Synthesis method of dopamine hydrochloride

Abstract

The invention discloses a method for synthesizing dopamine hydrochloride. The method comprises: (1) subjecting a compound represented by formula I to a nitration reaction to obtain a compound represented by formula II; (2) subjecting the compound represented by formula II to a reduction reaction to obtain a compound represented by formula III; (3) mixing the compound represented by formula III with hydrochloric acid and performing a crystallization treatment to obtain a compound represented by formula IV, i.e., dopamine hydrochloride. The method has the advantages of a short process route, a small amount of wastewater, simple operation, and easy production.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for synthesizing dopamine hydrochloride. Background Art

[0002] Dopamine hydrochloride, chemical name 4-(2-aminoethyl)-1,2-benzenediol hydrochloride. Dopamine has β receptor stimulatory effect, and also has certain α receptor stimulatory effect, can enhance myocardial contractility, increase cardiac output, accelerate heart rate to a lesser extent, has a mild contraction effect on peripheral blood vessels, increases arterial pressure, dilates visceral blood vessels, increases blood flow, increases renal blood flow and glomerular filtration rate, thereby promoting urine volume and sodium excretion, can improve peripheral circulation, significantly increase urine volume, and has no significant effect on heart rate, which is its advantage over other vasoconstrictors or vasodilators. It can be mainly used in various types of shock in clinical practice.

[0003] The prior art generally uses vanillin as a raw material to prepare dopamine hydrochloride, and the specific method is as follows: 3-methoxy-4-hydroxybenzaldehyde (vanillin) is used as a raw material, first condensed with nitromethane under the catalysis of methylamine to obtain 4-hydroxy-3-methoxy-β-nitroethylbenzene, reduced to obtain 4-hydroxy-3-methoxyphenylethylamine hydrochloride, catalyzed by hydrogen bromide to remove the methyl group to obtain dopamine hydrobromide, and then reacted with hydrochloric acid to obtain dopamine hydrochloride, and refined to obtain the finished product. However, this method has the disadvantages of a long process route and a large amount of wastewater, and the existing dopamine hydrochloride synthesis method still needs to be improved. Summary of the invention

[0004] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, one object of the present invention is to provide a method for synthesizing dopamine hydrochloride. The method has the advantages of short process route, small amount of wastewater, simple operation, and easy production.

[0005] In one aspect of the present invention, the present invention provides a method for synthesizing dopamine hydrochloride. According to an embodiment of the present invention, the method comprises: (1) subjecting the compound of formula I to a nitration reaction to obtain a compound of formula II; (2) subjecting the compound of formula II to a reduction reaction to obtain a compound of formula III; (3) mixing the compound of formula III with hydrochloric acid and performing a crystallization treatment to obtain a compound of formula IV, dopamine hydrochloride;

[0006]

[0007]

[0008] According to the synthesis method of dopamine hydrochloride of the above embodiment of the present invention, 3,4-dihydroxybenzaldehyde is used as a raw material, a nitro group is first introduced into the substrate through a nitration reaction, the nitro group is reduced to an amino group, and then the product is reacted with hydrochloric acid to generate a hydrochloride, and then crystallized to obtain the product. Therefore, the process route of the method is short, the amount of wastewater generated is small, and the operation is simple and easy to produce.

[0009] In addition, the method for synthesizing dopamine hydrochloride according to the above embodiment of the present invention may also have the following additional technical features:

[0010] In some embodiments of the present invention, the nitration reaction is carried out in the presence of nitromethane, methylamine hydrochloride and a first solvent.

[0011] In some embodiments of the present invention, the first solvent is selected from at least one of an alcohol solvent and an ester solvent.

[0012] In some embodiments of the present invention, the first solvent is selected from at least one of ethanol and ethyl acetate.

[0013] In some embodiments of the present invention, the molar ratio of the compound represented by formula I, the nitromethane, and the methylamine hydrochloride is 1:(1.0-2.5):(2.0-7.0).

[0014] In some embodiments of the present invention, the nitration reaction is carried out at 45-60° C. for 2-4 hours.

[0015] In some embodiments of the present invention, after the nitration reaction is completed, the method further comprises: performing crystallization treatment on the nitration reaction product to obtain the compound represented by formula II.

[0016] In some embodiments of the present invention, the reduction reaction is carried out in the presence of hydrogen, a Pd / C catalyst, an acid, and a second solvent.

[0017] In some embodiments of the present invention, the pressure of the hydrogen is 0.2-0.5 MPa, the mass fraction of the Pd / C catalyst is 10%-30%, and the reduction reaction is carried out for 5-7 hours.

[0018] In some embodiments of the present invention, the second solvent is selected from at least one of water, ethanol, methanol, and tetrahydrofuran.

[0019] In some embodiments of the present invention, the acid is selected from at least one of hydrochloric acid and glacial acetic acid.

[0020] In some embodiments of the present invention, after the reduction reaction is completed, the method further comprises: performing crystallization treatment on the reduction reaction product to obtain the compound represented by formula III.

[0021] In some embodiments of the present invention, the crystallization treatment further includes: purifying the compound represented by formula IV using ethanol and water.

[0022] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION

[0023] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0024] In addition, the terms "first", "second", and "third" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first", "second", and "third" may explicitly or implicitly include at least one of the features. In the description of the present invention, the meaning of "plurality" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0025] In one aspect of the present invention, the present invention provides a method for synthesizing dopamine hydrochloride. The method for synthesizing dopamine hydrochloride according to an embodiment of the present invention is further described in detail below.

[0026] First, according to an embodiment of the present invention, a nitration reaction is performed on the compound represented by formula I to obtain a compound represented by formula II.

[0027]

[0028] According to some embodiments of the present invention, the nitration reaction can be performed in the presence of nitromethane, methylamine hydrochloride, and a first solvent.

[0029] According to some embodiments of the present invention, the first solvent may be selected from at least one of an alcohol solvent and an ester solvent. Preferably, the first solvent is selected from at least one of ethanol and ethyl acetate. More preferably, the first solvent is ethanol.

[0030] According to some embodiments of the present invention, the molar ratio of the compound shown in Formula I, nitromethane, and methylamine hydrochloride can be 1: (1.0-2.5): (2.0-6.0), that is, relative to the feeding amount of the compound shown in Formula I, the feeding amount of nitromethane can be 1.0eq-2.5eq, for example, it can be 1.0eq, 1.2eq, 1.5eq, 2.0eq, 2.5eq, etc., and the feeding amount of methylamine hydrochloride can be 2.0eq, 3.0eq, 4.0eq, 5.0eq, 6.0eq, etc. The inventors found that if the feeding amount of nitromethane is too much, it may cause the product yield to decrease (because nitromethane is an excellent solvent for the product). If the feeding amount of methylamine hydrochloride is too little, the raw material reaction may be incomplete and the reaction time may be too long; if the feeding amount of methylamine hydrochloride is too much, the impurity content generated in the reaction may increase, the reaction is too fast, and the product is violently separated.

[0031] According to some embodiments of the present invention, the nitration reaction can be carried out at 45-60°C for 2-4 hours. The inventors have found that if the nitration reaction temperature is too low or the reaction time is too short, more raw materials may remain and the reaction may be incomplete; if the nitration reaction temperature is too high or the reaction time is too long, the impurity content generated in the reaction may increase, reducing the purity of the product.

[0032] According to some embodiments of the present invention, after the nitration reaction is completed, the process further comprises: crystallizing the nitration reaction product to obtain the compound of formula II. Specifically, the nitration product can be precipitated by adding hydrochloric acid to the system obtained by the nitration reaction and then cooling it, and the nitration product can be separated by suction filtration to obtain the nitration product.

[0033] Further, according to an embodiment of the present invention, the compound represented by formula II is subjected to a reduction reaction to obtain a compound represented by formula III.

[0034]

[0035] According to some embodiments of the present invention, the reduction reaction may be performed in the presence of hydrogen, a Pd / C catalyst, an acid, and a second solvent.

[0036] According to some embodiments of the present invention, the pressure of hydrogen can be 0.2-0.6 MPa, the mass fraction of the Pd / C catalyst can be 10%-30%, and the reduction reaction time can be 5-7 hours. Preferably, the pressure of hydrogen is 0.4-0.6 MPa, and the mass fraction of the Pd / C catalyst is 20%-30%. The inventors found that if the hydrogen pressure is too low or the reaction time is too short, the reaction may not be complete, and too much intermediate nitrate may remain; if the hydrogen pressure is too high or the reaction time is too long, it may cause safety risks. If the mass fraction of the Pd / C catalyst is too low, the reaction may not be complete, and too much intermediate nitrate may remain.

[0037] According to some embodiments of the present invention, the second solvent may be selected from at least one of water, ethanol, methanol, and tetrahydrofuran. Preferably, the second solvent is a mixture of water and methanol or a mixture of water and tetrahydrofuran. This can further facilitate the hydrogenation reaction and post-processing operations.

[0038] According to some embodiments of the present invention, the acid may be at least one of hydrochloric acid and glacial acetic acid.

[0039] According to some embodiments of the present invention, after the reduction reaction is completed, the method further comprises: crystallizing the reduction reaction product to obtain the compound represented by formula III. Specifically, the reduction product can be precipitated by adding hydrochloric acid to the system obtained by the reduction reaction and then cooling it, and the reduction product can be separated by suction filtration to obtain the reduction product.

[0040] Further, according to an embodiment of the present invention, the compound represented by formula III is mixed with hydrochloric acid and subjected to crystallization treatment to obtain dopamine hydrochloride, a compound represented by formula IV.

[0041]

[0042] According to some embodiments of the present invention, the crystallization process further includes: refining the compound represented by Formula IV using ethanol and water, thereby further improving the yield of the product dopamine hydrochloride.

[0043] The present invention is described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0044] Example 1

[0045] (1) Place 10 g of 3,4-dihydroxybenzaldehyde, 30 mL of ethanol, and 2.0 eq of nitromethane in a 250 mL three-necked flask and heat to 40°C to dissolve.

[0046] (2) After the system is dissolved, methylamine hydrochloride-ethanol solution (converted to 5 eq of methylamine hydrochloride) is added and the temperature is raised to 55° C. for reaction. The reaction process is monitored by TLC.

[0047] (3) After the reaction is completed, the temperature is lowered to room temperature, 50 mL of dilute hydrochloric acid (25% by volume concentrated hydrochloric acid + 75% by volume purified water) is added for crystallization, and the orange-yellow nitration product is obtained by suction filtration.

[0048] (4) 2.0 g of the nitration product, 10 mL of tetrahydrofuran, 2 mL of purified water, 0.4 g of a dry basis 20% Pd / C catalyst, and 0.5 mL of concentrated hydrochloric acid were added to a hydrogenation kettle, and the mixture was reacted at 15° C. and a hydrogen pressure of 0.5 MPa for 6 h to obtain a hydrogenated liquid.

[0049] (5) The hydrogenated liquid was dried by rotation at 60° C. and −0.1 MPa, and 1.4 times the volume of concentrated hydrochloric acid and 1.5 times the volume of anhydrous ethanol were added. The mixture was beaten at 75° C. for one hour, then cooled and filtered to obtain crude dopamine hydrochloride.

[0050] (6) Add 1 times the mass of 85% ethanol to the crude dopamine hydrochloride, heat to 70°C and dissolve for 1 hour, add 1.5 times the mass of concentrated hydrochloric acid, cool and crystallize to obtain the finished dopamine hydrochloride with a yield of 60.2% and a purity of 99.65%.

[0051] (7) The quality index of the obtained dopamine hydrochloride finished product was tested. The obtained dopamine hydrochloride finished product met the release standard and shelf life standard of dopamine hydrochloride in the 2020 edition of the Chinese Pharmacopoeia in terms of HPLC characterization, IR characterization, melting point, pH value, impurity content, solvent residue, drying loss, ignition residue, heavy metal content, etc.

[0052] Example 2

[0053] The compound of formula II was prepared according to the method of Example 1, except that the molar ratio of the compound of formula I, nitromethane and methylamine hydrochloride was different. The yield and purity of the intermediate compound of formula II were as follows.

[0054]

[0055] Comparative Example 1

[0056] The compound of formula II was prepared according to the method of Example 1, except that when the molar ratio of the compound of formula I, nitromethane and methylamine hydrochloride was 1:1:1, the yield was 11.2% and the purity was 32.46%.

[0057] Example 3

[0058] The compound of formula II was prepared according to the method of Example 1, except that the type of solvent for the nitration reaction was different. The yield and purity of the intermediate compound of formula II were as follows.

[0059] Solvent for nitration reaction Yield / % purity / % Isopropyl alcohol 38.71 92.00 Ethyl acetate 78.57 91.00

[0060] Comparative Example 2

[0061] The compound of formula II was prepared according to the method of Example 1, except that when the solvent for the nitration reaction was ethanol / water, the intermediate could not be crystallized.

[0062] Example 4

[0063] The compound of formula II was prepared according to the method of Example 1, except that the nitration temperature was different. The yield and purity of the intermediate compound of formula II were as follows.

[0064] Nitration temperature / ℃ Yield / % purity / % 45 69.7 79.90 50 80.8 89.80 60 86.4 95.40

[0065] Comparative Example 3

[0066] The compound of formula II was prepared according to the method of Example 1, except that when the nitration temperature was 30°C, the yield was 32.6% and the purity was 41.5%.

[0067] Example 5

[0068] The compound of formula IV was prepared according to the method of Example 1, except that the hydrogen pressure was different. The yield and purity of the obtained product, compound IV, were as follows.

[0069] Hydrogen pressure / MPa Yield / % purity / % 0.2 20.7 54.32 0.3 20.5 57.78 0.4 39.2 76.82 0.6 51.4 98.90

[0070] Comparative Example 4

[0071] The compound represented by formula IV was prepared according to the method of Example 1, except that when the hydrogen pressure was selected to be 0.1 MPa, the yield was 10.9% and the purity was 32.12%.

[0072] Example 6

[0073] The compound represented by formula IV was prepared according to the method of Example 1, except that when methanol was selected as the solvent for the hydrogenation reaction, the yield was 33.5% and the purity was 75.44%.

[0074] Comparative Example 5

[0075] The compound of formula IV was prepared according to the method of Example 1, except that when acetonitrile was selected as the solvent for the hydrogenation reaction, the purity of the hydrogenation liquid was 13.93%, which was too low to obtain the product.

[0076] Example 7

[0077] The compound of formula IV was prepared according to the method of Example 1, except that the time of hydrogenation reaction was different. The yield and purity of the obtained product, compound IV, were as follows.

[0078] Hydrogenation reaction time / h Yield / % purity / % 5 56.7 96.00 5.5 54.3 98.64 6.5 56.8 98.40 7 53.7 98.85

[0079] Comparative Example 6

[0080] The compound represented by formula IV was prepared according to the method of Example 1, except that when the hydrogenation reaction time was selected as 3 h, the yield was 36.1% and the purity was 40.50%.

[0081] Comparative Example 7

[0082] Dopamine hydrochloride was prepared in a method substantially the same as that in Example 1, except that in step (4), zinc powder was used to reduce the nitration product. Specifically, the method comprises: adding excess zinc powder to a reactor based on 2.0 g of the nitration product, reacting for 3 h in an acidic environment at a temperature of 10° C., removing unreacted zinc powder by suction filtration, adding sodium carbonate to neutralize the pH to 7-8, removing zinc carbonate by suction filtration, and removing part of the solvent by rotary evaporation to obtain a reduction product, wherein the product yield is about 11.5% and the purity is about 95%.

[0083] Comparative Example 8

[0084] The compound of formula IV was prepared according to the method of Example 1, except that in step (1), the solvent was replaced with 12 mL of methanol, no acid was added during the reaction, the reaction temperature was 30° C., the hydrogen pressure was 1 MPa, and the purity of the hydrogenated liquid was 27.49%. The purity was too low to obtain a crude product.

[0085] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0086] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for synthesizing dopamine hydrochloride, characterized in that: include: (1) subjecting the compound represented by formula I to a nitration reaction to obtain a compound represented by formula II; The nitration reaction is carried out in the presence of nitromethane, methylamine hydrochloride and a first solvent, wherein the first solvent is selected from at least one of ethanol and ethyl acetate, and the nitration reaction is carried out at 45 to 60° C. for 2 to 4 hours; The molar ratio of the compound represented by formula I, the nitromethane and the methylamine hydrochloride is 1:(1.0-2.5):(4.0-6.0); (2) subjecting the compound represented by formula II to a reduction reaction, adding hydrochloric acid to the system obtained by the reduction reaction, then cooling the system to precipitate a reduction product, and separating the reduction product by suction filtration; The reduction reaction is carried out in the presence of hydrogen, a Pd / C catalyst, an acid, and a second solvent; The pressure of the hydrogen is 0.5-0.6 MPa, the mass fraction of the Pd / C catalyst is 10%-30%, and the reduction reaction is carried out for 5-7 hours; The second solvent is a mixture of water and tetrahydrofuran; (3) mixing the reduction product with hydrochloric acid and performing crystallization treatment to obtain dopamine hydrochloride, a compound represented by formula IV; 2. The method for synthesizing dopamine hydrochloride according to claim 1, characterized in that: After the nitration reaction is completed, the method further includes: performing crystallization treatment on the nitration reaction product to obtain the compound represented by formula II.

3. The method for synthesizing dopamine hydrochloride according to claim 1, characterized in that: The acid is selected from at least one of hydrochloric acid and glacial acetic acid.

4. The method for synthesizing dopamine hydrochloride according to claim 1, characterized in that: Before the crystallization treatment, the method further comprises: refining the compound represented by formula IV using ethanol and water.

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