CA1050542A - Process for the preparation of 2-amino-benzylamines - Google Patents
Process for the preparation of 2-amino-benzylaminesInfo
- Publication number
- CA1050542A CA1050542A CA208,640A CA208640A CA1050542A CA 1050542 A CA1050542 A CA 1050542A CA 208640 A CA208640 A CA 208640A CA 1050542 A CA1050542 A CA 1050542A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- amino
- acid addition
- formula
- preparation
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to a new process for the preparation of certain 2-amino-benylamine derivatives having valuable physiolo-gical properties, in particular a secretolytic and/or anti-tussive activity. The new process comprises the reaction of the corresponding methyl or phenyl 2-amino-benzyl ether with an appropriate amine and the optional subsequent conversion of the compound thus prepared into an acid addition salt.
The new process is examplified.
This invention relates to a new process for the preparation of certain 2-amino-benylamine derivatives having valuable physiolo-gical properties, in particular a secretolytic and/or anti-tussive activity. The new process comprises the reaction of the corresponding methyl or phenyl 2-amino-benzyl ether with an appropriate amine and the optional subsequent conversion of the compound thus prepared into an acid addition salt.
The new process is examplified.
Description
5 ~
This invention relates to a new process for the prepara-tion of certain 2-amino-benzylamine derivatives having valuable physiological properties, in particular a secretolytic activity which may be accompanied by an antitussive activity.
US Patent Spcifications Nos 3,336,308, 3,536,713 and 3,661,903 - describe inter alia compounds of general formula ' R
3 (I
` B Hal NH2 `, :
[wherei.n Hal represents a bromine or chlorine atom, Rl represents a hydrogen or bromine atom, ~.
.' R2 represents a cyclohexyl, hyclroxycyclohexyl or morphoIino- .
. carbonylmethyl group and R3 represents a hydrogen atom or a methyl group] and ~acid addition salts thereof~ and also processes for the . preparation of these compounds.
According to the present invention we now provide a new ..
process for the preparation of compounds of general formula I
as hereinberore defined and acid addition salts thereof which f comprises reacting a compound of formula CH2 R4 (II) . . ~
5~a~
~wherein Hal and Rl are as hereinbefore defined and R~ represents a methyl or phenyl group) with a compound of formula ~ H - N (III) ~ R2 -- (wherein R2 and R3 are as hereinbefore defined) the reaction being ef-fected at a temperature of from 140 to 220C and in an excess of the compound of formula ~III) as solvent, and, if desired, subsequently con-~` verting the compound of formula I ~hereby obtained into an acid addition salt thereof.
Using the process according to the invention we have prepared compounds of general formula I as hereinbefore defined and acid addition ` 10 salts thereof in excellent yield. The reaction may be effected under normal or elevated pressure.
The compounds of general formula II used as starting material and acid addition salts thereof are new compounds and constitute a further eature of the present invention. They may be prepared, for example, by ~; reaction of the corresponding N-acylated benzyl halides with an alkali metal ', . ~., :' : I .
'1 '' .
~, ,.
: ' '' :~ ... .
~ 3 ~ . :
, ~,, , :
salt of phenol or methanol and by subsequent removal of the acyl group. The co~pounds of general for~ula II there-by obtained may, if desired, be subsequently converted into their acid addition salts, preferably their physiologically compatible acid addition salt, by reaction with inorganic and organic acids.
Suitable acids for the preparation of physiologically compatible acid addition salts of both the compounds of general formula I ancl the compounds of general formula II include for example hydrochloric acid, hydrobromic acid, sulfuric acid T
phosphoric acid, lact c acid and malleic acid.
The following Examples serve to illustrate the new process according to the invention. Example A illustrates ~, the preparation of the ethers of general ormula II used as starting materialsO
Example A
.
This invention relates to a new process for the prepara-tion of certain 2-amino-benzylamine derivatives having valuable physiological properties, in particular a secretolytic activity which may be accompanied by an antitussive activity.
US Patent Spcifications Nos 3,336,308, 3,536,713 and 3,661,903 - describe inter alia compounds of general formula ' R
3 (I
` B Hal NH2 `, :
[wherei.n Hal represents a bromine or chlorine atom, Rl represents a hydrogen or bromine atom, ~.
.' R2 represents a cyclohexyl, hyclroxycyclohexyl or morphoIino- .
. carbonylmethyl group and R3 represents a hydrogen atom or a methyl group] and ~acid addition salts thereof~ and also processes for the . preparation of these compounds.
According to the present invention we now provide a new ..
process for the preparation of compounds of general formula I
as hereinberore defined and acid addition salts thereof which f comprises reacting a compound of formula CH2 R4 (II) . . ~
5~a~
~wherein Hal and Rl are as hereinbefore defined and R~ represents a methyl or phenyl group) with a compound of formula ~ H - N (III) ~ R2 -- (wherein R2 and R3 are as hereinbefore defined) the reaction being ef-fected at a temperature of from 140 to 220C and in an excess of the compound of formula ~III) as solvent, and, if desired, subsequently con-~` verting the compound of formula I ~hereby obtained into an acid addition salt thereof.
Using the process according to the invention we have prepared compounds of general formula I as hereinbefore defined and acid addition ` 10 salts thereof in excellent yield. The reaction may be effected under normal or elevated pressure.
The compounds of general formula II used as starting material and acid addition salts thereof are new compounds and constitute a further eature of the present invention. They may be prepared, for example, by ~; reaction of the corresponding N-acylated benzyl halides with an alkali metal ', . ~., :' : I .
'1 '' .
~, ,.
: ' '' :~ ... .
~ 3 ~ . :
, ~,, , :
salt of phenol or methanol and by subsequent removal of the acyl group. The co~pounds of general for~ula II there-by obtained may, if desired, be subsequently converted into their acid addition salts, preferably their physiologically compatible acid addition salt, by reaction with inorganic and organic acids.
Suitable acids for the preparation of physiologically compatible acid addition salts of both the compounds of general formula I ancl the compounds of general formula II include for example hydrochloric acid, hydrobromic acid, sulfuric acid T
phosphoric acid, lact c acid and malleic acid.
The following Examples serve to illustrate the new process according to the invention. Example A illustrates ~, the preparation of the ethers of general ormula II used as starting materialsO
Example A
.
2-Amino-3,5-dibromo-benzyl ~henyl ether . .
19.7 g of phenol and 12.5 g of potassium hydroxide were dissolved in 0.2 1 of absolute ethanol and added dropwise to a refluxing mixture of 85.6 g of 2-diacetylamino-3,5-dibromo-benzyl bromide in 0.5 l of absolute ethanol over a period of 20 minutes. The mixture was refluxed ~Or 2 hours, whereby the benzyl bromide dissolved in the mixture and potassium bromide precipitated out. After cooling, the inorganic precipitate was removed by suction filtration.
The filtrate was mixed with 100 ml o~ lON sodium hydroxide " .
. ~,, ~1 ,, : .. ..
~ 5 ~
solution and refluxed for a further 15 hours. Subsequently, the reaction mixture was filtered and the filtrate was evaporated. The residue was mixed with 0.5 1 of water and extracted twice with chloroform. The organic extracts were dried with sodium sulfate and evaporated. The residue was ` purified by chromatography on a silica gel column using I chloroform as eluant, whereby pure 2-amino-3,5-dibromo-benæyl phenyl ether was obtained as an oily substance. The structure of this compound was established from its UV, IR and NMR
spectra.
VV maxima at 247 nm and 310 nm IR 3450 cm 1 and 3365 cm 1 2 112~ cm 1 ether band NMR 2 aromatic protons at 7.2 and ~.5 ppm 5 aromatic protons at 6~8 to 7 4 ppm ` CH2 at 4.9 ppm NH2 at 4.4 ppm i , . .
Example 1 1.0 g (0.0028 mol) of 2-~mino-3,5-dibromo-benzyl phenyl ether and 3.2 g (0.028 mol) of N-methyl-cyclohexylamine were heated in a closed vessel at 200C or 15 hours. The pressure rose to about 5 atmospheres. The reaction solution was subsequently taken up in chloroform, and the chloroform solution was extracted three times with water, dried with sodium sulfate ~. ' ; 5 - ' `
~ 5~
and evaporated. The residue was dissolved in a small quantity of absolute ethanol, acidified with ethanolic hydrochloric acid and ether was added until the 2-amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine hydrochloride started to crystallize out~
Yield: 0.97 g (84.0 % of theory).
M.p.: 233 to 234.5C ~decomp~).
2-Amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamlne M.p. of the hydrochloride: 233 to 234.5C (decomp.).
Prepared from 2-amino-3,5-d;bromo-benzyl phenyl ether and t~ns-4-amino-cyclohexanol analogously to Example 1.
`
, ~
2~Amino-6-ch_oro-N-methyl-N~morpholinocarbonylmethyl-benzylamine ~', , M.p.: 116 to 118C
Prepared from 2-amino-6-chloro-benzyl -methyl ether and sarcosine~morpholide analogously ~o Example 1.
, ~ ' ' ' ''' ,' .
.
_ 6 -.
i.
.. .
19.7 g of phenol and 12.5 g of potassium hydroxide were dissolved in 0.2 1 of absolute ethanol and added dropwise to a refluxing mixture of 85.6 g of 2-diacetylamino-3,5-dibromo-benzyl bromide in 0.5 l of absolute ethanol over a period of 20 minutes. The mixture was refluxed ~Or 2 hours, whereby the benzyl bromide dissolved in the mixture and potassium bromide precipitated out. After cooling, the inorganic precipitate was removed by suction filtration.
The filtrate was mixed with 100 ml o~ lON sodium hydroxide " .
. ~,, ~1 ,, : .. ..
~ 5 ~
solution and refluxed for a further 15 hours. Subsequently, the reaction mixture was filtered and the filtrate was evaporated. The residue was mixed with 0.5 1 of water and extracted twice with chloroform. The organic extracts were dried with sodium sulfate and evaporated. The residue was ` purified by chromatography on a silica gel column using I chloroform as eluant, whereby pure 2-amino-3,5-dibromo-benæyl phenyl ether was obtained as an oily substance. The structure of this compound was established from its UV, IR and NMR
spectra.
VV maxima at 247 nm and 310 nm IR 3450 cm 1 and 3365 cm 1 2 112~ cm 1 ether band NMR 2 aromatic protons at 7.2 and ~.5 ppm 5 aromatic protons at 6~8 to 7 4 ppm ` CH2 at 4.9 ppm NH2 at 4.4 ppm i , . .
Example 1 1.0 g (0.0028 mol) of 2-~mino-3,5-dibromo-benzyl phenyl ether and 3.2 g (0.028 mol) of N-methyl-cyclohexylamine were heated in a closed vessel at 200C or 15 hours. The pressure rose to about 5 atmospheres. The reaction solution was subsequently taken up in chloroform, and the chloroform solution was extracted three times with water, dried with sodium sulfate ~. ' ; 5 - ' `
~ 5~
and evaporated. The residue was dissolved in a small quantity of absolute ethanol, acidified with ethanolic hydrochloric acid and ether was added until the 2-amino-N-cyclohexyl-3,5-dibromo-N-methyl-benzylamine hydrochloride started to crystallize out~
Yield: 0.97 g (84.0 % of theory).
M.p.: 233 to 234.5C ~decomp~).
2-Amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-benzylamlne M.p. of the hydrochloride: 233 to 234.5C (decomp.).
Prepared from 2-amino-3,5-d;bromo-benzyl phenyl ether and t~ns-4-amino-cyclohexanol analogously to Example 1.
`
, ~
2~Amino-6-ch_oro-N-methyl-N~morpholinocarbonylmethyl-benzylamine ~', , M.p.: 116 to 118C
Prepared from 2-amino-6-chloro-benzyl -methyl ether and sarcosine~morpholide analogously ~o Example 1.
, ~ ' ' ' ''' ,' .
.
_ 6 -.
i.
.. .
Claims
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula (I) [wherein Hal represents a bromine or chlorine atom, R1 represents hydrogen or bromine atom, R2 represents a cyclohexyl, hydroxycyclohexyl or morpholino-carbonylmethyl group and R3 represents a hydrogen atom or a methyl group]
and acid addition salts thereof which comprises reacting a compound of for-mula (II) (wherein Hal and R1 are as hereinbefore defined and R4 represents a methyl or phenyl group) with a compound of formula (III) (wherein R2 and R3 are as hereinbefore defined), the reaction being affected at a temperature of from 140° to 220°C and in an excess of the compound of formula III as solvent, and, if desired, subsequently converting the compound of formula I thereby obtained into an acid addition salt thereof.
and acid addition salts thereof which comprises reacting a compound of for-mula (II) (wherein Hal and R1 are as hereinbefore defined and R4 represents a methyl or phenyl group) with a compound of formula (III) (wherein R2 and R3 are as hereinbefore defined), the reaction being affected at a temperature of from 140° to 220°C and in an excess of the compound of formula III as solvent, and, if desired, subsequently converting the compound of formula I thereby obtained into an acid addition salt thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19732345443 DE2345443C3 (en) | 1973-09-08 | Process for the preparation of 2-amino-benzylamines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050542A true CA1050542A (en) | 1979-03-13 |
Family
ID=5892074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA208,640A Expired CA1050542A (en) | 1973-09-08 | 1974-09-06 | Process for the preparation of 2-amino-benzylamines |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS594413B2 (en) |
| AT (1) | AT327875B (en) |
| BG (1) | BG23896A3 (en) |
| CA (1) | CA1050542A (en) |
| CH (1) | CH612662A5 (en) |
| CS (1) | CS167212B2 (en) |
| DK (2) | DK473074A (en) |
| ES (1) | ES429698A2 (en) |
| FI (1) | FI60551C (en) |
| HU (1) | HU167685B (en) |
| NL (1) | NL7410820A (en) |
| PL (1) | PL91734B1 (en) |
| SE (2) | SE439158B (en) |
| YU (1) | YU37109B (en) |
-
1974
- 1974-08-02 FI FI2317/74A patent/FI60551C/en active
- 1974-08-08 AT AT650974A patent/AT327875B/en not_active IP Right Cessation
- 1974-08-13 NL NL7410820A patent/NL7410820A/en not_active Application Discontinuation
- 1974-08-31 ES ES429698A patent/ES429698A2/en not_active Expired
- 1974-09-05 YU YU2392/74A patent/YU37109B/en unknown
- 1974-09-05 JP JP49102496A patent/JPS594413B2/en not_active Expired
- 1974-09-06 HU HUTO979A patent/HU167685B/hu unknown
- 1974-09-06 CH CH1218774A patent/CH612662A5/en not_active IP Right Cessation
- 1974-09-06 CS CS6151A patent/CS167212B2/cs unknown
- 1974-09-06 CA CA208,640A patent/CA1050542A/en not_active Expired
- 1974-09-06 SE SE7411313A patent/SE439158B/en not_active IP Right Cessation
- 1974-09-06 DK DK473074A patent/DK473074A/da not_active Application Discontinuation
- 1974-09-07 PL PL1974173960A patent/PL91734B1/pl unknown
- 1974-09-07 BG BG7400027655A patent/BG23896A3/en unknown
-
1976
- 1976-12-22 DK DK579676A patent/DK579676A/en not_active Application Discontinuation
-
1977
- 1977-09-01 SE SE7709868A patent/SE427178B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE2345443A1 (en) | 1975-03-27 |
| SE7411313L (en) | 1975-03-10 |
| JPS5053347A (en) | 1975-05-12 |
| PL91734B1 (en) | 1977-03-31 |
| AT327875B (en) | 1976-02-25 |
| BG23896A3 (en) | 1977-11-10 |
| ES429698A2 (en) | 1977-07-01 |
| JPS594413B2 (en) | 1984-01-30 |
| CS167212B2 (en) | 1976-04-29 |
| FI60551C (en) | 1982-02-10 |
| YU37109B (en) | 1984-08-31 |
| DK473074A (en) | 1975-05-05 |
| DK579676A (en) | 1976-12-22 |
| SE7709868L (en) | 1977-09-01 |
| YU239274A (en) | 1983-04-27 |
| ATA650974A (en) | 1975-05-15 |
| DE2345443B2 (en) | 1976-01-02 |
| SE439158B (en) | 1985-06-03 |
| FI231774A (en) | 1975-03-09 |
| FI60551B (en) | 1981-10-30 |
| HU167685B (en) | 1975-11-28 |
| SE427178B (en) | 1983-03-14 |
| NL7410820A (en) | 1975-03-11 |
| CH612662A5 (en) | 1979-08-15 |
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