GB2219294A - Preparation of methyl 3-aminocrotonate - Google Patents
Preparation of methyl 3-aminocrotonate Download PDFInfo
- Publication number
- GB2219294A GB2219294A GB8912679A GB8912679A GB2219294A GB 2219294 A GB2219294 A GB 2219294A GB 8912679 A GB8912679 A GB 8912679A GB 8912679 A GB8912679 A GB 8912679A GB 2219294 A GB2219294 A GB 2219294A
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- United Kingdom
- Prior art keywords
- methyl
- water
- reaction
- ammonia
- aminocrotonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
2219294 A- PROCESS FOR.THE PREPARATION OF METHYL 3-AMINOCROTONATE t, e
This invention relates to a new process for preparing methyl 3aminocrotonate which can be used at an industrial scale, too. This product is an important starting substance for the synthesis of drugs of the 1,4-dihydropyridine-3,5-dicarboxylic acid ester type which are useful in the therapy of cardiovascular diseases.
It is known from the literature that M. Conrad and W. Epstein /-Ber. 20, 3054 (188727 prepared methyl 3-aminocrotonate by reacting methyl acetoacetate with anhydrous ammonia gas in an ethereal solution, in the presence of ammonium nitrte as catalyst.
After introducing the gas, the reaction mixture is left to stand in a closed vessel for 2 days, then the ether is evaporated to give a crude mass in a yield of 71%. The yield of the product purified by recrystallization from ethanol is not given; it is only described that the methyl 3-aminocrotonate obtained after sublimation melts at 85 0 C.
According to J. Kashun /-Ber. 38, 1129 (1905)7, methyl acetoacetate and methyl A-chloroethyl ketone are reacted with aqueous ammonia to obtain methyl 3-aminocrotonate instead of the corresponding substituted pyrrolidone derivative expected. No yield is given for this process. The pure product (with a melting point of 82 to 84 DC) is obtained by three recrystallization steps from petroleum ether.
According to an other method /-H. Meyer: Arzn. Forsch. 31/1, 409 (198127, dry ammonia gas is introduced into a toluene solution of methyl acetoacetate in the presence of p-toluenesulfonic acid as catalyst while boiling the reaction mixture under reflux (at the boiling point of toluene, i.e. 110 OC until the formation of water arising from the reaction ceases. After filtering the hot mixture the solution is evaporated under reduced pressure and the residue is fractionally distilled unter reduced pressure-. No yield is given. A single description has only been found in the literature /-C. H. Meyer: Monatshefte fUr Chemie 28, 4 (1907)7 according to which methyl acetoa- cetate is reacted with an ammonium hydroxide solution of 15% at room temperature but methyl 3-aminocrotonate is obtained in a yield of only 7% by this method whilst the main product of the reaction is acetoacetic acid amide.
According to the literature (Houben-Weyl: Methoden der Organischen Chemie 11/1, page 173) the reaction of ketocarboxylic acid esters (such as methyl acctoacetate) with amines (such as ammonia) to give enamine-type compounds proceeds in two steps. The first step is an addition whereas water is eliminated in the second step. It is emphasized that the removal of water is required.
The most important drawback of the processes described above consists in that the methyl 3-aminocrotonate obtained is contaminated by acetoacetic acid amide which has to be removed by separate purifying operations (e.g. by fractional distillation or several recrystallisations). An other drawk v 1 h back consists in the fact that a solvent has to be used, then dried and evaporated; particularly, the use of ether implies an increased danger of fire and explosion.
In opposition to the literature data, it has surprisingly been found that methyl 3-aminocrotonate containing no side product can be obtained in a good yield by reacting methyl acetoacetate with ammonia in an aqueous medium at a temperature from 40 to 70 oc.
The purity of the product, particularly its freedom from acetoacetic acid amide, is a very important requirement because, in the synthesis of the known 1,4-dihydropyridine-3,5-dicarboxylic acid esters, the side-products being present in the methyl 3-aminocrotonate react with P-dicarboxylic acid esters to give traces of contaminations which in many cases cannot be removed from the final product obtained.
The aim of the present invention is to eliminate the above disadvantages of the known processes.
Thus, the present invention relates to a process for preparing methyl 3aminocrotonate by reacting methyl acetoacetate with ammonia, which comprises carrying out the reaction in the presence of water at a temperature ranging from 35 to 70 OC.
According to the process of the invention, methyl acetoacetate is reacted with 1.5 to 4.0 molar equivalents, preferably with 1.6 to 1.75 molar equivalents, of ammonia in the presence of 0.05 to 3.0 molar equivalents of water in such a way that ammonia is portionwise added to the k, mixture of methyl acetoacetate and water under stirring or, if desir-ed, ammonium hydroxide is portionwise added to methyl acetoacetate.
When working with a defined rate of portionwise addition and at a constant rate of stirring, the reaction heat and thereby the temperature of the reaction mixture are defined. Ammonium hydroxide is portionwise added at a rate of 2.5 to 4.5 ml/minute (ml/min), preferably at a rate of 3.0 to 3.35 ml/miR while the temperature of the reaction mixture is maintained at 35 to 50 OC, suitably at 40 to 45 OC. The product precipitates from the reaction mixture in crystalline form, the precipitation is accelerated or-promoted, respectively, by cooling, optionally by cooling with ice-salt. The methyl 3-aminocrotonate obtained is filtered, washed with water and dried.
Alternatively, when gaseous ammonia is introduced, the mixture of methyl acetoacetate with water is saturated with the gas, then the product is precipitated from the warm reaction mixture by adding a further amount of water.
The advantages of the process according to the invention can be summarized as follows: - The yield is good. - The methyl 3-aminocrotonate obtained is not contaminated by acetoacetic acid amide side-product. - The efficiency of utilizing the manufacturing equipment is optimum since the reaction rapidly proceeds. - No solvent has to be used in the reaction. - Saving in equipment, power and manpower appear since tl 1 g, m evaporation and fractional distillation are not required in the synthesis.
Based on the above facts, the process according to the invention is useful for the the simple preparation of methyl 3-aminocrotonate at an industrial scale, too.
The process of the invention is illustrated in detail by the following non-limiting Examples.
Example 1 rd (59.8 g, ammonia-contact: 0. 73 moles) of amTcnium hyde solution (containing 191 mg/ml of NH3) are po rtionwise added to 58.0 g (0.5 mole) of methyl acetoacetate at 25 OC during 20 minutes under stirring. In the course of the addition, the temperature of the mixture reaches 40 to 45 OC. The mixture is maintained at the same temperature for 1 hour (when the temperature decreases, a warm bath is optionally used).
Thereafter, the mixture is cooled to 0 DC, stirred at the same temperature for 1 hour and after filtration the crystalline precipitate is washed with water and dried to give 44.3 g (76.8%) of methyl 3- aminocrotonate, m.p.: 85-86 OC.
Based on the gas-liquid chromatography analysis, this product contains 99. 8% of methyl 3-aminocrotonate.
Example 2
Gaseous ammonia is introduced into 46.3 9 (0.4 mole) of methyl acetoacetate containing 0.36 9 of water at 55 to - 6 65 0 C at such a rate that the reaction mixture is capable to absorb the gas. The end of the re-action is indicated by the fact that the amount of the leaving gas is equal to that of the introduced gas. The saturation lasts about 2 hours. After cooling the mixture under stirring, 80 ml of water are portionwise added while the product precipitates in crystalline form. The mixture is stirred at a temperature of 0 to 5 0 C for 30 minutes, filtered, washed and dried to obtain 42.4 g (92.2%) of methyl 3-aminocrotonate, m.p.: 84-86 0 C.
Based on the gas-liquid chromatography analysis, this product consists of 100% of methyl 3-aminocrotonate.
11
Claims (7)
1. A process for the preparation of methyl 3-amino- crotonate by reacting methyl acetoacetate with ammonia, which c o m p r i s e s carrying out the reaction at a temperature of 35 to 70 0 C in the presence of water.
2. A process as claimed in claim 1, which c o m p r i s e s using 1.5 to 4.0 moles of ammonia calculated for 1 mole of methyl acetoacetate.
3. A process as claimed in claim 1, which c o m p r i s e s carrying out the reaction in the presence of 0.05 to 3.0 moles of water calculated for 1 mole of methyl acetoacetate.
4. A process as claimed in claim 1, which c o m p r i s e s adding ammonium hydroxide to methyl aceto- acetate and carrying out the reaction at a temperature of to 50 0 C, preferably at 40 to 45 0 C.
5. A process as claimed in claim 1, which c o m p r i s e s saturating a mixture of methyl acetoacetate and water with gaseous ammonia at a temperature of 55 to 0 c.
6. A process for the preparation of methyl 3-ariino-cronate subs tanti ally as hereinbefore described in Example 1 or in Example 2.
7. Methyl 3-amino crotonate produced by the process of any one of claims 1 to 6.
1 1 Published 1989 at The Patent Office, State House, 66'71 High Holborn, London WCIR4TP. Further copies maybe obtained from The Patent Office. Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Con. 1/87
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU882877A HU202474B (en) | 1988-06-03 | 1988-06-03 | Process for producing methyl 3-aminocrotonate |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8912679D0 GB8912679D0 (en) | 1989-07-19 |
| GB2219294A true GB2219294A (en) | 1989-12-06 |
| GB2219294B GB2219294B (en) | 1992-02-19 |
Family
ID=10961478
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8912679A Expired - Lifetime GB2219294B (en) | 1988-06-03 | 1989-06-02 | Process for the preparation of methyl 3-aminocrotonate |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPH0285237A (en) |
| DE (1) | DE3918122A1 (en) |
| FR (1) | FR2632303B1 (en) |
| GB (1) | GB2219294B (en) |
| HU (1) | HU202474B (en) |
| IT (1) | IT1230856B (en) |
| NL (1) | NL8901409A (en) |
| RU (1) | RU1836334C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2336262B (en) * | 1996-04-16 | 2001-04-25 | William M Sunlin | Material penetrating imaging radar |
| WO2012147103A3 (en) * | 2011-04-25 | 2012-12-20 | Council Of Scientific & Industrial Research | PROCESS FOR CONTINUOUS FLOW SYNTHESIS OF β-ΑΜΙΝΟ CROTONATE |
| CN106748974A (en) * | 2017-01-06 | 2017-05-31 | 蚌埠丰原医药科技发展有限公司 | A kind of synthetic method of the double methyl esters of butyrate clevidipine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4046803A (en) * | 1976-10-27 | 1977-09-06 | Armstrong Cork Company | Method of preparing β-amino derivatives of α,β-unsaturated esters |
-
1988
- 1988-06-03 HU HU882877A patent/HU202474B/en not_active IP Right Cessation
-
1989
- 1989-06-02 FR FR898907293A patent/FR2632303B1/en not_active Expired - Lifetime
- 1989-06-02 RU SU894614192A patent/RU1836334C/en active
- 1989-06-02 IT IT8920747A patent/IT1230856B/en active
- 1989-06-02 NL NL8901409A patent/NL8901409A/en not_active Application Discontinuation
- 1989-06-02 DE DE3918122A patent/DE3918122A1/en not_active Withdrawn
- 1989-06-02 GB GB8912679A patent/GB2219294B/en not_active Expired - Lifetime
- 1989-06-02 JP JP1139419A patent/JPH0285237A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2336262B (en) * | 1996-04-16 | 2001-04-25 | William M Sunlin | Material penetrating imaging radar |
| WO2012147103A3 (en) * | 2011-04-25 | 2012-12-20 | Council Of Scientific & Industrial Research | PROCESS FOR CONTINUOUS FLOW SYNTHESIS OF β-ΑΜΙΝΟ CROTONATE |
| US9199913B2 (en) | 2011-04-25 | 2015-12-01 | Council Of Scientific & Industrial Research | Process for continous flow synthesis of beta-amino crotonate |
| CN106748974A (en) * | 2017-01-06 | 2017-05-31 | 蚌埠丰原医药科技发展有限公司 | A kind of synthetic method of the double methyl esters of butyrate clevidipine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0285237A (en) | 1990-03-26 |
| NL8901409A (en) | 1990-01-02 |
| FR2632303B1 (en) | 1992-06-05 |
| RU1836334C (en) | 1993-08-23 |
| GB2219294B (en) | 1992-02-19 |
| FR2632303A1 (en) | 1989-12-08 |
| IT1230856B (en) | 1991-11-08 |
| HU202474B (en) | 1991-03-28 |
| GB8912679D0 (en) | 1989-07-19 |
| HUT50098A (en) | 1989-12-28 |
| DE3918122A1 (en) | 1989-12-14 |
| IT8920747A0 (en) | 1989-06-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930602 |