JP5188475B2 - Process for producing 2- (3-nitrobenzylidene) isopropyl acetoacetate - Google Patents

Description

  The present invention relates to a novel process for producing isopropyl 2- (3-nitrobenzylidene) acetoacetate.

  {2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinecarboxylic acid 3- (1-diphenylmethylazetidine-3) represented by the following formula (3) -Yl) ester 5-isopropyl ester} (hereinafter sometimes abbreviated as “azernidipine”) is used as a calcium antagonistic antihypertensive agent. This azelnidipine is usually synthesized by the following method.

  As shown in the above reaction formula, azelnidipine is composed of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester represented by the above formula (1) and 3,3-diaminoacrylic acid (1-diphenyl) represented by the above formula (2). It is produced by a condensation reaction with methylazetidin-3-yl) acetate (see Patent Document 1).

  In order to increase the yield of this azelnidipine, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) acetate as raw materials Yield is also important. One of the raw materials, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is synthesized by the following method.

  As described above, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester, which is a raw material of azelnidipine, is obtained by combining isopropyl acetoacetate represented by the above formula (4) in isopropyl alcohol in the presence of a base such as piperidine acetate. It can be synthesized by a dehydration condensation reaction with 3-nitrobenzaldehyde represented by the above formula (5) (Non-patent Document 1). According to this method, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester having a yield of 65% and high purity can be produced.

JP 63-253082 A

Chemical and Pharmaceutical Britain 43 (5) 797-817 (1995)

  In recent years, drug substances such as azelnidipine have been desired to be cheaper, and it has been desired to efficiently produce substances as raw materials. As described above, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester, which is a raw material of azelnidipine, can be produced only in a yield of about 65% according to the conventional method. Therefore, in order to produce azelnidipine at a lower price, it has been desired to produce this 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester in a higher yield.

  Accordingly, an object of the present invention is to provide a method capable of producing high-purity 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester in high yield. Accordingly, an object of the present invention is to provide a method capable of producing azelnidipine with high yield.

  The inventors of the present invention have made extensive studies to solve the above problems. And when it examined paying attention to the solvent at the time of synthesize | combining 2- (3-nitro benzylidene) acetoacetic acid isopropyl ester, the improvement of the yield was seen by using an aprotic solvent. However, it has also been found that depending on the reaction conditions, the effect cannot be obtained even when an aprotic solvent is used. When the cause was investigated, it was thought that it might have influenced the stability of 2- (3-nitro benzylidene) acetoacetic acid isopropyl ester.

  Usually, in the reaction of organic synthesis, if the reaction temperature is increased, the reaction proceeds faster and is completed in a short time. However, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is decomposed by heat if the reaction temperature is too high or it is processed at a high temperature, the yield decreases, and many impurities are contained. There was found.

  Therefore, the present inventors further increased the yield and purity of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester, and did not decrease the reaction rate. A reaction solvent capable of producing isopropyl ester was examined. As a result, it has been found that the above point can be improved by carrying out the reaction in a specific temperature range using an aprotic solvent, and the present invention has been completed.

That is, the present invention
In a method for producing 2- (3-nitrobenzylidene) acetoacetate isopropyl by dehydrating condensation reaction of isopropyl acetoacetate and 3-nitrobenzaldehyde in the presence of a base, the temperature is from 40 ° C. to 70 ° C. in an aprotic solvent. This is a method for producing isopropyl 2- (3-nitrobenzylidene) acetoacetate, wherein the dehydration condensation reaction is carried out in a temperature range.

In the present invention, the aprotic solvent is an aprotic solvent composed of acetonitrile, chloroform, or toluene. Among these, it is preferable to use toluene.

  Furthermore, the present invention provides 2- (3-nitrobenzylidene) acetoacetate isopropyl and 3- (3-nitrobenzylidene) acetoacetate isopropyl and 3,3-diaminoacrylic acid (1 -2-phenyl-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinecarboxylic acid by reacting with -diphenylmethylazetidin-3-yl) acetate 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester}.

  The present invention can produce isopropyl 2- (3-nitrobenzylidene) acetoacetate with high yield and high purity in a relatively short time. Therefore, 2- (3-nitrobenzylidene) acetoacetate isopropyl obtained by the present invention can be used as a raw material for azelnidipine.

  The present invention relates to a method for producing isopropyl 2- (3-nitrobenzylidene) acetoacetate by subjecting isopropyl acetoacetate and 3-nitrobenzaldehyde to dehydration condensation reaction in the presence of a base. And the characteristic is performing this dehydration condensation reaction in a specific temperature range in an aprotic solvent. I will explain in order.

(base)
In the present invention, dehydration condensation reaction is performed between isopropyl acetoacetate and 3-nitrobenzaldehyde in the presence of a base. As the base to be used, known ones can be used, and specifically, organic bases such as triethylamine, tributylamine and pyridine, salts such as piperidine acetate and piperidine hydrochloride, and the like can be used. Of these, piperidine acetate is preferred. In addition, these bases can use a commercially available thing.

  Moreover, the usage-amount of a base should just be made into a normal catalyst amount, and it is preferable to use 0.02-0.10 mol with respect to 1 mol of 3-nitrobenzaldehyde.

(Isopropyl acetoacetate)
Isopropyl acetoacetate used in the present invention can be produced by a known method. Specifically, as described in Patent Document 1, A.I. B. Boese, Jr. , Industrial and Engineering Chemistry, 32, 16 (1940).

  In the present invention, the amount of isopropyl acetoacetate used is not particularly limited, but considering the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester, 1 mol of 3-nitrobenzaldehyde is considered. It is preferable to use 1.00 to 2.00 mol.

(3-Nitrobenzaldehyde)
The 3-nitrobenzaldehyde used in the present invention is not particularly limited, and commercially available products can be used.

  In the present invention, as described above, the amount of 3-nitrobenzaldehyde used is the same or less than the number of moles of isopropyl acetoacetate in consideration of the yield of 2- (3-nitrobenzylidene) acetoacetate isopropyl ester. It is preferable that Therefore, the amount of 3-nitrobenzaldehyde used is preferably 0.50 to 1.00 mol per 1 mol of isopropyl acetoacetate.

(Reaction conditions)
In the present invention, the isopropyl acetoacetate and 3-nitrobenzaldehyde are subjected to a dehydration condensation reaction in the presence of the base, and the reaction is carried out in an aprotic solvent. This aprotic solvent will be described.

(Aprotic solvent)
In the present invention, the dehydration condensation reaction is carried out in an aprotic solvent.

  An aprotic solvent is a solvent that cannot give a hydrogen atom as a proton and does not self-dissociate. Although the reason why the method of the present invention exhibits a superior effect than when a protic solvent is used is not clear, the present inventors presume as follows. That is, for example, when a protic solvent such as isopropyl alcohol is used, the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester decreases because isopropyl alcohol itself acts as a nucleophile and causes side reactions. It is considered a thing. On the other hand, when an aprotic solvent is used, since such a side reaction does not occur, it is considered that the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is increased.

  Examples of aprotic solvents include ethers such as diethyl ether, aliphatic hydrocarbons such as hexane and heptane, nitriles such as acetonitrile, halogenated hydrocarbons such as dimethylethane, chloroform and carbon tetrachloride, benzene, Aromatic hydrocarbons such as toluene are exemplified. Among these, nitriles, aromatic hydrocarbons, and halogenation are considered in consideration of easy availability, ease of handling, solubility of raw materials, and yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester obtained. It is preferable to use at least one aprotic solvent selected from the group consisting of hydrocarbons.

  Among the above aprotic solvents, it is preferable to use an aprotic solvent having a boiling point of 120 ° C. or lower in order to facilitate post-treatment and further suppress the formation of decomposition products. That is, in the present invention, in order to produce 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester with high yield, an aprotic solvent that is easy to remove and does not require post-treatment at high temperature is used. It is preferable to do.

  According to the study by the present inventors, it was found that 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is a compound that is easily decomposed by heat. Therefore, in order to increase the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester, it is relatively low not only during the reaction but also in the post-treatment after the reaction, which is a short time compared to the reaction time. Treatment at temperature is preferred. Therefore, by using an aprotic solvent having a boiling point of 120 ° C. or lower in the dehydration condensation reaction, the removal (evaporation) is facilitated, and 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is further decomposed. Can be suppressed. The lower limit of the boiling point of the aprotic solvent is not particularly limited, but is preferably 30 ° C. or higher, more preferably 40 ° C. or higher, considering the reaction rate of the dehydration condensation reaction. In particular, the temperature is preferably 60 ° C.

  Such an aprotic solvent having a boiling point of 120 ° C. or lower may be appropriately selected from the above aprotic solvents. Among these aprotic solvents, considering availability, handling, solubility of raw materials, and yield of the resulting 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester, nitriles, aromatic carbonization In hydrogens or halogenated hydrocarbons, it is preferable to select a solvent having a boiling point of 120 ° C. Among these, specific examples of preferred solvents include acetonitrile, dimethylethane, chloroform, and toluene.

  Further, as described in detail below, among these preferred solvents, acetonitrile is considered to be because it easily dissolves water produced as a by-product during the reaction, but the reaction rate is relatively fast, and the conversion rate of the raw material may be increased. it can.

  This is also described in detail below. Among these preferred solvents, toluene can easily remove by-product water by azeotropic concentration. Therefore, water can be removed by simply distilling off toluene after completion of the reaction without using a desiccant or distilling off water. As a result, the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester can be increased in a series of post-treatments. Furthermore, toluene has an advantage that it is easily available as compared with acetonitrile.

  In addition, these solvents can also be used independently and can also be used in mixture of 2 or more types. However, considering operability, evaporation of the solvent, reuse, etc., it is preferable to use it alone.

  In the present invention, the amount of the aprotic solvent used is not particularly limited, but it is preferable to use an amount capable of sufficiently dispersing and mixing isopropyl acetoacetate and 3-nitrobenzaldehyde as raw materials. . In consideration of post-treatment and evaporation of the aprotic solvent, it is preferable to use 2 to 5 ml of the aprotic solvent with respect to 1 g of 3-nitrobenzaldehyde.

  In the present invention, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is produced by subjecting isopropyl acetoacetate and 3-nitrobenzaldehyde to dehydration condensation reaction in the above aprotic solvent in the presence of a base. This reaction can be carried out by mixing isopropyl acetoacetate and 3-nitrobenzaldehyde in the above aprotic solvent in the presence of a base. At this time, the reaction temperature is set to a range of 40 ° C. or higher and 70 ° C. or lower. This is very important.

(Reaction temperature, reaction time)
In the present invention, the temperature during the dehydration condensation reaction is important. As described above, since 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is easily decomposed by heat, the reaction temperature (temperature of the aprotic solvent during the reaction) must be 40 ° C. or higher and 70 ° C. or lower. When reaction temperature exceeds 70 degreeC, since the decomposition product of 2- (3-nitro benzylidene) acetoacetic acid isopropyl ester will increase and a yield will fall, it is unpreferable. On the other hand, when the reaction temperature is less than 40 ° C., the dehydration condensation reaction is difficult to proceed and the reaction time is prolonged, which is not preferable. Therefore, the reaction temperature is more preferably 45 ° C. or more and 65 ° C. or less, more preferably 50 ° C. or more and 65 ° C. or less in consideration of the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and the reaction rate. Is particularly preferred.

  The temperature of the dehydration condensation reaction may be controlled to a constant temperature during the reaction or may be varied within the temperature range as long as the temperature range is satisfied. However, in consideration of operability, it is preferable to keep the temperature constant during the reaction.

  In the present invention, the completion of the dehydration condensation reaction may be confirmed by the presence or absence of raw materials by high performance liquid chromatography (HPLC) analysis or the like. Although the reaction time is affected by the reaction temperature, raw material concentration, mixing conditions, etc., it is usually 1 hour to 5 hours.

  In the present invention, the dehydration condensation reaction can be carried out by mixing isopropyl acetoacetate and 3-nitrobenzaldehyde in the temperature range within the aprotic solvent in the presence of a base. Next, other reaction conditions will be described.

(Dehydration condensation reaction: mixing method)
In the present invention, a dehydration condensation reaction can be carried out by mixing a base, isopropyl acetoacetate, and 3-nitrobenzaldehyde in the aprotic solvent. The method of mixing these catalyst (base) and raw materials (isopropyl acetoacetate, 3-nitrobenzaldehyde) is not particularly limited, but the following methods are exemplified. For example, a method in which a base diluted in the above aprotic solvent and a raw material are simultaneously introduced into a reaction vessel and mixed as necessary, a raw material is dissolved in the aprotic solvent in a reaction vessel, and the aprotic solvent is used as necessary. A method in which a diluted base is added to a protic solvent and mixed, a method in which a base is dissolved in the aprotic solvent in a reaction vessel, and a raw material dissolved in the aprotic solvent is added and mixed as necessary. Examples thereof include a method in which one raw material is dissolved in the aprotic solvent in a container, and the other raw material dissolved in the aprotic solvent and a base are added and mixed as necessary. Especially, as above-mentioned, since 2- (3-nitro benzylidene) acetoacetic acid isopropyl ester is easy to decompose | disassemble with respect to a heat | fever, it is preferable to mix by the method which can control the temperature at the time of reaction more. Therefore, among the above methods, it is preferable to employ a method in which both raw materials are dissolved in the aprotic solvent in a reaction vessel, and a diluted base is added to the aprotic solvent as necessary.

(Water by-produced in dehydration condensation reaction)
As the above reaction proceeds, water is by-produced in the reaction system. In the present invention, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester can be obtained in high yield without removing by-product water during the reaction.

  For example, when acetonitrile is used as the aprotic solvent, it is considered that by-product water is sufficiently diffused with the above-mentioned preferred amount of solvent used, but 2- (3- The selectivity of nitrobenzylidene) acetoacetic acid isopropyl ester can be increased.

  In the following description, the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester confirmed by HPLC without removing the aprotic solvent (yield calculated by area% by HPLC) May be the selectivity.

  On the other hand, when aromatic hydrocarbons, preferably toluene, are used as the aprotic solvent, the aromatic hydrocarbons are retained after completion of the reaction without removing by-product water during the reaction. Water can be easily removed when leaving. Therefore, the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester can be increased only by distilling off the solvent. For example, when toluene is used, it is confirmed by HPLC that the selectivity of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester in the reaction system has become constant, and the reaction is regarded as completed. Thereafter, toluene is distilled off to remove 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester from the reaction system. At this time, since water can be easily removed, the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester can be increased simply by distilling off toluene. Although influenced by the reaction conditions, according to the study by the present inventors, the yield is more than 85% and not more than 98% after distilling off the toluene having a selectivity of about 70 to 85%. It was found that it can be improved.

  As described above, according to the method of the present invention, the yield of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester can be increased without removing by-product water during the reaction. However, water produced as a by-product during the reaction can be removed from the reaction system by the following method. For example, examples of the method for removing water from the reaction system include a method in which a desiccant such as calcium chloride and magnesium sulfate is present in the reaction system, a method for removing water by distillation, and the like.

(Post-processing method)
By performing a dehydration condensation reaction according to the above method, isopropyl 2- (3-nitrobenzylidene) acetoacetate can be produced. As described above, the completion of the reaction may be confirmed by confirming that the selectivity of 2- (3-nitrobenzylidene) isopropyl acetoacetate does not change by HPLC. The purified 2- (3-nitrobenzylidene) acetoacetate isopropyl acetate is obtained by first distilling off the aprotic solvent used and removing the crude product, and purifying the crude product by a known method such as recrystallization. Can do.

  The temperature at which the aprotic solvent is distilled off is not particularly limited. However, when the temperature is too high, the decomposition product of 2- (3-nitrobenzylidene) isopropyl acetoacetate tends to increase. is there. If it is too low, the operability tends to be lowered. Therefore, the temperature when distilling off the aprotic solvent is preferably 20 to 70 ° C, more preferably 40 to 70 ° C, still more preferably 45 to 65 ° C, and more preferably 50 to 65 ° C. It is particularly preferable that the temperature is set to ° C. At this time, it is preferable to concentrate under reduced pressure in order to sufficiently distill off the aprotic solvent.

  The crude product obtained by distilling off the aprotic solvent is preferably recrystallized using an alcohol such as methanol, ethanol or isopropyl alcohol, or a solvent of an aliphatic hydrocarbon such as hexane or heptane. . Among these solvents, isopropyl alcohol is preferably used in order to obtain high-purity isopropyl 2- (3-nitrobenzylidene) acetoacetate.

  In addition, when recrystallization is performed using the above solvent, although not particularly limited, in order to further reduce the decomposition product of 2- (3-nitrobenzylidene) acetoacetate, the temperature is 70 ° C. or lower. It is preferable to dissolve the crude product. Therefore, in order to reduce the amount of solvent to be used and obtain high-purity 2- (3-nitrobenzylidene) acetoacetate isopropyl, the temperature at which the crude product is dissolved in the solvent is preferably 40 to 70 ° C. More preferably, it is 45-65 degreeC.

  In addition, other conditions for recrystallization, such as the amount of solvent used, the temperature during cooling, and the time for allowing the crystals to precipitate, are determined. The purity and yield of isopropyl 2- (3-nitrobenzylidene) acetoacetate required What is necessary is just to adjust suitably according to etc.

  After recrystallization, the crystals may be filtered off by a known method, and the obtained crystals of 2- (3-nitrobenzylidene) acetoacetate may be dried. The temperature at which 2- (3-nitrobenzylidene) isopropyl acetoacetate is dried is preferably 20 to 70 ° C. and more preferably 40 to 70 ° C. in order to further suppress the formation of decomposition products. Preferably, it is 45-65 degreeC.

  According to the method of the present invention, side reactions are unlikely to occur, and since there is little formation of 2- (3-nitrobenzylidene) acetoacetate isopropyl acetate, high purity 2- (3-nitrobenzylidene) acetoacetate is obtained by recrystallization. Isopropyl can be obtained.

  The obtained 2- (3-nitrobenzylidene) acetoacetate isopropyl acetate has high yield and high purity. The purity is more than 99%. Therefore, by using the obtained isopropyl 2- (3-nitrobenzylidene) acetoacetate, {2-amino-1,4-dihydro-6-methyl-4- (3- Nitrophenyl) -3,5-pyridinecarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester} (azelnidipine) can be prepared.

(Method for producing azelnidipine)
Isopropyl 2- (3-nitrobenzylidene) acetoacetate obtained by the method of the present invention can be suitably used as a raw material for azelnidipine. The method for producing azelnidipine is not particularly limited, and a known method such as the method described in Patent Document 1 can be employed. Specifically, 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) acetate and 2- (3-nitrobenzylidene) acetoacetate isopropyl obtained by the above method are mixed. Good.

  The amount of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester used is not particularly limited, but considering the ease of purification, 1 mol of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester is used. Thus, the amount of 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) acetate is preferably 0.8 to 2.0 mol, and more preferably 1.0 to 1.2 mol. It is preferable.

  In order to mix both, it is preferable to stir and mix both in a reaction solvent, and in this case, heating is particularly preferable. When a reaction solvent is used, the solvent to be used is preferably an alcohol solvent, and isopropyl alcohol is particularly preferable in consideration of the purity of the obtained azelnidipine. The reaction temperature is preferably 40 ° C. to 70 ° C., particularly preferably 50 ° C. to 60 ° C. in terms of the conversion rate and the purity of azelnidipine. Although reaction time does not have a restriction | limiting in particular, Usually, it carries out in 0.5 to 24 hours.

  Azelnidipine can be synthesized by reacting 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) acetate with 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester under the above conditions. it can. The method for removing azelnidipine from the above reaction system is not particularly limited, but first, after completion of the reaction, the reaction solvent is distilled off, a solvent that is difficult to dissolve in water is added, and a basic aqueous solution is further used. To neutralize. Next, the aqueous layer is separated, the organic layer is dried as necessary, and then the azelnidipine can be taken out by distilling off the solvent of the organic layer.

  The reaction solvent may be distilled off under the condition that the amount of impurities does not increase, but it is usually preferable to distill off under reduced pressure at a temperature of 40 ° C. or lower. The solvent added after distilling off the reaction solvent is not particularly limited, but ester solvents such as methyl acetate and ethyl acetate, aliphatic hydrocarbon solvents such as hexane and peptane, and chlorine solvents such as dichloromethane and chloroform. Aromatic solvents such as toluene and xylene can be used. The base used for the neutralization treatment is not particularly limited, but includes a base containing an alkaline earth metal such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate, or an alkali metal such as sodium hydroxide or potassium hydroxide. An inorganic base such as a base can be used. As these bases, an aqueous solution in which the above bases having at least the number of moles of acetic acid contained in the raw material compound are previously dissolved can be used. Further, the solvent that is difficult to dissolve in water may be distilled off under the condition that the decomposition products described in detail below do not increase, but it is usually preferable to concentrate under reduced pressure at a temperature of 40 ° C. or lower.

  Azelnidipine taken out according to the above method is preferably purified by recrystallization from an alcohol solvent such as methanol, ethanol, isopropyl alcohol or the like. Moreover, when it recrystallizes with the said solvent etc., it becomes an adduct of alcohol. Therefore, after the adduct was dissolved in an aliphatic hydrocarbon solvent, for example, a solvent such as hexane, heptane, or cyclohexane, the alcohol was also removed when the aliphatic hydrocarbon solvent was distilled off. Azelnidipine is preferred.

  According to the present invention, isopropyl 2- (3-nitrobenzylidene) acetoacetate can be produced with high yield. As a result, by using the obtained isopropyl 2- (3-nitrobenzylidene) acetoacetate as a raw material for azelnidipine, the yield of the azelnidipine can be increased.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited at all by these Examples. In the following Examples and Comparative Examples, the selectivity and purity of 2- (3-nitrobenzylidene) acetoacetate isopropyl were calculated as HPLC area%. The yield of isopropyl 2- (3-nitrobenzylidene) acetoacetate is a value determined from the yield after drying based on 3-nitrobenzaldehyde.
Example 1
In the reaction vessel, 15.1 g (0.10 mol) of 3-nitrobenzaldehyde and 19.71 g (0.13 mol) of isopropyl acetoacetate were dissolved in 75.5 mL of acetonitrile. The obtained solution was brought to 50 ° C., 0.74 g (0.005 mol) of piperidine acetate was added, and the mixture was reacted at 50 ° C. (reaction temperature 50 ° C.) for 3 hours with stirring. The selectivity for 2- (3-nitrobenzylidene) isopropyl acetoacetate was confirmed by HPLC and found to be 90.0%.

  After completion of the reaction, vacuum concentration was performed at 50 ° C., and water and acetonitrile by-produced were distilled off. 30 ml of isopropyl alcohol was added to 25.81 g of the obtained crude product and dissolved at 50 ° C., and then cooled to 10 ° C. for recrystallization. The obtained crystals were collected by filtration and dried under vacuum to obtain 23.23 g of yellowish white crystals (2- (3-nitrobenzylidene) isopropyl acetoacetate). The yield based on 3-nitrobenzaldehyde was 83.8%, and the purity was 99.7%.

Example 2
In Example 1, the same operation as in Example 1 was performed except that chloroform was used instead of acetonitrile. The selectivity for isopropyl 2- (3-nitrobenzylidene) acetoacetate when reacted for 3 hours was 80.0%.

  The operation after completion of the reaction was carried out in the same manner as in Example 1. As a result, 20.65 g of yellowish white crystal (2- (3-nitrobenzylidene) acetoacetate isopropyl) was obtained. The yield based on 3-nitrobenzaldehyde was 74.5%, and the purity was 99.7%.

Example 3
In Example 1, the same operation as in Example 1 was performed except that toluene was used instead of acetonitrile and the reaction temperature was 60 ° C. The selectivity for isopropyl 2- (3-nitrobenzylidene) acetoacetate when reacted for 3 hours was 80.0%.

  After completion of the reaction, the same operation as in Example 1 was performed, except that vacuum concentration was performed at 60 ° C. As a result, 24.45 g of yellowish white crystals (2- (3-nitrobenzylidene) acetoacetate isopropyl) was obtained. The yield based on 3-nitrobenzaldehyde was 88.2%, and the purity was 99.7%. Since the yield was higher than the selectivity, it was found that the selectivity (yield) was improved when toluene was concentrated.

Example 4 (Method for producing azelnidipine)
6.90 g (0.02 mol) of isopropyl 2- (3-nitrobenzylidene) acetoacetate obtained in Example 3, 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate 10.00 g (0.03 mol) and 50 mL of isopropyl alcohol were mixed in a reaction vessel and reacted at a reaction temperature of 50 ° C. for 1 hour. After completion of the reaction, concentration under reduced pressure was performed at 40 ° C. or lower, and 50 mL of ethyl acetate was added to the concentrated residue and dissolved. Next, 30 mL of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting solution and stirred for 30 minutes. After standing, the aqueous layer was separated, 20 mL of a saturated aqueous sodium chloride solution was further added to the organic layer, and the mixture was stirred for 30 minutes. After standing, the aqueous layer was separated, and the organic layer was concentrated under reduced pressure at 40 ° C. or lower. Isopropyl alcohol was added to the resulting concentrated residue and dissolved at 40 ° C., and then cooled to 10 ° C. for recrystallization. The obtained crystal was separated by filtration and vacuum-dried to obtain 11.60 g of yellowish white crystal (azelnidipine). The yield of azelnidipine based on 3-nitrobenzaldehyde was 70.6% and the purity was 99.5%.

Comparative Example 1
In Example 3, the same operation as in Example 3 was performed except that the reaction temperature was 80 ° C. The selectivity for isopropyl 2- (3-nitrobenzylidene) acetoacetate when reacted for 3 hours was 61.0%.

  When the operation after completion of the reaction was carried out in the same manner as in Example 3, 17.13 g of yellowish white crystals (2- (3-nitrobenzylidene) acetoacetate isopropyl) was obtained. The yield based on 3-nitrobenzaldehyde was 61.8%, and the purity was 99.7%.

Comparative Example 2
In Example 1, the same operation as in Example 1 was performed except that isopropyl alcohol was used instead of acetonitrile. The selectivity for isopropyl 2- (3-nitrobenzylidene) acetoacetate when reacted for 3 hours was 68.0%.

  The operation after completion of the reaction was carried out in the same manner as in Example 1. As a result, 18.71 g of yellowish white crystals (isopropyl 2- (3-nitrobenzylidene) acetoacetate) was obtained. The yield based on 3-nitrobenzaldehyde was 67.5%, and the purity was 99.7%.

Comparative Example 3 (Method for producing azelnidipine)
The same operation as in Example 4 was carried out except that 2-isopropyl (3-nitrobenzylidene) acetoacetate obtained in Comparative Example 2 was used. The obtained yellowish white crystal (azernidipine) was 11.60 g, the yield based on 3-nitrobenzaldehyde was 35.2%, and the purity was 99.5%.

Claims (3)

In a method for producing 2- (3-nitrobenzylidene) acetoacetate isopropyl by dehydrating condensation of isopropyl acetoacetate and 3-nitrobenzaldehyde in the presence of a base,
A method for producing isopropyl 2- (3-nitrobenzylidene) acetoacetate, wherein the dehydration condensation reaction is carried out in an aprotic solvent comprising acetonitrile, chloroform, or toluene at a temperature range of 40 ° C to 70 ° C.   The method for producing isopropyl 2- (3-nitrobenzylidene) acetoacetate according to claim 1, wherein the aprotic solvent is toluene. After producing 2- (3-nitrobenzylidene) acetoacetate isopropyl by the production method according to claim 1 or 2 , the obtained 2- (3-nitrobenzylidene) acetoacetate isopropyl and 3,3-diaminoacrylic acid ( By reacting with 1-diphenylmethylazetidin-3-yl) acetate, {2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinecarboxyl Acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester}.