Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-26
2001-09-25
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S321000
Reexamination Certificate
active
06294673
ABSTRACT:
The invention relates to a new process for the preparation of nifedipine.
The compound dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate of the formula:
is known as the pharmaceutical active compound nifedipine (U.S. Pat. No. 3,485,847).
Nifedipine is a recognized pharmaceutical active compound which is used worldwide in large amounts medicinally. For such pharmaceutical active compounds, there is a particular interest in an economical preparation process which produces the active compound in high purity and good yields.
U.S. Pat. No. 3,485,847 describes its preparation from methyl acetoacetate, 2-nitro-benzaldehyde and ammonia. A yield of about 72% of theory is achieved here.
The nifedipine obtained by this process, however, does not have the purity which is demanded for use as a pharmaceutical active compound.
Thus DD 294 392 and DD 290 878 describe special purification processes for (I) which for the first time make possible use as a pharmaceutical active compound.
Such purification operations are associated with yield losses, such that the yields of pure nifedipine are significantly below those of the synthesis processes.
In view of the disadvantages of the process of U.S. Pat. No. 3,485,847, the inventors of DE-A-33 12 216 (EP-A-0 124 742) set themselves the task of making available an improved process for the preparation of the 1,4-dihydropyridines in which these are obtained in higher purity. To this end, DE-A-33 12 216 discloses a process for the preparation of nifedipine by reaction of methyl 2-(2-nitrobenzylidene)acetoacetate and methyl 3-aminocrotonate in which the starting substance methyl 2-(2-nitrobenzylidene)acetoacetate is prepared by a specific catalytic process. The reaction of the methyl 2-(2-nitrobenzylidene)acetoacetate with the methyl 3-aminocrotonate is carried out in methanol under reflux (about 65° C.) in the example. To achieve a high yield, very long reaction times are needed according to this process. Thus the benzylidene compound and the aminocrotonic acid ester are heated under reflux for 36 hours. In this case, yields of about 80 to 87% of theory are obtained. The (I) obtained according to DE-A-33 12 216, however, still does not show the purity which is demanded for use as a pharmaceutical active compound. Thus by means of HPLC analysis the presence of the valence isomer (II) in the per cent range can be detected, whose removal/rearrangement makes an additional pure crystallization necessary. The yield is then only 70-75% of theory.
DE-A-44 23 445 was based on the object of overcoming the disadvantages of DE-A-33 12 216 (EP-A-0 124 742) described above. DE-A-44 23 445 describes a process for the preparation of nifedipine by reaction of methyl 2-(2-nitrobenzylidene)acetoacetate and methyl 3-aminocrotonate in methanol as solvent at temperatures between 40 and 100° C., characterized in that the reaction is carried out in the presence of catalytic amounts of a lower carboxylic acid. In the examples of DE-A-44 23 445, the reaction is carried out in boiling methanol (64.5° C.) and the isolation of the nifedipine is carried out at approximately 0° C.
Through the use of the catalyst the process of DE 44 23 445 admittedly does lead to a shortening of the reaction times, but the products obtained also show a purity which is inadequate for use as a pharmaceutical active compound. Thus in the products obtained, in addition to the abovementioned valence isomer (II), pyrimidine derivatives and lactones occur which necessitate a pure crystallization which leads to a total yield of below about 80% of theory.
The inventors therefore undertook intensive investigations with the aim of making available a process for the preparation of nifedipine in high purity and with high yields and at the same time with a short reaction time, which allows the nifedipine obtained to be used immediately as an active compound in medicaments without further purification operations. In the course of these, they discovered that the catalyst used in the process of DE 44 23 445, in addition to the desired acceleration of the reaction to give nifedipine, also leads to the increased formation of by-products. Additionally, they surprisingly discovered that when carrying out the reaction in the absence of a catalyst at temperatures above the boiling point of the (C
1
-C
3
)alkanol, in particular of methanol, i.e. at elevated pressure, the formation of the desired product, nifedipine, is accelerated, whereas, however, the formation of the by-products is not accelerated, and the nifedipine is obtained in such pure form after a short reaction time that it can be isolated without further purification and used as an active compound in pharmaceutical preparations. The present invention was completed on the basis of these findings.
The present invention makes available a process for the preparation of nifedipine, which comprises the reaction of methyl 2-(2-nitrobenzylidene)acetoacetate and methyl 3-aminocrotonate in at least one (C
1
-C
3
)alkanol as solvent, and is characterized in that the reaction is carried out under pressure at a temperature between 70 and 110° C. Carrying out the reaction under pressure means a pressure which is above atmospheric pressure, i.e. above approximately 1 bar.
The process for the preparation of nifedipine of the invention is carried out in the absence of catalytic amounts of a lower carboxylic acid, preferably in the absence of any catalyst.
The process for the preparation of nifedipine of the invention is carried out in at least one (C
1
-C
3
)alkanol as solvent. The (C
1
-C
3
)-alkanols include methanol, ethanol, n- and iso-propanol, and mixtures thereof. Since the reaction is carried out at above atmospheric pressure, the temperature ranges of the reaction for the (C
1
-C
3
)alkanols follow accordingly.
Preferably, the reaction is carried out in methanol at temperatures between 75 and 95° C., particularly preferably at approximately 85° C. Since the boiling point of the solvent (methanol) at normal pressure is approximately 65° C., the reaction must be carried out at elevated pressure above atmospheric pressure. In this case, the temperature range from 70 to 100° C. corresponds approximately to a pressure range of approximately 1 bar to approximately 3 bar.
The process for the preparation of nifedipine of the invention is preferably carried out in such a way that the methyl 2-(2-nitrobenzylidene)acetoacetate and the methyl 3-aminocrotonate are reacted in a molar ratio of methyl 2-(2-nitrobenzylidene) acetoacetate/methyl 3-aminocrotonate of 1 to 1.5.
The process for the preparation of nifedipine of the invention is preferably carried out such that at the start of the reaction the concentration of the methyl 2-(2-nitrobenzylidene)acetoacetate is up to 55% by weight of the reaction mass.
The process for the preparation of nifedipine of the invention is preferably carried out such that the reaction time of the reaction of the methyl 2-(2-nitrobenzylidene)acetoacetate and of the methyl 3-aminocrotonate is between 2 and 20 hours.
In a particularly preferred embodiment of the invention, the nifedipine formed in the reaction is isolated at a temperature which is above room temperature (25° C.), preferably between 30° C. and 50° C., particularly preferably between 35° C. and 45° C. and very particularly preferably at approximately 40° C.
The nifedipine formed by the process for the preparation of nifedipine of the invention contains less than 1000 ppm, preferably less than 700 ppm, of by-products.
The invention further relates to the use of the nifedipine prepared by the process of the invention for the production of a medicament.
It is the preferred embodiment here to use the nifedipine prepared by the process of the invention without further purification for the production of a medicament.
The reaction mixture of the invention forms a clear solution above 90° C., such that under these conditions a filtration customary in the synthesis of pharmaceutical active compounds can be carried out, which represents a further advantage of working at
Berwe Mathias
Diehl Herbert
Rittner Karl
Wahl Karl-Heinz
Wirges Hans-Peter
Bayer Aktiengesellschaft
Chiu Jerrie L.
Desai Rita
Rotman Alan L.
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