GB2148284A - Quinoline derivatives and homologues - Google Patents

Abstract

Novel Compounds III may be converted into compounds via compounds II. <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. Compounds III may be prepared by reaction of compound IV with the appropriate carbonyl compound. The present invention concerns the novel compounds III, their carboxylic esters and acid addition salts wherein R<1>, R<2>, R<3>, R<4>, R<5> and n are as defined above and R<6> and R<7> are other than hydrogen when R<1>, R<2>, R<3>, R<4> and R<5> are all hydrogen and R<6> and R<7> are not both methyl when R<4> is methyl. Preparation of compounds III is also covered. <IMAGE>

Description

SPECIFICATION Quinoline derivatives The invention relates to quinoline derivatives and especially to intermediates for 5,6-dihydroquinolines and related compounds, to novel processes for preparing the intermediates.

In our copending application 8401333 (Serial No. 2136799), from which the present application is divided, we have described a process for preparing dihydro compounds of formula I

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 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 hydrogen, alkyl, cycloalkyl, or aralkyl radicals, which process comprises re-arranging a compound of formula II

wherein R1, R2, R3, R4, P, R6, R7 and n are as defined above.

The re-arrangement of compound II 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[(C6H5)3P]3 Ru3(CO)12 or Ircl(co)[(c6H5)3p]2 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 I and other compounds of the invention.

When any of R1, 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 cycloalkoxy the 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 R1, R2, R3, R4 of R5 is an aryl group it is preferably phenyl or substituted phenyl (substituted by e.g. alkyl, alkoxy or trifluoromethyl). The aryl portion of an aralkyl group may be substituted as described for a phenyl group.

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

wherein R', R2, R3, R4, R5, R5, R7 and n are as defined above. The present invention is concerned with the compounds of formula Ill and their acid addition salts and esters of carboxylic acids wherein R1, R2, R3, R4, R5 and n are as defined above in connection with formula I and R6 and R7 are other than hydrogen when R1, R2, R3, R4 and R5 are all hydrogen and R6 and R7 are not both methyl when R4 is methyl.

Preferred compounds of formula III are the sub group of formula 1IIA

or an acid addition salt thereof wherein R1 is lower alkyl and R6 and R7 are selected from hydrogen, lower alkyl, cycloalkyl, or lower aralkyl radicals. Examples are [8R*]-5,6,7,8-tetrahydro-8-([2S*]-2-(2-hydroxy-1- phenyl)propyl)-3-methylquinoline, 5,6,7,8-tetrahydro-8-(2(2-hydroxy)propyl )-3-methylquinoline and their acid addition salts.

The compounds of formula Ill may be prepared by treatment of a compound of formula IV

wherein R1, R2, R3, R4, R5 and n are as defined in connection with formula I, and M is hydrogen, an alkali metal (e.g. sodium, potassium or lithium) or MgHaI, where Hal is chlorine, bromine or iodine, with a carbonyl compound of formula V

wherein R6 and R7 are as defined in connection with formula I, with the proviso that when RB and R7 are both hydrogen then M is hydrogen.

The invention is illustrated by the following Examples, Nos. 1,2,3 and 8 are reference 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 anhydride (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 (409) bp. 126-1 801 5 mm. Chromatography on silica gel (500g, Woelm 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 (1g) 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 (22g) bp. 124'115 mm.

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, first paragraph, was followed in a time course experiment, samples being taken at intervals and composition analysed by glc. (Pye 104 C2OM T = 200 ). Results were as follows: Compound Present

Starting Material (A) (B) (C) Time 11/2 hours 20% 66% 7% 21/2 hours 21% 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 Catalyst/Reaction Reaction time Percentage of Conditions (hours) Compound C CH3CO2H, reflux 30 100 NaOAc, 5% Pd-C, EtOH, reflux 21.6 85.4 BF3-Et2O, dioxan, reflux 24 83 PPA, 100 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 f8R*j-5, 6,7, 8-tetrah ydro -8-(f2S*j-2-(2-h ydroxy- 1-phen yl)prop yl)-3-meth ylquin oline

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20g) and toluene (100 ml) was added 1.63 molar n-BuLi in hexane (93 ml) at -400C. 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 100ml). The extracts were dried (MgSO4) and the solvent removed by evaporation.The mixture of products was separated by chromatography [SiO2; cyclohexane - CH3CO2CH3 (4:1)1. Upon removal of the solvent by evaporation the product crystallised to give the title compound (2.25 g), mp. 99-1 01 C.

(Found: C,81.1; H,8.1; N,4.7. C19H23NO requires C, 81.1; H, 8.2; N,5.0%).

EXAMPLE 5 18R*j-5, 6,7, 7,8-tetrahydro-8-z[2R*z-2-r2-hydroxy- 1-phen yl)prop yl)-3-methylquin oline

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) 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 resulting solution was allowed to warm to room temperature. The excess n-BuLi was quenched by adding 2N-HCI (90 ml). 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 (50 ml) 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 (2.09 g) m.p. 98-100"C.

(Found: C,66.2; H,7.5; N,3.9. C18H23NO.HCl. 3/2 H2O requires C,66.2; H,7.9; N,4.1%).

EXAMPLE 6 5,6, 7,8-tetraXydro-8-{1-hydroxyethyl)-3-methylquinoline

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) 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 100 ml). 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-h ydroxy)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)1 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. C13H1gNO.HCI.1/4H2O requires C,63.4; H,8.4; N,5.7%).

EXAMPLE 8 5,6,7,8- Tetrahydro-3-methyl-8-r2-propylidene)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 (20 g) 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 [SiO2; hexanepropan-2-ol(1 :1)] and bulb-to-bulb distillation gave the title compound (1.855 g, 67%) as a colourless oil, b.p. 1 50-5'/0.1 mm Hg (Found: C,83.25; H,9.3; N, 7.5 C73H17N requires C,83.4; H,9.15; N,7.5%).

Claims (8)

1. A compound of formula Ill

or an acid addition salt thereof, wherein R1, R2, R3, R4 and R5, R5 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 and esters of carboxylic acids wherein R1, R2, R3, R4, R5 and n are as defined above and R6 and R7 are other than hydrogen when R', R2, R3, R4 and R5 are all hydrogen and R6 and R7 are not both methyl when R4 is methyl.

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

3. A compound of formula IIIA

or an acid addition salt thereof wherein R1 is alkyl of 1 to 6 carbon atoms and R6 and R7 are selected from hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl, or aralkyl of 1 to 12 carbon atoms.

4. [8R*]-5,6,7,8-([2S*]-2-(2-hydroxy-1 -phenyl)propyl)-3-methylquinoline, the 2R* isomer thereof, or an acid addition salt thereof.

5. 5,6,7,8-Tetra hydro-8-(2-hydroxy)propyl-3-methyl-quinoline or an acid addition salt thereof.

6. A process for preparing a compound of formula III as claimed in Claim 1, which process comprises treating a compound of formula IV

wherein R1,R2,R3,R4,R5 and n are as defined in Claim 1 and M is hydrogen, an alkali metal, or MgHal where Hal is chlorine, bromine or iodine with a carbonyl compound of formula V

wherein R6 and R7 are as defined in Claim 1, with the proviso that when R6 and R7 are both hydrogen then M is hydrogen.

7. A process as claimed in Claim 6, substantially as hereinbefore described in any one of Examples 4,5,6 or7.

8. A compound of formula Ill, whenever prepared by a process as claimed in Claim 6 or Claim 7.