CA1041545A

CA1041545A - Process for the preparation of 4-amino-3,5-dihalogen-phenyl-ethanolamines

Info

Publication number: CA1041545A
Application number: CA212,850A
Authority: CA
Inventors: Johannes Keck; Gerd Kruger; Helmut Pieper; Klaus-Reinhold Noll
Original assignee: Dr Karl Thomae GmbH
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1973-11-02
Filing date: 1974-11-01
Publication date: 1978-10-31
Also published as: SE411546B; DE2354959B2; CH609040A5; DK134484B; DK134484C; NO139479B; SU549079A3; HU168133B; JPS5855133B2; PL96537B1; CS175487B2; ES430587A1; DE2354959A1; NL7414223A; RO68703A; FI60858C; NO743946L; YU285074A; FI60858B; AT340394B

Abstract

.beta.

ABSTRACT OF THE DISCLOSURE
This invention relates to a new process for the prepar-ation of certain 4-amino-3,5-dihalogeno-phenyl ethanol-amines and acid addition salts thereof having valuable physiological properties, in particular an activity on .beta.-receptors. The new process comprises the reduction of the corresponding phenyl-glyoxal or hydrate thereof in the presence of an appropiate amine and the optional subsequent conversion of the compound thus prepared into an acid addition salt thereof. The phenyl-glyoxal deri-vatives used as starting materials are new compounds and constitute a further feature of the invention. Processes for their preparation are given.

Description

!
i 104i545 The present invention relates to a new process for the preparation of certain 4-amino-3,5-dihalogeno-phenyl-ethanolamines having valuable physiological ~, properties, in particular an actiYity on the ~-receptors. ~ .
According to one feature of the present invention ;
we thus provide a process for the preparation of compounds of general formula ::
- ,- ', ,.

Ha ~ 8H - CH2 - N~ H (I) H2N ~LJ ' ', ;.
al -(wherein Hal represents a chlorine or bromine atom and R represents an alkyl (including cycloalkyl) group con-taining 3 to 5 carbon atoms) and acid addition salts ~.
thereof which comprises reducing a compound of formuLa ~' , ' ' qF ~.. . ... .
, ' '' . .

- 2 - .
"

~04~S45 Hal ~ CO--CHO (II) H~N
. Hal (wherein Hal is as hereinbefore defined) or the hydrate :
thereof in the presence of a compound of formula ~:~

H -N / R . - :
~ H (III) (wherein R is as hereinbefore defined) and if desired subsequently converting the compound of formula I thereby produced into an acid addition salt thexeof.
It is well known that in general compounds con- :
taining both an aldehyde and an amino group are unstable and are susceptable to self-condensation especially in the presence of bases. Nevertheless, using the process ;.

~, . .

~ -, . : ' . :
~ , ~

, . ', . I

according to the invention, we have prepared compounds of general formula I and acid addition salts thereof in excellent yield.
The reduction is conveniently effected by means of catalytically activated hydrogen (e.g. hydrogen in the presence of Raney nickel or Raney cobalt), nascent hydrogen (eOg. from activated metallic aluminium and water, sodium a algam and ethanol or zinc and hydrocloric acid), or a complex metal hydride (e.g. sodium boro-hydride or lithium aluminium hydride) in the presence of a solvent such as methanol, ethanol, ethanol/water, ether, tetrahydrofuran,dioxane or dioxane/water)~
In all cases the reduction is preferably effected in ~ -the presence of a solvent, appropriate solvents in `~
general being for example methanol, ethanol, dioxane, benzene or toluene, using an apparatus incorporating a water separator funnel; alternatively an excess of the amine of formula III may if desired be used as solvent. The reduction is preferably effected at ~ -temperatures from 0 to 115C, conveniently at temp- ~`
eratures up to the boiling temperature of the solvent used.
: -.. '. ~`'`~ .' ! ' ' According to one embodiment of the process ~ -~.

.' ' .. - ' .. , . .' . - . .. :

according to the invention a compound of formula O . ~: .
! - ~ N - R
Hal ~ C - C (IIa) ~al (wherein Hal and R are as hereinbefore defined) is first prepared in situ and is subsequently reduced.
The compounds of general formula I obtained .
may, if desired, be subsequently converted into their acid addition salts, preferably their physiologically compatible acid addition salts. Suitable acids for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, .- .
lactic acid, citric acid, tartaric acid, maleic acid and fumaric acid~ ;
The compounds of general formula O
Ha1 . C - CHO
~ (II) :
H2N ~ ' .

. . . .
_ 5 _ . .. ... . ; .... ... - . . - , . .
~,. , -;..""

104~54S :
,, ,~

(wherein Hal represents a chlorine or bromine atom) and :
hydrates thereof used as starting materials are new compounds. .
They may be prepared either by oxidation of a compound of formula O ~ .
..
Hal ~ C - CH3 Hal (wherein Hal is as hereinbefore defined), a suitable oxidising ~
agent being selenium dioxide, or by oxidation of a compound of ,::
formula :. .

O ~ ' -Hal ~ C - CH2Br l ll (IV) H N
Hal (wherein Hal is as hereinbefore defined), a suitable oxidising agent being dimethyl sulphoxide. , The following Examples serve to illustrate the new process for the preparation of compounds of general ~;
formula I according to the invention and ,' ' :
- , .. ., , ~

~ - - 6 - ~ ~

~O 4 ~59~5 also the preparation of the starting materlals therefor Exam~ele A
4-Amino-3 5-dichloro-phenylglyoxal hydrate 40.8 g of 4-amino-3,5-dichloro-acetophenone were added in small amounts to a solution of 22.2 g of selenium dioxide in 200 ml of dioxane and 6 ml of water at 60 to J0~C with stirring. After refluxing for 4 hours, the mixture was cooled and a small quantity of char-coal was addedO The mixture was filtered and evaporated under a water pump va¢uum.i The residue was dissolved in ethyl acetate-benzene (1:4) and cyclohexane was -added until the solution became turbid. The mixture was filtered and left to standard room temperature for 2 hours for the slow crystallization of the 4-amino-

3,5-dichloro-phenylglyoxal hydrate to beginO M.p.: 95 . to 98C.
Example 1 1_(4_Amino-3 5-dichloro-phenvl~-2-tertO-butYlamino -ethanol

4.7 g (0.02 mol) of 4-amino-3,5-dichloro-phenylglyoxal *
hydrate in 50 ml gf methanol were added to 8.8 g (0.12 mol) of tert.-butylamine. On heating slightly a clear solution was first formed and then later a . . .
.

t ~:
. . .

precipitate was obtainedO After stirring for 1 hour, a solution of 1,9 g (0005 mol) of sodium borohydride in 10 ml of water was added dropwise whereby the precipitate began to dissolve on gentle heatingO After stirri~g for 2 hours, concentrated hydrochloric acid was added dropwise to the solution until it was strongly acid whereby the excess of sodium borohydride ~as des- ~-troyed. The mixture was filtered and made alkaline with concentrated ammonia to precipitate the 1-(4-amino-3,5-dichloro-phenyl)-2-tertO_butylamino-ethanol.
...
Yield: 4,8 g (86,6 % of theory), m.p.: 110 to 118C.
M~po of the hydrochloride: 174 to 175G (decompO).
Example 2 , .:, ,-~ . .. ..
1-(4-Amino-3,5-dichloro-phenyl~-2-cyclopropylamino-ethanol M.p.: 125 to 127C.
Prepared from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclopropylamine and sodium borohydride analogously to Example 1.
Example 3 1-(4-Amino-3 5-dichlnro-phenyl)-2-cyclobutylamino-ethanol M.p. of the hydrochloride: 148 to184.5C ~ecomp.).
- Prepared from 4-amino-3~5-dichloro-phenylglyoxal hydrate, cyclobutylamin~ and sodium borohydride analogously to Example 1.

'' ,;

104154S ,- - -Example 4 1_(4_Amino-3,5-dichloro-Phenyl)-2-cyc].opentylamino-ethanol m.p. of the hydrochloride: 184 to 150C (decompO).
, ! Prepared from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclopentylamine and sodium analogously to Example 1.

, _ 9 _ .
., . , -. . ~ - -- , .

.
- ' . ,~ - .
- . ~ . ,. , . :
:: ;

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
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 chlorine or bromine atom and R represents an alkyl (including cycloalkyl) group containing 3 to 5 carbon atoms) and acid addition salts thereof which comprises reducing a compound of formula (II) as hereinbefore defined) or the hydrate thereof in the presence of a compound of formula (III) (wherein R is as hereinbefore defined) and if desired subsequently converting the compound of formula I thereby produced into an acid addition salt thereof.

2. A process as claimed in claim 1 wherein the reduction is effected by means of catalytically activated hydrogen, nascent hydrogen, or a complex metal hydride.

3. A process as claimed in claim 1 wherein the reduction is effected at temperatures from 0 to 115°C.

4. A process as claimed in claim 1 wherein the reduction is effected in the presence of a solvent.

5. A process as claimed in claim 1 wherein a compound of formula (IIa) (wherein Hal and R are as defined in claim 1) is first formed in situ and is subsequently reduced.

6. A process according to claim 5 wherein the reduction is effected by means of catalytically activated hydrogen, nascent hydrogen, or a complex metal hydride.

7. A process according to claim 1 wherein the compound of general formula II is prepared by oxidising a compound of formula (III) wherein Hal is a chlorine or bromine atom.

8. A process as claimed in claim 7 wherein the oxidation is effected with selenium dioxide.

9. A process according to claim 1 wherein the compound of general formula II is prepared by oxidising a compound of formula (IV) wherein Hal is a chlorine or bromine atom.

10. A process as claimed in claim 9 wherein the oxidation is effected with dimethyl sulfoxide.

11. A process according to claim 1 in which 1-(4-amino-3,5-dichloro-phenyl)-2-tertiary butylaminoethanol is prepared by reducing 4-amino-3,5-dichlorophenylglyoxal hydrate in the presence of tertiary butylamine.

12. A process according to claim 11 in which the reduction is effected by reaction with sodium borohydride.

13. A process according to claim 11 or 12 in which the 4-amino-3,5-dichlorophenylglyoxal hydrate is prepared by oxidizing 4-amino-3,5-dichloro-acetophenone.

14. A process according to claim 11 or 12 in which the 4-amino-3,5-dichlorophenylglyoxal hydrate is prepared by oxidizing 4-amino-3,5-dichloro-acetophenone by reaction with selenium dioxide.

15. A process according to claim 1 in which 1-(4-amino-3,5-dichloro-phenyl)-2-cyclopropylamino ethanol is prepared by reducing 4-amino-3,5-di-chlorophenylglyoxal hydrate in the presence of cyclopropylamine.

16. A process according to claim 15 in which the reduction is effected by reaction with sodium borohydride.

17. A process according to claim 1 in which 1-(4-amino-3,5-dichloro-phenyl)-2-cyclobutylamino ethanol is prepared by reducing 4-amino-3,5-dichloro-phenylglyoxal hydrate in the presence of cyclobutylamine.

18. A process according to claim 17 in which the reduction is effected by reaction with sodium borohydride.

19. A process according to claim 1 in which 1-(4-amino-3,5-dichloro-phenyl)-2-cyclopentylamino ethanol is prepared by reducing 4-amino-3,5-di-chlorophenylglyoxal hydrate in the presence of cyclopentylamine.

20. A process according to claim 19 in which the reduction is effected by reaction with sodium borohydride.