Synthesis method of high-purity dioxopromethazine hydrochloride

Abstract

Belonging to the technical field of phenothiazine derivative synthesis, the invention relates to a synthesis method of high purity dioxopromethazine hydrochloride, which comprises: adding toluene and dioxophenothiazine into a reaction kettle, stirring, adding a sodium hydroxide solid and a 2-chloro-N, N-dimethyl-1-propylamine toluene solution, carrying out heating reflux reaction, liquid separation, washing, concentration, adding a solvent, heating, adding an acid to adjust the pH value, and cooling to room temperature to obtain the high purity dioxopromethazine hydrochloride. Stirring, cooling and crystallizing, filtering and drying to obtain dioxopromethazine oxalate; the preparation method comprises the following steps: adding toluene and purified water into a reaction kettle, adding dioxopromethazine oxalate while stirring, adjusting the pH value, separating liquid, washing with water, concentrating, adding acetone, decolorizing, filtering, transferring into a reaction bottle, heating, introducing hydrochloric acid gas to adjust the pH value, stirring, cooling, continuing stirring for crystallization, filtering, and drying to obtain dioxopromethazine hydrochloride. The whole process is free of dangerous reaction, the post-treatment method is conventional liquid separation, salting and crystallization, the operation is simple, and the dangerous process that oxidizing agents such as oxygen and hydrogen peroxide are used for oxidation reaction in the conventional synthesis process is avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of phenothiazine derivatives, and relates to a method for synthesizing high-purity dioxopromethazine hydrochloride. Background Art

[0002] The chemical name of dioxopromethazine hydrochloride is 10-(2-dimethylamino-propyl)phenothiazine-5,5-dioxide hydrochloride, and its English name is Dioxopromethazine Hydrochloride. It is a white or off-white powder or crystalline powder, odorless and bitter. It is extremely soluble in water and very slightly soluble in ethanol. Its structural formula is as follows:

[0003]

[0004] Dioxopromethazine hydrochloride is a phenothiazine derivative, also known as Ke Kemin, and has the efficacy of relieving cough and asthma, comparable to codeine. It can anti-inflammatory and relieve smooth muscle spasm, and is suitable for the treatment of chronic bronchitis, allergic asthma and other diseases. It has antihistamine and local anesthetic effects, and also has a therapeutic effect on pruritus and urticaria.

[0005] At present, the main production route of this drug is to use promethazine hydrochloride as the starting synthetic raw material, and obtain the finished product (dioxopromethazine hydrochloride raw material) through alkalization, oxidation, salting, decolorization and pressure filtration, crystallization separation, vacuum drying, pulverization, sieving, mixing, inner packaging and outer packaging. The reaction route is as follows:

[0006]

[0007] Patent CN106749098B discloses a process for preparing dioxopromethazine hydrochloride using oxygen as an oxidant; Patent CN111943910A discloses a process for preparing dioxopromethazine hydrochloride using potassium peroxymonosulfate as an oxidant. Both patents use promethazine hydrochloride as the starting material and use an oxidant to carry out an oxidation reaction to obtain dioxopromethazine hydrochloride. This production process is relatively complex, uses precious metal catalysts such as palladium acetate, increases the production cost. At the same time, this type of oxidation reaction belongs to a dangerous process, has certain requirements for production equipment, needs to be strictly monitored, and the cost of using promethazine hydrochloride as a raw material is relatively high. Promethazine hydrochloride itself is an active pharmaceutical ingredient. Summary of the Invention

[0008] The present invention provides a method for synthesizing high-purity dioxopromethazine hydrochloride to solve the above problems in the prior art, and high-purity dioxopromethazine hydrochloride is prepared using dioxophenothiazine as a substrate.

[0009] The technical solution adopted by the present invention to achieve its purpose:

[0010] A method for synthesizing high-purity dioxopromethazine hydrochloride, comprising the following steps:

[0011] S1. Synthesis of dioxopromethazine oxalate:

[0012] Add the first purified water to 2-chloro-N,N-dimethyl-1-propanamine hydrochloride. After stirring until it is dissolved and clarified, adjust the pH, add the first toluene, stir, let it stand for liquid separation, retain the toluene layer, dry it, filter it, and obtain the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine.

[0013] Add the second toluene and dioxophenothiazine to the reaction kettle, stir, add solid sodium hydroxide and the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine, heat up to reflux for reaction. After the reaction is completed, cool down, add the second purified water, stir, separate the liquid, retain the toluene layer, wash it until it is neutral, concentrate it to dryness, add a solvent, heat up and add acid to adjust the pH, stir while maintaining the temperature, cool down to crystallize, filter, dry it, and obtain dioxopromethazine oxalate.

[0014] S2. Synthesis of promethazine hydrochloride:

[0015] Add toluene and purified water to the reaction kettle. While stirring, add the dioxopromethazine oxalate prepared in step S1, adjust the pH, separate the liquid, retain the toluene layer, wash the toluene layer with water, concentrate it to dryness, add acetone, decolorize it, filter it, transfer it to a reaction flask, heat up and introduce hydrogen chloride gas to adjust the pH, stir, continue to stir while cooling down, filter, and dry it under vacuum to obtain the finished product of promethazine hydrochloride. The process route is as follows:

[0016]

[0017] Preferably, in step S1, the mass ratio of 2-chloro-N,N-dimethyl-1-propanamine hydrochloride, the first purified water, and the first toluene is 1.0:(3.0 - 4.0):(3.5 - 5.5).

[0018] Preferably, in step S1, the mass ratio of dioxophenothiazine, 2-chloro-N,N-dimethyl-1-propanamine hydrochloride, and the second toluene is 1.0:1.3:(1.0 - 2.0).

[0019] Preferably, in step S1, add 2-chloro-N,N-dimethyl-1-propanamine hydrochloride to the first purified water, adjust the pH to 12 - 14 with sodium hydroxide with a mass concentration of 40% under stirring, add the first toluene and stir for 30 min; add anhydrous sodium sulfate for drying for 0.5 h;

[0020] Heat up to above 110 °C for reflux reaction for 4 h, then cool down to 55 °C - 65 °C again, add the second purified water, stir for 30 min; wash the toluene layer with 60 °C hot water until it is neutral;

[0021] Add the solvent methanol, heat up to 60 °C, add oxalic acid to adjust the pH to 3 - 4, maintain the temperature at 60 °C and stir for 30 min, then cool down to 15 °C - 25 °C for crystallization for 1 - 2 h.

[0022] Preferably, in step S2, the mass ratio of toluene, purified water, dioxopromethazine oxalate and acetone is (3.0 - 4.0) : 5.0 : 1.0 : (3.0 - 4.0).

[0023] Preferably, in step S2, use an aqueous sodium hydroxide solution with a mass concentration of 40% to adjust the pH to 11 - 12;

[0024] Add activated carbon to the acetone system for decolorization for 30 min;

[0025] Heat up to 35 °C - 45 °C, introduce hydrochloric acid gas to adjust the pH to 3 - 4, stir for 1 h, cool down to 15 °C and continue to stir for 2 h, then filter, and dry in vacuum at 50 °C for 8 h.

[0026] The beneficial effects of the present invention are as follows:

[0027] The reaction conditions of the present invention are mild, there is no dangerous reaction in the whole process, the post - treatment method is conventional liquid - liquid separation and salt - forming crystallization, without special operations, the operation is simple, and the dangerous processes of using oxidants such as oxygen and hydrogen peroxide for oxidation reactions in the conventional synthesis process are avoided.

[0028] The raw materials used in the present invention are cheap and easily available, the generation of three wastes is less, it is green and environmentally friendly, no heavy - metal catalysts are used, the finished product will not cause drug safety risks due to heavy - metal over - standard, there is no high - temperature and high - pressure reaction, the reaction conditions are mild, the required equipment is simple, the operation is convenient, it has good controllability, and is suitable for large - scale industrial production. Description of the Drawings

[0029] Figure 1 It is the liquid - phase chromatogram of the intermediate dioxopromethazine oxalate in Example 1.

[0030] Figure 2 It is the liquid - phase chromatogram of the finished product dioxopromethazine hydrochloride in Example 1.

[0031] Figure 3 It is the liquid - phase chromatogram of the intermediate dioxopromethazine oxalate in Example 2.

[0032] Figure 4 It is the liquid - phase chromatogram of the finished product dioxopromethazine hydrochloride in Example 2. Detailed Embodiments

[0033] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention. Where the present invention is not described in detail is the prior art.

[0034] Example 1

[0035] Step 1: Synthesis of dioxopromethazine oxalate

[0036] Weigh 13.0 g of 2-chloro-N,N-dimethyl-1-propanamine hydrochloride, add 40.0 g of first purified water, stir until dissolved and clear, then use 40% sodium hydroxide solution to adjust the pH to 12, add 50.68 g of first toluene, stir for 30 min, let it stand for liquid separation, retain the toluene layer, add 10.0 g of anhydrous sodium sulfate to dry for 30 min, filter to obtain the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine;

[0037] Add 16.89 g of second toluene and 10.0 g of dioxophenothiazine to the reaction flask, stir, add 5.2 g of solid sodium hydroxide, add the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine, heat up to above 110 °C and reflux for 5 h, monitor the reaction by TLC until it is completed, cool down to 60 °C, add 50.0 g of second purified water, stir for 30 min, separate the liquid, retain the toluene layer, wash the toluene layer with 60 °C hot water 3 times, 50.0 g each time. After washing, concentrate the toluene layer to dryness, add 38.6 g of methanol, heat up to 60 °C, use 3.86 g of oxalic acid to adjust the pH to 3, keep stirring at this temperature for 30 min, cool down to 15 °C and crystallize for 1 h, filter, dry to obtain 10.05 g of dioxopromethazine oxalate, with a mass yield of 57.20%, an HPLC purity of 98.87%, and an isomer content of 0.61%.

[0038] Step 2: Synthesis of promethazine hydrochloride

[0039] Add 34.64 g of toluene and 50.0 g of purified water to a 250 ml reaction flask, stir and add 10.0 g of dioxopromethazine oxalate, use an aqueous sodium hydroxide solution to adjust the pH to 12, heat up to 60 °C and stir for 30 min, separate the liquid, retain the toluene layer, concentrate the toluene layer to dryness, add 31.6 g of acetone, add 0.5 g of activated carbon for decolorization, filter, transfer to another 250 ml reaction flask, heat up to 35 °C and introduce hydrochloric acid gas to adjust the pH to 4, stir for 1 h, cool down to 15 °C and continue stirring for 2 h, filter, and dry in vacuo at 50 °C for 8 h to obtain 6.62 g of promethazine hydrochloride, with a mass yield of 76.3%, an HPLC purity of 99.87%, and an isomer content of 0.13%.

[0040] Example 2

[0041] Step 1: Synthesis of dioxopromethazine oxalate

[0042] Weigh 130.0 g of 2-chloro-N,N-dimethyl-1-propanamine hydrochloride, add 500.0 g of first purified water, stir until dissolved and clear, then adjust the pH to 13 with 40% sodium hydroxide solution. Add 520.0 g of first toluene, stir for 30 min, let it stand for liquid separation, retain the toluene layer, add 75 g of anhydrous sodium sulfate to dry for 30 min, and filter to obtain the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine;

[0043] Add 200.0 g of second toluene and 100.0 g of dioxophenothiazine to the reaction flask, stir, add 67.45 g of solid sodium hydroxide and the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine, heat up to above 110 °C and reflux for 5 h. Monitor the reaction by TLC until it is completed, cool down to 60 °C, add 520.0 g of second purified water, stir for 30 min, separate the liquid, retain the toluene layer. Wash the toluene layer with hot water at 60 °C three times, 520.0 g each time. After washing, concentrate the toluene layer to dryness, add 514.47 g of methanol, heat up to 60 °C, adjust the pH to 4 with 50.60 g of oxalic acid, stir at this temperature for 30 min, cool down to 15 °C for crystallization for 1 h, filter, and dry to obtain 111.15 g of promethazine oxalate, with a mass yield of 56.33%, HPLC purity of 99.15%, and isomer content of 0.37%.

[0044] Step 2: Synthesis of promethazine hydrochloride

[0045] Add 366.2 g of toluene and 525.0 g of purified water to a 2000 ml reaction flask, stir and add 105.0 g of promethazine oxalate, adjust the pH to 12 with an aqueous sodium hydroxide solution, heat up to 60 °C and stir for 30 min, separate the liquid, retain the toluene layer. Concentrate the toluene layer to dryness, add 330.96 g of acetone, add 5.2 g of activated carbon for decolorization, filter, transfer to a 1000 ml reaction flask, heat up to 45 °C and pass in hydrochloric acid gas to adjust the pH to 4, stir for 1 h, cool down to 15 °C and continue to stir for 2 h, filter, and dry under vacuum at 50 °C for 8 h to obtain 69.26 g of promethazine hydrochloride, with a mass yield of 75.94%, HPLC purity of 99.91%, and isomer content of 0.04%.

[0046] Finally, it should be noted that the above-described embodiments are only specific implementation manners of the present invention, used to illustrate the technical solutions of the present invention, rather than limiting it. The protection scope of the present invention is not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that any technician familiar with the technical field of the present invention can still modify the technical solutions recorded in the foregoing embodiments, or can easily think of changes, or perform equivalent replacements on some of the technical features; and these modifications, changes or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be covered within the protection scope of the present invention.

Claims

1. A method for synthesizing dioxopromethazine hydrochloride with high purity, characterized in that, It includes the following steps: S1. Synthesis of dioxopromethazine oxalate: Add first purified water to 2-chloro-N,N-dimethyl-1-propanamine hydrochloride. After stirring until dissolved and clear, adjust the pH, add first toluene, stir, let stand for liquid separation, retain the toluene layer, dry, filter, and obtain the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine; Add second toluene and dioxophenothiazine to the reaction kettle, stir, add solid sodium hydroxide and the toluene solution of 2-chloro-N,N-dimethyl-1-propanamine, heat up to reflux for reaction. After the reaction is completed, cool down, add second purified water, stir, separate the liquid, retain the toluene layer, wash until neutral, concentrate to dryness, add a solvent, heat up, add acid to adjust the pH, stir while maintaining the temperature, cool down for crystallization, filter, dry, and obtain dioxopromethazine oxalate; S2. Synthesis of promethazine hydrochloride: Add toluene and purified water to the reaction kettle. Under stirring, add the dioxopromethazine oxalate prepared in step S1, adjust the pH, separate the liquid, retain the toluene layer, wash the toluene layer with water, concentrate to dryness, add acetone, decolorize, filter, transfer to a reaction flask, heat up, introduce hydrogen chloride gas to adjust the pH, stir, cool down and continue stirring, filter, and vacuum dry to obtain the finished product of promethazine hydrochloride.

2. The synthesis method of dioxopromethazine hydrochloride with high purity according to claim 1, wherein In step S1, the mass ratio of 2-chloro-N,N-dimethyl-1-propanamine hydrochloride, first purified water and first toluene is 1.0:(3.0 - 4.0):(3.5 - 5.5).

3. The synthesis method of high-purity dioxopromethazine hydrochloride according to claim 1, characterized in that, In step S1, the mass ratio of dioxophenothiazine, 2-chloro-N,N-dimethyl-1-propanamine hydrochloride and second toluene is 1.0:1.3:(1.0 - 2.0).

4. A method for synthesizing high-purity dioxopromethazine hydrochloride according to claim 1, characterized in that, In step S1, add 2-chloro-N,N-dimethyl-1-propanamine hydrochloride to first purified water. Under stirring, use sodium hydroxide with a mass concentration of 40% to adjust the pH to 12 - 14, add first toluene and stir for 30 min; add anhydrous sodium sulfate for drying for 0.5 h; Heat up to above 110 °C for reflux reaction for 4 h, cool down to 55 °C - 65 °C again, add second purified water, stir for 30 min; wash the toluene layer with hot water at 60 °C until neutral; Add the solvent methanol, heat up to 60 °C, add oxalic acid to adjust the pH to 3 - 4, stir at 60 °C for 30 min, cool down to 15 °C - 25 °C for crystallization for 1 - 2 h.

5. The synthesis method of dioxopromethazine hydrochloride of high purity according to claim 1, characterized in that, In step S2, the mass ratio of toluene, purified water, dioxopromethazine oxalate and acetone is (3.0 - 4.0):5.0:1.0:(3.0 - 4.0).

6. The synthetic method of dioxopromethazine hydrochloride with high purity according to claim 1, wherein, In step S2, use an aqueous solution of sodium hydroxide with a mass concentration of 40% to adjust the pH to 11 - 12; Add activated carbon to the acetone system for decolorization for 30 min; Heat up to 35 °C - 45 °C, introduce hydrogen chloride gas to adjust the pH to 3 - 4, stir for 1 h, cool down to 15 °C and continue stirring for 2 h, filter, and vacuum dry at 50 °C for 8 h.

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