IE880805L

IE880805L - Process for the manufacture of isoquinolines

Info

Publication number: IE880805L
Application number: IE880805A
Authority: IE
Inventors: Philippe Peter
Original assignee: Hoffmann La Roche
Priority date: 1987-03-20
Filing date: 1988-03-18
Publication date: 1988-09-20
Also published as: DE3862787D1; PH25036A; AU613605B2; DK168625B1; EP0283848B1; EP0283848A1; JP2507523B2; DK102388A; AU1307488A; JPS63238062A; DK102388D0; IE61069B1; CA1310012C; HUT49123A; HU203876B; NZ223879A; ATE63545T1; ZA881811B

Abstract

Process for the preparation of isoquinolines of the formula <IMAGE> in which R is methyl or benzyl and R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl, characterised in that a solution of an enamine of the formula <IMAGE> in which R and R' have the above meaning, is reacted in a hydrocarbon with an anhydrous solution of p-toluenesulphonic acid in toluene or xylene at elevated temperature.

Description

6 r\ b 9 ^5) C The present invention is concerned with a process for the manufacture of the isoquinolines of the formula wherein R is methyl or benzyl and R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl„ which process comprises reacting a solution of an enamine of the formula wherein R and R1 have the above significance„ in a hydrocarbon with an anhydrous solution of p-toluene-sulphonic acid in toluene or xylene at an elevated temper ature.

Aliphatic hydrocarbons such as n-hexane or, preferably, aromatic hydrocarbons such as toluene or xylene are conveniently used as the hydrocarbon. The reaction is conveniently carried out at between about 90 and 115°C„ preferably at about 110°C where R is methyl and at about 100°C where R is benzyl. 9 «> In addition to the isoquinoline of formula I there are ; also obtained small amounts (4-7%) of the isomeric isoquinolines of the formulae [/ la lb 10 therein a and R' have the above significance. If desired,, these byproducts can be isomerised to the isoquinolines of formula I, which can be carried out under the same process conditions as in the case of the conversion of the enamines of formula II into the isoquinolines of formula I by reaction urith p-toluene-sulphonic acid.

The starting enamines of formula II can be prepared by a) reacting a solution of an amine of the formula III wherein R is methyl or benzyl, in toluene or xylene while heating with a solution of an aldehyde of the formula R'Ct^CHO, wherein R' is phenyl, p-hydrophenyl or especially p-raethoxyphenyl„ in toluene or xylene,, or b) reacting a solution of the amine III in a hydrocarbon, especially an aliphatic hydrocarbon such as n-hexane, while heating, optionally under reduced pressure, with an ethereal solution of the aldehyde R'CH^CHO.~ As the hydrocarbon in process variant b) there can be used one which is suitable for the conversion of a compound of formula II into a compound of formula I, preferably n-hexane. Mater and toluene or xylene are distilled off in process variant a) and aater and ether are distilled off in process variant b).

The solution of the aldehyde R'CB^CHO in toluene or xylene, which is used in process variant a)„ can be obtained by heating to reflux temperature a suspension of an alkali metal salt or alkaline earth metal salt of the corresponding glycidic acid of the formula R1 CH-CHCOOH \ / T. T preferably potassium glycidate, in toluene or xylene in the presence of aqueous acetic acid. The ethereal aldehyde solution which is used in process variant b) can be obtained by treating a suspension of a sulphonate of the formula R'CH-CH^ ^ 0S02Na V in aqueous diethyl ether in the presence of potassium carbonate at a temperature of about 1-3°C.

The compounds of formula 1 can be converted as described e.g. in Swiss Patent Specification No. 543514. into morphinans such as dextromethorphan.

Example 1 a) 70 ml of an aqueous solution of 3.64 g. of acetic acid are added dropwise to a mixture, heated to the boiling point,, of 14 g (59 mmol) of potassium (E)-a„fi-epoxy-p- -raetho xy einnamace„ 112 ml of toluene and 28 ml of water. After 5 minutes the mixture is cooled to room temperature. The organic phase is washed with water and then with aqueous potassium carbonate solution. The aqueous washings are extracted with toluene. The organic phase is dried azeotropically. The yield of p-raethoxyphenylacetaldehyde in the solution obtained amounts to 92-94%. b) The solution of p-methoxyphenylacetaldehyde in 200 ml of toluene, prepared according to Example la),, is added under reflux within one hour to a mixture of 78 g (55.5 mmol) of N-methyl-2- (cyclohexen-l-yl) ethyl amine in 20 ml of toluene. After 1 hour under reflux there is obtained N-[ (E)-p-methoxystyryl]-!>J-methyl-2- (cyclohexen-1--yl)ethylamine (yield 95.3%) dissolved in toluene. c) The solution prepared according to Example lb) is added to a solution of dry p-toluenesulphonic acid (corresponding to 60 g of monohydrate) in 600 ml of toluene. After heating under reflux for 3 hours the mixture is cooled and made alkaline with 40% sodium hydroxide solution. After extraction with toluene, washing with water and concentration of the organic phase there is obtained an oil which is distilled at 190°C under 1 mbar.

There are obtained 13„6 g of a clear oil with a content of 1-(p-methoxybenzyl)-2-methyl-l» 2.3,4,5,6,7,8-octahydro-isoquinoline of 90.8% (yield 83%) and a content of the isomers 1-(p-methoxybenzyl)-2-methyl-l,2.3,4,6,7„8„8a--octahydroisoquinoline„ l-(p-methoxybenzyl)-2-methy1--1„2.3,4„4a,5,6,7-octahydroisoquinoline and 1-(p--methoxybenzyl)-2-methyl-l2, 3, 5, 6,7, 8, 8a-octahydro-isoquinoline of all together 5%, d) 16.3 g of oxalate are precipitated by means of 4.5 g of oxalic acid in 190 ml of acetone. The mixture of isomeric isoquinolines isolated from the mother liquor is isomerized to a large part to 1-(p-methoxvbenzyl)-2--methy1-1,2,3,4,5,S,7,8-octahydroisoquinoline by treatment with p-toluenesulphonic acid as described in Example 1c). 0.66 g of oxalate is obtained from this mixture by again precipitating with 0.5S g of oxalic acid in 15 ml of acetone. After liberation of the oxalate there are obtained 12.7 g (yield 83.5% based on the starting amine) of more than 99% pure 1-(p-methoxybenzyl)-2-methyl--1,2,3,4,5,6,7,8-isoquinoline.

Example 2 a) 16.8 ml of an aqueous solution of 10 g of potassium carbonate are added within 5 minutes to a mixture, cooled to 1-3 °Cof 8.2 g (33 ramo 1) of sodium 1-hydroxy-2- (p--methoxyphenyl)ethylsulphonate. 8.4 ml of water and 84 ml of diethyl ether. The mixture is left to warm to room temperature for 1 hour and 126 ml of water are then added. The organic phase is washed with water and the aqueous phase is washed with ether. The organic phase is then dried over sodium sulphate. The yield of p-methoxyphenyl-acetaldehyde amounts to 57%. b) The 125 ml of Che ethereal p-methoxyphenylacetaldehyde solution prepared according to Example 2a) are added slowly to a solution of 3.48 g (16 ramol) of N-benzyl-2--(cyclohexen-l-yl)ethylamine in hexane at 50°C. The reaction water and the ether are distilled off. After reaction for 4 hours the resulting solution of N-benzyl-2-(cyclo-hexen-l-yl)-N-[(E)-p-methoxvstyryl]ethylamine is added at 100°C to a solution of 36 g of p-toluenesulphonic acid in 250 ml of toluene. After reaction for 2 hours the mixture is cooled and made alkaline with sodium hydroxide solution. The organic phase is washed with water. The aqueous phase is extracted with toluene. The organic phase is dried over sodium sulphate,, filtered and evaporated. There are obtained 5.72 g of an oil with a content of 2-benzyl--1- (p-methoxybenzyl) -1„ 2 „ 3 , 4 „ 5, 6, 7» 8-octahyd.roisoquino line of 76.5%. Yield 79% based on the starting amine. 8

Claims

1. A process for Che manufacture of the isoquinolines of the formula R I wherein R is methyl or benzyl and R' is phenyl, p-hydroxyphenyl or p-mechoxyphenyl„ which process comprises reacting a solution of an enamine of the formula wherein R and R' have the above significance, in a hydrocarbon with an anhydrous solution of p-toluene-sulphonic acid in toluene or xylene at an elevated temperature .

2. A process according to claim 1, wherein R' is p-methoxyphenyl, an aromatic hydrocarbon such as toluene or xylene is used as the hydrocarbon and the reaction temperature amounts to between about 90 and 115°C\, especially about 110°C where R is methyl and about 100°C where R is benzyl. II R*

3. A process foe the preparation formula II according to claim 1» which of the enamines of process comprises a) reacting a solution of an amine of the formula R wherein R is methyl or benzyl,, in toluene or xylene whlie heating with a solution of an aldehyde of the formula R'CH^CHO, wherein E1 is phenyl, p-hydrophenyl or especially p-methoxyphenyl, in toluene o xylene, or b) reacting a solution of the amine III in a hydrocarbon especially an aliphatic hydrocarbon such as n-hexanee while heating, optionally under reduced pressure, with an ethereal solution of the aldehyde R'CH?CHO.

4. A process according to claim 1 for the manufacture of an isoquinoline of the formula (I) given and defined in claim 1, substantially as hereinbefore described and exemplified.

5. An isoquinoline of the formula (I) given and defined in claim 1, whenever manufactured by a process claimed in any one of claims 1, 2 or 4.

6. A process according to claim 3 for the preparation of an enamine of the formula (II) given and defined in claim 1, substantially as hereinbefore described and exemplified.

7. An enamine of the formula (II) given and defined in claim 1, whenever prepared by a process claimed in claim 3 or 6. Dated this the 18th day of March, 1988 F. R. KELLY & C0„ BY: EXECUTIVE 1/ ' ^ 27 Clyde RoadP Ballsbridge? Dublin 4 AGENTS FOR THE APPLICANTS.