PROCESS FOR PRODUCING HYDROXYALKANE CARBOXYLIC ACID AMIDES

PROCEDE D'OBTENTION D'AMIDES D'ACIDE HYDROXYALCANECARBOXYLIQUE

English Abstract

Abstract
A process is described for the production of hydroxyalkane
carboxylic acid amides of general formula I
<IMG> (I),
in which
n represents a whole number from 1 to 20 and
R1 and R2 each mean alkyl groups with a maximum of 8 carbon
atoms or together mean an alkylene group with 4 to 8 carbon atoms
optionally interrupted by an oxygen atom or a nitrogen atom, from
hydroxyalkane carboxylic acids of general formula II
HO-CnH2n-COOH (II),
in which
n has the above-mentioned meaning and amines of general
formula III
<IMG> (III),
in which
R1 and R2 have the above-mentioned meanings
that is characterized in that

the hydroxyalkane carboxylic acid is refluxed in a one-pot
reaction with 10 to 30 mol of acetyl chloride per mol of acid
each, the excess acetyl chloride is distilled off after
acetylation has taken place, the residue is refluxed with 1.5 to
5 mol of thionyl chloride per mol of acid, the thionyl chloride
is removed by distillation after acid chloride formation has
taken place, the residue is dissolved in a dialkyl ether with 4
to 8 carbon atoms, the solution obtained is placed
proportionately in an aqueous solution of the amine cooled to 0°C
to 10°C and the acetate group is cleaved off after amide
formation has taken place by treatment with aqueous sodium
hydroxide solution at a reaction temperature of 10°C to 30°C.

Claims

Claims
Process for the production of hydroxyalkane carboxylic acid
amides of general formula I
<IMG> (I),
in which
n represents a whole number from 1 to 20 and
R1 and R2 each mean alkyl groups with a maximum of 8 carbon
atoms or together mean an alkylene group with 4 to 8 carbon atoms
optionally interrupted by an oxygen atom or a nitrogen atom, from
hydroxyalkane carboxylic acids of general formula II
HO-CnH2n-COOH (II),
in which
n has the above-mentioned meaning and amines of general
formula III
<IMG> (III),
in which
R1 and R2 have the above-mentioned meanings
characterized in that

the hydroxyalkane carboxylic acid is refluxed in a one-pot
reaction with 10 to 30 mol of acetyl chloride per mol of acid
each, the excess acetyl chloride is distilled off after
acetylation has taken place, the residue is refluxed with 1.5 to
5 mol of thionyl chloride per mol of acid, the thionyl chloride
is removed by distillation after acid chloride formation has
taken place, the residue is dissolved in a dialkyl ether with 4
to 8 carbon atoms, the solution obtained is placed
proportionately in an aqueous solution of the amine cooled to 0°C
to 10°C and the acetate group is cleaved off after amide
formation has taken place by treatment with aqueous sodium
hydroxide solution at a reaction temperature of 10°C to 30°C.

Description

2 1 2 7 ~
Pro¢esq for the production of ; ~
" . .
hydroxyalkane carboxylic aci~ ami~es
,~
. . . ~ -, - . .
~he invention relates to a process for the production of ~: :
hydroxyalkane carboxylic acid amides of general formula I ; -
~ R
EIO-C~ ,-CO~
~R~
in which
n represents a whole number from 1 to 20 and
R1 and F~ each mean alkyl groups with a maximum of 8 carbon
atoms or together mean an alkylene group with 4 to 8 carbon atoms ;~
optionally interrupted by an oxygen atom or a nitrogen atom, from .
hydroxyalkane carboxylic acids of general formula II
HO-C~H2n-COOH (II), ' ~
in which : ~:
n has the above-mentioned meaning and amines of general
formula III .
/~1
HN
R~
~:
. ~

21~72~2
in which
R1 and F7 have the above-mentioned meanings
that is characterized in that
the hydroxyalkane carboxylic acid is refluxed in a one-pot
reaction with 10 to 30 mol of acetyl chloride per mol of acid,
the excess acetyl chloride is distilled off after acetylation has
taken place, the residue is refluxed with 1.5 to 5 mol of thionyl
chloride per mol of acid, the thionyl chloride is removed by
distillation after acid chloride formation has taken place, the
residue is dissolved in a dialkyl ether with 4 to 8 carbon atoms,
the solution obtained is placed proportionally in an aqueous
solution of amine cooled to oC to 10C and the acetate qroup is
cleaved off after amide formation has taken place by treatment
with aqueous sodium hydroxide solution at a reaction temperature
of 10C to 30C.
The invention especially relates to the production of
hydroxyalkane carboxylic acid amides of general formula I in
which the group
R2
~ . '~'''"
means a dialkylamino group with 1 to 4 carbon atoms each in the
alkyl radicals or the grouping
~3 ~;
~4 ;:
'.. ' ~:'''

; :~
2127~9
in which R5 and R4 independently of one another represent a
hydrogen atom or a methyl group and X means a methylene group, an .
oxygen atom or a N-CH3.group.
As is generally known, the hydroxyalkane carboxyiic acid
amides of general formula I are valuable intermediate products
. and/or pharmacologically effective substances.
Thus, for example, hydroxyalkane carboxylic acid amides of
general formula Ia
/~1
Rs-CH-CON (~a)J
~H \ R2 ~:
in which
R~ represents a hydrogen atom or an alkyl group, are
valuable intermediate products for the production of herbicides ~ -
(DE-A 30 38 598).
Hydroxyalkane carboxylic acid amides of general formula Ib
~ Rl ;.
HO-(C~m-CO~ \ (Ib),
R2
in which
m means the numbers 7 to 18 are especially suitable for the
production of pharmaceutical agents for the local treatment of :
diseases of the skin or mucous membrane (WO 90/09373) or can be

2127~
used as intermediate products for the production of detergents
(US-A 2,936,325). However, the synthesis of these hydroxyalkane
carboxylic acid amides is quite expensive as a rule and the yield
and purity of the obtained products is often unsatisfactory. In
contrast, the one~pot reaction according to the invention offers
both ecological and economic advantages. It iæ relatively simple
to perform in comparison with the previously known processes and
provides the products of the process in surprisingly high yield
and purity.
The process accordinq to the invention is performed in such
a way that the hydroxyalkane carboxylic acid is dissolved or
suspended in 10 to 30 mol of acetyl chloride per mol of acid and
the reaction mixture is refluxed. After acetylation has taken
place (recognizable by thin-layer chromatographic analysis, or in
that no more hydrogenchloride generation takes place) the excess
acetyl chloride is distilled off, and by application of a vacuum
care i8 taken to achieve as complete as possible removal of the
acetyl chloride. ~ ;
:. ;.
The residue obtained is then mixed with 1.5 to 5 mol of
thionyl chloride per mol of acid used and the mixture obtained is
refluxed. After the acid chloride formation has taken place, the
thionyl chloride is removed as completely as possible in the same ~ ;-
way as previously the acetyl chloride and the residue obtained is
dissolved in a dialkyl ether with 4 to 8 carbon atoms. As
dialkyl ether, for example, diethyl ether, diisopropyl ether,
dibutyl ether or especially methyl-tert.-butyl ether are
suitable. ;~
.:,',
:~ ' ' .
~ ~ ~ o

2~27~
The ethereal solution of the acid chloride is then
introduced proportionately in an aqueous solution, preferably
stirred and optionally mixed with the same ether, cooled to 0C
to 10C, of preferably 2 to 5 mol of amine per mol of acid used,
so that the reaction temperature does not exceed 10C. Then the
reaction mixture i8 allowed to stand for 20-60 minutes at room -~
temperature for completion of the reaction and it is mixed with - -;~
an excess of aqueous or aqueous/alcoholic sodium hydroxide
solution and stirred for 20-60 minutes at room temperature.
The working up of the reaction mixture takes place in the
usual way, by, for example, the organic phase being separated,
washed, concentrated by evaporation and the residue being
purified by recrystallization.
The following embodiments serve to further explain the
process according to the invention.
:
~,3~

2127~
General instructions for the production of ~-hydroxyalkane
carboxylic acid amides of aeneral formula I
a g of ~-hydroxyalkanoic acid is suspended in b ml of acetyl
chloride and refluxed and stirred for 30 minutes. Then the
acetyl chloride is distilled off in a vacuum, the residue is
mixed with c ml of thionyl chloride and the mixture is heated for
one hour at 60C. Then the thionyl chloride is distilled off in
a vacuum and the residue is dissolved in d ml of methyl-tert.-
butyl ether.
e ml of 40% aqueous dimethylamine solution is mixed with f
ml of methyl-tert.-butyl ether and cooled with stirring to 0C.
Then the ethereal acid chloride solution is instilled in this
mixture so that the reaction temperature does not exceed 10C, it
is stirred for 30 minutes more at room temperature, a solution of
h g of sodium hydroxide in a mixture of i ml of methanol and k ml
of water is added to the reaction mixture and stirred for another
30 minutes at room temperature.
Then the mixture is diluted with water and methyl-tert.-~;
butyl ether, the organic phase is separated, washed and
concentrated by evaporation in a vacuum. The residue is
recrystallized from ethyl acetate/hexane and 1 g of ~-
hydroxyalkanoic acid dimethylamide of a melting point mC (= p %
of theory) is obtained. ; ~ -

,
,=...
21272~i~f
Fxample 1 ~-
13-Hydroxytridecanoic acid-dimethylamide from 13-
hydroxytridecanoic acid ` -
Cl5H31N02(257-42) Cld. C 69.99 H 12.14 N 5.44
Fnd. C 70.38 H 11.98 N 5.43
~mplo 2
ll-Hydroxyundecanoic acid-dimethylamide from 11-
hydroxyundecanoic acid
C~6H33N02(227l-44) Cld. C 68.08 H 11.87 N 6.11
Fnd. C 68.45 H 11.76 N 6.13
Ex~mple 3
14-Hydroxytetradecanoic acid-dimethylamide from 14-
hydroxytetradecanoic acid
C13H2jN02(229.36) Cld. C 70.80 H 12.25 N 5.16 ;
Fnd. C 71.16 H 12.27 N 5.20 !~
Ex~ple
15-Hydroxypentadecanoic acid-dimethylamide from 15-
hydroxypentadecanoic acid
C1~H3sNo2(285-47) Cld. C 71.53 H 12.36 N 4.91
Fnd. C 71.6S H 12.19 N 4.93

2127?.92
Example 5
4-(13-Hydroxy-1-oxotridecyl)morpholine from 13-
hydroxytridecanoic acid
Cl7H33N03(299.45)Cld. C 68.19 H 11.11 N 4.68
Fnd. C 68.16 H 11.03 N 4.74
Fx. ~ b c d e f h i k 1 m ~
128.0 252 24.673 40 73 22.4 1906726.9 69-71 86.0
219.5 200 19.558 32 58 17.7 1515317.7 57-58 80.0
315.5 131 12.838 21 38 11.7 9935 14.3 70-71 83.1
411.4 91 8.9 26 15 26 8.1 6924 10.7 73-74 82.6
53.5 31 3.1 9 8 9 2.8 24 8 2.8 75-76 62.1
''-'".: . '.
: ' ~' '.'''
''';; '-..'.~''

Representative Drawing