AU613605B2 - Process for the manufacture of isoquinolines - Google Patents
Process for the manufacture of isoquinolines Download PDFInfo
- Publication number
- AU613605B2 AU613605B2 AU13074/88A AU1307488A AU613605B2 AU 613605 B2 AU613605 B2 AU 613605B2 AU 13074/88 A AU13074/88 A AU 13074/88A AU 1307488 A AU1307488 A AU 1307488A AU 613605 B2 AU613605 B2 AU 613605B2
- Authority
- AU
- Australia
- Prior art keywords
- formula
- solution
- toluene
- hydrocarbon
- xylene
- 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.)
- Ceased
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
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
613605 S F Ref: 50556 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: Address for Service: F Hoffmann-La Roche Co Aktiengesellschaft Grenzacherstrasse 124-184 4002 Basle
SNITZERLAND
Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Process for the Manufacture of Isoquinolines The following statement is a full description of this best method of performing it known to me/us invention, including the 5845/5
B
I-
RAN 4001/111 Abstract A process for the manufacture of the isoquinolines of the formula 00 0000 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
NR
CJ^
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 temperature.
1/ I L 71r 1A- RAN 4001/111 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
N
wherein R and R' have the above significance, 3 in a hydrocarbon with an anhydrous solution of p-toluenesulphonic acid in toluene or xylene at an elevated temperature.
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 0
C,
preferably at about 110 0 C where R is methyl and at about 100 0 C where R is benzyl.
M4/13.1.88 Irl_ I -r :Ih 2 In addition to the isoquinoline of formula I there are also obtained small amounts of the isomeric isoquinolines of the formulae 'R 'R
R
R' R' R' la lb 1c 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 conversion of the enamines of formula II into the isoquinolines of formula I by reaction with p-toluene-sulphonic acid.
According to a second embodiment of this invention, there is provided 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 SNH III
R
wherein R is methyl or benzil, in toluene or xylene while heating with a solution of an aldehyde of the formula R'CH 2 CHO, 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 while heating, optionally under reduced pressure, with an ethereal solution of the aldehyde R'CH 2
CHO.
LMM/548Z
J
3 Typically, in the process variant a) of the second embodiment, R' is p-methoxyphenyl and the vhdrocarbon is n-hexane.
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 variant a) and water and ether are distilled off in process variant b).
Fhe solution of the aldehyde R'CH 2 CHO in toluene or xylene, which is used in process variant can be obtained by heating to reflux temperature a suspension of an alkali metal salt or alkaline earth metal salt of the corresponding clycidic acid of the formula
R'CH-CHCOOH
0 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
2 CH V OSO2Na 2 LMM/548Z LMM/548Z I f I-4 in aqueous diethyl ether in the presence of potassium carbonate at a temperature of about 1-3 0
C.
i The compounds of formula I can be converted as i described e.g. in Swiss Patent Specification No. 543514 i into morphinans such as dextromethorphan.
Ij Example 1 Sa) 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,3-epoxy-p- -methoxycinnamate, 112 ml of toluene and 28 ml of water.
After 5 minutes the mixture is cooled to room temperature.
i 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 j azeotr.opically. The yield of p-methoxyphenylacetaldehyde in the solution obtained amounts to 92-94%.
Sb) 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 ml of toluene. After 1 hour under reflux there is obtained N-[(E)-p-methoxystyryl]-N-methyl-2-(cyclohexen-l- 30 -yl)ethylamine (yield 95.3%) dissolved in toluene.
c) The solution prepared according to Example Ib) 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 0 C under 1 mbar.
Ii A There are obtained 13.6 g of a clear oil with a content of 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline 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, 1-(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-octahydroisoquinoline of all together 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 Ic).
*0.66 g of oxalate is obtained from this mixture by again 0 precipitating with 0.56 g of oxalic acid in 15 ml of 0; .acetone. After liberation of the oxalate there are obtained 12.7 g (yield 83.5% based on the starting amine) Sof more than 99% pure 1-(p-methoxybenzyl)-2-methyl- -1,2,3,4,5,6,7,8-isoquinoinoline.
S. 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 S to 1-3 0 C. of 8.2 g (33 mmol) of sodium l-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-methoxyphenylacetaldehyde amounts to 57%.
6 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 0 C. The reaction water and the ether are distilled off. After reaction for 4 hours the resulting solution of N-benzyl-2-(cyclohexen-l-yl)-N-[(E)-p-methoxystyryljethylamine is added at 100 0 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-octahydroisoquinoline of 76.5%. Yield 79% based on the starting amine.
J*
Claims (6)
1. A process for the manufacture of the isoquinolines of the formula NI iTR 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 ,N 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 temperature.
2. A process according to claim 1, wherein R' is p-methoxyphenyl, an aromatic hydrocarbon is used as the hydrocarbon and the reaction temperature is between about 900 and 115°.
3. A process according to claim 1 or 2, wherein the hydrocarbon S ;is toluene or xylene and wherein the reaction temperature is about 110C where R is methyl and about 1000C where R is benzyl.
4. 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 H III R y R< wherein R is methyl or benzyl, 0 in toluene or xylene while heating with a solution of an aldehyde of the LMM/548Z .4 Al 8 formula R'CH 2 CHO, 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 while heating, optionally under reduced pressure, with an ethereal solution of the aldehyde R'CH 2 CHO. A process according to claim 4, wherein R' is p-methoxyphenyl and the hydrocarbon is n-hexane.
6. A process for the manufacture of isoquinolines of formula I as defined in claim 1, which process is substantially as herein described with reference to Example 1 or Example 2.
7. A process for the preparation of enamines of formula II as defined in claim 1, which process is substantially as herein described with reference to Example 1 or Example 2. DATED this THIRTY-FIRST day of MAY 1991 F Hoffmann-La Roche Co Aktiengesellschaft Patent Attorneys for the Applicant SPRUSON FERGUSON LMM/548Z P
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1064/87 | 1987-03-20 | ||
| CH106487 | 1987-03-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1307488A AU1307488A (en) | 1988-09-22 |
| AU613605B2 true AU613605B2 (en) | 1991-08-08 |
Family
ID=4201606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU13074/88A Ceased AU613605B2 (en) | 1987-03-20 | 1988-03-14 | Process for the manufacture of isoquinolines |
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) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU242661A (en) * | 1960-03-18 | 1963-03-14 | F. Hoffmann-Laroche G Co. Aktiengesellschaft | Octahydroisoquinoline derivatives and process forthe manufacture thereof |
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 EP EP88103666A patent/EP0283848B1/en not_active Expired - Lifetime
- 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
- 1988-03-14 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 HU HU881239A patent/HU203876B/en not_active IP Right Cessation
- 1988-03-16 JP JP63060667A patent/JP2507523B2/en not_active Expired - Lifetime
- 1988-03-18 PH PH36664A patent/PH25036A/en unknown
- 1988-03-18 IE IE80588A patent/IE61069B1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU242661A (en) * | 1960-03-18 | 1963-03-14 | F. Hoffmann-Laroche G Co. Aktiengesellschaft | Octahydroisoquinoline derivatives and process forthe manufacture thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3862787D1 (en) | 1991-06-20 |
| PH25036A (en) | 1991-01-28 |
| DK168625B1 (en) | 1994-05-09 |
| EP0283848B1 (en) | 1991-05-15 |
| EP0283848A1 (en) | 1988-09-28 |
| JP2507523B2 (en) | 1996-06-12 |
| DK102388A (en) | 1988-09-21 |
| AU1307488A (en) | 1988-09-22 |
| JPS63238062A (en) | 1988-10-04 |
| DK102388D0 (en) | 1988-02-26 |
| IE61069B1 (en) | 1994-09-21 |
| CA1310012C (en) | 1992-11-10 |
| HUT49123A (en) | 1989-08-28 |
| HU203876B (en) | 1991-10-28 |
| NZ223879A (en) | 1991-01-29 |
| IE880805L (en) | 1988-09-20 |
| ATE63545T1 (en) | 1991-06-15 |
| ZA881811B (en) | 1988-09-20 |
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