GB2122992A

GB2122992A - Preparation of tetrahydroquinolines and related compounds

Info

Publication number: GB2122992A
Application number: GB08316271A
Authority: GB
Inventors: Robin Gerald Shepherd
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1982-06-25
Filing date: 1983-06-15
Publication date: 1984-01-25
Also published as: US4526970A; GB2122992B; GB8316271D0; US4609748A; GB2142037B; GB2142037A; GB8419500D0

Description

1 GB 2 122 992 A 1

SPECIFICATION Preparation of tetrahydroquinolines and related compounds

The invention relates to a new process for preparing fused carbocyclic ring derivatives of pyridine and to novel silyl reagents used in the process.

In our United Kingdom Specification No. 1463666 we described a process for preparing tetra hyd roqu ino I i ne-8-thioca rboxa m ides, nitriles and carboxamides and related compounds by treating a corresponding sodio, lithio, potassio or magnesium halide derivative with a silyl compound of formula R),Si(NCY)4-x wherein R is alkyl, aryl or aralkyl, Y is oxygen or sulphur and x has a value from 0 to 3 and subjecting the product to hydrolysis or alcoholysis. The reaction is conducted under anhydrous conditions preferably in an inert solvent for example a hydrocarbon solvent such as benzene, toluene or 10 n-hexane. It is also stated in that patent specification that ethers, including cyclic ethers such as tetrahydrofuran should be avoided.

We have now suprisingly found that ethers can be used as solvents if the silyl reagent is modified to contain selected hydrocarbon groups and furthermore the yields are often better than with the solvents described in UK Specification No. 1463666. Our new process can also be used to prepare compounds related to those described in Patent Specification 1463666.

Accordingly this invention provides in one aspect, a process for preparing compounds of formula I 44. F R 2 (CH2, R,, '), X "N R1 5 - N R or acid addition salts thereof, wherein R', R', R', R' and R' are the same or different and represent hydrogen oralkyl, cycloalkyl, aralkyl, or aryl radicals, any of which radicals maybe substituted or R' and 20 R' taken together or R 2 and R 3 taken together, form a 5, 6 or 7 membered ring which may be saturated ' or unsaturated and substituted or unsubstituted, and when R' and R' form a ring the ring has the same number of carbon atoms as the ring carrying X, R' and R' may also represent alkoxy, n is 1, 2 or 3 and X is CN, CONH2 or CSM2, which process comprises treating a compound of formula 11 4 R 3 RW R2 RS---_ m R wherein R', R', R', R 4, R' and n are as defined in connection with formula 1, and M is sodium, potassium, lithium, or MgHal, where Hal is chlorine, bromine or iodine, with a silyl compound of formula III, Rasi(NCY)4-x wherein R' is alkyl, cycloalkyl, aralkyl or aryl, at least one group R' being a X branched chain alkyl, cycloalkyl, aryl, or branched chain aralkyl, Y is oxygen or sulphur, x has a value 30 from 1 to 3, then subjecting the product to hydrolysis with the proviso that when a compound of formula I in which X is CN is desired the molar ratio of compound RaSi(NCY)4-x to compound 11 is at X least 2:1 and x is 3 and Y is S and if desired isolating the product as an acid addition salt.

If at least one Ra is not t-alkyl then preferably at least two groups Ra are selected from branched chain alkyl, cycloalkyl, aryl or branched chain aralkyl.

The compounds of formula I and 11 are, in general, known compounds which are described in UK 35 Patent Specifications 1463666, 1432378, 1463668, 1465651 and 1495993 or are analogous to compounds described therein. Compounds of formula 11 in which M is MgHal are also described in UK Patent 1463665 or are analogous to compounds described therein. The compounds of formula I in which X is CSNH, are anti-ulcer agents which display anti-ulcer and/or anti-secretory activity in standard test procedures. The nitriles of formula I where X is CN are intermediates for the corresponding thioamides and usually also display anti-ulcer and/or anti- secretory activity. The amides of formula I in which X is CONH, are intermediates for the corresponding nitriles and thioamides.

The reaction medium for the process of the present invention preferably comprises an ether solvent e.g., a dialkyl ether, wherein the alkyl group has from 1 to 6 carbon atoms, e.g. diethyl ether, or a cyclic ether such as tetrahydrofuran or dioxan. The solvents described in UK Patent Specification 45

1463666 e.g., hydrocarbons such as benzene and toluene may also be used. With some compounds of formula 11 e.g., those containing, 5 and 7 membered rings (where n is 1 or 3) and some tetrahydroquinolines such as those having R 3 as an alkyl group the reagents of formula III often give 2 GB 2 122 992 A 2 better yields than the reagents specifically disclosed in 1463666 e.g., trimethylsilyl isothiocyanate. Mixtures of solvents may be used e.g., an ether/hydrocarbon such as tetra hydrofu ra n/h exan e.

Preferably R' is an alkyl group of 1 -10 carbon atoms and at least one group R' is a tertiary alkyl group e.g., t-butyl or t-amyi. Preferably x is 3. Good results have been obtained with silyl compound of 5 formula R'SiNCY wherein one group R' is t-butyl and the other two are lower alkyl e.g., 3 t-butyidimethyisiiyi isothiocyanate.

When any of W, R', R 3, R' or R' is an alkyl radical it is preferred that this is a lower alkyl radical of 1 to 6 carbon atoms which may have a straight or branched chain e.g., methyl, ethyl, n- and iso-propyl and n-, s- and t-butyl. When R' is a lower alkyl radical it may be any of the values just discussed. When RlorR 5 is an alkoxy radical it is preferred that the radical is lower alkoxy in which the alkyl portion has 10 1 to 6 carbon atoms and is as defined above, for an alkyl radical.

When any of W, R', R', R', R' or R' is a cycloalkyl radical such radicals having from 4 to 8 carbon atoms in the ring are preferred e.g., cyclobutyl, cyclopentyl or cyclohexy]. Such rings may be substituted by alkyl of 1 to 6 carbon atoms.

An aralkyl group may be an arylalkyl group in which the alkyl portion is as described herein for an 15 alkyl group. Preferred aralkyl groups are those having from 7-12 carbon atoms. R' when aralkyl may be phenyl alkyl, naphthyimethyl or naphthyl ethyl.

When any of R', R', R', R', R' or R' is an aryl group it is preferably phenyl or substituted phenyl (substituted by e.g. alkyl, alkoxy, or trifl uoro methyl).

Apart from the question of solvent, already discussed above the reaction may be carried out as 20 described generally in UK Patent Specification No. 1463666. Conveniently the starting material of formula 11 is prepared in situ by reaction of a compound of formula 11, wherein M is hydrogen with a suitable organometallic compound such as an alkyl, aryl or aralkyl lithium, sodium or potassium compound as described in UK Patent Specification 1432378 or using the modification described in UK

Patent Specification 1463666, wherein a metal amide is reacted with a compound of formula 11 wherein M is hydrogen. The metal amide may be formed in situ and may be any of those described in UK Patent Specification 1463666 viz. an amide derived from a secondary amine such as a dialkylamine e.g. diethylamine, di-isopropyia mine, ditertiary butylamine, di-n-decyla mine, dicyclohexylamine, N-t-amyi-N-t-butylamine, N-isopropyi-N-cyclohexyia mine, or N(1 -ethylcyclohexyi) 1, 1 3,3-tetra methyl butyl a mine or a cyclic compound e.g. piperidine, or 2,2,6,6-tetramethylpiperidine. 30 Alternatively any of the metal amides described in our co-pending UK Application 8306456 filed 9th March 1983 may be used. These metal amides have the formula IV R11 R 14 1 ----1J '1JR13 12 R wherein R14 is a straight or branched chain alkyl group of 1 to 6 carbon atoms or an aryl group, R is hydrogen, aryl ora tertiary alkyl group of 4-6 carbon atoms, R 12 is aryl or a tertiary alkyl group of 46 carbon atoms, W' is a branched chain alkyl of 3 to 6 carbon atoms; X' is lithium, sodium or potassium. These metal amides are conveniently prepared by a novel process described in UK Application 8306456 namely reacting a compound of formula V.

R" C= R 13 R 12/' V wherein R", R" and R11 areas defined above with a metal alkyl MR 14 where R" is as defined above 40 and M is lithium sodium or potassium, in an inert non-polar solvent to obtain a compound of formula IV.

A particularly preferred compound of formula IV is lithium N-t-butyl-N-(l -phenylpentyl)amide.

The starting compounds of formula 11, wherein X is MgHal may be prepared by the general method described in UK Patent Specification 1463665. However, in our UK Patent Specification 45

1463666 it is said that the ether solvent has to be removed and the reaction with the silyl compound conducted in a different solvent. Since the process of the present invention can be conducted in ethers it is not usually necessary to remove the ether when the MgHal compound 11 has been prepared in an ether solvent. However it is usually desirable to reduce the volume of ether before reaction with the silyl compound.

The silyl compounds of formula III which are used in the process of the present invention may be prepared by reacting a thiocyanate, such as ammonium thiocyanate, or a cyanate with a silyl halide 3 GB 2 122 992 A 3 e.g., R' SiHal where R' is as defined above and Hal is chlorine bromine or iodine.

3 Some sily] compounds of formula Ill are novel. These novel compounds are included in the scope of the invention and are represented by formula Ill A, R b RIR d SiNCY- wherein R b is a branched chain alkyl, cycloalky], aryi, branched chain aralkyl and R' and R d are selected from alkyl, cycloalkyl, aralkyl or aryl with the proviso that R' and Rd are not the same radical as Rb, and Y is oxygen or sulphur.

Processes for preparing compounds IIIA are also included.

Preferably R' and R d are alkyl radicals at least one and preferably both being n-alkyl radicals.

A particularly preferred compound of formula IIIA is t-butyidimethyisilyl isothiocyanate.

When it is desired to prepared nitriles by the above reaction instead of using 2 or more moles of compound Ra Si(NCY4-x to compound 11 the reaction may be carried out by reacting 1 mol of X compound RaSi (NC%, with compound 11 followed by addition of 1 or more mols of RISU wherein X X 4-x R' and x are as defined previously. Ra and x in this reagent need not be the same as Ra and x in the reagent RaSi a X (NCY)4-x. A compound FIXSiBr4, may be used instead of the corresponding chloride. The following Examples illustrate the invention.

Example 1

Preparation of silyl isothiocyanates General method Ammonium thiocyanate (1.1 molar equivalents) in cyclohexane (100 mi) was refluxed with stirring under a Dean-Stark apparatus until water had been removed. The suspension was cooled and treated with a silyl chloride (50 g) and the mixture was heated at reflux with stirring until the reaction 20 was complete (usually 24 hours). Precipitated ammonium chloride was removed by filtration and the product purified by distillation. in this manner were prepared the following:- Silyl chloride Silyllsothiocyanate bplmm Yield a) t-BuMe2S'Cl t-BuMe2SiNCS 621/16 93% b) i-Pr3S'Cl i-Pr3SiNCS 1260/15 71% 25 c) PhMe2S'Cl PhMe2SiNCS 1441/15 80% Example 2

5,6,7 8-Tetrahydro-3,8-dimethyiquinoline-8-thiocarboxamide 1.55 molar solution of butyl lithium in hexane (12.9 mi, 20 mM) maintained below 101 was treated with a solution of 5,6,7,8-tetrahydro-3,8-dimethyiquinoline (3.22 g, 20 mM) in tetrahydrofuran 30 (10 mi). After 0.5 hours a 22% solution of t-butyidimethyisily] isothiocyanate in benzene (13.7 g, 20 mM) was added dropwise. After a further 0.5 hours the reaction was quenched with water (100 m[.) then acidified (to pH 1). After 1 hour the layers were separated, the aqueous layer basified (to pHg) and extracted with dichloromethane (2 x50 mi). The organic extracts were dried and evaporated.

Recrystallisation of the residue from toluene gave the title thioamide (3. 3 g, 75%) mp. 160-21. 35 (Found: C, 65.45; H, 7.2; N, 12.9% C1,1-1,^S requires C, 65.4; H, 7.3; N, 12.7%) Example 3

8-Cyano-5,6,7,8-tetrahydro-3,8-dimethylquinoline A solution of 5,6,7,8-tetrahydro-8-lithio-3,8-dimethyiquinoline (20 mM) was generated as described in Example 2 and allowed to react with t-butyidimethyisilyl isothiocyanate (20 mM) as described in Example 2. After 0.5 hours a solution of t-butyidimethyisilyl chloride (3.1 g, 20 mM) in THF (10 mi) was added and the mixture allowed to stand for 16 hours at ambient temperature. The reaction was quenched with 2N hydrochloric acid (50 mi). After 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2x50 mi) and the organic extracts were dried and evaporated. Kugelrohrdistillatio ' n of the residue gave the nitrile title compound. 45 (2.8 g, 75%) bp. 901)/0.01 mm (bath temp.).

(Found: C, 77.1; H, 8.1; N, 14.5% C12H14N2 requires: C, 77.4; H, 7.6; N, 15.0%).

Example 4 5.6,7,8-Tetrahydro-3-methyiquinoline-8-thiocarboxamide Following the procedure of Example 2, but using 5,6,7,8-tetrahydro-3methyiquinoline as 50 starting material the title compound was obtained in 50% yield mp 1491C., identical with authentic material.

4 GB 2 122 992 A 4

Claims

1. A process for preparing compounds of formula 1 4 FP R 2 R (CHl, R S.,' ?' - X N or acid addition salts thereof, wherein W, R', R', R' and R' are the same or different and represent hydrogen or 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 and when R' and R 2 form a ring, the ring has the same number of carbon atoms as the ring carrying X, R' and R' may also represent alkoxy, n is 1, 2, or 3 and X is CN, CONI- 12 or CSNI-1, which process comprises treating a compound of formula 11 4 R 3 R R2 (CH?1 R] R55 --- m wherein W, R 2, R', R', R' and n are as defined in connection with formula 1, and M is sodium, potassium, lithium, or MgHal, where Hal is chlorine, bromine or iodine, with a silyl compound of formula Ill, RaSi(NCY)4-x wherein Ra is alkyl, cycloalkyl, aralkyl or aryl, at least one group Ra being a X branched chain alky], cycloalkyl, aryl or branched chain aralkyl, Y is oxygen or sulphur, x has a value from 1 to 3, then subjecting the product to hydrolysis or alcoholysis with the proviso that when a a compound of formula 1 in which X is M is desired the molar ratio of compound RXSi(NCY)4-X to compound 11 is at least 2:1 and x is 3 and Y is S and if desired isolating the product as an acid addition salt.

2. A process as claimed in Claim 1, wherein x is 3 and at least one group R' in the compound of formula Ill isat-alkyl group.

3. A process as claimed in Claim 2, wherein one group Ra in the compound of formula Ill is t-butyl and the other two are lower alkyl.

4. A process as claimed in Claim 3, wherein the compound of formula Ill is t-butyidimethyisilyi isothiocyanate.

5. A process as claimed in Claim 1, wherein x is 3 and at least two groups Ra in the compound of 25 formula Ill are selected from branched chain alkyl, cycloalky], aryl or branched chain aralkyl groups.

6. A process as claimed in Claim 1, wherein the compound of formula Ill is dimethylphenylsilyl isothiocyanate.

7. A process as claimed in Claim 5, wherein the compound of formula Ill is tri-isopropylsilyl isothiocyanate.

8. A process as claimed in any one of the preceding claims, wherein a compound of formula 11 is used in which R', R 2, R 3, R4 and R5 are selected from hydrogen and alkyl of 1-6 carbon atoms.

9. A process as claimed in any one of the preceding claims, wherein the reaction between compounds 11 and Ill is carried out in a reaction medium comprising an ether solvent.

10. A process as claimed in Claim 9, wherein the reaction medium comprises diethyl ether or a 35 cyclic ether.

11. A process as claimed in Claim 9, wherein the reaction medium comprises tetra hydrofu ran.

12. A process as claimed in Claim 11, wherein the reaction medium comprises tetrahydrofuran and a hydrocarbon solvent.

13. A process as claimed in Claim 12, wherein the reaction medium comprises tetrahydrofuran 40 and hexane.

14. A process as claimed in Claim 1, substantially as hereinbefore described with reference to Example 2 or 4.

15. A compound of formula 1, whenever prepared by a process as claimed in any one of Claims 1-14.

16. A modification of the process claimed in Claim 1 for preparing a compound of formula 1, as defined in Claim 1, wherein X is CN, which process comprises treating a compound of formula 11, as defined in Claim 1, with 1 mol of a silyl compound of formula Ill as defined in Claim 1, followed by one Q i GB 2 122 992 A 5 or more mols of a compound of formula R8Sil-1al4-, wherein Ra and x are as defined in Claim 1, and Hal X is chlorine or bromine.

17. A process as claimed in Claim 16, wherein the compound of formula Ill is as defined in any one of Claims 2 to 7.

18. A process as claimed in Claim 16 or Claim 17, wherein the compound of formula 11 is as defined in Claim 8.

19. A process as claimed in Claim 18, wherein the reaction is carried out in a solvent as defined in any one of Claims 9 to 13.

20. A process as claimed in any one of Claims 16 to 19, wherein the compound RaSiHai-x is one X 4 in which xis 3 and one group Ra is t-alkyl and the othertwo are n-alkyl.

2 1. A process as claimed in Claim 20, wherein the compound RISil-la 4 X 1 _x is t-butyidimethyisilyl chloride.

22. A process as claimed in Claim 16, substantially as hereinbefore described with reference to Example 3.

23. A compound of formula 1, wherein X is CN, whenever prepared by a process as claimed in any15 one of Claims 16-22.

24. A compound of formula IIIA R b RcR dS iNCY wherein R b is a branched chain alkyl, cycloalky], aryl or branched chain aralkyl and R' and R d are selected from alkyl, cycloalkyl, aralkyl or aryl with the proviso that Rc and Rd are not the same radical as 20 Rb, and Y is oxygen or sulphur.

25. A compound of formula IIIA, as claimed in Claim 24, wherein Rc and Rd are both alkyl radicals.

26. A compound of formula IIIA as claimed in Claim 25, wherein Rc and R' are both n-alkyl radicals.

1C.

27. A compound as claimed in Claim 24, 25 or 26, wherein R' is t-butyl.

28. A compound as claimed in Claim 24, 25 or 26, wherein R' is phenyl.

29. t-Butylclimethylsilyl isothiocyanate.

30. Phenylclimethylsilyl isothiocyanate.

3 1. Tri-isopropylsilyl isothiocyanate.

32. A process for preparing a compound of formula Ilia as claimed in Claim 24, which process comprises reacting a silyl halide of formula R b, R', RdSil-lal wherein R b, Rc and R d are as defined in Claim 24 and Hal is chlorine, bromine or iodine, with a thiocyanate or a cyanate.

33. A process as claimed in Claim 32, substantially as hereinbefore described in Example 1 a or

34. A compound of formula Illa whenever prepared by a process as claimed in Claim 32 or 33.

35. A process for preparing tri-isopropylsilyl isothiocyanate which process comprises reacting a tri-isopropylsilyl chloride, bromide or iodine with a thiocyanate.

36. A process as claimed in Claim 35, substantially as described in Example 1 b.

37. Tri-isopropyl isothiocyanate whenever prepared by a process as claimed in Claim 35 or 36. 40 Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.