Note: Descriptions are shown in the official language in which they were submitted.
l~C~S~ '
This invention relates to a novel process for the preparation of
carboxylic amides.
N,N-Dialkyl carboxylic amides have extensive utilization in various
fields. Thus, great amounts of N,N-dimethyl-~,a-diphenyl-acetamide are used
in the agriculture as a herbicidal agent for plant protection purposes. Some
other disubstituted carboxylic amides, having insecticidal properties, are
also us~d as plant protecting agentsO Such compounds are also applied in
the human therapyJ furthermore in the dyestuff industryO
According to the most widespread method, these compounds are
p~epared by chlorinating the appropriate carboxylic acid derivatives, and
reacting the thus-obtained acid chlorides with the appropriate dialkylamines.
In the majority of the synthesesstartin~ from carboxylic acid
derivatives the carboxylic acid derivatives are reacted first with chlor m at-
ing agents, and then the obtained acid chlorides are treated with a great
excess of the appropriate dialkyl amine optionally in the presence of a
solvent. The well-known disadvantages of this method are as follows: the
acid chloride formation proceeds frequently with a low rate and with an
inappropriate yield, the isolation of the acid chlorides is difficult, and,
even when the reaction conditions are controlled very carefully, their
2~ liability to hydrolysis decreases the yield of the amination procedure to
a considerable extent.
Now it has been found that carboxylic acids can be converted
I with very good yields into the appropriate N,N-disubstituted carboxylic
I amides when an adduct formed from a
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disubstituted forma~ide and a chlorinating agent, such as thionyl chloride,
is used as aminating agent.
Adducts of the above type are ~ell known in the literature and
have known and identified structures. When contacting a disubstituted
formamide (e.g. an N,N-dialkyl compound) with a chlorinating agent either
in the presence of a solvent or in a solvent-free medium, an adduct of the
general formula CI)
~RlR2N - C~10 - X) Cl (I)
is obtained with quantitative yield. Upon hea~ing to higher temperatures,
these compounds convert into the unsaturated derivatives having the general
formula ~II)
(RlR2N = CHCl) Cl ~II)
The above-identified adducts, known in the literature as
; Vilsmeier complexes, have been applied so far as formylating agents`~ ~Ann. PharmO 24, 793 /1966/), isonitrile-forming agents ~J. Org. Chem. 37,
~; 187 /1972/), reactants for replacing alcoholic hydroxy groups by halogen
atoms (Chem. and IndO 16, 664 /1974/), as well as for the conversion of
carboxylic acids into acid chlorides ~Ann. Quim. 65 1167 /1969/).
~ Now it has been detected that these complexes can be used to a
;' 20 great advantage for the conversion of carboxylic acid derivatives into the
respective N,N-disubstituted carboxylic amides. The reaction proceeds
smoothly and provides the desired end-products with almost quantitative
yields. When the reaction is performed at 110 to 150C, optionally in
the presence of a solvent, both types of the above-men*ioned adducts
can be used.
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Accordingly, the invention relates to a novel process for the pre-
paration of N,N-disubstituted carboxylic amides having the general formula (III),
" ,1 :
R - C - N - R2 ~III)
wherein Rl and R2 each represent an aliphatic hydrocarbyl group, or Rl and R2, ~ :
together with the adjacent nitrogen atom, form a heterocyclic group containing
optionally further hetero atom(s), and R3 is an aliphatic, aromatic, araliphatic
or cycloaliphatic hydrocarbyl group or a saturated or aromatic heterocyclic
group, all of them optionally substituted by one or more halogen atoms and/or
by a -CONRlR2 group, in which a compound of the general formula ~IV),
1 0 0 ,' ~ '
R3 - C - OH (IV) .
wherein R3 has the same meanings as defined above, is reacted, at a temperature :
not exceeding the boiling point of the reaction mixture, with an adduct of
the general formula (I) or (II),
(RlR2N - CHO - X) Cl (I) -.
(RlR2N = CHCl) Cl (II)
wherein Rl and R2 each have the same meanings as defined above and X is a group
of the formula -SOCl, ~POC12, _PC14J PC12, ~CO-CO-Cl or -CO-Cl, said adduc~s
being prepared by
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mixing a compound of the general formula HC0NRlR2 (wheIein Rl and R2 each
have the same meanings as defined above) with at least equimolar amount
of thionyl chloride, phosphorous oxychloride, phosphorous pentachloride,
phosphorous trichloride, oxalyl chloride or phosgene> and the obtained
product of the general formula (III) is isolated from the reaction mixture.
One may proceed e~g. by preparing first an adduct of the general
formula ~I) or (II) and reacting it in a further step with the appropriate
acid derivative of the general formula ~IV), equally good results can be
achieved, however, when the adduct is formed in the presence of the acid
derivative. As solvent, preferably the disubstituted formamide used in
the adduct ormation is appliedO
The process of the invention can be used for the conversion of
the most diverse carboxylic acids, such as optionally substituted aliphatic,
cycloaliphatic, heterocyclic aliphatic, aromatic, polycyclic aromatic,
araliphatic or heteroaromatic mono- or dicarboxylic acids into their N,N-
disubstituted amidesO Similarly, the most diverse N,N-disubsti~uted
formamides containing aliphatic, cycloaliphatic, heterocyclic aliphatic
or aromatic substituents can be applied in the preparation of the adducts.
As mentioned above, the novel reaction according to the invention - -
2Q provides the aimed products with excellent yields. The reaction proceeds
smoothly and quickly, and no difficult reaction or isolation conditions
are to be met with.
Thus, for example, when 1 le of diphenylacetic acid is treated ;
at 130C for one hour with a complex prepared from l.l moles of thionyl
chloride and 2 moles of dimethyl formamide, and then the reaction mixture
is poured onto ice, the separated crystals are filtered off, washed with
water, and dried, the aimed N,N-dimethyl-diphenylacetamide is obtained
with a yield of 97 %.
Since the amidation according to the invention proceeds under -
3Q far milder conditions than the known procedures, the side-reactions can be
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suppressed to a great extent, as a result of which the end-products are
obtained with high yields or the non-reacted starting substances can be
recovered with a good efficiency, respectively.
The process of the invention is elucidated in detail by the aid
of the following non-limiting Examples.
Exam~le_l
,
N,N-Dimethyl-a, ~diphenyl=acetamide
21.2 g. of diphenylacetic acid and 14.1 g. of chloromethylene-
dimethyl-ammonium chloride are dissolved in 10 ml. of dimethyl formamide,
and the mixture is stirred at 130C for one hourO Thereafter the mixture
is poured into 200 ml. of water under stirring, and the pH of the obtained
mixture is adjusted to 8 using aqueous sodium hydroxide solution~ The
separated white substance is filtered off, washed with water, and dried.
2302 g. ~96.9 %) of N,N dimethyl-~,~-diphenyl-acetamide are obtained; m.p.:
130-131.5C.
` Analysis:
calculated: C: 8Q.30 % H: 7.16 % N: 5.86 %
found: C: 8Q.27 % H: 7.19 % N: 5.84 %
ple 2
2a - N- ethyl-a,-diphenyl-acetamide
A solution of 22.88 g. of phosphorous pentachloride in 14~6 g.
of dimethyl formamide is maintained at 90 to 100C for 5 minutes. Thereafter
21.2 g. of diphenylacetic acid are added to the solution, and the mixture
is stirred at 130C for one hour. The mixture is poured into 200 ml. of
water under stirring, and the pH of the obtained mixture is adjusted to 8
~; using aqueous sodium hydroxide solution. The separated substance is filtered
off, washed with water9 and dried. 23.3 g. (97.3 %) of N,N-dimethyl-a,~-
diphenyl-acetamide are obtained; m.p.: 130-132C~
3Q
-6-
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21.9 g. of dimethyl formamide are treated with 14085 g. of phosgene
at O to 5CJ and then the mixture is maintained at 40 ~o 45~C foT one hour. ~-
21.2 g. of diphenylacetic acid are added, and the mixture is stirred at 130C
for one hour. Thereafter the mixture is processed as described in Example 1
to obtain 22.85 g. ~95.4 %) of N,N-dimethyl~ diphenyl-acetamide; mOp.:
130-132C.
Example 4
N N-Dimethyl-~,~-diphenyl-acetamide
13.09 g. of thionyl chloride are added to a stirred solution of
a 21.2 g. of diphenylacetic acid in 14.6 g. of dimethyl formamide at 110C
within 10 minutes, and the mixture is stirred at 130C for one hour. There-
after the mixture is processed as described in Example 1 to obtain 22.9 g.
C95.6 %) of N,N-dimethyl-~,~-diphenyl-acetamide; m.p.: 130-131C.
Example 5
N ~_ D ethyl~ henyl-acetamide
One proceeds aS described in ~xample 4 with the difference tha~
16.88 g. of phosphorous oxychloride are substituted for the 13.09 g. of
thionyl chloride. 23.0 g. (96.1 %~ of the title compound are obtained;
m.p.: 130-13105C.
2~ ~
N,N ~ -acetamide
. _
One proceeds as described in Example 4 with the difference that
6.87 g. of phosphorous trichloride are substituted for the 13.09 g. of
thionyl chloride. 23005 g. ~96.3 %) of the title compound are obtained;
m.p.: 130-132C.
Example 7
N N- methyl-p~ ylacetamide
~ _ _
26018 g. of thionyl chloride are added, at 110C, to a stirred
solution of 27.2 g. of phenylacetic acid in 29.2 g. of dimethyl formamide.
3~ The~eafter the mixture is maintained at 130 to 140C for 1.5 hours~ The
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reaction mixture is poured into 300 ml. of water, and the pH of the solution
is adjusted to 8 using aqueous sodium hydroxide solution. The aqueous- ;
alkaline mixture is extracted with 3 x 50 ml. of dichloroethane, and the
extract is fractionatedO 27.1 g. (83.5 %) of N,N-dimethyl-phenylacetamide
are obtained; m.p.: 42-43C, b.p.: 162-165C/25 mm Hg.
Exa~æ e 8
N-~æeridyl~ diphenyl-acetamide
_ _
26018 g. of thionyl chloride are added, at llO~C, to a stirred
mixture of 45.0 g. of N-formyl-piperidine and 42.4 g. of diphenylacetic
acid, and the mixture is maintained at 135C for one hour. Thereafter the
mixture is processed as described in Example 1 to obtain 50.3 g. ~90.0 %) of `
the title compound; m.p.: 116-117C.
Analysis:
calculated: C: 81.68 ~ ~: 7,58 % N: 5.01 %
found: C: 81.74 % H: 7.58 % N: 5.09 %
~9
N N- met~ ,o-dichloro-acetamide
_~ _ _ _ _ _ _
39.27 g. of thionyl chloride are added, at 110C, to a stirred
solution of 38.7 g. of dichloroacetic acid in 44.4 g. of dimethyl formamide.
The reaction mixture is maintained at 135C for 2 hours, thereafter it is
diluted with 150 ml. of water, and the pH of the mixture is adjusted to 8
using aqueous sodium hydroxide solution. The aqueous-alkaline solution is
extracted with 3 x 100 ml. of chloroform, and the extract is subjected to
fractional distillation. 38.9 g. ~83.1 %) of N,N-dimethyl~ -dichloro-
acetamide are obtained; b.p.: 78-80C/1.5-2 mm Hg; nD5 = 1.4946.
_xample 10
~ _-Dieth ~
39.27 g. of thionyl chloride are added, at 110 C, to a stirred
solution of 38.7 g. of dichloroacetic acid in 60.0 gO of diethyl formamide.
e reaction mixture is maintained at 135C for 2 hours, thereafter it is
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diluted with 150 ml. of water, and the pH of the mixture is adjusted to 8
using aqueous sodium hydroxide solution. The aqueous-alkaline solution is
extracted with 3 x 100 ml. of chloroform, and the extract is subjected to
fractional distillation. 44.6 g. (80.8 %) of the title compound are
obtained; b.p.: 100 C/4 mm Hg, nD = 1.4930.
E~ æle 11
N,N-Diallyl-a,a-dichloro-acetamide
39.27 g. of thionyl chloride are added, at 110C, to a stirred
solution of 38.7 g. of dichloroacetic acid in 75.0 g. of diallyl formamide.
The mixture is maintained at 135C for 2 hours, thereafter it is diluted
with 150 mlO of water, and the pH of the mixture is adjusted to 8 using
aqueous sodium hydroxide solution. The aqueous-alkaline solution is
extracted with 3 x 100 ml. of chloroform, and the extract is subjected to
fractional distillationO 31.2 g. ~52.8 %) of NJN-diallyl-a~a-dichlor
acetamide are obtained; b.p.: 93C/2 mm Hg, nD5 = 1.5021.
le 12
N,N,N~,N'-Tetramethyl-adipic acid diamide
143.0 g. of thionyl chloride are added, at 110C, to a stirred
solution of 73O0 g. of adipic acid in 146.0 g. of dimethyl formamide, and
the mixture is maintained at 135 to 140C for 2 hours. The mixture is
diluted with 300 ml. of water, and the pH of the solution is adjusted to 8
using aqueous sodium hydroxide solution. The aqueous-alkaline mixture is
extracted with 4 x 150 mlO of chloroform, and the extract is subjected to
fractional distillation. 57.0 g. (56.9 %) of the title compound are
obtained; b.p.: 190-192C/4 mm Hg; m.p.: 79-79.5C.
Exam~le 13
N~N-Dimethyl-ca~ryli _ amide
26.18 g. of thionyl chloride are added, at 110C, to a stirred
suluticn of 28.2 g. of caprylic acid in 29.6 g. of dimethyl formamide, and
3Q the mixture is maintained at 135 C for 1.5 hours. The mixture is diluted
_g_
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9541
with 200 ml. of water, the pH of the solution is adjusted to 8 using aqueous
sodium hydroxide solution, and the aqueous-alkaline mixture is extracted with
3 x 50 ml. of chloroform. The extract is subjected to fractional distillation
to obtain 27.7 g. (8Q~8 %) of N,N-dimethyl-caprylic amide; b.p.: 119-122C/60
mm Hg.
Analysis:
calculated: C: 70.12 % H: 12.36 % N: 8.18 %
found: C: 70.40 % H: 12.35 % N: 8.29 %
Ex~ple _14
~N ___ ethyl-oleic a~ide
13.08 g. of thionyl chloride are added, at 110C, to a stirred
solution of 28.2 g. of oleic acid in 14.6 g. of dimethyl formamide, and
the mixture is maintained at 135C for 1.5 hours. The mixture is diluted
with 100 ml. of water, and its pH is adjusted to 8 with aqueous sodium
hydroxide solution. The aqueous-alkaline solution is extracted with
3 x 50 ml. of chloroform, and the extract is subjected to fractional
distillation. 26.0 g. (84.0 %) of N,N-dimethyl-oleic amide are obtained;
n2D0 = 1.4644, m.p.: -8.5 C.
Example _15
2Q N,N-Dimethyl-benzoic amide
; 3~o27 g. of thionyl chloride are added~ at 110C, to a stirred
solution o 36.6 g. of benzoic acid in 43.8 g. of dimethyl formamide, and
the mixture is maintained at 135 to 140C for 3 hours. The mixture is
diluted with 150 ml. of water, its pH is adjusted to 8 with aqueous sodium
hydroxide solution, and the aqueous-alkaline solution is extracted with
`~ 3 x 80 ml. of chloroform. The extract is subjected to fractional distillation
to obtain 36.1 g. (80.7 %) of N,N-dimethyl-benzoic amide; b~po 150-160C/35
mm Hg.
Analysis:
3Q calculated; C: 72.46 % H: 7.43 % N: 9.39 %
fo~nd: C: 72.36 % H: 7.47 % N: 9.38 %
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Exam~l _ 16
N,N-Dimethyl-l-n~ yl-amide
13008 gO of thionyl chloride are added, at 110C, to a stirred
solution of 17.2 g. of a naphthoic acid in 14.6 g. of dimethyl formamide,
and the mixture is maintained at 135C for one hour. The mixture is diluted
with 100 ml. of water, its pH is adjusted to 8 with aqueous sodium hydroxide
solution, and the aqueous-alkaline solution is extracted with 3 x 40 ml. of
chloroform. The extract is subjected to fractional distillation to obtain
17.9 g. ~89.8 %~ of the title compound; b.p.: 134-136C/0.15 mm Hg; m.p.:
61-62C.
N N-Di-~tA~
13.08 g. of thionyl chloride are added, at 110C, to a stirred
solution of 11.2 g. of a-furanecarboxylic acid in 14.6 g. of dimethyl
formamide, and the mixture is maintained at 135C for 1.5 hours. Thereafter
the mixture is diluted with 150 ml. of water, its pH is adjusted to 8 with
aqueous sodium hydroxide solution, and the aqueous-alkaline mixture is
extracted with 3 x 50 mlO of chloroform. The extract is dried, the solvent
is evaporated, and the residue is triturated with petroleum ether. 11.5 g.
2Q (82.6 %) of the title compound are obtained; m.p.: 43-45C.
Analysis: -
~; calculated: C: 60.41 % H: 6.52 % N: 10.07 %
found: C: 60.40 % H: 6.39 % N 10.15 %
Exam~le 18
N-Dimethyl-2-chloro-nicotinic amide
26.2 g~ of thionyl chloride are added, at 110C, to a stirred
i solution of 31.5 g. of 2-chloro-nicotinic acid in 29.2 g. of dimethyl
formamide, and the mixture is maintained at 130 to 135C for one hour.
Thereafter the mixture is diluted with 150 ml. of water, its p~ is adjusted
3Q to 8 with aqueous sodium hydroxide solution, and the aqueous-alkaline
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mixture is extracted ~ith 3 x 100 ml. of chloroform. The extract is subjected
to fractional distillation to obtain 28.0 g. ~75.6 %) of the title compound;
b.p.: 162-164 C/4 mm Hg; m.p.: 68-69C.
Example 19
N N- e~y~ _ ic inic amide
___
A suspension of 61.5 g. of nicotinic acid in 73.0 g. of dimethyl
formamide is heated to 110C, and 71.5 g. of thionyl chloride are added with
stirring to the obtained homogeneous solution. The mixture is maintained
at 130 to 135C for 2 hours, thereafter it is diluted with 200 ml. of water,
la and the pH of the mixture is adjusted to 8 with aqueous sodium hydroxide
solution. The mixture is extracted with 3 x 200 ml. of chloroform, and the
extract is subjected to fractional distillation. 52.5 g. ~69.9 %) of the
title compound are obtained; b.p.: 162-165C/12 mm Hg, m.p.: 44-45C.
le 20
NJN-Dimethyl-cinnamic amide
_ ___ _ ~
26.2 g. of thionyl chloride are added, at 110C, to a stirred
solution of 29.6 g. of cinnamic acid in 29.2 g. of dimethyl formamide, and
the mixture is maintained at 135 to 140C for one hour. The reaction
mixture is poured into 200 ml. of water, and the pH of the obtained mixture
2a is adjusted to 8 using aqueous sodium hydroxide solution. The separated
substance is filtered off, washed with water, and dried. 30.6 g. ~87.3 %)
of the title compound are obtained; m.p.: 95-97C.
Analysis:
calculated: C: 75.40 % H: 7.48 % N: 7.99 %
found: C: 75.47 % H: 7.50 % N: 7.93 %
-12-
