IE61069B1

IE61069B1 - Process for the manufacture of isoquinolines

Info

Publication number: IE61069B1
Application number: IE80588A
Authority: IE
Inventors: Philippe Peter
Original assignee: Hoffmann La Roche
Priority date: 1987-03-20
Filing date: 1988-03-18
Publication date: 1994-09-21
Also published as: DE3862787D1; PH25036A; AU613605B2; DK168625B1; EP0283848B1; EP0283848A1; JP2507523B2; DK102388A; AU1307488A; JPS63238062A; DK102388D0; CA1310012C; HUT49123A; HU203876B; NZ223879A; IE880805L; 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

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-hydroxvphenyl or p-raethoxyphenyl, 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-toluenesulphonic acid in toluene or xylene at an elevated temper ature. i ' 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. ti In addition to the isoquinoline of formula I there are also obtained small amounts (4-7%) of the isomeric isoquinolines of the formulae la Ib Ic wherein R and S' 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 with p-toluenesulphonic acid.

The starting enamines of formula II can be prepared by a) reacting a solution of an amine of the formula ( R III i wherein R is methyl or benzyl, in toluene or xylene while heating with a solution of an aldehyde of the formula R'CH^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. Hater and toluene or xylene are distilled off in process variant a) and water and ether are distilled off in process variant b).

The solution of the aldehyde R'CH^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 R'CH-CHCOOH \ / IV 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 OH R'CH^CH OSO2Na \ 25 in aqueous diethyl ether in the presence of potassium carbonate at a temperature of about 1-3°C.

The compounds of formula Ϊ 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 3.54 g. of acetic acid are added dropwise to a mixture, heated to the boiling point, of 14 g (59 mmol) of potassium (E)-a„B-epoxy-p-methoxycinnamate, 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-raethoxyphenylacecaldehyde 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)ethylamine in 20 ml of toluene. After 1 hour under reflux there is obtained W-[(E)-p-methoxystyryl]-N-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-oetahyd.roisoquinoline of 90.8% (yield 83%) and a content of the isomers 1-(p-methoxybenzyl)-2-methyl-l,2,3,4,6,7.,8,8a5 -octahydroisoquinoline. 1-(ρ-methoxybenzyl)-2-methyl-1,, 2.3.4.4a „ 5 . 6 . 7-octahydroisoquinol ine and l-(p-methoxybenzyl)-2-methyl-l. 2,, 3,5.6,, 7« 8,8a-octahydroisoquinoline of all together 5%. d) 16.3 g of oxalate are precipitated by means of 4.5 g oxalic acid in 190 ml of acetone. The mixture of isomeric isoquinolines isolated from the mother liquor is isomerized to a large part to X-(p-methoxybenzyl)-2-methyl-1,2»3.4.5.6.7.8-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 0.56 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 l-(p-methoxybenzyl)-2-methyl2o -1.2.3.4.5.6.7.8-isoqulnoline.

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°C„, of 8.2 g (33 mmol) of sodium l-hydroxy-2-(p25 -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 3Q dried over sodium sulphate. The yield of p-methoxyphenylacetaldehyde amounts to 57%. b) The 125 ml of the ethereal p-methoxyphenylacetaldehyde solution prepared according to Example 2a) are added slowly to a solution of 3.48 g (16 mmol) of N-benzyl-2-(cyclohexen-l-yl)ethylamine in hexane at 50°C. The react5 ion water and the ether are distilled off. After reaction for 4 hours the resulting solution of N-benzyl-2-(cyclohexen-l-yl)-M-[(E)-p-methoxyscyrylJethylamine is added at 100°C to a solution of 36 g of p-toluenesulphonie acid in 250 ml of toluene. After reaction for 2 hours the mixture -^q 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)-!» 2.3,4,5,6,7.8-octahydroisoquinoline of 76.5%. Yield 79% based on the starting amine. r ί.

L/'

Claims

1. ο

1. A process for the manufacture of the isoquinolines of the formula 5 wherein R is methyl or benzyl and R' is phenyl, p-hydroxy phenyl or p-methoxyphenyl, which process comprises reacting a solution of an enamine of the formula 1q wherein R and R' have the above significance, in a hydrocarbon with an anhydrous solution of p-toluenesulphonic acid in toluene or xylene at an elevated temper ature.

2. A process according to claim 1, wherein R' is 15 p-methoxyphenyl, an aromatic hydrocarbon such as toluene ♦j or xylene is used as the hydrocarbon and the reaction , temperature amounts to between about 90 and 115°C, especi ’ ially about 110°C where R is methyl and about 100°C where R is benzyl.

3. A process for the preparation of the enamines of formula II according to claim 1, which process comprises 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'CH^CHO, wherein R' 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-hexane, 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. 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 IQ 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.