GB2116553A

GB2116553A - Preparation of nitriles and thioamides of fused ring pyridine derivatives

Info

Publication number: GB2116553A
Application number: GB08306456A
Authority: GB
Inventors: Robin Gerald Shepherd
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1982-03-11
Filing date: 1983-03-09
Publication date: 1983-09-28
Also published as: GB2116553B; GB8306456D0

Abstract

Nitriles and thiomides of fused ring pyridine compounds such as 5,6,7,8-tetrahydroquinolines are prepared from metal derivatives of the starting compounds (such as 8-lithio- 5,6,7,8-tetrahydroquinolines) which have been prepared by treating the starting compounds (e.g. 5,6,7,8- tetrahydroquinoline) with a metal amide prepared in situ from a metal alkyl and an N-benzylidine-N- alkylamine.

Description

SPECIFICATION Preparation of nitriles and thioamides of fused ring pyridine derivatives The invention relates to an improved method for preparing nitriles and thioamides of fused ring pyridine compounds such as those described in UK Patent No. 1432378. The method is an improvement on that described in UK Patent Application 8135212 (Serial No. 2088860A).

The nitriles and thioamides are anti-ulcer agents.

In UK Patent Application Serial No. 2088860A there is described a method of preparing nitriles and thioamides of fused ring pyridine compounds, such as 5,6,7,8-tetrahydroquinolines in which a metal derivative of the starting fused ring pyridine compound, such as an 8-lithio-5,6,7,8-tetrahydroquinoline, is treated with a dialkylcyanamide followed by treatment of the product with a proton source. The starting metal compound may be formed in situ by reaction of a 5,6,7,8-tetrahydroquinoline compound with a metal amide especially one derived from a hindered amine. We have now found that if the metal derivative of the tetrahydroquinoline is prepared using particular metal am ides, which are conveniently prepared in situ in a particular way, then very good yields of the nitrile are obtained.

Accordingly the method of the invention comprises in one aspect a method of preparing nitriles of formula I

or acid addition salts thereof, wherein R", R12, R13, R14 and R15 are the same or different and represent hydrogen, alkyl of 1-6 carbon atoms, cycioalkyl of 4-6 carbon atoms, aralkyl of 7-12 carbon atoms or aryl radicals, any of which radicals may be substituted or R11 and R12 taken together, or R12 and R13 taken together, form a 5, 6 or 7 membered ring which may be saturated or unsaturated and substituted or unsubstituted, R14 and R15 may also represent alkoxy of 1-6 carbon atoms, n is 1,2 or 3, in which a compound of formula II

where R' is hydrogen, aryl or a tertiary alkyl group of 4 to 6 carbon atoms;R2 is aryl or a tertiary alkyl group of 4 to 6 carbon atoms; R3 is a branched chain alkyl of 3 to 6 carbon atoms; is reacted with a metal alkyl MR where R is an alkyl group of 2 to 6 carbon atoms, or an aryl group, and M is lithium, sodium or potassium, in an inert nonpolar solvent, to obtain a compound of formula Ill

wherein R, R1, R2, R3 and M are as defined above, and this compound is treated with a compound of formula IV

-where R", R'2, R13, R14, R15 and n are as defined in connection with formula I to obtain a compound of formula V

where M, R11, R'2, R13, R14, R15 and n are as defined above and the compound of formula V is treated with a compound of formula RaRbNCN wherein Ra and Rb are the same or different and represent alkyl of 1-6 carbon atoms, cycloalkyl of 4-6 carbon atoms or aralkyl of 7-12 carbon atoms, or Ra and Rb may be joined to form a heterocyclic ring with the nitrogen atoms to which they are attached and the product is treated with a proton source to obtain the nitrile of formula I.

The inert non-polar solvent for reaction of compound II with MR is preferably a hydrocarbon solvent such as benzene, toluene, xylene and hexane.

The reaction with the metal alkyl MR is preferably carried out at a temperature from -40 to +400C preferably about 0--5 OC.

Compound IV may be added to the reaction mixture in a hydrocarbon solvent as mentioned above or an ether solvent, e.g. ether, tetrahydrofuran or dioxan. When R11 and R12 are joined to form a ring the left and right hand rings are preferably of equal size.

The proton source is preferably water or an aqueous acid, e.g. hydrochloric, hydrobromic, sulphuric or nitric acid or ammonium chloride which can be added as a solid or in solution.

When the proton source is an aqueous acid that product may be readily isolated in the form of an acid addition salt.

The alkyl group R may be ethyl, n- and iso propyl, n-, s, t-butyl, pentyl or hexyl. When aryl R rnay be phenyl or substituted phenyl.

The tertiary alkyl groups R' and R2 are preferably t-butyl.

When R' and R2 are aryl they are preferably phenyl which may be substituted by alkyl of 1 to 6 carbon atoms. R3 may be isopropyl, s- and t-butyl or a branched chain pentyl or hexyl group.

Preferably R3 is a tertiary alkyl radical such as tbutyl. R can be a primary, secondary or tertiary alkyl radical. Preferably the metal derivatives are the lithium compounds.

The acid addition salts include 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.

The method of the present invention is especially useful when the compound of formula IV is a 5,6,7,8-tetrahydroquinoline containing a 4alkyl substituent.

It is preferred to react the compound II with 2 mols of the metal alkyl to produce a mixture of the metal amide Ill and the metal alkyl and to react this in situ with the compound IV followed by the compound RaRbNCN. When R'3 is alkyl or aralkyl containing a hydrogen atom on the carbon atom adjacent to the pyridine ring this procedure has considerable advantages as it gives higher yields of the compound I than when no metal amide is present during the reaction with RaRbNCN.

The invention also includes a process for preparing thioamides of formula Vl, wherein X is CSNH2

nitriles of formula VI wherein X is CN, or acid addition salts thereof, wherein R", R'2, R13, R14, R'5 and n are as defined above in connection with formula I in which a compound of formula II as defined above is reacted with a metal alkyl MR as defined above to obtain a compound of formula III as defined above, wherein M is lithium, sodium or potassium and this is reacted with a compound of formula IV as defined above, to obtain a compound of formula V as defined above and this is reacted with a silicon compound of formula R'5Si(NCS)4~X wherein R16 is alkyl, aryl or aralkyl and x has a value from 0 to 3, and when x is 2 or 3 the radicals R16 may be the same or different and then subjecting the product of hydrolysis or alcoholysis, with the proviso that when a compound of formula VI where Xis CN is desired the molar ratio of the silicon compound to compound V is at least 2:1, and xis 3.

The reaction between the compound V and the silicon compound may be conducted as described in UK Specification 1463666.

The preparation of the metal amides of formula Ill in situ from compounds II in the method of the present invention has advantages over their preparation from the corresponding amines.

The usual way of preparing such amines is by condensation of a ketone with a primary amine to prepare a ketimine which is then reduced. It has been reported [J. Organic Chem. 24, 657 (1959)] that methyl lithium can be reacted with Nbenzylidene-t-butylamine in refluxing ether followed by treatment with water to give t-butyl (a-methylbenzyl)amine. However, the yield is only 20%. An improvement on the conventional route for preparing sterically hindered secondary amines, especially those containing t-butyl groups is described in Synthesis 1 974, 127-8. This involves formation of the ketimine in the presence of titanium (IV) chloride and hydrogenation in situ.

Yields of t-butyl secondary amines by this route are reported to range from 5078%.

Pharmazie 31, H.6 (1976) pages 374-381 describes the preparation of various benzylamine derivatives and their investigation for antitubercular activity. This reference describes several routes to prepare these benzylamine derivatives including reaction of an N-alkylbenzylidineamine with a Grignard reagent or a lithium alkyl followed by hydrolysis and purification to give the desired amine. There is no mention in this reference of metal amide derivatives although it can be assumed that they would be formed.

In general it would be assumed from reading the above reference that if a metal amide was desired for use in an organic reaction it would be necessary to first prepare it from the corresponding pure amine. The yields in the Pharmazie reference are variable so that even in the case of that reference it would be assumed that it would be necessary to first prepare the amine, isolate and purify it and then convert it to the metal derivative. However, we have found that the metal derivatives III prepared in situ from compounds II can be used in situ without purification to react with compound IV as the yields in this first stage are so high and the product is free from significant impurities.

The invention is illustrated by the following Examples: Example 1 Lithium N-t-butyl-N-(1-phenylpentyl)amide A solution of N-benzylidine-t-butylamine (16.1 g, 0.1 M) in toluene (30 ml) was added to a mixture of a 1.55 M solution of butyl lithium in hexane (64.5 ml, 0.1 M) and toluene (20 mi) at OOC under argon to form lithium N-t-butyl-N-(1phenylpentyl)amide.

Example 2 8-Cyano-$methyl-5,6,7,8-tetrahydro- quinoline A solution of N-benzylidine-t-butylamine' (19.3 g, 0.12 M) in benzene (20 ml) was added to a solution of 1.55 M butyl lithium in hexane (142 ml, 0.22 M) maintained at OOC under argon to form lithium N-t-butyl-N-( 1 -phenylpentyl)amide2.

After 0.5 h. a solution of 4-methyl-5,6,7,8-tetrahydroquinoline (14.7 g, 0.1 M) in tetrahdyrofuran (30 ml) was added. After a further 0.5 h. a solution of diisopropylcyanamide (14.0 g, 0.11 M) in tetrahydrofuran (30 ml) was added, the mixture stirred 0.5 h. then quenched with water (100 ml).

The aqueous phase was extracted with toluene. The combined organic extracts were washed with water, dried and evaporated. The residue crystallised on trituration with hexane to yield 14.1 g (84%) of a crystalline mixture containing 95% of the title compound and 5% isomeric nitrile [(5,6,7,8-tetrahydro-4-quinolyl)- acetonitrile]3.

The mixture is dissolved in methanol and treated with an excess of ethereal hydrogen chloride. Removal of the resulting crystals by filtration gives the title compound as the hydrochloride (12.7 g, 76%) m.p. 254--5 OC identical with authentic material.

1. Reference: J. Organic Chem. 24 657 (1959) 2. At this point GLC indicates (after water quench) complete conversion N-t-butyl-N-(1phenylpentyl)-amine.

3. Can recover N-t-butyl-N-(1-phenylpentyl)amine by treating mother liquors with 5N hydrochloric acid and removing amine hydrochloride by filtration (ca 70% recovery), recovering to free base and distilling (Bp 100--40C/5 mbar).

The recorered amine can be used in the process described in UK Specification 2088860A to prepare more of the title compound. (Yields identical to above process).

Example 3 4-Methyl-5,6,7,8-tetrahydroquinoline-8-thio- carboxamide 1.55 M n-Butyl lithium in hexane (35.5 ml, 55 mM) at OOC under argon was heated with a solution of N-benzylidine-tert-butylamine (8.75 g, 50 mM) in toluene (40 ml) to form lithium N-t butyl-N-(1 -phenylpentyl)amide. After 2 hours a solution of 4-methyl-5,6,7,8-tetrahydroquinoline (7.35 g 50 mM) in toluene (10 ml) was added and after a further 0.5 h the mixture was heated with a solution of trimethylsilyl isothiocyanate (7.7 g, 55 mM) in toluene (10 ml). After 0.5 h. the reaction was quenched with water, acidified (pH 1) with sulphuric acid and the layers separated. The aqueous phase was mixed with an equal volume of cyclohexane and the pH adjusted to 10 with sodium hydroxide solution. The resultant precipitate was removed by filtration, washed with water and cyclohexane and dried in vacuo to give the title compound (7.4 g, 71%) identical with authentic material. (See Example 11 UK Patent Specification 1463666).

Example 4 4-Methyl-5,6,7,8-tetrnhydrnquinoline-8-thio- carboxamide Example 3 was repeated using 1.55 M t-butyl lithium in hexane instead of n-butyl lithium. The title compound was obtained in 46% yield.

Claims

1. A method of preparing nitriles of formula I

or acid addition salts thereof, wherein R11, R'2, R'3, R14 and R15 are the same or different and represent hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 21 6 carbon atoms, aralkyl of 7-12 carbon atoms or aryl radicals any of which radicals may be substituted or R" and R12 taken together, or R12 and R13 taken together, form a 5,6 or 7 membered ring which may be saturated or unsaturated and substituted or unsubstituted, R14 and R15 may also represent alkoxy of 1-6 carbon atoms, n is 1,2 or 3, in which a compound of formula II

where R1 is hydrogen, aryl or a tertiary alkyl group of 4 to 6 carbon atoms; R2 is aryl or a tertiary alkyl group of 4 to 6 carbon atoms; R3 is a branched chain alkyl of 3 to 6 carbon atoms; is reacted with a metal alkyl MR where R is an alkyl group of 2 to 6 carbon atoms, or an aryl group and M is lithium, sodium or potassium, in an inert non-polar solvent to obtain a compound of formula Ill

wherein R, R', R2, R3 and M are as defined above, and this compound is treated with a compound of formula IV

where R11, R'2, R13, R14, R15 and n are as defined in connection with formula I to obtain a compound of formula V

where M, R11, R12, R13, R14 R15 and n are as defined above and the compound of formula V is treated with a compound of formula RaRbNCN wherein Ra and Rb are the same or different and represent alkyl of 1-6 carbon atoms, cycloalkyl of 4-6 carbon atoms or aralkyl of 7-12 carbon atoms, 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 the nitride of formula I.

2. A method as claimed in Claim 1, wherein the compound II is reacted with 2 moles of the metal alkyl MR per mol of compound II to produce a mixture of the metal amide III and the metal alkyl and this mixture is treated in situ with the compound IV followed by the compound RaRbNCN.

3. A method as claimed in Claim 1 or 2, wherein a compound V is used and R13 is alkyl or aralkyl containing a hydrogen atom on the carbon atom adjacent to the pyridine ring.

4. A method as claimed in Claim 1,2 or 3 wherein the compound of formula IV is a tetrahydroquinoline derivative in which n is 2.

5. A method as claimed in Claim 4, wherein the compound of formula IV is 4-methyl-5,6,7,8tetrahydroquinoline.

6. A method for preparing thioamides or nitriles of formula VI

or acid addition salts thereof, wherein X is CSNH2 or CN, R1l, R12, R13, R14, R15 are the same or different and represent hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 4-6 carbon atoms, aralkyl of 7-12 carbon atoms or aryl radicals, any of which radicals may be substituted or R" and R12 take together, or R12 and R13 taken together, form a 5,6, or 7 membered ring which may be saturated or unsaturated and substituted or unsubstituted R'4 and R15 may also represent alkoxy and n is 1,2, or 3, in which a compound of formula II

wherein R1 is hydrogen, aryl or a tertiary alkyl group of 4 to 6 carbon atoms;; R2 is aryl or a tertiary alkyl group of 4 to 6 carbon atoms; R3 is a branched chain alkyl of 3 to 6 carbon atoms, is reacted with a metal alkyl MR where M is lithium, sodium or potassium and R is an alkyl group of 2 to 6 carbon atoms or an aryl group in an inert non-polar solvent to obtain a compound of formula III

where R, R', R2, R3 and M are as defined above and compound Ill is reacted with a compound of formula VI as defined above wherein X is hydrogen to obtain a compound of formula VI, as defined above, wherein X is M and this is reacted with a silicon compound of formula RX'5Si(NCS)4~x wherein R16 is alkyl of 1-6 carbon atoms, aryl, or aralkyl of 7-12 carbon atoms and S is sulphur and x has a value from 0 to 3, and when x is 2 or 3 the radicals R16 may be the same or different, and then subjecting the product to hydrolysis and alcoholysis, with the proviso that when a compound of formula VI is desired the molar ratio of the silicon compound of compound VI when Xis at least 2:1 and xis 3.

7. A method as claimed in Claim 6, wherein the compound of formula VI is a tetrahydroquinoline derivative in which n is 2.

8. A method as claimed in Claim 7 wherein the compound of formula VI is a 5,6,7,8-tetrahydroquinoline.

9. A method as claimed in Claim 1, substantially as hereinbefore described with reference to Example 2.

10. A method as claimed in Claim 6, substantially as hereinbefore described with reference to Example 3 or Example 4.

11. A nitriie whenever prepared by a method as claimed in any one of claims 1 to 5 or 9.

1 2. A nitrile or thioamide whenever prepared by a method as claimed in any one of claims 6,7,8, or 10.