A process for the preparation of cinnamyl 3-amino-2-butenoate

Abstract

The application discloses a preparation method of cinnamyl 3-amino-2-butenoate, and relates to the technical field of preparation of cinnamyl 3-amino-2-butenoate which is a intermediate of cinaldipine. In the method, cinnamyl acetoacetate is added into a mixed reaction solvent, liquid ammonia is continuously introduced for reaction at low temperature, after cinnamyl 3-amino-2-butenoate is generated, ammonia is removed by reduced pressure, and then the temperature is reduced for crystallization, filtration is performed, and the obtained product is washed by a solvent to obtain white cinnamyl 3-amino-2-butenoate solid. In the application, mixed solvents are used for reaction, and after the reaction is completed, the solvents are not removed by reduced pressure, the heat generated by ammonia removal by reduced pressure is used to reduce the temperature of the liquid, and crystallization is performed, so that energy consumption is saved, the whole process is performed at low temperature, decomposition of the product caused by high temperature is avoided, and cinnamyl 3-amino-2-butenoate with high purity can be prepared, and the intermediate with high purity is provided for preparation of cinaldipine.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of preparation of cilnidipine intermediate 3-amino-2-butenoic acid cinnamate, and particularly relates to a preparation method of 3-amino-2-butenoic acid cinnamate. BACKGROUND

[0002] Cilnidipine is a third-generation dual-channel dihydropyridine calcium channel blocker, and its chemical name is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-2-methoxy ethyl (E)-cinnamate. It was developed by Fuji Corporation of Japan and first marketed in Japan in 1995. Cilnidipine is a lipophilic dihydropyridine calcium antagonist that can bind to the dihydropyridine site of the L-type calcium channel on the membrane of vascular smooth muscle cells, inhibit the transmembrane influx of Ca 2+ through the L-type calcium channel, thereby relaxing and dilating vascular smooth muscle and lowering blood pressure. It can also inhibit the release of norepinephrine and sympathetic nerve activity by inhibiting the transmembrane influx of Ca 2+ through the N-type channel on the membrane of sympathetic nerve cells.

[0003] 3-amino-2-butenoic acid cinnamate is an important intermediate for preparing cilnidipine. Because it has a low melting point, a large solubility, and is unstable above 20℃, it brings certain difficulties to industrial production. At present, the preparation method of 3-amino-2-butenoic acid cinnamate mainly involves dissolving cinnamyl acetoacetate in methanol or ethanol, and then introducing liquid ammonia for reaction. After the reaction is completed, 3-amino-2-butenoic acid cinnamate can be obtained in two ways. In the first way, the liquid ammonia and ethanol are evaporated to obtain a viscous liquid under reduced pressure at a certain temperature, and 3-amino-2-butenoic acid cinnamate is obtained after cooling. This method has a high yield but a low purity. In the second way, 3-amino-2-butenoic acid cinnamate is obtained by cooling crystallization after the reaction is completed. This method has a high purity but a low yield. Therefore, it is very meaningful to develop a preparation process of 3-amino-2-butenoic acid cinnamate with high purity and high yield. SUMMARY

[0004] The present application aims to provide a preparation method of 3-amino-2-butenoic acid cinnamate, so as to solve the problems of low purity and low yield of cilnidipine intermediate 3-amino-2-butenoic acid cinnamate.

[0005] The object of the present application can be achieved by the following technical solutions. A preparation method of 3-amino-2-butenoic acid cinnamate comprises the following steps: Cinnamyl acetoacetate is added into a mixed reaction solvent, and the reaction is carried out under the condition of continuously passing liquid ammonia at low temperature; after the reaction is completed, ammonia is removed under reduced pressure, and crystallization is carried out by reducing temperature; then, filtration is carried out, and the product is washed with a solvent to obtain cinnamyl 3-amino-2-butenoate.

[0006] Compared with the prior art, the present application has the following beneficial effects: The present application provides a preparation method of cinnamyl 3-amino-2-butenoate, which is prepared by nucleophilic addition and elimination reaction of cinnamyl acetoacetate and liquid ammonia in a mixed solvent under low temperature condition; after the reaction is completed, the solvent is not removed by evaporation under reduced pressure, and the heat generated by removing ammonia under reduced pressure is used to reduce the temperature of the liquid, so that crystallization is carried out, and the energy consumption is saved; the whole process is carried out under low temperature, so that the decomposition of the product caused by high temperature is avoided; the prepared cinnamyl 3-amino-2-butenoate has high purity and high yield; and the present application provides an intermediate with high purity for preparing cinnidipine, so that the present application can be effectively applied to the preparation of cinnidipine. BRIEF DESCRIPTION OF DRAWINGS

[0007] Figure 1 The present application provides a preparation method of cinnamyl 3-amino-2-butenoate, which is prepared by nucleophilic addition and elimination reaction of cinnamyl acetoacetate and liquid ammonia in a mixed solvent under low temperature condition; after the reaction is completed, the solvent is not removed by evaporation under reduced pressure, and the heat generated by removing ammonia under reduced pressure is used to reduce the temperature of the liquid, so that crystallization is carried out, and the energy consumption is saved; the whole process is carried out under low temperature, so that the decomposition of the product caused by high temperature is avoided; the prepared cinnamyl 3-amino-2-butenoate has high purity and high yield; and the present application provides an intermediate with high purity for preparing cinnidipine, so that the present application can be effectively applied to the preparation of cinnidipine. DETAILED DESCRIPTION

[0008] The specific embodiments of the present application are described in detail below, but it should be understood that the protection scope of the present application is not limited by the specific embodiments.

[0009] The terms used in the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the embodiments of the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0010] It should be understood that in various embodiments of the present application, the magnitude of the serial number of each process does not mean the order of execution, and part or all of the steps can be executed in parallel or in sequence, and the execution order of each process should be determined according to its function and inherent logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0011] The weight of the related components mentioned in the specification of the embodiments of the present application can not only refer to the specific content of each component, but also represent the weight ratio relationship between each component, therefore, as long as the content of the related components in the specification of the embodiments of the present application is enlarged or reduced in proportion, it is within the scope disclosed in the specification of the embodiments of the present application. Specifically, the mass mentioned in the specification of the embodiments of the present application can be μg, mg, g, kg and other mass units commonly known in the chemical field.

[0012] Unless otherwise defined, all terms used in the description, examples and claims are to be interpreted as having the meanings commonly understood by one of ordinary skill in the art. The professional terms used in the description are merely used to describe specific embodiments and are not intended to limit the scope of the present application.

[0013] Unless otherwise specified, all the raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or prepared by the existing methods.

[0014] The present application provides a preparation method of cinnamyl 3-amino-2-butenoate, please refer to the preparation flow chart shown in Figure 1 Specifically, the method comprises the following steps: Cinnamyl acetoacetate is added into a mixed reaction solvent and reacted at low temperature with continuous introduction of liquid ammonia. After the reaction is completed, ammonia is removed under reduced pressure, and the product is crystallized by cooling, filtered, and washed with a solvent to obtain cinnamyl 3-amino-2-butenoate.

[0015] In the cinnamyl acetoacetate molecule, the hydrogen atom of the methylene (-CH2-) in the β-dicarbonyl structure (-CO-CH2-CO-) has extremely strong acidity (pKa≈9~11) due to the electron-withdrawing effect of the two adjacent carbonyl groups. Under the action of liquid ammonia (NH3, basic conditions, the conjugate acid NH4 + pKa≈9.25, which can form an acid-base equilibrium with the methylene hydrogen), the methylene hydrogen is removed to form a resonance-stable enol anion intermediate (which has two resonance structures, each carrying a negative charge on the two carbonyl oxygen atoms, and has high stability). The NH3 molecule in liquid ammonia acts as a nucleophile to attack the β-carbon atom with partial positive charge in the enol anion intermediate. Due to the influence of the enol anion conjugation effect, the electron cloud density of the β-carbon atom is reduced, forming a tetrahedral intermediate of a β-hydroxycarbonyl compound containing a -NH2 group. The tetrahedral intermediate is unstable and rapidly loses a molecule of water (or forms a structure more easily eliminated by proton transfer), forming a conjugated C=C double bond, and finally forming cinnamyl 3-amino-2-butenoate (the product molecule contains a -NH2 group and a conjugated double bond, and has a stable structure). In the post-processing process, the excess ammonia is completely removed under reduced pressure to avoid product deterioration caused by residual ammonia, such as oxidation of the amino group. Cooling and crystallization ensure that the product is precipitated as a high-purity crystal. Washing removes the solvent and by-products adsorbed on the surface of the filter cake, and the final product purity can reach more than 98%, meeting the production requirements of cinnidipine. High-efficiency separation by centrifugal filtration reduces the loss of crystals in the mother liquor. The low solubility of the product in n-hexane avoids product loss caused by washing, and the final product yield can be stabilized at more than 80%.

[0016] In a specific embodiment, the mixed solvent is composed of a lower alcohol and an alkane. Preferably, the lower alcohol is isopropyl alcohol, and the alkane is n-hexane.

[0017] Cinnamyl acetoacetate molecular structure contains both polar ester group (-COO-) and non-polar cinnamyl group (aromatic ring + olefin chain), which belongs to "polar-non-polar mixed type molecule". In mixed solvents, low alcohol relies on the polarity of hydroxyl group (-OH) to form hydrogen bond with the ester group of cinnamyl acetoacetate to realize the dissolution of the polar part; the alkane solvent relies on the non-polar carbon chain to combine with the cinnamyl group (non-polar part) of cinnamyl acetoacetate through van der Waals force to realize the dissolution of the non-polar part. The synergistic effect of the two can uniformly disperse cinnamyl acetoacetate into a molecular level solution, providing a prerequisite for the subsequent full contact of liquid ammonia and raw materials. The preferred isopropanol-n-hexane system has a low freezing point (isopropanol freezing point -89.5℃, n-hexane freezing point -95℃), and will not freeze in the subsequent low-temperature reaction, and has a large difference in solubility with the product, providing a good solvent and product system for subsequent cooling crystallization.

[0018] In a specific embodiment, the mixed solvent is composed of low alcohol and alkane in a mass ratio of 1:(0.5-2.5); preferably, the mass ratio of low alcohol and alkane is 1:(1.4-1.8). The low alcohol and alkane need to match the polarity ratio of the raw material - if the alcohol content is too high, the overall polarity of the solvent is too strong, which may lead to less precipitation of the subsequent aminolysis product (3-amino-2-butenoic acid cinnamate), affecting the yield; if the alkane content is too high, the solvent polarity is too weak, which will lead to the precipitation of impurities, reducing the purity of 3-amino-2-butenoic acid cinnamate.

[0019] In a specific embodiment, the mass ratio of cinnamyl acetoacetate to mixed reaction solvent is 1:(1-3); preferably, the mass ratio of cinnamyl acetoacetate to mixed reaction solvent is 1:(1.5-2.0). This amount not only ensures the effective precipitation of the subsequent product, avoids the precipitation of impurities caused by insufficient solvent, but also avoids the excessive solvent, which leads to less product precipitation, affecting the yield.

[0020] In a specific embodiment, the low-temperature environment temperature is -10-5℃; preferably, the low-temperature environment temperature is -5-0℃. Liquid ammonia (NH3) has strong volatility and reactivity, and is prone to side reactions at high temperatures; therefore, by controlling the temperature under this condition, the side reaction rate can be slowed down by reducing the molecular kinetic energy, while ensuring that the main reaction (aminolysis) proceeds at a reasonable rate, and the main reaction is not completely inhibited at low temperature due to the strong electrophilicity of the α-carbon atom.

[0021] In a specific embodiment, the total amount of liquid ammonia introduced is 0.2-1.0 times the weight of cinnamyl acetoacetate, preferably 0.3-0.5 times. NH3 is used as a reactant, and sufficient amount is needed to promote the forward reaction. Theoretically, 1 mol of cinnamyl acetoacetate requires 1 mol of NH3, which is about 0.15 times the weight of the raw material. The actual amount is slightly higher to compensate for the loss of liquid ammonia due to volatilization and to ensure complete reaction. However, excessive use will lead to longer time for subsequent vacuum ammonia removal and increased energy consumption.

[0022] In a specific embodiment, the total reaction time of liquid ammonia is 10-24 hours, preferably 14-18 hours. The main reaction rate is slow at low temperature, and sufficient time is needed for NH3 to fully react with the raw material. If the time is too short (<10 hours), the residual rate of the raw material will be high, and the yield will decrease. If the time is too long (>24 hours), the risk of cumulative side reactions will increase (even at low temperature, a small amount of side reactions may still occur), and the production efficiency will decrease.

[0023] In a specific embodiment, during the centrifugal filtration process, the washing solvent is the alkane used in the reaction. The reason for choosing the alkane (n-hexane) used in the reaction as the washing solvent is that n-hexane has weak polarity and very low solubility for the product, so it will not dissolve the product during washing, avoiding yield loss. N-hexane can dissolve non-polar impurities (such as unreacted cinnamyl acetoacetate and alkane-soluble byproducts) remaining in the mother liquor, and can also replace isopropyl alcohol adsorbed on the surface of the crystals (isopropyl alcohol has strong polarity and will affect the purity of the dried product if it remains), further improving the purity of the product.

[0024] The following will be further illustrated with specific examples.

[0025] Example 1

[0026] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200 L reaction kettle, 60 kg of cinnamyl acetoacetate, 40.8 kg of isopropyl alcohol, and 61.2 kg of n-hexane were added. The reaction temperature was reduced to -5-0°C, and liquid ammonia was continuously introduced for reaction at this temperature. The reaction time was 16 h, and the total amount of liquid ammonia introduced was 24 kg. After the reaction was completed, the excess liquid ammonia was removed by vacuum evaporation until the vacuum degree was stable and the liquid temperature did not decrease. Centrifugal filtration was performed, followed by n-hexane washing and centrifugation to dryness to obtain white cinnamyl 3-amino-2-butenoate.

[0027] Example 2

[0028] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200L reactor, 60kg of cinnamyl acetoacetate, 37.5kg of isopropanol and 52.5kg of n-hexane were added, the reaction temperature was reduced to -5~0℃, and the reaction was carried out by continuously introducing liquid ammonia at this temperature for 14h, and the total amount of liquid ammonia introduced was 18kg; After the reaction was completed, the excess liquid ammonia was removed by evaporation under reduced pressure until the vacuum degree was stable and the liquid temperature did not decrease, and then the filter was shaken by centrifugation, washed with n-hexane, and centrifuged to dryness to obtain white cinnamyl 3-amino-2-butenoate.

[0029] Example 3

[0030] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200L reactor, 60kg of cinnamyl acetoacetate, 42.9g of isopropanol and 77.1kg of n-hexane were added, the reaction temperature was reduced to -5~0℃, and the reaction was carried out by continuously introducing liquid ammonia at this temperature for 18h, and the total amount of liquid ammonia introduced was 30kg; After the reaction was completed, the excess liquid ammonia was removed by evaporation under reduced pressure until the vacuum degree was stable and the liquid temperature did not decrease, and then the filter was shaken by centrifugation, washed with n-hexane, and centrifuged to dryness to obtain white cinnamyl 3-amino-2-butenoate.

[0031] Example 4

[0032] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200L reactor, 60kg of cinnamyl acetoacetate, 40.8kg of isopropanol and 61.2kg of n-hexane were added, the reaction temperature was reduced to -5~0℃, and the reaction was carried out by continuously introducing liquid ammonia at this temperature for 14h, and the total amount of liquid ammonia introduced was 24kg; After the reaction was completed, the excess liquid ammonia was removed by evaporation under reduced pressure until the vacuum degree was stable and the liquid temperature did not decrease, and then the filter was shaken by centrifugation, washed with n-hexane, and centrifuged to dryness to obtain white cinnamyl 3-amino-2-butenoate.

[0033] Example 5

[0034] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200L reactor, 60kg of cinnamyl acetoacetate, 40.8kg of isopropanol and 61.2kg of n-hexane were added, the reaction temperature was reduced to -5~0℃, and the reaction was carried out by continuously introducing liquid ammonia at this temperature for 18h, and the total amount of liquid ammonia introduced was 24kg; After the reaction was completed, the excess liquid ammonia was removed by evaporation under reduced pressure until the vacuum degree was stable and the liquid temperature did not decrease, and then the filter was shaken by centrifugation, washed with n-hexane, and centrifuged to dryness to obtain white cinnamyl 3-amino-2-butenoate.

[0035] Comparative Example 1

[0036] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 100 L reactor, 60 kg of cinnamyl acetoacetate and 12 kg of methanol were added, and the temperature was lowered to 0°C. Liquid ammonia was slowly introduced, and the temperature was controlled below 10°C. When the ammonia saturation was reached, the ammonia bottle valve was closed. After the ammonia introduction was completed, the reaction was maintained at 0-10°C for 38 h. After the reaction was completed, the material was discharged and centrifuged to filter. The centrifugation was continued until dryness. Then, 15 kg of 30% methanol solution was used to rinse the material. White cinnamyl 3-amino-2-butenoate was obtained.

[0037] Comparative Example 2

[0038] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 100 L reactor, 60 kg of cinnamyl acetoacetate and 12 kg of methanol were added, and the temperature was lowered to 0°C. Liquid ammonia was slowly introduced, and the temperature was controlled below 10°C. When the ammonia saturation was reached, the ammonia bottle valve was closed. After the ammonia introduction was completed, the reaction was maintained at 0-10°C for 38 h. After the reaction was completed, the material was discharged and centrifuged to filter. The centrifugation was continued until dryness. Then, 15 kg of 30% methanol solution was used to rinse the material. White cinnamyl 3-amino-2-butenoate was obtained.

[0039] Comparative Example 3

[0040] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200 L reactor, 60 kg of cinnamyl acetoacetate, 40.8 kg of isopropyl alcohol, and 61.2 kg of n-hexane were added. The reaction temperature was lowered to -5-0°C, and liquid ammonia was continuously introduced at this temperature for 8 h. The total amount of liquid ammonia introduced was 24 kg. After the reaction was completed, the excess liquid ammonia was removed by vacuum evaporation until the vacuum degree was stable and the material temperature did not decrease. The material was centrifuged and filtered, and then washed with n-hexane. After centrifugation to dryness, cinnamyl 3-amino-2-butenoate was obtained.

[0041] Comparative Example 4

[0042] A method for preparing cinnamyl 3-amino-2-butenoate, comprising the following steps: Into a 200 L reactor, 60 kg of cinnamyl acetoacetate, 40.8 kg of isopropyl alcohol, and 61.2 kg of n-hexane were added. The reaction temperature was lowered to -5-0°C, and liquid ammonia was continuously introduced at this temperature for 8 h. The total amount of liquid ammonia introduced was 24 kg. After the reaction, the excess liquid ammonia was evaporated under reduced pressure until the vacuum degree was stable and the temperature of the material liquid did not decrease, and then the liquid was centrifuged, washed with n-hexane, and centrifuged to dryness to obtain 3-amino-2-butenoic acid cinnamyl ester.

[0043] The ratio of the relevant parameters in the preparation of Examples 1-5 and Comparative Examples 1-4 is shown in Table 1, and the weight, molar yield [(product weight ÷ product molecular weight) ÷ (cinnamyl acetoacetate weight ÷ cinnamyl acetoacetate molecular weight)] and purity of the product 3-amino-2-butenoic acid cinnamyl ester prepared in Examples 1-5 and Comparative Examples 1-4 are shown in Table 2.

[0044] Table 1

[0045] Table 2

[0046] As can be seen from the yield and purity of the product 3-amino-2-butenoic acid cinnamyl ester in Table 2, the reactants in Examples 1-3 can maintain a high yield and purity under a certain weight ratio; the product yield and purity of Comparative Example 1 and Comparative Example 2, which are treated after processing at different temperatures using the conventional solvent methanol, cannot be well matched; and the flow rate of the liquid ammonia in Comparative Examples 1, 4 and 5 and Comparative Examples 3 and 4 can further improve the yield and purity of the product within a certain range.

[0047] It should be noted that the relational terms herein such as first and second are used only to differentiate one entity or action from another, and do not necessarily require or imply that these entities or actions occur in any such actual relationship or order. Moreover, the terms "include", "contain" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed or inherent to such a process, method, article or device.

[0048] The above disclosure is only several specific embodiments of the present application, but the embodiments of the present application are not limited thereto, and any changes that can be thought of by those skilled in the art shall fall within the protection scope of the present application.

Claims

1. A process for the preparation of cinnamyl 3-amino-2-butenoate, characterized in that, The method comprises the following steps: Cinnamyl acetoacetate is added into a mixed reaction solvent, and liquid ammonia is introduced for reaction at low temperature; after the reaction is completed, ammonia is removed under reduced pressure, and the product is crystallized, filtered, and washed to obtain cinnamyl 3-amino-2-butenoate.

2. The process for the preparation of cinnamyl 3-amino-2-butenoate according to claim 1, characterized in that, The mixed reaction solvent is composed of a lower alcohol and an alkane in a mass ratio of 1:(0.5-2.5).

3. The process for the preparation of cinnamyl 3-amino-2-butenoate according to claim 2, characterized in that, The mixed reaction solvent is composed of a lower alcohol and an alkane in a mass ratio of 1:(1.4-1.8).

4. The process for the preparation of cinnamyl 3-amino-2-butenoate according to claim 2, characterized in that, The lower alcohol is isopropyl alcohol, and the alkane is n-hexane.

5. The method for preparing cinnamon ester of 3-amino-2-butenoic acid according to claim 1, characterized in that, The mass ratio of cinnamyl acetoacetate to the mixed reaction solvent is 1:(1-3).

6. The process for the preparation of cinnamyl 3-amino-2-butenoate according to claim 5, characterized in that, The mass ratio of cinnamyl acetoacetate to the mixed reaction solvent is 1:(1.5-2).

7. The method for preparing cinnamon ester of 3-amino-2-butenoic acid according to claim 1, characterized in that, The low-temperature environment temperature is -10-5 ℃.

8. The method for preparing cinnamon ester of 3-amino-2-butenoic acid according to claim 1, characterized in that, The total amount of introduced liquid ammonia is 0.2-1.0 times the weight of cinnamyl acetoacetate.

9. The process for the preparation of cinnamyl 3-amino-2-butenoate according to claim 8, characterized in that, The total amount of introduced liquid ammonia is 0.3-0.5 times the weight of cinnamyl acetoacetate.

10. The method for preparing cinnamon ester of 3-amino-2-butenoic acid according to claim 1, characterized in that, The total time for introducing liquid ammonia for reaction is 10-24 hours.

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