahydroquinoline 2-t-buty]-8-cyano-5,6,7,8tetra hydroqu inoline 8-cyano-2-methyl-5,6,7,8tetrahydroquinoline 4-eyano-sym-octa hydro acridine 4 GB 2 088 860 A 4 Starting Material RaRbNW Product e) 3,4-Dimethyi-5,6, 7,8-tetrahydroquinoline f) 3,4-Dimethyi-5,6, 7,8-tetrahydro quinoline g) 3,6-Dimethyi-5,6,7, 8-tetrahydro quinoline h) 1,2,3,4,7,8,9,10 Octahydrophen anthridine i) 2,3,5,6,7,8 Hexahydro-1-H cyclopenta[b] quinoline j) 3-Methyl-cyclo penteno[b] pyridine diisopropyl cyanamide 1 -cyanopiperidine diethyl cyanamide diisopropyl cyanamide dimethyl cyanamide N-t-buty], Ncyclohexyl cyanamide 8-cya no-3,4-di m ethyl5,6,7,8-tetra hydroquinoline 8-cya no-3,5-d i methyl5,6,7,8-tetrahydroquinoline 8-cya no-3,6-di methyl5,6,7,8-tetra hydroquinoline 4-cyano-1,2,3,4,7,8, 9,1 O-OctaKydrophenanththridine 5-cyatio-2,3,5,6,7,8hexahydro-1 -H-cyclopenta [blquinoline 7-cya no-3 -methylcyclopenteno[b] pyridine Example 6

3-rnethy]-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide A) 8-Cyano-3-methyi-5,6,7,8tetrahydroquinoline (8.8 g, 50 mM) in dichloromethane (50 ml) and diethyl dithiophosphate (8.4 mi, 50 mM) were treated with HCI gas at reflux. After 2.5 hours reaction mixture was cooled to ambient temp and ether (250 mi) added. The resulting precipitate was 25 removed by filtration, washed with ether and recrystallised from ethanol to give the title compound as the hydrochloride (11.1 g, 90%). mp 2191C identical with an authentic sample-see Example 18 of U.K. Patent 1,432,378.

B) The above reaction was repated using dichloroethane as solvent instead of dichloromethane.

The reaction was complete in 1 hour giving the title compound as the hydrochloride in 95% yield. 30 Example 7

4-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide A mixture of 8-cyano-4-methyl-5,6,7,8-tetrahydroquinoline (73 g, 0.35 M), diethyl dithlophosphate (60 m], 0.36 M) and dichloroethane (350 mi) was treated with HCl gas at reflux over 4 hours. The mixture was then cooled to ambient temperature, filtered and the product washed with 35 dichloroethane, then recrystaffised from methanol-ether to give the title compound as the hydrochloride (74.5 g, 88%) mp 21311C identical with an authentic sample- see Example 1 of UK Patent 1,463,669.

Example 8

Following the procedure of Example 6A the nitriles listed in Example 5 are converted to the 40 corresponding thioamides:

a) 2-Phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide. b) 2-t-butyi-5, 6,7,8-tetrahydroquinoline-8-thiocarboxamide. c) 2-methyl-5,6,7,8tetrahydroquinoline-8-thiocarboxamide. d) sym-octahydroacridine-4thiocarboxamide. e) 3,4-dimethy]-5,6,7,8-tetrahydroquinoline-8thiocarboxamide. f) 3,5-dimethyl-5,6,7,8-tetrahydroquinoline-8thlocarboxamide. g) 3,6-dimethy]-5,6,7,8-tetrahydroquinoline-8thiocarboxamide. h) 1,2,3,4,7,8,9,1 0-octahyd rophena nth ridi ne-4thioca rboxa m ide. i) 2,3,5,6,7,8-hexahydro-1 -H-cyclopenta[blquinoline5-thlocarboxamide. j) 3-methyi-cyclopentano[blpyridine-7-thiocarboxamide Example 9 5,6,7,8-Tetrahydroquinoline-8-thiocarboxamide A mixture of 8-cyano-5,6,7,8-tetrahydroquinoline (5.4 9, 34 mM) dichioromethane (100 mO and 55 diethyl dithiophosphate (5.75 m]) was maintained at reflux and treated with hydrogen chloride gas.

i-- t GB 2 088 860 A 5 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 (7.0 9 90%) mp 2630C.

Example 10 5 8-Cyano-4-methy]-5,6,7.8-tetrahydroquinoline A solution of 1. 55 M butyl lithium in hexane (35.5 mi, 55 mM) maintained at 00 to 5IC under argon was treated successively with N-t-butylcyclohexylamine (4.65 g, 30 mM) and a solution of 4methyi-5,6,7,8-tetrahydroquinoline (3.67 g, 25 mM) in tetrahydrofuran (10 mi). After 0.5 hours at about 51C a solution of di- isopropylcyanamide (3.5 g, 28 mM) was added in tetrahydrofuran (10 mi) and the mixture stirred a further 0.5 hours at OIC. The mixture was quenched with water (50 mi), the 10 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-cyanomethyi-5,6,7,8-tetrahydroquinoline. Pure title compound was isolated by conversion to the hydrochloride in methanol as in Example 1.

Example 11 7-Cyanocyclopenteno[b]-pyridine A solution of lithium diisopropylamide [made ex 1.55 M BuLiMexane (64.5 mi, 0.1 M) diisopropyla mine (14 mi, 0.1 M) tetrahydrofuran (30 m])] maintained at OIC under argon ws treated with a solution of cyclopenteno[b] pyridine (5.96 g, 50 mM) in tetrahydrofuran (10 mi). After 0,5 hours a solution of diisopropylcyanamide (7.0 g, 55 mM) in tetrahydrofuran (10 mi) 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 residue was dissolved in etherPisopropanol and treated with an excess of ethereal hydrogen chloride. Removal of the resulting precipitate by filtration gave the title compound as the hydrochloride (5.6 g) mp 1701C (sublimes).

Example 12

4-Cyano-1,2,3,4,5,6,7,8-octahydroacridine A solution of lithium diisopropylamide [ex 1.55 M BuLi/hexane (32.3 mi, 50 mM), diisopropylamine (3.5 mi, 25 mM), tetrahydrofuran (20 mi)l maintained at OIC under an argon atmosphere was treated with a solution of octahydroacridine (4.68 g, 25 mM) in the tetrahydrofuran (10 mi). After 0.5 hours a solution of N-t-butyi-N-eyclohexylcyanamide (4. 6 g, 28 mM) in tetrahydrofuran (10 mi) 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. (3.8 9) mp. 88-901C.

Claims

Claims 1

A process for preparing compounds of Formula F R2 (CH)n RS 5, H "N R' or acid addition salts thereof, wherein R', R 2, R', R 4 and R 5 are the same or different and represent hydrogen, alkyl, cycloalkyl, aralkyl, or aryl radicals, any of which radicals may be substituted or R' and R 2 taken together, or R 2 and R 3 taken together, form a 5, 6 or 7 membered ring which may be saturated 40 or unsaturated and substituted or unsubstituted, R' and R' may also represent alkoxy, n is 1, 2 or 3 and X is CN or CS1\1HR wherein R is hydrogen or lower alkyl characterised in that a compound of Formula U 4 R 3 R R 2 (CH 1 t"NR M H wherein R', R 2, R 3, R', R' 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 RaRbNCN wherein Ra 45 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 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 GB 2 088 860 A 6 obtain a thioamide of Formula 1 wherein X is CSNHR and optionally the compound of Formula 1 wherein X is CN or CS1\11-1R is isolated as an acid addition salt.
2. A process as claimed in Claim 1, wherein the compound RaRbWN 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, wherein the compound RaRbWN is diisopropylcyanamide or 5 N-t-buty]-N-cyclohexylcyanamide.
4. A process as claimed in any one of the preceding claims wherein the reaction of Compound 11 and RaRbNW is carried out by adding Compound 11 to a solution of RaRbNCN.
5. A process as claimed in any one of Claims 1-3, wherein the reaction of Compound 11 with RaRbWN is carried out in the presence of a metal amide.
6. A process as claimed in Claim 5, wherein the metal amide has Formula MA wherein M is sodium, potassium, or lithium and A is a secondary amine radical -NRIRIO wherein R' and RIO have the same meanings as Ra and Rb.
7. A process as claimed in Claim 6, wherein the compound RaRbWN is diisopropylcyanamide and the secondary amine radical is N-t-butyl-N-cyclohexylarnine.
8. A process as claimed in any one of the preceding claims, wherein 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, wherein a nitrile is prepared and treated with a dithiocompound of formula (R%PSSH wherein R' is alkyl, aralkyl, aryl, alkoxy, aralkoxy, 20 aryloxy, in the presence of a hydrogen halide to obtain a thioamide of formula 1 wherein X is CSNI-1, and this is isolated as the free base or an acid addition salt thereof.
10. A process as claimed in claim 9, wherein the dithiocompound is diethyidithiophosphate.
11. A process as claimed in any one of the preceding claims wherein the compound of formula 1 which is prepared has the formula (111) 4 F R R2 1 R /\ N R1 X [Li (111) wherein 91, R 2 and R 3 are the same or different and represent hydrogen or alkyl of 1 to 6 carbon atoms, R' and R' 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 CSNH,, in which a compound of formula Ill wherein X is M and M is sodium potassium or lithium is reacted with the compound RaRbNW, wherein Ra and Rb. 30 are as defined in Claim 1, and the product of formula lit is isolated as a free base or an acid addition salt.
12. A process as claimed in Claim 11, wherein the starting compound is one in which W, R', R' and R' are hydrogen and R' is lower alky].
13. A process as claimed in Claim 12, wherein the compound prepared is one in which R 3 is 35 methyl.
14. A process as claimed in Claim 11, 12 or 13 wherein the starting compound of formula Ill is prepared by adding a corresponding compound where X is hydrogen to solution of a small excess of a metal alkyl MR' where R' 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 40 amine radical.
15. A process as claimed in Claim 1, substantially as hereinbefore described in any one of Examples 1 to 4 or 5a to 5j.
16. A process as claimed in Claim 1, substantially as hereinbefore described in Examples 10 or 11.
17. A process for preparing thioamides as claimed in in Claim 1, substantially as hereinbefore described with reference to any one of Examples 6A, 6B, 7, 8a to 8j, 9 or 12.
18. A compound of formula 1 whenever prepared by a process as claimed in any one of the preceding claims.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1982. Published by the Patent Office, Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.

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