A kind of preparation method of nifedipine
A technology for nifedipine and methyl nitrobenzylidene acetoacetate, applied in the field of preparation of nifedipine, can solve problems such as reducing yield and product loss
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[0023] The preparation method of nifedipine, under the effect of nitrogen-containing heterocyclic carboxylic acid catalyst, methyl o-nitrobenzylidene acetoacetate and methyl 3-aminocrotonate in C 1 -C 4 Addition reaction occurs in lower aliphatic alcohol solvent to obtain nifedipine.
[0024] After the above-mentioned nitrogen-containing heterocyclic carboxylic acid catalyst is used for the addition reaction of methyl o-nitrobenzylidene acetoacetate and methyl 3-aminocrotonate, impurities (especially special simple impurity) content, thereby obtaining higher purity nifedipine crude product and finished product. At the same time, the reaction time is obviously shortened and the reaction efficiency is improved.
[0025] Among them, the nitrogen-containing heterocyclic carboxylic acid is that the ortho or meta position of the pyridine heterocyclic nitrogen atom is replaced by C 1 -C 3 Substituted pyridinecarboxylic acid derivatives substituted with lower fatty acids.
[0026...
experiment example
[0050] A kind of preparation method of nifedipine, its reaction formula is specifically as follows:
[0051]
[0052] Wherein, in the above reaction formula, methanol solvent is a specific choice of lower aliphatic alcohol solvent, but not limited to methanol solvent, the specific selection of solvent refers to the solvent conditions in Table 1. The reflux 10-11h in the above reaction formula is a specific reaction time, but not limited to the above reaction time, because the reaction conditions (such as catalysts) are different, the specific time of the reaction is different, and even the difference is relatively large (see Table 2).
[0053] Further, the preparation method is as follows: in a reaction flask with a capacity of 500ml equipped with a magnetic stirrer, a thermometer and a condenser, first pour a lower aliphatic alcohol solvent, and then add 50.0g of o-nitrobenzylidene acetoacetate methyl Esters, start stirring, add nitrogen-containing heterocyclic carboxylic ...
Embodiment 1
[0072] The nifedipine finished product provided by the preparation method of Example 1 has three consecutive batches of detection results (see Table 3).
[0073] Table 3 Continuous three batches of nifedipine crude drug sample (refined product) testing results
[0074]
[0075]
[0076] Remarks: The content data in Table 3 are the calculation results of the external standard method, not the purity results directly measured by the area normalization method. The content of relevant substances was tested according to the methods specified in the Chinese Pharmacopoeia (CP2015). Among them, impurity D is methyl 3-aminocrotonate (raw material impurity), which is an impurity inspection item stipulated in the European Pharmacopoeia (EP 10.0), and has not yet been regulated in CP2015.
[0077] The genotoxic impurity content data of the 3 batches of samples in Table 3 is far below the limit value specified in the "Standard", and the impurities Ⅰ, Ⅱ and impurity D in the 3 batches...
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