GB2122615A - Preparation of fused carboxylic ring derivatives of pyridine - Google Patents

Abstract

A process for preparing compounds of formula I <IMAGE> or acid addition salts thereof, wherein R<1>, R<2>, R<3>, R<4> and R<5> are the same or different and represent hydrogen or alkyl, cycloalkyl, aralkyl, or aryl radicals, any of which radicals may be substituted, or R<1> 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 or unsaturated and substituted or unsubstituted, and when R<1> and R<2> form a ring, the ring has the same number of carbon atoms as the ring carrying X, R<4> and R<5> may also represent alkoxy, n is 1, 2 or 3 and X is CN, CONH2, or CSNH2 which process comprises treating a compound of formula II <IMAGE> wherein R<1>, R<2>, R<3>, R<4>, R<5> and n are as defined in connection with formula I, and M or is sodium, potassium, lithium, or MgHal, where Hal is chlorine, bromine or iodine, with a silyl compound of formula III, R<a>xSi(NCY)4-x wherein R<a> is selected from electron donating substituents including alkoxy, cycloalkoxy, aralkoxy, aryloxy, the group R<b>R<c>N-wherein R<b> and R<c> are selected from alkyl, cycloalkyl, aryl and aralkyl or R<b> and R<c> may be joined to form a heterocyclic ring with the nitrogen atom, alkylthio, cycloalkylthio, aralkylthio, arylthio and hydrocarbon substituents selected from alkyl, cycloalkyl, aralkyl or aryl, at least one group R<a> being an electron donating substituent, 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 compound of formula I in which X is CN is desired the molar ratio of compound R<a>xSi(NCY)4-x to compound II is at least 2:1 and x is 3 and Y is S and if desired isolating the product as an acid addition salt. The nitriles and thioamides are anti-ulcer and/or anti-secretory agents. Some compounds of the formula III are claimed together with compounds of the formulae VI and VII <IMAGE>

Description

SPECIFICATION Preparation of fused carbocyclic ring derivatives of pyridine The invention relates to a new process for preparing fused carbocyclic ring derivatives of pyridine.

In our United Kingdom Patent Specification No. 1463666 we described a process for preparing tetrahydroquinoline-8-thiocarboxamides, nitriles and carboxamides and related compounds by treating a corresponding sodio, lithio, potassio or magnesium halide derivative with a silyl compound of formula RXSi(NCY)4-x wherein R is alkyl, aryl or aralky, 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 n-hexane. It is also stated in the patent specification that ethers, including cyclic ethers such as tetrahydrofuran should be avoided.

We have now surprisingly found that ethers can be used as solvents if the silyl reagent is modified to contain an alkoxy group or other electron donating substituent. Our new process an also be used to prepare compounds related to those described in Patent Specification 1463666. The new reagents can also be used in the same solvents described in UK Specification 1463666.

Accordingly this invention provides in one aspect, a process for preparing compounds of formula I

or acid addition salts thereof, wherein R', R2, R3, R4 and R5 are the same or different and represent hydrogen or alkyl cycloalkyl, aralkyl, 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 substituted or unsubstituted, and when R1 and R2 form a ring, the ring has the same number of carbon atoms as the ring carrying X, R4 and R5 may also represent alkoxy, n is 1,2 or 3 and Xis CN, CONH2, or CSNH2which process comprises treating a compound of formula II

wherein R1, R2, R3, R4, R5 and n are as defined in connection with formula i, and M is sodium, potassum, lithium, or MgHal, where Hal is chlorine, bromine or iodine, with a silyl compound of formula Ill, RXSi(NCY)4-x wherein Ra is selected from electron donating substituents including alkoxy, cycloalkoxy, aralkoxy, aryloxy, the group RbRCN-wherein Rb and RC are selected from alkyl, cycloalkyl, aryl and aralkyl or Rb and Rc may be joined to form a hetercyclic ring with the nitrogen atom (eg., a piperidinyl or pyrrolidinyl ring, which may be substituted eg., by alkyl), alkylthio, cycloalkylthio, aralkylthio, arylthio and hydrocarbon substituents selected from alkyl, cycloalkyl, aralkyl or aryl, at least one group Ra being an electron donating substituent, 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 compound of formula I in which Xis CN is desired the molar ratio of compound RXSi(NCY)4-x to compound II is at least 2:1 and xis 3 and Y is Sand if desired isolating the product as an acid addition salt.

The compounds of formula land Il are, in general, known compounds which are described in UK Patent Specifications 1463666, 1432378, 1463668, 1465651 and 1495993 or are analogous to compounds described therein. Compounds of formula Il in which M is MgHal are also described in UK Patent 1463665 or are analogous to compounds described therein. The compounds offormula I in which Xis CSNH2 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 Xis CONH2 are intermediates for the corresponding nitriles and thioamides.

In general the preferred reaction medium for the process of the present invention comprises an ether solvent eg., a dialkyl ethere, wherein the alkyl group has from 1 to 6 carbon atoms, eg., diethyl ether or a cyclic ether such as tetrahydrofuran or dioxan. Other reaction media which may be used are hydrocarbon solvents such as benzene, toluene or n-hexane, or mixtures of two or more of the above mentioned solvents.

Preferably at least one electron donating group Ra is alkoxy of 1-10 carbon atoms, cycloalkoxy of 4-8 carbon atoms, aryloxy, aralkoxy of 7-12 carbon atoms or di(C1-Cs alkyl)amino. Good results have been obtained with a silyl compound of formula R3SiNCY wherein one group Ra is lower alkoxy or aryloxy and these other two are lower alkyl eg., methoxy dimethylsilyl isothiocyanate isopropoxydimethylsilyl.

sothiocyanate 2,6-di-t-butyl-4-methyl phenoxydimethylsilyl isothiocyanate.

However two or all three of the Ra groups may be alkoxy eg., trimethoxy or triethoxy, or dialkylamino eg dimethylamino. Branched chain alkoxy or arloxy groups are preferred. A particularly useful compound Ill is tri(dimethylamino)silyl isothiocyanate. Ra may have from 1-10 carbon atoms when alkyl or alkylthio.

When any of R1, R2, R3, R4, R5, Ra, Rb or Re 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 eg., methyl, ethyl, n-and iso-propyl and n-, and t-butyl. When R4, R5, or Ra is an alkoxy radical it is preferred that the radical is lower alkoxy in which the alkyl portion has 1 to 6 carbon atoms and is as defined above, for an alkyl radical. Similarly when Ra is an alkylthio group the alkyl portion is as defined for an alkyl group.

When any of R1, R2, R3, R4, R5, Ra, Rb or Rc is a cycloalkyl radical such radicals having from 4 to 6 carbon atoms are preferred ie., cyclobutyl, cyclopentyl or cyclohexyl. If Ra is cycloalkoxy or cycloalkylthio the cycloalkyl portion of this group preferably has from 4 to 8 carbon atoms but may be as just described for a cycloalkyl group.

An aralkyl group may be an arylalkyl group in which the alkyl portion is as described herein for an alkyl group. Preferred aralkyl groups are those having from 7-12 carbon atoms.

An aralkyloxy group may be such a group in which the aralkyl portion is as just described for an aralkyl group. The aryl portion is preferably phenyl.

When any of R1, R2, R3, R4, R5, Ra, Rb or Re is an aryl group it is preferably phenyl or substituted phenyl (substituted by eg., alkyl, alkoxy, ortrifluoromethyl). Similarly an aryloxy or arylthio group may be such a group in which the aryl portion is as defined for an aryl group, 2,6-disubstituted phenyl being a preferred group.

Apart from the question of solvent, already discussed above, the reaction may be carried out as described generally in UK Patent Specification No. 1463666. Conveniently the starting material of formula II is prepared in situ by reaction of a compound of formula II, 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 improvement described in UK Patent Specification 1463666, wherein a metal amide is reacted with a compound of formula II 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 eg., diethylamine, di-isopropylamine, ditertiary butylamine, di-n-decylamine, dicyclohexylamine, N-t-amyl N-t-butylamine, N-isopropyl-N-cyclohexylamine, or N(1 -ethylcyclohexyl)-1 1 ,3,3,-tetramethylbutylamine or a cyclic compound eg., piperidine or 2,2,6,6, tetramethylpiperidine. 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

wherein R14 is a straight or branched chain alkyl group of 1 to 6 carbon atoms or an aryl group, R'1 is hydrogen, aryl or a tertiary alkyl group of 4-6 carbon atoms, R12 is aryl or a tertiary alkyl group of 4-6 carbon atoms, R'3 is a branched chain alkyl of 3 to 6 carbon atoms; X1 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.

wherein R11, R12 and R13 are as defined above with a metal alkyl MR14 where R14 is as defined above 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-(1-phenylpentyl)amide.

The starting compounds of formula II, wherein Xis MgHal may be prepared by the general method described in UK Patent Specification 1463665. However, in our UK Patent Specification 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 II has been prepared in an ether solvent.

The silyl compounds of formula Ill 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, RxSiHal4~x eg., R3a SiHal where Ra is as defined above and Hal is chlorine or bromine.

Some of the silyl isothiocyanates or isocyanates of formula III are novel compounds and the novel compounds are included in the invention. They have formula Illa.

RXaSi(NCY)4-x Illa wherein Ra, x and Y are as defined in connection with formula III with the provisos that (i) when xis 3 and all three Ra groups are the same alkoxy then the alkoxy group has at least 3 carbon atoms; (ii) when Ra is alkoxy and xis 1 then Ra is other than propoxy; (iii) when one or more Ra are alkylthio and the others (if any) are alkyl then the alkylthio group has at least 2 carbon atoms;; (iv) when Ra is aryloxy and xis 3 then at least one group Ra is other than aryloxy Novel compounds of the invention include compounds of formula Illa, wherein one or two groups Ra are alkoxy or aryloxy and another group Ra is alkyl and x is 3 eg., Me2(OMe)SiNCS Me2(OiPr)SiNCS Me(OMe)2SiNCS 2,6,di-t-butyl-4-methylphenoxy (Me)2SiNCS and where one or more groups Ra are dialkylamino eg., (MeN2)3SiNCS.

The compounds of formula Ill (including the novel compounds of formula Illa) may be prepared by reacting a silylhalide RxSi(Hal)4~x, wherein Hal is chlorine, bromine or iodine, preferably chlorine, [Ra and x being as defined above] with a thiocyanate eg., ammonium thiocyanate, or a cyanate. Methods of preparing the novel compounds of formula Ill are included in the invention.

When it is desired to prepare nitriles of formula I by the above reaction instead of using 2 or more moles of compound RXaSi(NCY)4-x to compound 11 the reaction may be carried out by reacting 1 mol of compound RXSi(NCY)4-x with compound II wherein M is Na, K or Li followed by addition of 1 or more mols of RXSiHal4-X wherein Ra and x are as defined previously and Hal is chlorine or bromine, Ra and x in this reagent need not be the same as in the reagent RXaSi(NCY)4-xB This process for preparing nitriles is also included in the invention.

The silylhalides are known or may be prepared by methods known for analogous compounds.

The invention also includes further novel compounds offormula VI

wherein R1, R2, R3, R4, R5, Ra, n, x, Y and M are as defined above. These novel compounds are the products of the first stage of reaction between the compound of formula II and the compound of formula Ill. This compound of formula VI is converted into the desired compound of formula I via an intermediate of formula VII, which may be transient,

wherein R1, R2, R3, R4, R5, Ra, n, x and Y are as defined above.

The intermediates of formula VII are also included in the invention.

The following Examples illustrate the invention.

EXAMPLE 1 Preparation of silyl isothiocyanates General Method Ammonium thiocyanate (1.1 molar equivalents) in cyclohexane (100 ml) was refluxed with stirring under a Dean-Stark apparatus until water had been removed. The suspension was cooled and treated with silyl chloride (50g) and the mixture was heated at reflux with stirring until the reaction was complete (usually 24 hour) Precipitated ammonium chloride was removed by filtration and the product purified by distiliation.In this mannerwere prepared the following: Silyl chloride Silylisothiocyanate bp/mm Yield a) Me2(OMe)SiCI Me2(OMe)SiNCS 148 C/760 68% b) Me2(OiPr)SiCI Me2(OiPr)SiNCS 68"C/15 79% c) Me(OMe)2SiCI Me(OMe)2SiNCS 58"C/15 66% d) (OEt)3SiCI (OEt)3SiNCS 98"C/15 95% e) (Me2N)3SiCI (Me2N)3SiNCS 140"C/15 15% EXAMPLE 2 Reaction of silyliso thiocyanates with tetrahydroquinolines General Method A 5,6,7,84etrahydroquinoline (0.01 mole) in the solvent indicated (approx. 15 ml) at OOC under nitrogen was treated with an alkyl lithium or a lithium amide (0.01 mole).To this solution of the 5,6,7,8-tetrahydro-8lithioquinoline was added, at around 0 C under nitrogen, the silyl isothiocyanate (0.01 mole) and the mixture was stirred 15 minutes. H2O(10ml) and 2N HCI (15ml) were added and the acid layer was separated and washed with ethyl acetate. The aqueous solution was basified (Na2CO3) and extracted with chloroform. The chloroform extracts were dried (MgSO4) and evaporated to give the 5,6,7,8-tetrahydroquinoline-8thiocarboxamide. In this manner the thioamides in the table were prepared.

Silyl Yield Expt. R15 derivatives Solvent Base (n.m.r) (a) 3-Me Me2Si(OMe)NCS THF n-BuLi 5% (b) 3-Me Me2Si(OiPr)NCS THF n-BuLi 30-35% (c) 3-Me Me2Si(OiPr)NCS toluene n-BuLi 15% (d) 4-Me Me2Si(OiPr)NCS toluene n-BuLi 5% (e) 4-Me Me2Si(OiPr)NCS THF n-BuLi 10% Ph (f) 4-Me Me2Si(OiPr)NCS toluene XN + 20% Bu L. (g) 4-Me Me2Si(OiPr)NCS THF II 25% (h) 3-Me (EtO)3SiNCS THF n-BuLi 10% (i) 3-Me Me(OMe)2SiNCS THF n-BuLi 10% (j) 3-Me (Me2N)3SiNCS THF n-BuLi 40% But (k) 3-Me G/ G THF n-BuLi 50% Me2 But

No product was obtained when the above reactions were carried out using Me3SiNCS in tetrahydrofuran (THF) instead of the named silyl derivative.

EXAMPLE 3 a) 2, 6-Di-t-butyl-4-methylphenoxydimethylchlorosilane A mixture of 2,6-di-t-butyl-4-methylphenol (110g,0.5M), acetonitrile (500ml), triethylamine (70ml,0.5M) and dichlorodimethylsilane (61 ml,0.5m) was refluxed for 16 hours. The solvent was evaporated and the residue extracted with toluene (500my). The toluene extract was evaporated and the residue recrystallised from acetonitrile to give the title compound (909,57%) m.p. 119-121"(Found: C,65 65; H,9.4%. C17 H29 ClOSi requires C,65.2; H,9.3%).

b) 2, 6-Di-t-butyl-4-methylphenoxydimethylsllyl isothiocyanate A mixture of the silyl chloride (78g,0.25M), ammonium thiocyanate (26g,0.28M) and toluene was refluxed for 48 hours. The mixture was filtered and the filtrate evaporated; recrystallisation of the residue from acetonitrile gave the title compound (409,48%) m.p.83-4 . (Found: C,64.8; H,9.0; N,4.05. C18 H29 NOSSi requires: C,64.6; H,8.7; 4.2.)

Claims (32)

1. A process for preparing compounds of formula I

or acid addition salts thereof, wherein R1, R2, R3, R4 and R5 are the same or different and represent hydrogen or alkyl, cycloalkyl, aralkyl, 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 substituted or unsubstituted, and when R1 and R2 form a ring, the ring has the same number of carbon atoms as the ring carrying X, R4 and R5 may also represent alkoxy, n is 1,2 or 3 and X is CN, CONH2, or CSNH2 which process comprises treating a compound of formula II

wherein R1, R2, R3, R4, R5 and n are as defined in connection with formula I, and M is sodium, potassium, lithium, or MgHal, where Hal is chlorine, bromine or iodine, with a silyl compound of formula Ill, RXSi(NCY)4-x wherein Ra is selected from electron donating substituents including alkoxy, cycloalkoxy, aralkoxy, aryloxy, the group RbRCN-wherein Rb and RC are selected from alkyl, cycloalkyl, aryl and aralkyi or Rb and Rc may be joined to form a heterocyclic ring with the nitrogen atom, alkylthio, cycloalkylthio, aralkylthio, arylthio and hydrocarbon substituents selected from alkyl, cycloalkyl, aralkyl or aryl, at least one group Ra being an electron donating substituent, 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 compound of formula I in which X is CN is desired the molar ratio of compound RXSi(NCY)4-xto compound II is at least 2::1 and xis 3 and Y is S and if desired isolating the product as an acid addition salt.

2. A process as claimed in Claim 1, when carried out in a solvent comprising an ether.

3. A process as claimed in Claim 2, wherein the ether solvent is a cyclic ether.

4. A process as claimed in Claim 3, wherein the ether solvent is tetrahydrofuran or dioxan.

5. A process as claimed in any one of claims 1 to 4, wherein the silyl compound Ill is R3SiNCY, wherein one group Ra is alkoxy of 1-10 carbon atoms or aryloxy and the other two are alkyl of 1-6 carbon atoms.

6. A process as claimed in Claim 5, wherein the silyl compound III is isopropoxydimethylsilyl isothiocyanate.

7. A process as claimed in Claim 5, wherein the silyl compound III is 2,6-di-t-butyl-4-methylphenoxydimethylsilyl isothiocyanate.

8. A process as claimed in any one of claims 1-4, wherein the siiyl compound Ill istri(dimethylamino)silyl isothiocyanate.

9. A process as claimed in any one of the preceding claims, wherein the starting compound of formula II is prepared in situ by reaction of a compound of formula II, where M is hydrogen with a metal amide.

10. A process as claimed in Claim 9, wherein the metal amide has the formula IV

wherein R14 is a straight or branched chain alkyl group of 1 to 6 carbon atoms or an aryl group, R71 is hydrogen, aryl or a tertiary alkyl group of 4 to 6 carbon atoms, R12 is aryl or a tertiary alkyl group of 4-6 carbon atoms, R13 is a branched chain alkyl group of 3 to 6 carbon atoms; X1 is lithium, sodium or potassium.

11. A process as claimed in Claim 10, wherein the metal amide is lithium N-t-butyl-N-(1 phenylpentyl)amide.

12. A process as claimed in any one of claims 1 to 11, wherein the compound offormula lisa tetrahydroquinoline derivative.

13. A compound of formula I, whenever prepared by a process as claimed in any one of claims 1-12.

14. A modification of the process claimed in any one of claims 1-l2for preparing nitriles offormula I, wherein X is CN, wherein 1 mol of a compound II, wherein M is lithium, sodium or potassium is reacted with 1 mol of compound Ill followed by one or more mols of a compound RxSiHa4~xwherein Ra and x are as defined previously and Hal is chlorine or bromine.

15. A nitrile of formula I whenever prepared by a process as claimed in Claim 14.

16. A compound of formula IIIA RxSi(NCY)4-x IIIA wherein Ra, x and Y are as defined in connection with formula Ill in Claim 1, with the provisos that: (i) when xis 3 and all three Ra groups are the same alkoxy then the alkoxy group has at least 3 carbon atoms; (ii) when Ra is alkoxy and xis 1 then Ra is other than propoxy; (iii) when one or more Ra are alkylthio and the others (if any) are alkyl then the alkylthio group has at least 2 carbon atoms; (iv) when Ra is aryloxy and xis 3 then at least one group Ra is other than aryloxy.

17. A compound of formula IIIA as claimed in Claim 16, wherein one or two groups Ra are alkoxy or aryloxy, another group Ra is alkyl and xis 3.

18. A compound of formula IIIA as claimed in Claim 17, wherein one or more groups Ra are dialkylamino.

19. Dimethylmethoxysilyl isothiocyanate.

20. Dimethylisopropoxysilyl isothiocyanate.

21. Methyldimethoxysilyl isothiocyanate.

22. 2,6,Di-t-butyl-4-methyl phenoxydimethylsilyl isoth iocyanate.

23. Tri(dimethylamino)silyl isothiocyanate.

24. A process for preparing a compound of formula lIlA as claimed in any one of claims 16 to 18, which process comprises reacting a silylhalide RxSi(Hal)4~x wherein Hal is chlorine, bromine or iodine, and Ra and x are as defined in Claim 16, 17 or 18, with a thiocyanate or a cyanate.

25. A process as claimed in Claim 24, substantially as hereinbefore described in Example 1.

26. A process as claimed in claim 24, substantially as hereinbefore described in Example 3b.

27. A compound of formula IIIA, whenever prepared by a process as claimed in Claim 24, 25 or 26.

28. Acompound of formula Vl

wherein R1, R2, R3, R4, R5, Ra, n, x, Y and M are as defined in Claim 1.

29. Acompound of formula Vll

wherein R1, R2, R3, R4, R5, Ra, n, x and Y are as defined in Claim 1.

30. A process as claimed in claim 1, substantially as hereinbefore described in Example 2 (general method).

31. A process as claimed in Claim 1, substantially as hereinbefore described in Example 2 (any one of experiments a to k).

32. A compound of formula I, whenever prepared by a process as claimed in Claim 31.