Note: Descriptions are shown in the official language in which they were submitted.
2L23a~ 3
The present 1nvent;on relates ~o a chemically
or;g;nal process for the preparat;on of known symmetrical
1,4 d;hydropyridinedicarboxylic esters.
Several processes.for ~heir preparation haYe al-
ready been d;sclosed. . .
Kirchner, Ber. 25,-2786 t1892) describes the reac-
t;on of aldehydes ~ith 3-ketocarboxyl;c esters and ammonia
in accordance with the react;on d;agram belo~:
. R
RC~O ~ 2 Rl--CO~C~2-COOR2 ~ N~3 ~_~ R2oo~ ~ QoR2
~ R
R1 ~ 1
Fox et al. J. Org. Chem~ 16, 1259 (1951~ mentions the
reaction of aldehydes with 3-ketocarboxylis esters and
enaminocarboxylic esters in accordance w~th the reaction
diagram belo~:
R \ / H
R20Oc` ~ COOR
RC~O ~ Rl-CO`C~2-COOR2 + R~-C-;C~-CR2 ~ ~ `~ 2
/ N ~R
Knoevenagel, Ber. 31, 743 (1898~ describes the
reaction of yl;dene-3-ketocarboxylic est~rs ~ith enamino~
carboxylic esters in accordance with the reaction diagram
belo~: . R H
. \/
. R200C ~ ~ COOR~
R-C~-C 1 + R1-C-C~-C00~2 ~~~~~ R ~ ~R
Le A 22 066
.
. ~
- 2 - ~23~S7~
S;n~e both aldehydes and ammon;a r~ac~ w;th keto-
carboxyl;c esters, it may be assumed that the yl;dene com-
pound and the enam;ne compound are aLso ini~ially formed
in the two processes mentioned f;rst.
. The d;sadvantages of the descr;bed pPOcesSeS are
regarded as being that the ylidene compounds can be ;so-
lated in the pure form only w;th d;ff;culty, and that
therefore the 1,4-dihydropyr;d;nedicarboxylic esters still
contain impur;ties which can be removed by pur;f;cat;on
processes only w;th great difficulty~
Ha~ing regard to the use of the 1,4~dihydropyridines
as medicaments~ there ;s a need to make these compounds
available in a high degree of purity. Thus, for exampleD
seven by products were demonstrated by thin-layer chroma-
tography in the preparation of 4 (2~-n;trophenyl)-2,6-di-
methyl-3,5 dicarboethoxy-1,4-dihydropyridine according-to
U.S. Patent 3,485,847.
Thus the invention relates to a process for the
preparat;on of symmetrical 1,4-dihydropyridines of the
formula I
R10OC ~ COOR1 -
C~/ N C~
;n wh;ch
R represents a phenyl radical which is optionally
subs~;tuted once or twice by nitro and/or chlorine9
25 ` and
R1 represents a C1-C4-alkyl radical which is option-
ally subst;tuted by a C1-C4-alkoxy group,
by reaction of an yl;dene compound of the formula II
/ C~C~3
R-CH=C (II~
Le A 22 066 COOR
~
3 ~23~
with an enamine co~pound of the formula III
CH3-C~C~-CCOR1
NH2 ~III),
which is charac~erised in that the ylidene csnpound of the
formula II is prepared by reaction of a ketocarboxylic
es~er of the formula IV
C~3-C-C~2-CooR1 (IV)
O
~ith an aldehyde of the formula RCH0 in a solvent, in the
presence of cataly~;c amounts of acetate salts of amines,
at temperatures fro0 -10C to 100Cn
Acetate salts of a~ines which may be mentioned as
preferred are: piperidine or alkylpiperidine ace~ate,
morpholine or alkylmorpholine acetate, piperazine or atkYl-
piperazine __ acetate, pyrrolidine and
a~kylpyrrolidine acetate. Piper;d;ne --
acetate may be particularly mentioned. The alkyl radicals
in the catalysts preferably have 1-4 C atoms.
The solvents which are preferably used are aliphatic
alcohols, such as methanol, ethanol and/or isopropanol.
Tie preferred reaction temperatures are 20 60C~
The catalyst is preferably added in amsunts from
0.01 to 0O7 mol, particularly preferably 0.02 - 0~2 mol,
especially 0.04 - 0.2 mol, per mol of ylidene compound.
Preferably 1 to 2 mol, especially 1 mol, of alde-
hyde can be employed per mol of ketocarboxyllc ester ~f the
formula I`l.
In ~he formula I,
R preferably denotes a 2- or 3-nitrophenyl rad;cal,
a 2- or 3~chlorophenyl radical or a 2,3-dichloro-
phenyl radical, and
R1 preferably denotes methyl, ethyl, propyl, iso~
propyl, isobutyl or a propoxiethyl rad1cal.
The reaction of the ylidene compound of the formula
Le A 22 066
.
,
:: .
.
~ 3
4 --
II with the enamine compound of the formula ~ 5 carr1ed
out at temperatures from -10 to 130C, preferably from 50
to 100C.
Preferably 1 to 1.5 mol, part;cularly preferably
1 to 1~3, especially 1 to 1.Z, mol of the enam;ne compound
can be employed per mol of ylidene compound.
According to a particular embodiment, the crystal-
line ylidene compound rema;ns in according to ~he reaction
and is reacted directly ~ith the enamine compound.
1û It has to be denoted extremely surprising that the
ylidene-3-ketocarboxylic esters are produced in high purity
and excellent yield and can be very readily isolated using
the reaction accord;ng to the invention in the presence
of the catalysts mentioned.
Furthermore, i~ has to be deno~ed surprising that
the 1,4 dihydropyridine compounds are produced in such
high purity and can be isolated in the manner describedO
W;thout further purification processes, they contain no
by-products.
The process according to the invention has a number
of advantages.
Thus9 the yield is higher than according to the
known processes, and the isolated product does not need
to be subjected to further pur;fication stepsO
When o-nitrobenzaldehyde, methyl acetoacetate and
methyl 3-aminocrotonate are used as the starting mater;als,
then the course of the reaction can be represented by the
diagram belo~:
A) ~ 0 ~ 0 2
Le A Z2 066 ~ EsO ~ ~ C0-OCE~
:. - :
~:
:
~23~5~
~,
~2
B ) ~ ~CO~ + E~ ~E CO~ 5
GO--C~CE3 .
o2
C~32C ~ C02CH3
C~I3 ~:E13
.~
Th~ invention may be illustrated by the examples
~hich follo~:
a) Ylidenecarboxylic ester
116 9 tl mol) of methyl acetoacetate, 151 9 51 mol)
of 2-n;trobenzaldehyde, 2~4 9 ~0.04 mol) of glacial acetic
ac;d and 3.4 9 tO.04 mol) of piperidine are added in that
sequence, w;th st;rring, to 650 ml of- ;sopropanol at room
temperature.
The mixture ;s warmed to 40C and kept at this
temperature for 15 minutes a
It is then cooled to Z0C and stirr`ed for 16 hoursa
Subsequently ;t ;s cooled to 0C and st;rred at th;s tempera-
ture for 1 hour~ The supernatant solut;on ;s then removed
by suct;on, and the crystals are cent-rifuged with 130 ml
of ;ce-cold ;sopropanol and removed by suct;on.
The resulting~methyt 2-~2~'-nitrobenzyl;dene)aceto-
ace~ate ;s ;mmed;ately re~acted ;n the same vessel as des-
cr;4ed ;n b).
2U ~ ~ When the meehyl 2-~Z'-n~it~robenzyl;dene~acetoacetate
;s ;solated~and dr;;ed, then 241.7~g of~yellow crystals ~97%
of the theoret;cal;yield) of melting point ~9-101C are
obta;n'ed.~
Wh~en other~amo~unts~ of c~alyst are empLoyed ;n
place~of 0.04 mol of piperidi~ne acet~ate, then ehe follow-
;ng~y~i~eld~s~ar~e;~obtained.
Le A 22 066 ~
.: . ,: ~ :,, . :
` - 6 - ~3~
Amount Y;eld ~X)
0~08 mol 96.5
0.16 mol 97~6
0.5 mol 99.9
b) 750 ml of me~hanol and 111~5 9 tO~97 ~ol) of me~hyl
30aminocrotonate are added to ~he methyl 2-~2'-n;troben2-
ylidene)acetoacetate ~hich has been prepared according to
a) and is moist ~ith isopropanol. The mixture ;s heated
to reflux ~about 65C) and kept at this temperature for
36 hours.
After cooling to 0C, the result;ng crystals are
isolated and ~ashed ~ith 130 ml of methanol and 500 ml of
water and sucked dry.
302 9 (0.87 mol) of ~-~2-nitrophenyl)-2,6-dimethyl~
3,5-dicarbomethoxy-1,4-dihydropyridine of melting point
171-175C ~87X o~ the theore~ical yield) are obtainedD~
Thin-layer chromatography on Merck sil;ca gel ready-
coated p~ates tmobile phase: chloroform : acetone : petro-
leum ether = 3 : 2 : 5) show no visible by-products.
Comparison_experiment
Example 1 in U.S. Patent Specification 3,485,847
~as repeated and 4-t2-nitrophenyl~2,6-dimethyl-3,5-di-
carboethoxy-1,4-dihydropyridine was obta;ned as follows:
Yield ~X) 80
8y-products ~number~ 7
Colour red-bro~n
The same compound was prepared according to the
above processes a and b according to the inven~ion. The
follow;ng corresponding figures were obtained:
Yield S%) 85
3y-producSs ~number) none
Colour yellow
.
' ' ' :
Le A 22 066
:
~:
,
.
