WO2000000460A1 - Process for preparation of substituted propenoic acid esters - Google Patents
Process for preparation of substituted propenoic acid esters Download PDFInfo
- Publication number
- WO2000000460A1 WO2000000460A1 PCT/IB1999/000321 IB9900321W WO0000460A1 WO 2000000460 A1 WO2000000460 A1 WO 2000000460A1 IB 9900321 W IB9900321 W IB 9900321W WO 0000460 A1 WO0000460 A1 WO 0000460A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid esters
- preparation
- methyl
- propenoic acid
- ethyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
Definitions
- the present invention relates to a novel process for the preparation of substituted propenoic acid esters using active methylene compounds and N, N dimethyl formamide-dimethyl sulfate complex.
- Substituted propenoic acid esters especially amino-substituted derivatives like ⁇ -amino acrylic acid esters are significantly important in the synthesis of quinolones (JP 02215749 A2, 1990; Leibigs Ann. Chem. 29-37, 1987).
- Nalidixic acid was the first quinolone introduced to clinical practice, and is still in use for treatment of urinary tract infections caused by gram- negative pathogens.
- the present invention discloses a safe, economical and facile route for the preparation of substituted propenoic acid esters.
- U S Patent No.4,772,711 discloses a method for the preparation of 3 anrino acrylic acid esters by reacting an alkali salt of a beta hydroxy acrylic acid ester with an amine salt.
- U S Patent No.5,030,747 discloses a method of preparation of beta amino acrylic acid esters by reaction of beta hydroxy acrylic acid ester alkali metal salts with ammomum salts in an aprotic organic solvent, or in an aprotic organic solvent in admixture with a protic organic solvent miscible with the aprotic solvent, to give high 90% yield of the reaction product compared to 75% yield of the Englaender method (U S Patent No.4, 772,711).
- the starting alkali salt of beta hydroxy acrylic acid ester for both the above methods of US Patent Nos.4,772,71 1 and 5,030,747 is obtained from carbon monoxide, alcoholate and acetic acid esters in a pressure reaction requiring 20 to 50 bar.
- both these methods requires high pressure apparatus.
- the high toxicity and flammability of carbon monoxide demands special safety devices.
- US Patent No.5,446, 192 discloses a method for production of ⁇ -amino acrylic acid esters by reacting acetic acid esters with
- amino acid esters at 0.5 to 10 bar (preferably 1 to 5 bar) and 50-70°C (preferably 80°C to 150°C) in an aprotic polar solvent. Apart from the high temperature and pressure required by the process, the amino acid esters are costly.
- the object of the invention is to provide for a safe, economical, facile route for the preparation of substituted propenoic acid esters.
- the present invention provides a process for the preparation of substituted propenoic acid esters of general formula I.
- R is C 1 -C 4 alkyl group
- said process comprises,
- Ri is Na + or K + and R 2 is C 1 -C 4 alkyl group, with,
- the present invention relates to a cost effective and safe process.
- the present invention provides a process for the preparation of substituted propenoic acid esters of formula (I) :
- R ⁇ is Na + or K + and R 2 is C r C 4 alkyl group, with, N, N-
- the R 2 group of the active methylene compound of general formula (II) used in the present invention is preferably methyl or ethyl.
- the active methylene compound is preferably cooled before the reaction, to a temperature range of 5-20°C and preferably to around 10°C.
- the reaction between compounds II and III is carried out in an inert atmosphere, preferably nitrogen atmosphere.
- N, N-dimethylfo ⁇ namide-dimethylsulfate complex i.e.
- N, N-d memylamino methoxymethylium methyl sulfate (III) was prepared according to literature procedure (Organic Synthesis, Collective Vol.V).
- reaction according to the process of the invention may be represented by the following scheme :
- Ethylene dichloride is preferably used as solvent, but benzene, toluene or chloroform can also be used.
- methyl alkali malonate such as methyl potassium malonate (II) was treated with N, N-dimethylamino methoxymethylium methyl sulfate (III) to give 2-propenoic acid, 3- (dimethylamino), methyl ester, (E) in 68% yield.
- EXAMPLE 1 Preparation of methyl potassium malonate by using dimethyl malonate.
- a 1 lit. round bottom flask was charged with 150ml. of methanol under nitrogen. To it was added 100 gm. of diethyl malonate and it was cooled to 0- 15°C, preferably to 10°C. To this cooled solution, methanolic potassium hydroxide solution (prepared by the slow addition of 40 gm. of potassium hydroxide in 150 ml. of methanol under nitrogen) was added. The reaction mixture was stirred for 7 hr. The reaction mixture was then cooled to 5°C for 30 min. The solid which separated out was filtered to give 85 gm. of methyl malonate.
- methyl sodium malonate was also prepared, using the above procedures.
- EXAMPLE 4 Preparation of ethyl potassium malonate by using diethyl malonate.
- a 250 ml. round bottom flask was charged with 40 ml. of ethanol under nitrogen. To it was added 20 gm. of diethylmalonate and it was cooled to 5- 20°C, preferably to 10°C. To this cooled solution, ethanolic potassium hydroxide solution (prepared by slow addition of 8 gm. of potassium hydroxide in 30 ml of ethanol under nitrogen) was added. The reaction mixture was stirred for 7 hr. The reaction mixture was then cooled to 0-10°C,
- EXAMPLE 5 Preparation of ethyl potassium malonate by using dimethyl malonate.
- a 250 ml. round bottom flask was charged with 40 ml. of ethanol under nitrogen. To it was added 20 gm. of dimethylmalonate and it was cooled to 0- 15°C, preferably to 10°C. To this cooled solution, ethanolic potassium hydroxide solution (prepared by slow addition of 9.9 gm. of potassium hydroxide in 30 ml. of ethanol under nitrogen) was added. The reaction mixture was stirred for 7 hr. The reaction mixture was then cooled to 5°C for 30 min. The solid which separated out was filtered to give 15 gm. of ethyl potassium malonate.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention is for a cost effective and safe process for the preparation of substituted propenoic acid esters of general formula (I) in good yields wherein R is C1-C4 alkyl group, which comprises reacting an active methylene compound with, N,N-dimethylaminomethoxymethylium methyl sulfate in the presence of a solvent.
Description
PROCESS FOR PREPARATION OF SUBSTITUTED PROPENOIC ACID ESTERS
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of substituted propenoic acid esters using active methylene compounds and N, N dimethyl formamide-dimethyl sulfate complex.
BACKGROUND OF THE INVENTION
Substituted propenoic acid esters, especially amino-substituted derivatives like β-amino acrylic acid esters are significantly important in the synthesis of quinolones (JP 02215749 A2, 1990; Leibigs Ann. Chem. 29-37, 1987).
Nalidixic acid was the first quinolone introduced to clinical practice, and is still in use for treatment of urinary tract infections caused by gram- negative pathogens.
Since the introduction of Nalidixic acid in the early 1960s, substantial improvements have been made in the antibacterial spectrum and potency of quinolones. Additionally, newer quinolones are well absorbed and distributed throughout the body making them useful for the treatment of a variety of systemic infections including those of the respiratory tract, gastrointestinal tract, the ear, nose, and throat, sexually transmitted diseases and bone infections (Kirk-Othmer, Encyclopedia of Chemical Technology, 4th Edition, 1991, Vol. 2, 855).
Along with the increase in the importance of quinolones as an
antibacterial agent, the synthesis of quinolones and the intermediates like β- amino acrylic acid esters used for their synthesis also gained importance.
The present invention discloses a safe, economical and facile route for the preparation of substituted propenoic acid esters.
DESCRIPTION OF THE PRIOR ART
There are various methods for the preparation of the useful β-amino acrylic acid esters.
U S Patent No.4,772,711 (Englaender et al, 1988) discloses a method for the preparation of 3 anrino acrylic acid esters by reacting an alkali salt of a beta hydroxy acrylic acid ester with an amine salt.
U S Patent No.5,030,747 (Blank et al 1991) discloses a method of preparation of beta amino acrylic acid esters by reaction of beta hydroxy acrylic acid ester alkali metal salts with ammomum salts in an aprotic organic solvent, or in an aprotic organic solvent in admixture with a protic organic solvent miscible with the aprotic solvent, to give high 90% yield of the reaction product compared to 75% yield of the Englaender method (U S Patent No.4, 772,711).
The starting alkali salt of beta hydroxy acrylic acid ester for both the above methods of US Patent Nos.4,772,71 1 and 5,030,747 is obtained from carbon monoxide, alcoholate and acetic acid esters in a pressure reaction requiring 20 to 50 bar. Thus, both these methods requires high pressure
apparatus. Moreover, the high toxicity and flammability of carbon monoxide demands special safety devices.
Lang & Cohen (Journal of Medicinal Chemistry, Vol. 18 No.4,441-443) describes a method for the production of ethyl-3-dimethyl amino aciylate by the reaction of ethyl propiolate with aqueous dimethyl amine in 47% yield.
However, the process warrants use of costly ethyl propiolate as one of the starting materials.
In the process described in Tetrahedron letters, 4061, 1976 and Liebigs Annalen Der Chemie Vol. 1980, No.7, 991, highly toxic iron pentacarbonyl is used in the reaction of methyl aciylate with t-butoxy bis (dimethylamino) methane. Moreover, there is polymerization of acrylic acid ester, which makes the reaction product more difficult to isolate, and is a disadvantage of the process.
β-Dimethyl amino acrylic acid ester is also obtained by the reaction of
t-butoxy bis (dimethylamino) methane with ethyl acetate at 170°C (Chemische Berichte 2709, 104, 1971). The process has to be carried out in a sealed tube and high pressures are attained at the end of a volatile reaction. It is also known, that when methoxy bis (dimethylamino) methane is reacted with ethyl butyrate, no reaction product is obtained at all (Organic Preparation Proceedings, International 67, 10, 1978).
US Patent No.5,446, 192 (Kraus et al, 1995) discloses a method for production of β-amino acrylic acid esters by reacting acetic acid esters with
amino acid esters at 0.5 to 10 bar (preferably 1 to 5 bar) and 50-70°C
(preferably 80°C to 150°C) in an aprotic polar solvent. Apart from the high temperature and pressure required by the process, the amino acid esters are costly.
The above described methods are both cumbersome and costly. Hence there arose a need to develop a facile, novel scheme to prepare substituted propenoic acid esters.
SUMMARY OF THE INVENTION
The object of the invention is to provide for a safe, economical, facile route for the preparation of substituted propenoic acid esters.
The present invention provides a process for the preparation of substituted propenoic acid esters of general formula I.
wherein R is C1-C4 alkyl group,
said process comprises,
reacting an active methylene compound of the general formula II,
II
wherein Ri is Na+ or K+ and R2 is C1-C4 alkyl group, with,
N, N-dimethyl amino methoxymethylium methyl sulfate of formula III
C H 3 0
I 3 II
N ^ ^ 0 C H 3 .0 S — 0C H .
(-)
C H . ι(+
H m in the presence of a solvent.
DETAILED DESCRIPTION OF THE INVENTION
The synthetic utility, of β-amino acrylic acid esters is ever increasing, as mentioned earlier, in the examples of quinolones, which are marketed worldwide. To make such products more economical, it is necessary to find a commercially viable and safe route. In literature, there are various methods of
reported for the synthesis of β-amino acrylic acid esters as described above. However, the risks involved in the processes are high due to high temperatures and/or pressures involved, hazards of reactant and product costs, all of which demand for a new route.
The present invention relates to a cost effective and safe process. The present invention provides a process for the preparation of substituted propenoic acid esters of formula (I) :
H
I wherein R is CJ-C4 alkyl group,
δ
by reacting active methylene compounds of general formula (II) :
dimethyl formamide-dimethylsulfate complex of general formula (III) :
C H 3 0
I 3 II
H
HI
The R2 group of the active methylene compound of general formula (II) used in the present invention is preferably methyl or ethyl.
The active methylene compound is preferably cooled before the reaction, to a temperature range of 5-20°C and preferably to around 10°C. The reaction between compounds II and III is carried out in an inert atmosphere, preferably nitrogen atmosphere.
N, N-dimethylfoπnamide-dimethylsulfate complex i.e.
N, N-d memylamino methoxymethylium methyl sulfate (III) was prepared according to literature procedure (Organic Synthesis, Collective Vol.V).
The reaction according to the process of the invention may be represented by the following scheme :
So l ven t Q U _
" N ^ H
Ethylene dichloride is preferably used as solvent, but benzene, toluene or chloroform can also be used.
According to the reaction scheme, methyl alkali malonate, such as methyl potassium malonate (II) was treated with N, N-dimethylamino methoxymethylium methyl sulfate (III) to give 2-propenoic acid, 3- (dimethylamino), methyl ester, (E) in 68% yield.
EXAMPLES EXAMPLE 1: Preparation of methyl potassium malonate by using dimethyl malonate.
A 20 lit. round bottom flask was charged with 3 lit. of methanol under nitrogen. To it was added 2 Kg. of dimethylmalonate and it was cooled to 0- 20°C, preferably to 10°C. To this cooled solution, methanolic potassium hydroxide solution (prepared by the slow addition of 960 gm. of potassium hydroxide in 3 lit. of methanol under nitrogen) was added. The reaction mixture was stirred for 5-10 hr., preferably 7 hr. The reaction mixture was then cooled to 0-10°C, preferably 5°C for 30 min. The solid which separated out was filtered to give 1.98 Kg. of methyl potassium malonate.
EXAMPLE 2: Preparation of methyl potassium malonate by using diethyl malonate.
A 1 lit. round bottom flask was charged with 150ml. of methanol under nitrogen. To it was added 100 gm. of diethyl malonate and it was cooled to 0- 15°C, preferably to 10°C. To this cooled solution, methanolic potassium hydroxide solution (prepared by the slow addition of 40 gm. of potassium hydroxide in 150 ml. of methanol under nitrogen) was added. The reaction mixture was stirred for 7 hr. The reaction mixture was then cooled to 5°C for 30 min. The solid which separated out was filtered to give 85 gm. of methyl malonate.
Similarly, methyl sodium malonate was also prepared, using the above procedures.
EXAMPLE 3: Preparation of 2-propenoic acid, 3 -(dimethylamino), methyl ester, (E).
In a 20 lit. round bottom flask, 1.98 kg. of methyl potassium malonate in 8 lit. of ethylene dichloride was added. The reaction mixture was cooled to 5-20°C, preferably to 10°C, and 3.2 Kg. of N, N-dimethylamino methoxymethylium methyl sulfate was added dropwise, under nitrogen. The temperature was raised to 20°C and maintained for 6 hrs. To it was added 2 lit. of 2% aq. sodium hydroxide solution and stirred for 10 min. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the product. It was further washed by hexane to give 1.325
kg.of pure, dry 2-propenoic acid, 3 -(dimethylamino)-, ethyl ester, (E). m.p.:44-
46°C.
IR: 3803, 1735, 1620, 1544 cm"'
H NMR (CDC13, 200MHz)δ :7.43(d, 1H, J=12.86 Hz), 4.51
(d, 1H,J=12.87 Hz), 3.66 (s, 3H), 2.88(s,6H)
Mass: 129(95%), 114(24%), 98(100%) and 82 (11%).
2-Propenoic acid, 3-(dimemylamino), methyl ester, (E) was also prepared by using sodium salt of malonate.
EXAMPLE 4: Preparation of ethyl potassium malonate by using diethyl malonate.
A 250 ml. round bottom flask was charged with 40 ml. of ethanol under nitrogen. To it was added 20 gm. of diethylmalonate and it was cooled to 5- 20°C, preferably to 10°C. To this cooled solution, ethanolic potassium hydroxide solution (prepared by slow addition of 8 gm. of potassium hydroxide in 30 ml of ethanol under nitrogen) was added. The reaction mixture was stirred for 7 hr. The reaction mixture was then cooled to 0-10°C,
preferably to 5°C for 30 min. The solid which separated out was filtered to give 13 gm. of ethyl potassium malonate.
EXAMPLE 5: Preparation of ethyl potassium malonate by using dimethyl malonate.
A 250 ml. round bottom flask was charged with 40 ml. of ethanol under nitrogen. To it was added 20 gm. of dimethylmalonate and it was cooled to 0-
15°C, preferably to 10°C. To this cooled solution, ethanolic potassium hydroxide solution (prepared by slow addition of 9.9 gm. of potassium hydroxide in 30 ml. of ethanol under nitrogen) was added. The reaction mixture was stirred for 7 hr. The reaction mixture was then cooled to 5°C for 30 min. The solid which separated out was filtered to give 15 gm. of ethyl potassium malonate.
EXAMPLE 6: Preparation of 2-propenoic acid, 3 -(dimethylamino), ethyl ester, (E).
In a 250 ml round bottom flask 10 gm. of ethyl potassium malonate in 40 ml. of ethylene dichloride was added. The reaction mixture was cooled to 5-20°C, preferably to 10°C, and 16 gm of N, N-dimethylamino methoxymethylium methyl sulfate was added dropwise under nitrogen.
The temperature was raised to 20°C and maintained for 6 hrs. To it was added 10 ml of 2% aq. sodium hydroxide solution and stirred for 10 min. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give 5.5 gm of the product i.e. 2-propenoic acid, 3-
(dimethylamino), ethyl ester, (E).
Claims
1. A process for the preparation of substituted propenoic acid esters of general formula I.
H I 0 II
I
wherein R is CrC4 alkyl group,
said process comprises, reacting an active methylene compound of the general formula II.
II
wherein Rj is Na+ or K+ and R2 is CrC4 alkyl group, with, N, N-
dmemylaminomethoxymethylium methyl sulfate of formula III
CH
N ^0CH3 0 S ΓÇö 0CH3
CH. 1 \( (++)1 II
m
in the presence of a solvent.
2. The process as claimed in claim 1 wherein said R2 is methyl or ethyl.
3. The process as claimed in claim 2, wherein said solvent is selected from the group consisting of ethylene dichloride, benzene, toluene or chloroform.
4. The process as claimed in claim 1, wherein methyl potassium malonate or ethyl potassium malonate of formula II is cooled to a range of 5-20┬░C, before reacting with the compound of formula III.
5. The process as claimed in claim 3, wherein methyl potassium malonate or ethyl potassium malonate of formula II is cooled from 9┬░C to 11┬░C before reacting with the compound of formula III.
6. The process as claimed in claim 1, wherein the said reaction is carried out in an inert atmosphere.
7. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of about 10┬░C to 30┬░C.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000557221A JP2002519337A (en) | 1998-06-29 | 1999-02-22 | Method for producing mono-substituted propenoic acid ester |
| EP99902780A EP1091927A1 (en) | 1998-06-29 | 1999-02-22 | Process for preparation of substituted propenoic acid esters |
| AU22959/99A AU2295999A (en) | 1998-06-29 | 1999-02-22 | Process for preparation of substituted propenoic acid esters |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1137/CAL/98 | 1998-06-29 | ||
| IN1137CA1998 | 1998-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000000460A1 true WO2000000460A1 (en) | 2000-01-06 |
Family
ID=11086028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB1999/000321 WO2000000460A1 (en) | 1998-06-29 | 1999-02-22 | Process for preparation of substituted propenoic acid esters |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1091927A1 (en) |
| JP (1) | JP2002519337A (en) |
| AU (1) | AU2295999A (en) |
| WO (1) | WO2000000460A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101293850B (en) * | 2008-06-10 | 2012-05-30 | 苏州开元民生科技股份有限公司 | Method for preparing 3-N,N-dimethylamino-ethyl acrylate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4772711A (en) * | 1985-08-30 | 1988-09-20 | Dynamit Nobel Ag | Method for the preparation of 3-aminoacrylic acid esters |
| EP0411417A1 (en) * | 1989-08-03 | 1991-02-06 | Bayer Ag | Process for preparing aminomethylene compounds |
| US5446192A (en) * | 1992-03-12 | 1995-08-29 | Bayer Aktiengesellschaft | Process for the preparation of β- aminoacrylic acid esters |
-
1999
- 1999-02-22 WO PCT/IB1999/000321 patent/WO2000000460A1/en not_active Application Discontinuation
- 1999-02-22 JP JP2000557221A patent/JP2002519337A/en active Pending
- 1999-02-22 AU AU22959/99A patent/AU2295999A/en not_active Abandoned
- 1999-02-22 EP EP99902780A patent/EP1091927A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4772711A (en) * | 1985-08-30 | 1988-09-20 | Dynamit Nobel Ag | Method for the preparation of 3-aminoacrylic acid esters |
| EP0411417A1 (en) * | 1989-08-03 | 1991-02-06 | Bayer Ag | Process for preparing aminomethylene compounds |
| US5446192A (en) * | 1992-03-12 | 1995-08-29 | Bayer Aktiengesellschaft | Process for the preparation of β- aminoacrylic acid esters |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101293850B (en) * | 2008-06-10 | 2012-05-30 | 苏州开元民生科技股份有限公司 | Method for preparing 3-N,N-dimethylamino-ethyl acrylate |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2295999A (en) | 2000-01-17 |
| EP1091927A1 (en) | 2001-04-18 |
| JP2002519337A (en) | 2002-07-02 |
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