Production method of adrenolone hydrochloride capable of increasing yield

Abstract

The invention discloses an adrenolone hydrochloride production method capable of increasing yield, and relates to the technical field of adrenolone hydrochloride, the method comprises the following steps: firstly, reacting 2-chloro-3, 4-dihydroxyacetophenone with a methylamine ethanol solution under the action of tetrabutylammonium bromide to generate adrenolone; wherein tetrabutylammonium bromide is used as a phase transfer catalyst to play a catalytic role; then carrying out salt forming reaction on the adrenolone and the hydrochloric acid ethanol solution in an alcohol-water solution to generate adrenolone hydrochloride; when the salt forming reaction is carried out, the hydrochloric acid ethanol solution is adopted to replace concentrated hydrochloric acid in the traditional process, and the proportion of water in the system during salt forming can be reduced, so that the loss of the adrenolone hydrochloride can be reduced, the yield of the adrenolone hydrochloride can be improved, and the production cost is further reduced.

Description

Technical Field

[0001] The invention relates to the technical field of adrenaline hydrochloride production, and in particular to a method for producing adrenaline hydrochloride capable of increasing the yield. Background Art

[0002] Adrenolide hydrochloride, molecular formula: C9H 11 NO3·HCl, molecular weight is 217.65, chemical name is 1-(3,4-dihydroxyphenyl)-2-methylaminoethyl ketone hydrochloride, structural formula is as follows:

[0003]

[0004] Adrenaline hydrochloride is an intermediate for the synthesis of adrenaline drugs. Domestic literature has rarely optimized the synthesis process of adrenaline hydrochloride, and the yield is generally low. In addition, adrenaline drugs are relatively expensive, so it is necessary to optimize its synthesis process on the existing basis, improve the yield and reduce production costs. Summary of the invention

[0005] The object of the present invention is to provide a method for producing adrenoceptor hydrochloride with improved yield, and to solve the following technical problems:

[0006] How to improve the yield of adrenaline hydrochloride.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] A method for producing adrenoceptor hydrochloride with increased yield, characterized in that it comprises the following steps:

[0009] S1: reacting 2-chloro-3,4-dihydroxyacetophenone and methylamine ethanol solution under the action of tetrabutylammonium bromide to generate adrenoceptor; wherein the tetrabutylammonium bromide acts as a phase transfer catalyst;

[0010] S2: allowing adrenaline and ethanol hydrochloric acid solution to undergo salt-forming reaction in an alcohol-water solution to generate adrenaline hydrochloride.

[0011] In a further embodiment of the present invention: in step S1, the molar mass ratio of 2-chloro-3,4-dihydroxyacetophenone, methylamine and tetrabutylammonium bromide is 1:8:0.02.

[0012] In a further embodiment of the present invention: in step S1, the mass fraction of methylamine in the methylamine ethanol solution is 30%.

[0013] In a further embodiment of the present invention: in step S1, the reaction temperature is 30°C-35°C, and the reaction time is 6 hours.

[0014] In a further embodiment of the present invention: in step S2, the mass fraction of the alcohol aqueous solution is 85%-95%.

[0015] In a further embodiment of the present invention: in step S2, the hydrochloric acid ethanol solution is a hydrogen chloride ethanol solution, and its mass fraction is 34%-38%.

[0016] In a further embodiment of the present invention: in step S2, the reaction temperature is 10°C-40°C;

[0017] Preferably, the reaction temperature is 20°C-30°C.

[0018] In a further embodiment of the present invention: in step S2, the pH value of the reaction system when generating adrenochrome hydrochloride is 1-5;

[0019] Preferably, the pH value of the reaction system when generating adrenoceptorone hydrochloride is 3-4.

[0020] Based on the above content, a preferred production method of adrenochrome hydrochloride with improved yield is obtained, which is as follows:

[0021] Step 1: Add 2-chloro-3,4-dihydroxyacetophenone with a molar mass ratio of 1:8:0.02, 30% methylamine ethanol solution and tetrabutylammonium iodide into a three-necked reaction bottle and stir evenly, pass nitrogen protection throughout the process, control the temperature to float within 30-35°C, react for 6 hours, cool to 15°C-20°C after the reaction is completed, keep warm and stir for 1 hour, filter, and wash the filter cake once with anhydrous ethanol to obtain adrenal ketone tide product;

[0022] Step 2: Add the adrenaline wet product to 85%-90% ethanol aqueous solution, stir evenly, then drop a 34%-38% mass fraction of hydrogen chloride ethanol solution, adjust the pH to 3-4, stir for 1 hour, monitor the pH during the process, and maintain the pH at 3-4. After the reaction is completed, filter and wash the filter cake with anhydrous ethanol to obtain the adrenaline hydrochloride wet product, and then vacuum dry to obtain the adrenaline hydrochloride.

[0023] Beneficial effects of the present invention:

[0024] In the method for producing adrenaline hydrochloride capable of increasing the yield of the present invention, during the salt-forming reaction, a hydrochloric acid ethanol solution is used instead of concentrated hydrochloric acid in the traditional process, so that the proportion of water in the system during the salt-forming reaction can be reduced, thereby reducing the loss of adrenaline hydrochloride, increasing the yield of adrenaline hydrochloride, and further reducing the production cost. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0027] Example 1

[0028] Step 1: Add 50 g (0.268 mol) of 2-chloro-3,4-dihydroxyacetophenone, 222 g (2.144 mol) of 30% methylamine ethanol solution by mass, and 2 g (0.00536 mol) of tetrabutylammonium iodide into a 500 mL three-necked reaction bottle and stir evenly. Nitrogen protection is passed throughout the process. The temperature is controlled at 32°C and the reaction is carried out for 6 hours. After the reaction is completed, the temperature is lowered to 18°C, and the mixture is stirred for 1 hour at a temperature of 100 °C. The filter cake is washed once with anhydrous ethanol to obtain adrenal ketone.

[0029] Step 2: Add the adrenaline ketone wet product to 150 mL of 85% ethanol aqueous solution, stir evenly, then drop a 36% ethanol solution of hydrogen chloride by mass, adjust the pH to 4, stir for 1 hour, monitor the pH during the process, and maintain the pH at 4; filter, wash the filter cake once with anhydrous ethanol to obtain the adrenaline hydrochloride wet product, and then place it in a vacuum drying oven at 50°C for vacuum drying.

[0030] Step 3: Collect the material. After weighing, 51.1 g of dry adrenaline hydrochloride was obtained. The appearance of the dry product was white crystalline powder. After testing, the purity was 99.5%. After calculation, the yield was 87.6%.

[0031] Example 2

[0032] Compared with Example 1, the only difference is:

[0033] 1. In step 2, the ethanol aqueous solution with a mass fraction of 85% is replaced with the ethanol aqueous solution with a mass fraction of 90%.

[0034] 2. In step 3, the material was collected and 51.5 g of dry adrenochrome hydrochloride was obtained by weighing. The appearance of the dry adrenochrome hydrochloride was off-white crystalline powder. The purity was 99.3% after testing. The yield was 88.3% after calculation.

[0035] Example 3

[0036] Compared with Example 1, the only difference is:

[0037] 1. In step 2, the ethanol aqueous solution with a mass fraction of 85% is replaced with the ethanol aqueous solution with a mass fraction of 95%.

[0038] 2. In step 3, the material was collected and 53.2 g of dry adrenochrome hydrochloride was obtained by weighing. The appearance of the dry adrenochrome hydrochloride was a pink solid powder. The purity was 97.8% after testing. The yield was 91.2% after calculation.

[0039] Comparative Example 1

[0040] Compared with Example 1, the only difference is:

[0041] 1. In step 2, the ethanol aqueous solution with a mass fraction of 85% is replaced with the ethanol aqueous solution with a mass fraction of 75%.

[0042] 2. In step 3, the material was collected and 48.2 g of dry adrenochrome hydrochloride was obtained by weighing. The appearance of the dry adrenochrome hydrochloride was white crystalline powder. The purity was 99.5% after testing. The yield was 82.6% after calculation.

[0043] Comparative Example 2

[0044] The preparation of adrenaline hydrochloride is carried out with reference to the patent document with publication number CN106748835A, as follows:

[0045] Step 1: Add 50 g (0.268 mol) of 2-chloro-3,4-dihydroxyacetophenone, 222 g (2.144 mol) of 30% methylamine ethanol solution by mass, and 2 g (0.00536 mol) of tetrabutylammonium iodide into a 500 mL three-necked reaction bottle and stir evenly. Nitrogen protection is passed throughout the process. The temperature is controlled at 32°C and the reaction is carried out for 6 hours. After the reaction is completed, the temperature is lowered to 18°C, and the mixture is stirred for 1 hour at a temperature of 100 °C. The filter cake is washed once with anhydrous ethanol to obtain adrenal ketone.

[0046] Step 2: Add the adrenaline ketone wet product to 150 mL of 90% ethanol aqueous solution, stir evenly, then drop 36% concentrated hydrochloric acid, adjust the pH to 4, stir for 1 hour, monitor the pH during the process, and maintain the pH at 4; filter, wash the filter cake once with anhydrous ethanol to obtain the adrenaline hydrochloride wet product, and then place it in a vacuum drying oven at 50°C for vacuum drying.

[0047] Step 3: Collect the material. After weighing, 48.3 g of dry adrenaline hydrochloride was obtained. The appearance of the dry product was white crystalline powder. After testing, the purity was 99.6%. After calculation, the yield was 82.8%.

[0048] The product appearance, purity results and yield results of the adrenolide hydrochloride obtained in Examples 1-3 and Comparative Examples 1-2 are listed in Table 1. Table 1 is as follows:

[0049] Table 1

[0050] Product Appearance purity(%) Yield (%) Example 1 White crystalline powder 99.5 87.6 Example 2 Off-white crystalline powder 99.3 88.3 Example 3 Pink solid powder 97.8 91.2 Comparative Example 1 White crystalline powder 99.5 82.6 Comparative Example 2 White crystalline powder 99.6 82.8

[0051] By analyzing the data in Table 1, it can be seen that the adrenaline hydrochloride prepared in Examples 1-3 has a higher yield than the adrenaline hydrochloride prepared in Comparative Examples 1-2. Therefore, the production method of the present invention can increase the yield of adrenaline hydrochloride.

[0052] In the description of the present invention, it is to be understood that "first" and "second" are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0053] The above is a detailed description of an embodiment of the present invention, but the content is only a preferred embodiment of the present invention and cannot be considered to limit the scope of implementation of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the scope of the patent coverage of the present invention.

Claims

1. A method for producing adrenaline hydrochloride with increased yield, characterized in that: The following steps are involved: S1: reacting 2-chloro-3,4-dihydroxyacetophenone and methylamine ethanol solution under the action of tetrabutylammonium bromide to generate adrenoceptor; S2: reacting adrenaline and ethanol hydrochloride solution in an alcohol-water solution to generate adrenaline hydrochloride.

2. The method for producing adrenaline hydrochloride with increased yield according to claim 1, characterized in that: In step S1, the molar mass ratio of the 2-chloro-3,4-dihydroxyacetophenone, methylamine and tetrabutylammonium bromide is 1:8:0.

02.

3. The method for producing adrenolide hydrochloride with increased yield according to claim 1, characterized in that: In step S1, the mass fraction of methylamine in the methylamine ethanol solution is 30%.

4. The method for producing adrenaline hydrochloride with increased yield according to claim 1, characterized in that: In step S1, the reaction temperature is 30°C-35°C, and the reaction time is 6 hours.

5. The method for producing adrenaline hydrochloride with increased yield according to claim 1, characterized in that: In step S2, the mass fraction of the alcohol aqueous solution is 85%-95%.

6. The method for producing adrenaline hydrochloride with increased yield according to claim 1, characterized in that: In step S2, the hydrochloric acid ethanol solution is a hydrogen chloride ethanol solution, and its mass fraction is 34%-38%.

7. The method for producing adrenaline hydrochloride with increased yield according to claim 1, characterized in that: In step S2, the reaction temperature is 10°C-40°C.

8. The method for producing adrenaline hydrochloride with increased yield according to claim 1, characterized in that: In step S2, the pH value of the reaction system is 1-5 when generating adrenolide hydrochloride.

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