GB2148283A

GB2148283A - Quinoline derivatives

Info

Publication number: GB2148283A
Application number: GB08423279A
Authority: GB
Inventors: Roger Crossley; Kenneth Heatherington
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1983-01-19
Filing date: 1984-09-14
Publication date: 1985-05-30
Also published as: GB2148283B; GB8423279D0

Abstract

Novel compounds II can be converted into compounds I. <IMAGE> In these formulae R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and R<7> 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, R<4> and R<5> may also represent alkoxy, or cycloalkoxy, n is 1, 2 or 3 and, if more than one R<4> radical is present the R<4> radicals may be the same or different and R<6> and R<7> represent hydrogen, alkyl, cycloalkyl, or aralkyl radicals. The present invention concerns novel compounds II, with the provisos that (1) when R<1>, R<2>, R<3>, R<4> and R<5> are all hydrogen, R<6> and R<7> are not both hydrogen and (2) when R<1> and R<3> are both phenyl and when R<1> is methyl and R<4> is methyl then R<6> and R<7> are not both methyl. Compounds II can be prepared by dehydration of alcohol III, by the Peterson reaction and by the Wittig Reaction.

Description

SPECIFICATION Quiniline derivatives The invention relates to quinoline derivatives and related compounds, to novel processes for preparing them and to novel compounds obtained by such processes.

The invention provides compounds of formula II

and acid addition salts thereof, wherein R1, R2, R3, R4, R5, R6 and R7 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 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, R4 and R5 may also represent alkoxy, or cycloalkoxy, n is 1,2 or 3 and, if more than one R4 radical is present the R4 radicals may be the same or different and R6 and R7 represent hydrogen, alkyl, cycloalkyl, or aralkyi radicals with the provisos that (1) when R', R2, R3, R4 and R5 are all hydrogen, R6 and R7 are not both hydrogen, and (2) when R1 and R3 are both phenyl and when R1 is methyl and R4 is methyl then R6 and R7 are not both methyl.

The compounds of formula II are useful as starting materials for the preparation of compounds offormula I

wherein R1, R2, R3, R4, Re, R6, R7 and n are as defined above, by a process which is described in our copending application 8401333 (Serial No. 2136799) from which the present application is divided.

The re-arrangement of compound ll to compound I may be carried out under acidic or basic conditions.

Examples of acid catalysts which may be used are organic acids such as carboxylic acids e.g. lower alkylcarboxylic acids such as acetic acid, inorganic acids such as phosphoric acid, or polyphosphoric acid, Lewis acids e.g. boron trifluoride, zinc chloride or acid anhydrides e.g. acetic anhydride. Alternatively a noble metal catalyst, e.g. a Pt or Pd catalyst may be used, optionally in the presence of a weak base such as sodium acetate or a heterogeneous or homogeneous catalyst, e.g. PdC12(PhCN)2, PhCl[CeHe)3P]3Ru3(CO)12 or IrCl(CO) [(C6H5)3P]2s Preferably the rearrangement is carried out in the presence of acetic acid, a noble metal catalyst in the presence of a base, or a Lewis acid.

The above mentioned acids may be used to prepare acid addition salts of compounds of formula land other compounds of the invention.

When any of R', R2, R3, R4, R5, R6 or R7 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 R4 or R5 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.

When any of R1, R2, R3, R4, R5, R6 or R7 is a cycloalkyl radical such radicals having from 4 to 6 carbon atoms are preferred i.e. cyclobutyl, cyclopentyl or cyclohexyl. If R4 or R5 is cycloalkoxythe cycloalkyl portion of this group 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.

When any of R', R2, R3, R4 or R5 is an aryl group it is preferably phenyl or substituted phenyl (substituted by e.g. alkyl, alkoxy ortrifluoromethyl). The aryl portion of an aralkyl group may be substituted as described for a phenyl group.

A preferred sub group of the compounds of formula Ii are those of formula IIA

or an acid addition salt thereof wherein R1 is lower alkyl and R6 and R7 are selected from hydrogen and lower alkyl. Examples are 5,6,7,8-tetrahydro-3-methyl-8-(2-propylidene)quinoline, 5,6,7,8-tetrahydro-3-methyl8(methylene)quinoline, and their acid addition salts.

The compounds of formula II may be prepared by dehydration of the corresponding compounds of formula Ill

wherein R1, R2, R3, R4, R5, Re, R7 and n are as defined above.

The dehydration may be carried out with usual dehydrating agents e.g. polyphosphoric acid or with acetic anhydride, (in which case an intermediate acetylated derivative may be formed, from which acetic acid is eliminated to give the compound of formula II).

It has been reported by Hahn and Epsztajn, Roczniki Chemie, 1964, 38, 989 that treatment of Vla or Vlb

with polyphosphoric acid gives the corresponding methylene compounds Vlla and Vllb

exclusively with no corresponding methyl isomer being formed. We have surprisingly found that compounds of formula I wherein R6 and R7 are hydrogen, can be obtained by treatment of a compound of formula IV wherein M is hydrogen with formaldehyde (which may be in the form of paraformaldehyde) in the presence of an organic acid anhydride, e.g. acetic anhydride.It is believed that an intermediate compound of formula Ill wherein R6 and R7 are both hydrogen is formed initially, this dehydrates to give a compound of formula II wherein Re and R7 are hydrogen and the compound of formula Il rearranges to give a compound of formula I wherein R6 and R7 are hydrogen. Previously compounds of formula I were relatively inaccessible see Rosen and Weber J. Org. Chem. 1977,42, 47-50 who obtained 8-methyl-5,6-dihydroquinoline by pyrolysis of 1-methyl-1(a-pyridinyl)-1,3-butadiene. However pyrolysis is not a satisfactory method of preparation especially for molecules carrying a variety of substituents.

Compounds of formula II may also be prepared by the Peterson reaction (J. Organic Chem. 1968,780; Carey and Toler ibid, 1976,41, 1966, Hudrik & Peterson J. Amer Chem Soc 1975,97, 1464) - see the scheme below.

An oxo compound of formula VIII is treated with a silicon compound IX under the conditions of the Peterson reaction to give a silyl compound X which is treated under acidic or basic conditions to give compound II. If the conditions of work up are acidic (e.g. sulphuric acid or trifluoroacetic acid) then compound X will usually be converted first into a compound X where M is H, but basic conditions (e.g.

sodium or potassium hydride) and use of fluoride ions (e.g. KF or LiF) usually result in direct formation of compound II. In the silicon compound IX, R6 and R7 are as previously defined in connection with formula I, M is an alkali metal especially lithium or MgHal where Mg denotes magnesium and Hal is chlorine, bromine or iodine, and the three R radicals may be the same or different and alkyl, cycloalkyl, aralkyl or aryl (which radicals may be as previously defined for R1, R2 etc.) or R is selected from electron donating substituents including alkoxy, cycloalkoxy, aralkoxy, aryloxy, alkylthio, cycloalkylthio, aralkylthio or arylthio, the group RbRCN- - wherein Rb and R0 are selected from alkyl, cycloalkyl, aryl and aralkyl (which radicals may be as previously defined for R1, R2 etc.) or Rb and RC may be joined to form a heterocyclic ring with the nitrogen atom (e.g. a piperidinyl or pyrrolidinyl ring, which may be substituted e.g. by alkyl). It is preferred that SiR3 is triloweralkylsilyl e.g. trimethylsilyl or triarylsilyl e.g. triphenylsilyl.

When the R radical is alkoxy or cycloalkoxy these radicals may be as defined above for R4 and R5. Aralkoxy and aryloxy radicals for R may be such radicals in which the aralkyl or aryl portions are as defined above for aralkyl or aryl radicals. Similarly when R radicals are alkylthio, cycloalkylthio, aralkylthio, or arylthio, the alkyl, cycloalkyl, aralkyl or aryl portions of these radicals may be as defined above for alkyl, cycloalkyl, aralkyl or aryl radicals.

The silicon compound IX starting materials may be prepared from corresponding compounds R3SiCHR6R7 by standard methods. The starting materials of formula VIII may be prepared as described in UK Patent Specification 1460457 or by analogous methods.

In a variation of the above reaction the compounds offormula II may be prepared by the following scheme:

A silicon compound of formula XI, where R1, R2, R3, R4, R5 R and n are as previously defined and Xis hydrogen, sodium, potassium or lithium is reacted with a carbonyl compound R6R7CO to obtain a silyl intermediate of formula XII which is converted to compound II by acid or base treatment as described for the previous reaction scheme. The starting compound Xl may be prepared as described in our UK Patent Application 8316273 (H-325) filed 15June 1983 or by analogous methods.Briefly a compound of formula

where M is sodium, potassium or lithium is treated with a silylating agent of formula R3SiHal where R is as defined above and Hal is chlorine, bromine or iodine, to obtain a compound of formula XI wherein Xis hydrogen and if desired treating this with a metal compound R M where M is sodium, potassium or lithium and R is alkyl, cycloalkyl, aralkyl or aryl or an amine residue to obtain a compound of formula Xl where X is sodium, potassium or lithium.

Alternatively compounds of formula II may be prepared by the Wittig reaction (see Peterson loc cit for references thereto).

The Wittig phosphorus reagent is prepared by reacting Ph3P with a compound R6R7CHBr. Compounds of formula I may be used as intermediates for the preparation of the corresponding

Compounds of formula XIV are intermediates for other compounds with anti-ulcer or anti-secretory activity e.g. the compounds of UK Patent Specification No. 1432378.

The invention is illustrated by the following Examples.

Example 1 3,8-Dimethyl-5, 6, 7,8-tetrahydroquinoline A mixture of 3-methyl-5,6,7,8-tetrahydroquinoline (100 ml) paraformaldehyde (309) and acetic an hydride (100 ml) was heated at reflux for 30 hours. The residue was distilled to give a mixture of starting tetrahydroquinoline and 3,8-dimethyl-5,6-dihydroquinoline and 3,8-dimethyl-5,6-dihydroquinoline (40g) bp. 126-180/15mm. Chromatography on silica gel (5009, Wo & m active, 100-200) using di-isopropyl ether gave 3,8-dimethyl-5,6-dihydroquinoline (229).

A solution of the dihydroquinoline (22g) in ethanol (200 ml.) was hydrogenated over 10% palladium on carbon (1 g) at 25 and 1 atmosphere. After the theoretical uptake had occurred (1.5 hours) the catalyst was removed by filtration, the filtrate evaporated and the residue distilled to give the title tetrahydroquinoline (229) bp. 1240/15mm C11H15N requires: C,81.9; H,9.4; N,8.7% Found: C,81.9, H,9.1, N,8.3%.

The catalyst in this example is a mixture of acetic anhydride and acetic acid, the acetic acid being produced in situ.

Example 2 The reaction described in Example 1, 1st paragraph, was followed in a time course experiment, samples being taken at intervals and composition analysed by glc. (Pye 104 C20M T = 200 ) Results were as follows: Compound Present

Starting Material Time 11/2 hours 20% 66% 7% 2l/2hours21% 61% 11% 41/4 hours 22% 51% 20% 61/2 hours 23% 42% 26% 30 hours 22% 0 68% Example 3 The reaction described in Example 1, first paragraph, was repeated employing various catalysts. The results are shown in the following table (for structures of compounds B and C - see Example 2).

Isomerisation of Compound B to Compound C using various Catalysts CatalystlReaction Reaction time Percentage of Conditions (hours) Compound C CH3CO2H, reflux 30 100 NaOAc, 5% Pd-C, EtOH, reflux 21.6 85.4 BR3-Et2O, dioxan, reflux 24 83 PPA, 1000 1.5 76a H3PO4, H2O, reflux 21.6 25.1 ZnCl2, dioxan, reflux 30 22.5 (CH3CO)2O, reflux 30 5 KOH, EtOH, 22" 30 5 a Severe decomposition of compound C was observed after 2 hours.

PPA = Polyphosphoric acid Example 4 f8Rti-5, 6, 7,8-tetrahydro-8-([2S"]-2-(2-hydroxy- 1-phenyl)propyl)-3-methylquinoline

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (209) and toluene (100 ml) was added 1.63 molar n-BuLi in hexane (93 ml) at -40 C. The resulting anion solution was added to a mixture of phenylacetone (50 ml) and toluene (100 ml) at -40 C. The solution was allowed to warm to room temperature and the excess n-BuLi was quenched by adding 2N HCI (90 ml). The excess solvent was removed by evaporation. The resultant aqueous mixture was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3 x 100 ml). The extracts were dried (MgS04) and the solvent removed by evaporation.The mixture of products was separated by chromatography [SiO2; cyclohexane - CH3CO2CH3 (4:1)]. Upon removal of the solvent by evaporation the product crystallised to give the title compound (2.25 g), m.p. 99-1 010C.

Found: C,81.1; H,8.1; N,4.7.

C19H23NO requires C,81.1; H,8.2; N,5.0%).

Example 5 [8R*]-5,6,7,8-tetrahydro-8-[(2R*]-2-(2-hydroxy- 1-phen yl)prop yl)-3-meth ylquinollne

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (209) and toluene (100ml) was added 1.63 molar n-BuLi in hexane (93ml) at -40 C. The resulting anion solution was added to a mixture of phenylacetone (50my) and toluene (100ml) at 400C. The resulting solution was allowed to warm to room temperature. The excess n-BuLi was quenched by adding 2N-HCl (90ml). The aqueous layer was separated, basified with saturated aqueous NaHCO3 solution, and extracted with Et2O (3 x 100 ml). The ethereal extracts were dried (MgSO4) and the solvent removed by evaporation.The mixture of products was separated by chromatography [SiO2; cyclohexane - methyl acetate (80:20)]. The solvent was removed by evaporation and the residue dissolved in Et2O, to which an ethereal solution of HCI (50ml) was added. The precipitate was collected by filtration, washed with Et2O, and dried in vacuo to give the title compound as a hydrochloride 11/2 hydrate (2.09g) m.p. 98-100"C.

(Found: C,66.2; H,7.5; N,3.9 C19H23NO.HCl. 312 H2O requires C,66.2; H,7.9; N,4.1%).

Example 6 5, 6, 7,8-tetrahydro-8-(l-hydroxyethyl)-3-methylquinollne

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20g) and dry THF (150 ml) was added 1.63 molar n-BuLi in hexane (108 ml) at -30 C. The resulting anion solution was added to a solution of acetaldehyde (50 ml) in anhydrous THF (50 ml) at -30 C. The solution was allowed to warm to room temperature. The excess n-BuLi was quenched with 2N-HCI (20 ml). The excess acetaldehyde and solvent were removed by evaporation. The resultant aqueous mixture was basified with saturated aqueous NaHCO3 solution and extracted with Et2O (3 x 100ml). The ethereal extracts were dried (MgSO4) and the solvent removed by evaporation.The mixture of products was separated by chromatography (SiO2; EtOAc). The solvent was removed by evaporation and the residue dissolved in Et2O to which ethereal HCI (50 ml) was added. The product was removed by filtration, washed with Et2O and dried in vacuo to give the title compound as the hydrochloride 1/4 hydrate (1.13 g) m.p. 172-175"C.

(Found: C,62.4; H,7.9; N,6.0 C12H17NO. HCI.1/4H2O requires C,62.1; N,8.0; N,6.0%).

Example 7 5,6,7,8- Tetrahydro-8-(2(2-hydroxy)propyl)-3-methylquinoline

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (23.44 g, 159 mmol) and toluene (200 ml) was added 1.63 molar n-BuLi in hexane (108 ml) at -40". After 15 mins. the resulting anion solution was added to a solution of acetone (100 ml) in toluene (200 ml). The solution was allowed to warm to room temperature and was treated with 2N-HCI (90 ml). The excess acetone was removed by evaporation in vacuo. The resultant aqueous mixture was basified with saturated aqueous NaHCO3 solution and extracted into Et2O (3 x 100 ml).

The ethereal extracts were dried (MgSO4) and the solvent removed by evaporation in vacuo. The mixture of products were separated by chromotography [SiO2; EtOAc-petrol (1:4)] to give the free base (7.303 g, 22%) of the title compound as a red oil.

A small quantity of the free base (0.744 g) was dissolved in Et2O and treated with ethereal HCI. The product was removed by filtration, washed with Et2O, and dried in vacuo to give the title compound as the hydrochloride, m.p. 140-144'.

(Found: C,63.2; H,8.3; N,5.5 C13H19NO.HCl. l/4H2O requires C,63.4; H,8.4; N,5.7%).

Example 8 5,6,7,8- Tetrah ydro-3-meth yl-8- (2-p rep yllden e)quinoline

Experimental Details A mixture of 5,6,7,8-tetrahydro-8-(2(2-hydroxy)propyl)-3-methylquinoline (3.044 g, 14.8 mmol) and polyphosphoric acid (20g) was vigorously stirred at 80-90" for 50 mins. and then poured into saturated aqueous Na2CO3 solution (200 ml). The aqueous solution was extracted with Et2O (2 x 100 ml) and the ethereal extracts dried (MgSO4) and evaporated in vacuo to give an oil. Purification by column chromatography trio2; hexanepropan-2-ol(1 :1)1 and bulb-to-bulb distillation gave the title compound (1.855 g, 67%) as a colourless oil, b.p. 150-5'/0.1 mm Hg (Found: C,83.25; H,9.3; N,7.5 C13H17N requires C,83.4; H,9.15; N,7.5%).

Claims

1. A compound of formula II

or an acid addition salt thereof, wherein R1, R2, R3, R4 and R5, Re and R7 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, R4 and R5 may also represent alkoxy, or cycloalkoxy, n is 1, 2 or 3 and, if more than one R4 radical is present the R4 radicals may be the same or different and R6 and R7 represent alkyl, cycloalkyl, or aralkyl radicals with the provisos that (1) when R1, R2, R3, R4 and R5 are all hydrogen, Re and R7 are not both hydrogen, and (2) when R1 and R3 are both phenyl and when R1 is methyl and R4 is methyl then R6 and R7 are not both methyl.

2. A compound of formula II, as claimed in Claim 1, wherein n is 2 and R1, R2, R3, R4 and R5 are selected from hydrogen and alkyl of 1 to 6 carbon atoms.

3. A compound of formula Ila

or an acid addition salt thereof wherein R1 is alkyl of 1 to 6 carbon atoms and Re and R7 are selected from hydrogen and alkyl of 1 to 6 carbon atoms.

4. 5,6,7,8-Tetrahydro-3-methyl-8-(2-propylidene) quinoline or an acid addition salt thereof.

5. 5,6,7,8-Tetrahydro-3-methyl-8(methylene) quinoline or an acid addition salt thereof.

6. A process for preparing a compound of formula II as claimed in Claim 1, which process comprises dehydrating a compound of formula Ill

or an acid addition salt thereof, wherein R1, R2, R3, R4 and R5, R6, R7 and n are as defined in Claim 1.

7. A process as claimed in Claim 6 wherein the compound of formula II is as defined in any one of Claims 2to5.

8. A process as claimed in Claim 6 or 7 wherein the dehydration is carried out using polyphosphoric acid or acetic anhydride.

9. A process as claimed in Claim 6 substantially as hereinbefore described in Example 8.

10. A compound of formula II whenever prepared by a process as claimed in any one of Claims 6 to 9.

11. A process for preparing a compound of formula II, as claimed in Claim 1, which process comprises treating under acidic or basic conditions, a compound of formula X

wherein R1, R2, R3, R4, Re, Re, R7 and n are as defined in Claim 1, M is an alkali metal or MgHal where Hal is chlorine, bromine or iodine, and the three R radicals may be the same or different and alkyl, cycloalkyl, aralkyl or aryl (which radicals may be as previously defined for R1, R2 etc.) or R is selected from electron donating substituents including alkoxy, cycloalkoxy, aralkoxy, aryloxy, alkylthio, cycloalkylthio, aralkylthio or arylthio, the group RbRCN- wherein Rb and Rc are selected from alkyl, cycloalkyl, aryl and aralkyl (which radicals may be as previously defined for R1, R2 etc.) or Rb and RC may be joined to form a heterocyclic ring with the nitrogen atom (e.g. a piperidinyl or pyrrolidinyl ring, which may be substituted e.g. by alkyl).

12. A process for preparing a compound of formula II, as claimed in Claim 1, which process comprises treating, under acidic conditions, a compound of formula XII

wherein R1, R2, R3, R4, Re, Re, R7 and n are as defined in Claim 1, Xis hydrogen, sodium, potassium or lithium and R is as defined in Claim 11.

13. A process for preparing a compound of formula II, as claimed in Claim 1,which process comprises reacting a compound of formula VIII

wherein R1, R2, R3, R4, R5 and n are as defined in Claim 1, with a Wittig phosphorus reagent of formula Ph3 = CR6R7 wherein R6 and R7 are as defined in Claim 1.

14. A compound of formula II whenever prepared by a process as claimed in any one of Claims 11 to 13.