CA1178605A - PROCESS FOR PREPARING ACID ADDITION SALTS OF 3,4- DIACYLOXY-.alpha.-[(METHYLAMINO)-METHYL]- BENZYLALCOHOL - Google Patents
PROCESS FOR PREPARING ACID ADDITION SALTS OF 3,4- DIACYLOXY-.alpha.-[(METHYLAMINO)-METHYL]- BENZYLALCOHOLInfo
- Publication number
- CA1178605A CA1178605A CA000395336A CA395336A CA1178605A CA 1178605 A CA1178605 A CA 1178605A CA 000395336 A CA000395336 A CA 000395336A CA 395336 A CA395336 A CA 395336A CA 1178605 A CA1178605 A CA 1178605A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- acid addition
- alpha
- addition salt
- diacyloxy
- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention concerns a method for preparing and isolating 3,4-diacyloxy-.alpha.-[(methylamino)-methyl]-benzyl- alco-hol of the formula
The invention concerns a method for preparing and isolating 3,4-diacyloxy-.alpha.-[(methylamino)-methyl]-benzyl- alco-hol of the formula
Description
~ .7B6~
The object of the present invention is a method of preparing and isolating O-acylsubstituted catecholamine de-rivatives, i.e. 3,4-diacyloxy-~-~ methylamino)-methy~ -ben-zylalcohol of the formula 1l ~<--C--O~
R-C- ~ CH-CH2-NH-CH3 (I) . :
wherein R denotes alkyl or aralkyl, preferably tert.~butyl, as its acid addition salt, preferably as its hydrochloride.
The compounds according to the invention are known ~.
for their sympathomimetic properties and they have been successfully used i.a. for the treatment of glaucoma. The . :~.
prolonged effect of said compounds compared to the correspond-ing 3,4-dihydroxy-compound, i.e.-to adrenallne, lS according to :
literature due to the O-acyl protection, which. in the case of adrenaline prevents the very rapid oxidation in the organism to compoùnds having no effect.
Irrespective of the protection of the reactive groups, the acyl compounds of the formula I are not stable under alkal1ne - conditions, as the hydrolysis of the acyloxy groups is immedi-ately followed by the formation of oxidation produots. In acid solutions the said compounds are, however, fairly stable. For ~
the above reasons the amines according to the formula I cannot -be isolated by means of conventi.onal methods used for preparing ~ .
amines.
. According to methods of preparation of the compounds of the formula -I described in literature, ortodiacylated cate-cholamines are treated as salts in alcohol type solvents, such as methanol or ethanol, whereb~ the afore mentioned disadvanta-geous phenomena do not occur. In the US patent specifications 3 809 714 and 4 035 405 such a compound is prepared from the - 1 - $
, - `~
:~7~6~5 hydrochloride salt of a compound containing a ke-to function and having ~he formula II
R-~-O\
R-C-O~ < ~ ~-CH2~NH-CH3 (II) , wherein R has the meaning given above, by means of catalytic r hydrogenation under pressure in methanol or ethanol in the presence of a platinum oxide catalyst. The produc-t is isola-ted in a conventional manner by filtering the ca-talyst from the reaction mixture, evaporating the solvent and crystalli-zing the compound of the formula I as a productfrom a suitable solvent mixture.
According to the FI patent specification 55 988 the compound of the formula I i5 prepared by reducing a compound 1, of the formula I-II
. j/O
~u ~ CH2 ~ ~ (III) wherein R has the meaning given above, by means of catalytic hydrogenation ln an aqueous solvent using palladium on active charcoal as a catalyst.
/
.~ . ~.
~ 2 8~(35 These known methods are, however, cumbersome, as catalytic hydrogenation requires the use of pressure vessels. There is also always a substantial danger of self-ignition associated with catalytic hydrogenation.
The method according to the invention for pre-paring the compounds of the formula I is characterized in that an acid addition salt of the afore mentioned compound of the formuIa II is reduced by means of sodium or potassium borohydride in an acid solvent, preferably acetic acid, and the acid addition salt of the compound of the formula I is isolated by adding water to the reaction mix-ture and extracting the reaction product into a chlorinated hydro-carbon and treating with the desired acid, preferably hydrochloric acid.
The reduction according to the invention may easily be carried out under ordinary condi-tions and using ordinary vessels thus eliminating the drawbacks associated with the afore mentioned catalytic hydrogenation.
The reducing effect of the reducing agent depends on the solvent, wherefore the selection of a proper solvent for the reduction is important, and glacial acetic acid has proven to be a very advantageous solvent.
The isolation of the reaction product may easily be carried out by extracting the same from its aqueous solution into chlorinated hydrocarbons, such as chloroform or methylene chloride. The solubility of the product in chlorinated hydrocarbons is better the larger the group R
is .
According to an advantageous mode of the inven-tion, the compound of the formula I is prepared by dissol-ving the hydrochloride salt of the amine of the formula II
into acetic acid and treating with sodium borohydride , whereby the temperature is from 0 to 50C and the reaction time from 1 to 2 hours. The reaction is especially advan-.~
- , . . . . .
, .~i ' . ' ' -.:, . ;
~, ', ` : ' :.
~'78~ 5 tageously performed at or below room temperature (rom 0 to 25C~ whereby the exothermic reaction requires cooling.
The reaction product is isolated by adding water to the reaction mixture and thereafter extracted, e.g.
into chloroform. Any possibly coex-tracted acetic acid is washed away from the chloroform e.g. with a sodium bi-carbonate solution, whereafter the chloroform phase is treated with diluted hydrochloric acid. From the chloro-form evaporation residue the hydrochloride of the com-pound of the formula I is obtained, which can be crystal-lized from a suitable solvent mixture.
The starting compound of the formula II may be prepared from adrenalone according to methods known from literature, e.g. as described in US patent specifications 3 809 714 and 4 035 405.
The following example illustrates the invention.
Example 7.7 g (0.02 moles) of dipivaloyl adrenalone hydro-chloride is dissolved at room temperature in 50 ml of acetic acid. Into the reaction mixture is added while cooling and stirring in the course of half an hour 2.5 g of sodium borohydride. The reaction mixture is stirred on an ice-water bath for still one hour, whereafter to the mixture 150 ml of water is carefuliy added. The reaction may be ~followed by means of thin layer chromatography using a 12:3:1-mixture of CH3-NO2, isopropanol and NH3 (95%). The aqueous solution is extracted with 3 x 50 ml of chloroform, whereafter the chloroform solution is washed with 50 ml of a concentrated NaHCO3 solution, 50 ml of 2N hydrochloric acid and 50 ml of water. The chloroform solution is dried and evaporated to dryness and the residue, 7.0 g, is crys-tallized from an acetone-hexane mixture. Yield 5.5 g (71%) of dipivaloyl-adrenaline hydrochloride, m.p. 158.5-160C
(lit. 159-160C), purity 99.9 % as determined titrimetri-cally.
' .~
., , ~ ' ' , ' .
The object of the present invention is a method of preparing and isolating O-acylsubstituted catecholamine de-rivatives, i.e. 3,4-diacyloxy-~-~ methylamino)-methy~ -ben-zylalcohol of the formula 1l ~<--C--O~
R-C- ~ CH-CH2-NH-CH3 (I) . :
wherein R denotes alkyl or aralkyl, preferably tert.~butyl, as its acid addition salt, preferably as its hydrochloride.
The compounds according to the invention are known ~.
for their sympathomimetic properties and they have been successfully used i.a. for the treatment of glaucoma. The . :~.
prolonged effect of said compounds compared to the correspond-ing 3,4-dihydroxy-compound, i.e.-to adrenallne, lS according to :
literature due to the O-acyl protection, which. in the case of adrenaline prevents the very rapid oxidation in the organism to compoùnds having no effect.
Irrespective of the protection of the reactive groups, the acyl compounds of the formula I are not stable under alkal1ne - conditions, as the hydrolysis of the acyloxy groups is immedi-ately followed by the formation of oxidation produots. In acid solutions the said compounds are, however, fairly stable. For ~
the above reasons the amines according to the formula I cannot -be isolated by means of conventi.onal methods used for preparing ~ .
amines.
. According to methods of preparation of the compounds of the formula -I described in literature, ortodiacylated cate-cholamines are treated as salts in alcohol type solvents, such as methanol or ethanol, whereb~ the afore mentioned disadvanta-geous phenomena do not occur. In the US patent specifications 3 809 714 and 4 035 405 such a compound is prepared from the - 1 - $
, - `~
:~7~6~5 hydrochloride salt of a compound containing a ke-to function and having ~he formula II
R-~-O\
R-C-O~ < ~ ~-CH2~NH-CH3 (II) , wherein R has the meaning given above, by means of catalytic r hydrogenation under pressure in methanol or ethanol in the presence of a platinum oxide catalyst. The produc-t is isola-ted in a conventional manner by filtering the ca-talyst from the reaction mixture, evaporating the solvent and crystalli-zing the compound of the formula I as a productfrom a suitable solvent mixture.
According to the FI patent specification 55 988 the compound of the formula I i5 prepared by reducing a compound 1, of the formula I-II
. j/O
~u ~ CH2 ~ ~ (III) wherein R has the meaning given above, by means of catalytic hydrogenation ln an aqueous solvent using palladium on active charcoal as a catalyst.
/
.~ . ~.
~ 2 8~(35 These known methods are, however, cumbersome, as catalytic hydrogenation requires the use of pressure vessels. There is also always a substantial danger of self-ignition associated with catalytic hydrogenation.
The method according to the invention for pre-paring the compounds of the formula I is characterized in that an acid addition salt of the afore mentioned compound of the formuIa II is reduced by means of sodium or potassium borohydride in an acid solvent, preferably acetic acid, and the acid addition salt of the compound of the formula I is isolated by adding water to the reaction mix-ture and extracting the reaction product into a chlorinated hydro-carbon and treating with the desired acid, preferably hydrochloric acid.
The reduction according to the invention may easily be carried out under ordinary condi-tions and using ordinary vessels thus eliminating the drawbacks associated with the afore mentioned catalytic hydrogenation.
The reducing effect of the reducing agent depends on the solvent, wherefore the selection of a proper solvent for the reduction is important, and glacial acetic acid has proven to be a very advantageous solvent.
The isolation of the reaction product may easily be carried out by extracting the same from its aqueous solution into chlorinated hydrocarbons, such as chloroform or methylene chloride. The solubility of the product in chlorinated hydrocarbons is better the larger the group R
is .
According to an advantageous mode of the inven-tion, the compound of the formula I is prepared by dissol-ving the hydrochloride salt of the amine of the formula II
into acetic acid and treating with sodium borohydride , whereby the temperature is from 0 to 50C and the reaction time from 1 to 2 hours. The reaction is especially advan-.~
- , . . . . .
, .~i ' . ' ' -.:, . ;
~, ', ` : ' :.
~'78~ 5 tageously performed at or below room temperature (rom 0 to 25C~ whereby the exothermic reaction requires cooling.
The reaction product is isolated by adding water to the reaction mixture and thereafter extracted, e.g.
into chloroform. Any possibly coex-tracted acetic acid is washed away from the chloroform e.g. with a sodium bi-carbonate solution, whereafter the chloroform phase is treated with diluted hydrochloric acid. From the chloro-form evaporation residue the hydrochloride of the com-pound of the formula I is obtained, which can be crystal-lized from a suitable solvent mixture.
The starting compound of the formula II may be prepared from adrenalone according to methods known from literature, e.g. as described in US patent specifications 3 809 714 and 4 035 405.
The following example illustrates the invention.
Example 7.7 g (0.02 moles) of dipivaloyl adrenalone hydro-chloride is dissolved at room temperature in 50 ml of acetic acid. Into the reaction mixture is added while cooling and stirring in the course of half an hour 2.5 g of sodium borohydride. The reaction mixture is stirred on an ice-water bath for still one hour, whereafter to the mixture 150 ml of water is carefuliy added. The reaction may be ~followed by means of thin layer chromatography using a 12:3:1-mixture of CH3-NO2, isopropanol and NH3 (95%). The aqueous solution is extracted with 3 x 50 ml of chloroform, whereafter the chloroform solution is washed with 50 ml of a concentrated NaHCO3 solution, 50 ml of 2N hydrochloric acid and 50 ml of water. The chloroform solution is dried and evaporated to dryness and the residue, 7.0 g, is crys-tallized from an acetone-hexane mixture. Yield 5.5 g (71%) of dipivaloyl-adrenaline hydrochloride, m.p. 158.5-160C
(lit. 159-160C), purity 99.9 % as determined titrimetri-cally.
' .~
., , ~ ' ' , ' .
Claims (4)
1. The method of preparing and isolating 3,4-diacyloxy-.alpha.-[(methylamino)-methyl]-benzylalcohol of the formula (I) wherein R denotes alkyl or aralkyl, as its acid addition salt, characterized in that an acid addition salt of the corresponding amine containing a keto function and having the formula (II) wherein R has the meaning given above, is reduced with sodium or potassium borohydride in an acidic solvent whereafter the acid addition salt of the compound of the formula (I) is isolated by adding water to the reaction mixture, extracting the product into a chlorinated hydrocarbon, and treating with the desired acid.
2. Method according to the Claim 1, character-ized in that as a chlorinated hydrocarbon, chloroform or methylene chloride is used.
3. Method according to claim 1, character-ized in that for the reduction, glacial acetic acid is used as a solvent and that the reaction temperature is from 0 to 50°C.
4. Method according to claim 3, characterized in that the reaction temperature is from 0 to 25°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI810700A FI61474C (en) | 1981-03-06 | 1981-03-06 | FAR OIL FRAMSTAELLNING AV SYRAADDITIONSSALTER AV 3,4-DIACYLOXI-ALPHA - ((METHYLAMINO) -METHYL) -BENYL ALCOHOL |
| FI810700 | 1981-03-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1178605A true CA1178605A (en) | 1984-11-27 |
Family
ID=8514202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000395336A Expired CA1178605A (en) | 1981-03-06 | 1982-02-01 | PROCESS FOR PREPARING ACID ADDITION SALTS OF 3,4- DIACYLOXY-.alpha.-[(METHYLAMINO)-METHYL]- BENZYLALCOHOL |
Country Status (15)
| Country | Link |
|---|---|
| AT (1) | AT380684B (en) |
| CA (1) | CA1178605A (en) |
| CS (1) | CS229927B2 (en) |
| DD (1) | DD202424A5 (en) |
| DK (1) | DK149121C (en) |
| ES (1) | ES509170A0 (en) |
| FI (1) | FI61474C (en) |
| GR (1) | GR76375B (en) |
| HU (1) | HU186483B (en) |
| IT (1) | IT8219944A0 (en) |
| NO (1) | NO151704C (en) |
| PL (1) | PL235313A1 (en) |
| PT (1) | PT74540B (en) |
| RO (1) | RO84817B (en) |
| SU (1) | SU1122219A3 (en) |
-
1981
- 1981-03-06 FI FI810700A patent/FI61474C/en not_active IP Right Cessation
-
1982
- 1982-01-13 AT AT0009182A patent/AT380684B/en not_active IP Right Cessation
- 1982-01-20 DK DK24082A patent/DK149121C/en not_active IP Right Cessation
- 1982-01-29 ES ES509170A patent/ES509170A0/en active Granted
- 1982-02-01 CA CA000395336A patent/CA1178605A/en not_active Expired
- 1982-02-24 CS CS127882A patent/CS229927B2/en unknown
- 1982-03-01 DD DD23779582A patent/DD202424A5/en not_active IP Right Cessation
- 1982-03-03 IT IT8219944A patent/IT8219944A0/en unknown
- 1982-03-04 PL PL23531382A patent/PL235313A1/xx unknown
- 1982-03-04 RO RO106810A patent/RO84817B/en unknown
- 1982-03-05 PT PT7454082A patent/PT74540B/en unknown
- 1982-03-05 NO NO820691A patent/NO151704C/en unknown
- 1982-03-05 HU HU68282A patent/HU186483B/en not_active IP Right Cessation
- 1982-03-05 SU SU823402587A patent/SU1122219A3/en active
- 1982-09-26 GR GR67430A patent/GR76375B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO820691L (en) | 1982-09-07 |
| FI61474C (en) | 1982-08-10 |
| DD202424A5 (en) | 1983-09-14 |
| DK24082A (en) | 1982-09-07 |
| AT380684B (en) | 1986-06-25 |
| PT74540B (en) | 1986-01-27 |
| DK149121C (en) | 1986-07-07 |
| HU186483B (en) | 1985-08-28 |
| NO151704C (en) | 1985-05-22 |
| RO84817B (en) | 1984-10-30 |
| RO84817A (en) | 1984-09-29 |
| ATA9182A (en) | 1985-11-15 |
| ES8301891A1 (en) | 1982-12-16 |
| PT74540A (en) | 1982-04-01 |
| SU1122219A3 (en) | 1984-10-30 |
| PL235313A1 (en) | 1982-09-27 |
| CS229927B2 (en) | 1984-07-16 |
| FI61474B (en) | 1982-04-30 |
| GR76375B (en) | 1984-08-06 |
| NO151704B (en) | 1985-02-11 |
| DK149121B (en) | 1986-02-03 |
| IT8219944A0 (en) | 1982-03-03 |
| ES509170A0 (en) | 1982-12-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEC | Expiry (correction) | ||
| MKEX | Expiry |