CA1310012C - Process for the manufacture of 1,2-disubstituted 1,2,3,4,5,6,7,8-octahydroisoquinolines - Google Patents
Process for the manufacture of 1,2-disubstituted 1,2,3,4,5,6,7,8-octahydroisoquinolinesInfo
- Publication number
- CA1310012C CA1310012C CA000559195A CA559195A CA1310012C CA 1310012 C CA1310012 C CA 1310012C CA 000559195 A CA000559195 A CA 000559195A CA 559195 A CA559195 A CA 559195A CA 1310012 C CA1310012 C CA 1310012C
- Authority
- CA
- Canada
- Prior art keywords
- solution
- formula
- toluene
- xylene
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
Abstract
Abstract A process for the manufacture of the isoquinolines of the formula (I) wherein R is methyl or benzyl and R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl, by reacting a solution of an enamine of the formula II
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 temper-ature.
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 temper-ature.
Description
R~N 4 o The present invention is concerned with a process for the manufacture of the isoquinolines of the formula ~)ÇN~R
R' wherein R is methyl or benzyl and R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl, 2G which process comprises reacting a solution of an enamine of the formula , l 11 1 ~ N~R
~ II
R' 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 temper-ature.
Aliphatic hydrocarbons such as n-hexane or, prefer-ably, aromatic hydrocarbons such as toluene or xylene are conveniently used as the hydrocarbon. The reaction is conveniently carried out at between about 90 and 115C, preferably at about 110C where R is methyl and at about 100C where R is benzyl.
Mé/13.1.88 ~31~3~2 In addition to the isoquinoline of formula I there are also obtained small amounts (4-7~) of the isomeric isoquinolines of the formulae ~`R GÇ R ~`R
R' R' R' la Ib Ic wherein R and R' have the above significance.
If desired, these byproducts can be isomerized to the isoquinolines of formula I, which can be carried out under the same process conditions as in the case of the con-version of the enamines of formula II into the isoquinolines of formula I by reaction with p-toluene-sulphonic acid.
The starting enamines of formula II can be prepared by a) reacting a solution of an amine of the formula ~~
~J N~i R III
~ 3 1 ~ 2 wherein R is methyl or benzyl, in toluene or xylene while heating with a solution of an aldehyde of the formula R~CH2CHO, wherein R~ is phenyl, p-hydcophenyl or especially p-methoxyphenyl, 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'CH2CHO.-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. Water and toluene or xylene are distilled off in process vaeiant a) and water and ether are distilled off in process variant b).
The solution of the aldehyde R'CHzCHO in toluene or xylene, which i6 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
o 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'CH2CH ~
OS02Na V
~ 3 ~
in aqueous diethyl ether in the presence of potassium carbonate at a tem~erature of abou~ 1-3C.
The compounds of formula I can be converted into morphinans such as dextromethorphan as described e.g.
in United States Patent 3,634,429 and Chemical Abstracts 51 (1957) 2876f.
Example 1 a) 70 ml of an aqueous solution of 3.64 g of ace~ic acid are added dropwise to a mixture, heated to the boiling point, of 14 g (59 mmol) of potassium (E)-a,~-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 2G are extracted with toluene. The organic ehase is dried azeotropically. The yield of p-methoxyphenylacetaldehyde 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-1-yl)ethylamine in 20 ml of toluene. After 1 hour under reflux there is obtained N-[(E)-p-methoxystyryl]-N-methyl-2-tcyclohexen-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 mix-ture 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 190C under 1 mbar.
There are obtained 13.6 g of a clear oil with a content of 1-(p-methoxybenzyl)-Z-methyl-1,2,3,4,5,6,7,8-octahydro-isoquinoline of 90.8% (yield 83%) and a content of the isomers l-(p-methoxybenzyl)-2-methyl-1,2,3,4,6,7,8,8a--octahydroisoquinoline, l-(p-methoxybenzyl)-2-methyl--1,2,3,4,4a,5,6,7-octahydroisoquinoline and l-(p--methoxybenzyl)-2-methyl-1,2,3,5,6,7,8,8a-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 l-(p-methoxybenzyl)-2--methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline by treatment with p-toluenesulphonic acid as described in Example lc).
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. Afte~ 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 1-3C, of 8.2 g (33 mmol) 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 L26 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 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 react-ion water and the ether are distilled off. ~fter reaction for 4 hours the resulting solution of N-benzyl-2-(cyclo-hexen-l-yl)-N-r(E)-p-methoxystyryl]ethylamine is added at 100C 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 hyd~oxide solu-tion. 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--l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline of 76.5%. Yield 79% based on the starting amine.
. -
R' wherein R is methyl or benzyl and R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl, 2G which process comprises reacting a solution of an enamine of the formula , l 11 1 ~ N~R
~ II
R' 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 temper-ature.
Aliphatic hydrocarbons such as n-hexane or, prefer-ably, aromatic hydrocarbons such as toluene or xylene are conveniently used as the hydrocarbon. The reaction is conveniently carried out at between about 90 and 115C, preferably at about 110C where R is methyl and at about 100C where R is benzyl.
Mé/13.1.88 ~31~3~2 In addition to the isoquinoline of formula I there are also obtained small amounts (4-7~) of the isomeric isoquinolines of the formulae ~`R GÇ R ~`R
R' R' R' la Ib Ic wherein R and R' have the above significance.
If desired, these byproducts can be isomerized to the isoquinolines of formula I, which can be carried out under the same process conditions as in the case of the con-version of the enamines of formula II into the isoquinolines of formula I by reaction with p-toluene-sulphonic acid.
The starting enamines of formula II can be prepared by a) reacting a solution of an amine of the formula ~~
~J N~i R III
~ 3 1 ~ 2 wherein R is methyl or benzyl, in toluene or xylene while heating with a solution of an aldehyde of the formula R~CH2CHO, wherein R~ is phenyl, p-hydcophenyl or especially p-methoxyphenyl, 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'CH2CHO.-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. Water and toluene or xylene are distilled off in process vaeiant a) and water and ether are distilled off in process variant b).
The solution of the aldehyde R'CHzCHO in toluene or xylene, which i6 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
o 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'CH2CH ~
OS02Na V
~ 3 ~
in aqueous diethyl ether in the presence of potassium carbonate at a tem~erature of abou~ 1-3C.
The compounds of formula I can be converted into morphinans such as dextromethorphan as described e.g.
in United States Patent 3,634,429 and Chemical Abstracts 51 (1957) 2876f.
Example 1 a) 70 ml of an aqueous solution of 3.64 g of ace~ic acid are added dropwise to a mixture, heated to the boiling point, of 14 g (59 mmol) of potassium (E)-a,~-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 2G are extracted with toluene. The organic ehase is dried azeotropically. The yield of p-methoxyphenylacetaldehyde 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-1-yl)ethylamine in 20 ml of toluene. After 1 hour under reflux there is obtained N-[(E)-p-methoxystyryl]-N-methyl-2-tcyclohexen-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 mix-ture 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 190C under 1 mbar.
There are obtained 13.6 g of a clear oil with a content of 1-(p-methoxybenzyl)-Z-methyl-1,2,3,4,5,6,7,8-octahydro-isoquinoline of 90.8% (yield 83%) and a content of the isomers l-(p-methoxybenzyl)-2-methyl-1,2,3,4,6,7,8,8a--octahydroisoquinoline, l-(p-methoxybenzyl)-2-methyl--1,2,3,4,4a,5,6,7-octahydroisoquinoline and l-(p--methoxybenzyl)-2-methyl-1,2,3,5,6,7,8,8a-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 l-(p-methoxybenzyl)-2--methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline by treatment with p-toluenesulphonic acid as described in Example lc).
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. Afte~ 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 1-3C, of 8.2 g (33 mmol) 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 L26 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 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 react-ion water and the ether are distilled off. ~fter reaction for 4 hours the resulting solution of N-benzyl-2-(cyclo-hexen-l-yl)-N-r(E)-p-methoxystyryl]ethylamine is added at 100C 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 hyd~oxide solu-tion. 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--l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline of 76.5%. Yield 79% based on the starting amine.
. -
Claims (6)
1. A process for the manufacture of the isoquinolines of the formula I
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 II
wherein R and R' have the above significance, in a hydrocarbon solvent with an anhydrous solution of p-toluene-sulphonic acid in touluene or xylene at a temperature between about 90° and 115°C.
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 II
wherein R and R' have the above significance, in a hydrocarbon solvent with an anhydrous solution of p-toluene-sulphonic acid in touluene or xylene at a temperature between about 90° and 115°C.
2. A process according to claim 1, wherein R' is p-methoxyphenyl, the hydrocarbon utilized is toluene or xylene, and the reaction temperature amounts to about 110°C where R is methyl, and about 100°C where R is benzyl.
3. A process for the preparation of the isoquinolines of formula I 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'CH2CHO, wherein R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl, in toluene or xylene, or (b) reacting a solution of the amine III in a hydrocarbon solvent, while heating with an ethereal solution of the aldehyde R'CH2CHO, and, (c) reacting the obtained enamine of formula II in claim 1, in the manner set out in claim 1.
wherein R is methyl or benzyl, in toluene or xylene while heating with a solution of an aldehyde of the formula R'CH2CHO, wherein R' is phenyl, p-hydroxyphenyl or p-methoxyphenyl, in toluene or xylene, or (b) reacting a solution of the amine III in a hydrocarbon solvent, while heating with an ethereal solution of the aldehyde R'CH2CHO, and, (c) reacting the obtained enamine of formula II in claim 1, in the manner set out in claim 1.
4. A process as in claim 3, wherein the hydrocarbon in step (b) is an aliphatic hydrocarbon.
5. A process as in claim 4, wherein the aliphatic hydrocarbon is n-hexane.
6. A process as in any one of claims 3, 4 or 5, wherein the heating in step (b) is carried out under reduced pressure.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1064/87 | 1987-03-20 | ||
| CH106487 | 1987-03-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1310012C true CA1310012C (en) | 1992-11-10 |
Family
ID=4201606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000559195A Expired - Fee Related CA1310012C (en) | 1987-03-20 | 1988-02-18 | Process for the manufacture of 1,2-disubstituted 1,2,3,4,5,6,7,8-octahydroisoquinolines |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0283848B1 (en) |
| JP (1) | JP2507523B2 (en) |
| AT (1) | ATE63545T1 (en) |
| AU (1) | AU613605B2 (en) |
| CA (1) | CA1310012C (en) |
| DE (1) | DE3862787D1 (en) |
| DK (1) | DK168625B1 (en) |
| HU (1) | HU203876B (en) |
| IE (1) | IE61069B1 (en) |
| NZ (1) | NZ223879A (en) |
| PH (1) | PH25036A (en) |
| ZA (1) | ZA881811B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE834103C (en) * | 1950-01-03 | 1952-03-17 | Bayer Ag | Process for the preparation of 1-benzyl-1, 2, 3, 4, 5, 6, 7, 8, -octahydroisoquinoline |
| DE908138C (en) * | 1951-01-16 | 1954-04-01 | Hoffmann La Roche | Process for the preparation of 1-benzyl-2-alkyl-1,2,3,4,5,6,7,8, -octa-hydroisoquinolines and their salts |
| DE1003211B (en) * | 1952-06-16 | 1957-02-28 | Hoffmann La Roche | Process for the preparation of 1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinolines optionally substituted in the benzyl radical and their salts |
| DE955769C (en) * | 1953-08-13 | 1957-01-10 | Hoffmann La Roche | Process for the racemization of optically active 1- (p-methoxybenzyl) -2-methyl-octahydroisoquinolines |
-
1988
- 1988-02-18 CA CA000559195A patent/CA1310012C/en not_active Expired - Fee Related
- 1988-02-26 DK DK102388A patent/DK168625B1/en not_active IP Right Cessation
- 1988-03-09 AT AT88103666T patent/ATE63545T1/en not_active IP Right Cessation
- 1988-03-09 DE DE8888103666T patent/DE3862787D1/en not_active Expired - Fee Related
- 1988-03-09 EP EP88103666A patent/EP0283848B1/en not_active Expired - Lifetime
- 1988-03-14 AU AU13074/88A patent/AU613605B2/en not_active Ceased
- 1988-03-14 ZA ZA881811A patent/ZA881811B/en unknown
- 1988-03-15 NZ NZ223879A patent/NZ223879A/en unknown
- 1988-03-16 JP JP63060667A patent/JP2507523B2/en not_active Expired - Lifetime
- 1988-03-16 HU HU881239A patent/HU203876B/en not_active IP Right Cessation
- 1988-03-18 PH PH36664A patent/PH25036A/en unknown
- 1988-03-18 IE IE80588A patent/IE61069B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ223879A (en) | 1991-01-29 |
| AU1307488A (en) | 1988-09-22 |
| DK102388A (en) | 1988-09-21 |
| DK168625B1 (en) | 1994-05-09 |
| PH25036A (en) | 1991-01-28 |
| ZA881811B (en) | 1988-09-20 |
| DE3862787D1 (en) | 1991-06-20 |
| JP2507523B2 (en) | 1996-06-12 |
| DK102388D0 (en) | 1988-02-26 |
| AU613605B2 (en) | 1991-08-08 |
| JPS63238062A (en) | 1988-10-04 |
| EP0283848A1 (en) | 1988-09-28 |
| ATE63545T1 (en) | 1991-06-15 |
| IE61069B1 (en) | 1994-09-21 |
| HUT49123A (en) | 1989-08-28 |
| IE880805L (en) | 1988-09-20 |
| HU203876B (en) | 1991-10-28 |
| EP0283848B1 (en) | 1991-05-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |