CA1234573A - Process for the preparation of symmetrical 1,4- dihydropyridinedicarboxylic esters - Google Patents
Process for the preparation of symmetrical 1,4- dihydropyridinedicarboxylic estersInfo
- Publication number
- CA1234573A CA1234573A CA000451158A CA451158A CA1234573A CA 1234573 A CA1234573 A CA 1234573A CA 000451158 A CA000451158 A CA 000451158A CA 451158 A CA451158 A CA 451158A CA 1234573 A CA1234573 A CA 1234573A
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Manufacture Of Tobacco Products (AREA)
- Mechanical Coupling Of Light Guides (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Steroid Compounds (AREA)
- Air Supply (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Magnetic Ceramics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
In the preparation of a 1,4-dihydropyridine of the formula in which R is a phenyl radical which is optionally sub-stituted once or twice by nitro and/or chlorine, R1 is a C1-C1-alkyl radical which is optionally substituted by a C1-C4-alkoxy group by preparing an ylidene compound of the formula and reacting such ylidene compound with an enamine compound of the formula the improvement which comprises preparing the ylidene compound by reaction of a ketocarboxylic ester of the formula with an aldehyde of the formula RCHO, in a solvent in the presence of a catalyst amount of any acetate salt of an amine at a tem-perature from about -10°C up to 100°C.
Le A 22 066
In the preparation of a 1,4-dihydropyridine of the formula in which R is a phenyl radical which is optionally sub-stituted once or twice by nitro and/or chlorine, R1 is a C1-C1-alkyl radical which is optionally substituted by a C1-C4-alkoxy group by preparing an ylidene compound of the formula and reacting such ylidene compound with an enamine compound of the formula the improvement which comprises preparing the ylidene compound by reaction of a ketocarboxylic ester of the formula with an aldehyde of the formula RCHO, in a solvent in the presence of a catalyst amount of any acetate salt of an amine at a tem-perature from about -10°C up to 100°C.
Le A 22 066
Description
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 .
. ~
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
~
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
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 :
~:
, .
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 :
~:
, .
Claims (7)
1. Process for the preparation of symmetrical 1,4-di-hydorpyridines of the formula I
(I) in which R represents a phenyl radical which is optionally substituted once or twice by nitro and/or chlorine, and R1 represents a C1-C4-alkyl radical which is option-ally substituted by a C1-C4-alkoxy group, by reaction of an ylidene compound of the formula II
(II) with an enamine compound of the formula III
(III) characterised in that the ylidene compound of the formula II is prepared by reaction of a ketocarboxylic ester of the formula IV
(IV) with an aldehyde of the formula RCHO in a solvent, in the presence of catalytic amounts of acetate salts of amines, at temperatures from -10°C and up to 100°C.
(I) in which R represents a phenyl radical which is optionally substituted once or twice by nitro and/or chlorine, and R1 represents a C1-C4-alkyl radical which is option-ally substituted by a C1-C4-alkoxy group, by reaction of an ylidene compound of the formula II
(II) with an enamine compound of the formula III
(III) characterised in that the ylidene compound of the formula II is prepared by reaction of a ketocarboxylic ester of the formula IV
(IV) with an aldehyde of the formula RCHO in a solvent, in the presence of catalytic amounts of acetate salts of amines, at temperatures from -10°C and up to 100°C.
Z. Process according to Claim 1, characterised in that the reaction is carried out at 20-60°C.
3. Process according to Claim 1, characterised in that Le A 22 066 0.01 to 0.7 mol of catalyst is employed per mol of ylidene compound.
4. Process according to Claim 1, characterised in that 0.02 to 0.2 mol of catalyst is employed per mol of ylidene compound.
5. Process according to Claim 1, characterised in that 0.04 to 0.2 mol of catalyst is employed per mol of ylidene compound.
6. Process according to Claim 1, characterised in that 1 to 2 mol of aldehyde is employed per mol of ketocarboxylic ester.
7. Process according to Claim 1, characterised in that 1 mol of aldehyde is employed per mol of ketocarboxylic ester.
Le A 22 066
Le A 22 066
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3312216A DE3312216A1 (en) | 1983-04-05 | 1983-04-05 | METHOD FOR PRODUCING SYMMETRIC 1,4-DIHYDROPYRIDINE CARBONIC ACID ESTERS |
| DEP3312216.4 | 1983-04-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1234573A true CA1234573A (en) | 1988-03-29 |
Family
ID=6195495
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000451158A Expired CA1234573A (en) | 1983-04-05 | 1984-04-03 | Process for the preparation of symmetrical 1,4- dihydropyridinedicarboxylic esters |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0124742B1 (en) |
| JP (1) | JPH0662564B2 (en) |
| KR (2) | KR900004038B1 (en) |
| AT (1) | ATE36849T1 (en) |
| AU (1) | AU558122B2 (en) |
| CA (1) | CA1234573A (en) |
| DE (2) | DE3312216A1 (en) |
| DK (1) | DK160488C (en) |
| ES (1) | ES531236A0 (en) |
| FI (1) | FI78471C (en) |
| GR (1) | GR81898B (en) |
| HU (1) | HU192546B (en) |
| IE (1) | IE57181B1 (en) |
| IL (1) | IL71425A (en) |
| NO (1) | NO166178C (en) |
| PH (1) | PH20992A (en) |
| PT (1) | PT78365B (en) |
| ZA (1) | ZA842510B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3312283A1 (en) * | 1983-04-05 | 1984-10-18 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING UNBALANCED 1,4-DIHYDROPYRIDINE CARBONIC ACID ESTERS |
| DE3508533A1 (en) * | 1985-03-09 | 1986-09-11 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING BENZYLIDE COMPOUNDS |
| US4771057A (en) * | 1986-02-03 | 1988-09-13 | University Of Alberta | Reduced pyridyl derivatives with cardiovascular regulating properties |
| DE4423445A1 (en) * | 1994-07-05 | 1996-01-11 | Bayer Ag | Rapid high yield prodn. of nifedipin |
| DE19727350C1 (en) | 1997-06-27 | 1999-01-21 | Bayer Ag | Process for the preparation of nifedipine |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1792764C3 (en) * | 1967-03-20 | 1981-04-23 | Bayer Ag, 5090 Leverkusen | Coronary drugs |
| DE1670824C3 (en) * | 1967-03-20 | 1978-08-03 | Bayer Ag, 5090 Leverkusen | 1,4-Dihydropyridine-33-dicarboxylic acid alkyl ester |
| DE2335466A1 (en) * | 1973-07-12 | 1975-01-30 | Bayer Ag | ALCOXY ALKYL-1,4-DIHYDROPYRIDINE, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
| US4370334A (en) * | 1975-07-02 | 1983-01-25 | Fujisawa Pharmaceutical Co., Ltd. | 1,4-Dihydro-pyridine derivatives and methods of using same |
| DE2549568C3 (en) * | 1975-11-05 | 1981-10-29 | Bayer Ag, 5090 Leverkusen | 2,6-Dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester, several processes for its preparation and pharmaceuticals containing it |
| JPS5936896B2 (en) * | 1976-10-21 | 1984-09-06 | 住友化学工業株式会社 | α-acetyl cinnamic acid ester derivatives, their production methods, and herbicides comprising the compounds |
| CA1117117A (en) * | 1978-10-10 | 1982-01-26 | Fujisawa Pharmaceutical Co., Ltd. | 2-methyl-dihydropyridine compound, processes for preparation thereof and pharmaceutical composition comprising the same |
| JPS5529990A (en) * | 1979-03-19 | 1980-03-03 | Wako Pure Chem Ind Ltd | Activity measurement of monoamine oxidase (mao) |
-
1983
- 1983-04-05 DE DE3312216A patent/DE3312216A1/en not_active Withdrawn
-
1984
- 1984-03-22 NO NO841142A patent/NO166178C/en not_active IP Right Cessation
- 1984-03-26 AT AT84103304T patent/ATE36849T1/en not_active IP Right Cessation
- 1984-03-26 EP EP84103304A patent/EP0124742B1/en not_active Expired
- 1984-03-26 DE DE8484103304T patent/DE3473756D1/en not_active Expired
- 1984-04-02 IL IL71425A patent/IL71425A/en not_active IP Right Cessation
- 1984-04-02 JP JP59063438A patent/JPH0662564B2/en not_active Expired - Lifetime
- 1984-04-03 ES ES531236A patent/ES531236A0/en active Granted
- 1984-04-03 CA CA000451158A patent/CA1234573A/en not_active Expired
- 1984-04-03 GR GR74294A patent/GR81898B/el unknown
- 1984-04-03 FI FI841336A patent/FI78471C/en not_active IP Right Cessation
- 1984-04-03 PT PT78365A patent/PT78365B/en unknown
- 1984-04-03 PH PH30491A patent/PH20992A/en unknown
- 1984-04-04 ZA ZA842510A patent/ZA842510B/en unknown
- 1984-04-04 AU AU26416/84A patent/AU558122B2/en not_active Expired
- 1984-04-04 IE IE828/84A patent/IE57181B1/en not_active IP Right Cessation
- 1984-04-04 DK DK178584A patent/DK160488C/en not_active IP Right Cessation
- 1984-04-04 KR KR1019840001767A patent/KR900004038B1/en not_active Application Discontinuation
- 1984-04-04 KR KR1019840001767A patent/KR840008647A/en not_active IP Right Cessation
- 1984-04-05 HU HU841337A patent/HU192546B/en unknown
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