A process for the preparation of tomoxetine hydrochloride

Abstract

This invention discloses a method for preparing atomoxetine hydrochloride. Specifically, it includes: (1) using compound I and compound II as raw materials, etherifying them to obtain compound III; (2) reacting compound III and a chiral resolving reagent solution in a microchannel reactor 1 to obtain compound IV; (3) reacting the filtrate from the previous step in a packed bed reactor to obtain a solution of compound III, which can be used to prepare compound IV in step (2); (4) converting compound IV prepared in step (2) into hydrochloride to obtain atomoxetine hydrochloride (compound V). The dextrorotatory isomer (compound VI) is repeatedly racemized and resolved using this method, increasing the theoretical yield from 50% to over 90%. Moreover, the racemate continuously generated in step (3) and the racemate obtained in step (1) can be processed simultaneously using a microchannel continuous reactor, avoiding the cumbersome process of multiple separate resolving processes, reducing equipment wear and shortening the production cycle.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for synthesizing atomoxetine hydrochloride. Background Technology

[0002] Atomoxetine hydrochloride, chemically known as ( R )-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride, with the following structural formula and molecular formula C 17 H 21 NO·HCl, molecular weight 291.82.

[0003]

[0004] Developed by Eli Lilly and Company, it was approved by the FDA in November 2002 for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. This product improves attention and behavioral control by selectively inhibiting the reuptake of norepinephrine and increasing the concentration of norepinephrine in the brain.

[0005] The following are the reported methods for synthesizing atomoxetine hydrochloride: US4314081 reports a route for the preparation of atomoxetine hydrochloride, using 3-chloro-1-phenylpropane as a starting material, via NBS bromination, substitution with sodium o-cresol, methylamine amination, and then salt formation with hydrochloric acid to obtain atomoxetine hydrochloride. US6541668 reports a synthetic route for atomoxetine, using 3-methylamino-1-phenylpropanol as a starting material, via substitution with o-fluorotoluene, chiral resolution, and salt formation to obtain atomoxetine hydrochloride. The resolution method has only a 50% theoretical yield, and the resolution solvent is a mixed solvent, which is not conducive to solvent recovery and poses a significant environmental hazard. Summary of the Invention

[0006] The purpose of this invention is to provide a more efficient and environmentally friendly method for preparing atomoxetine hydrochloride.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing atomoxetine hydrochloride includes the following steps: , X = F, Cl, Br, I, Starting with 3-methylamino-1-phenylpropanol (compound I) and 2-halotoluene (compound II), the reaction mixture of atomoxetine (compound III) was obtained by etherification. The reaction mixture was then extracted with solvent A to obtain material A. (2) Prepare material B by mixing chiral resolving agent with solvent B; feed material A and material B into microchannel reactor at 5~10℃ through their respective feed pumps, collect the reaction liquid, filter to obtain compound IV, and collect the filtrate for later use. (3) Concentrate the filtrate from the previous step, add solvent C to prepare material C, input material C into a packed bed reactor filled with ruthenium catalyst for racemic reaction, and connect the outflowing reaction liquid to the storage tank of material A for use in step (2). (4) The compound IV prepared in step (2) was dechiralized using a base and acid was added to obtain atomoxetine hydrochloride.

[0008] Further, the 2-halotoluene (compound II) used in step (1) is 2-fluorotoluene, 2-chlorotoluene, 2-bromotoluene or 2-iodotoluene, preferably 2-fluorotoluene.

[0009] Further, in step (1), the molar ratio of compound I to compound II is 1:(1.2~1.8), preferably 1:(1.4~1.6).

[0010] Furthermore, the reaction temperature in step (1) is 80~130℃, preferably 90~110℃.

[0011] Further, in step (1), solvent A is one or more of toluene, ethyl acetate and methyl tert-butyl ether in any proportion; the concentration of compound III in material A is 1.5~2.0 mol / L.

[0012] Further, in step (2), the chiral resolving agent is L-oxalic acid, L-mandelic acid or L-tartaric acid; the molar ratio of the chiral resolving agent to compound III is (1~1.5):1; solvent B is one or more of toluene, ethyl acetate and methyl tert-butyl ether in any proportion; the concentration of the chiral resolving agent in material B is 1.5~2.0 mol / L.

[0013] Furthermore, in step (2), the input flow rate of material A is 10~50 mL / min; the input flow rate of material B is 5~25 mL / min.

[0014] Further, in step (3), solvent C is one or more of toluene, ethyl acetate and methyl tert-butyl ether in any proportion; the concentration of compound VI in material C is 1.5~2.0 mol / L.

[0015] Furthermore, in step (3), the flow rate of material C is 5~20 mL / min.

[0016] Further, the alkali used in step (4) is one or more of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate in any proportion. When using it, the alkali is dissolved in water to prepare an alkali solution of 10-20 wt%, and the molar ratio of compound IV to the alkali is 1:(1.5-2).

[0017] Further, the acid used in step (4) is hydrogen chloride gas, hydrochloric acid methanol solution or hydrochloric acid ethanol solution, the HCl concentration in the hydrochloric acid methanol solution and hydrochloric acid ethanol solution is 20~50wt%, and the molar ratio of compound IV to HCl is 1:(1~1.1).

[0018] This invention utilizes a racemic-resolution technique for the dextrorotatory isomer (compound VI), which increases the theoretical yield during resolution from 50% to over 90%, significantly improving product yield. However, with each resolution cycle, the yield halves, resulting in large batch variations and demanding equipment requirements. Furthermore, the repetitive "racemic-resolution-crystallization-racemic" process greatly increases the workload. By introducing continuous production technology, compound III, converted in a packed-bed reactor, and the racemic mixture from the etherification reaction can be simultaneously resolved in a microchannel reactor, simplifying the operation and improving production efficiency. Moreover, continuous production equipment reduces solvent consumption, alleviates environmental pressure, and lowers labor and time costs. With increasingly stringent national safety and environmental protection requirements, continuous flow technology will inevitably find wider application in the pharmaceutical manufacturing field. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of a microchannel reactor; in the diagram, 1 / 2 is the storage tank; 3 / 4 is the metering pump; 5 is the microchannel reactor reaction unit; 6 is the temperature control system; and 7 / 8 is the reaction liquid receiving tank. Figure 2 This is a schematic diagram of a packed bed reactor; in the diagram, 9 is the storage tank; 10 is the metering pump; 11 is the fixed bed; and 12 is the catalyst. Figure 3 The HPLC chromatogram of atomoxetine hydrochloride prepared in Example 1 is shown below. Figure 4 The HPLC chromatogram of atomoxetine hydrochloride prepared in Example 2 is shown. Detailed Implementation

[0020] The microchannel reactors used in the following examples are as follows: Figure 1As shown, the system includes storage tank 1, storage tank 2, microchannel reactor reaction unit 5, temperature control system 6, reaction liquid receiving tank 7, and reaction liquid receiving tank 8. Storage tank 1 serves as the storage tank for material A; storage tank 2 serves as the storage tank for material B. Storage tanks 1 and 2 are connected to the inlet of microchannel reactor reaction unit 5 (specific dimensions: 25cm × 22cm × 5.5cm) via pipes. The outflow pipes of storage tanks 1 and 2 are equipped with flow metering pumps 3 and 4 corresponding to the two storage tanks. Microchannel reactor reaction unit 5 and temperature control system 6 are electrically connected. Reaction liquid receiving tanks 7 and 8 are connected in parallel via pipes to the outlet of microchannel reactor reaction unit 5.

[0021] The packed bed reactor is as follows Figure 2 As shown, the system includes a storage tank 9 and a fixed bed 11 (the fixed bed is a cylinder with a diameter of 16 mm and a height of 300 mm) connected by a pipeline; a flow metering pump 10 is installed on the pipeline between the storage tank 9 and the fixed bed 11; the fixed bed 11 is filled with a catalyst 12 [the catalyst 12 is specifically (chlorine (η) 5 -Pentamethylcyclopentadienyl)(1,3-dicyclohexylimidazol-2-ylidene)ruthenium(II), Cp*Ru(ICy)Cl, is a known reagent, described in the literature Bosson, J.; Nolan, SP The Journal of Organic Chemistry, 2010, 75, 2039-2043 and Baratta, W., et al. Journal of Organometallic Chemistry, 2000, 593-594, 489-493, with a catalyst packing height of 10 cm; the outlet of the fixed bed 11 is connected to the storage tank 1 of the microchannel reactor via a pipe. Example 1

[0022] Add 200.0 g (1.21 mol) of methylphenylpropanol, 500.0 g of dimethyl sulfoxide, and 3.6 mol of potassium hydroxide to a 1000 mL reaction flask. Stir at 110 °C for 30 min. Add 199.9 g (1.82 mol) of 2-fluorotoluene dropwise to the reaction system. Stir the reaction at 110 °C. Monitor the reaction for completion by TLC. Stop the reaction. Extract with 800 mL of ethyl acetate. Dry with anhydrous sodium sulfate (40.0 g) and filter to obtain material A.

[0023] Material A is transferred to storage tank 1 of the microchannel reactor for later use. L-mandelic acid (184.1 g; 1.21 mol) is added to ethyl acetate (800 mL), stirred and dissolved to prepare material B. Material B is transferred to storage tank 2 of the microchannel reactor for later use. Temperature control system 6 controls the temperature of reaction unit 5 of the microchannel reactor to 5~10℃. The flow rates of metering pumps 3 and 4 are adjusted, setting the flow rate of material A to 15.0 mL / min and the flow rate of material B to 6.8 mL / min. The reaction liquid flowing out of the reactor is collected in reaction liquid receiving tank 7. After collecting the reaction liquid for 10 min, reaction liquid receiving tank 7 is switched to reaction liquid receiving tank 8. The material in reaction liquid receiving tank 7 is filtered to obtain a filter cake (compound IV, molecular weight 407.15) of 55.2 g, which is set aside for later use. The filtrate is washed once with 50 mL of water, and the organic phase is concentrated under reduced pressure until no liquid flows out, leaving a residue of 29.5 g. 70 mL of ethyl acetate is added to the residue to prepare material C. Material C was transferred to tank 9 of the packed bed reactor. The flow rate of metering pump 10 was adjusted to 7.0 mL / min. The effluent from the packed bed reactor was then transferred to tank 1 of the microchannel reactor to continue participating in the reaction. Every 10 minutes, the effluent from the microchannel reactor was switched, and the reaction solution was treated as described above. After the microchannel reactor had been running continuously for 70 minutes, the remaining material in tank 1 was less than a batch, and the collection of the reaction solution was stopped. A total of 7 treatments were performed on the reaction material, yielding 365.5 g of wet compound IV, approximately 299.7 g dry, with a molar yield of approximately 62.0%.

[0024] Sodium hydroxide (50 g) was added to water (350 mL) and stirred to dissolve, preparing an alkaline solution. Compound IV (365.5 g) was added to the alkaline solution, stirred, extracted, and the aqueous phase was discarded. A 35 wt% hydrochloric acid-methanol solution (78.2 g) was added to the organic phase and stirred for 2 h; a large amount of solid precipitated, filtered, and dried under vacuum at 60 °C to constant weight, yielding 201.2 g of atomoxetine hydrochloride, with a molar yield of 57.0%. HPLC analysis of atomoxetine hydrochloride was performed. Figure 3 As shown, the purity is 99.93%. Example 2

[0025] Add 200.0 g of methylphenylpropanol (1.21 mol), 500.0 g of dimethyl sulfoxide, and 200.0 g of potassium hydroxide to a 1000 mL reaction flask. Stir at 110 °C for 30 min. Add 186.6 g of 2-fluorotoluene (1.69 mol) dropwise to the reaction system. Stir at 105 °C. Monitor the reaction for completion by TLC. Stop the reaction. Extract with 700 mL of methyl tert-butyl ether. Dry with anhydrous sodium sulfate (40.0 g) and filter to obtain material A.

[0026] Material A is transferred to storage tank 1 of the microchannel reactor for later use. L-mandelic acid (184.1 g; 1.21 mol) is added to methyl tert-butyl ether (700 mL), stirred and dissolved to prepare material B. Material B is transferred to storage tank 2 of the microchannel reactor for later use. Temperature control system 6 controls the temperature of reaction unit 5 of the microchannel reactor to 5~10℃. The flow rates of metering pumps 3 and 4 are adjusted, setting the flow rate of material A to 13.0 mL / min and the flow rate of material B to 5.8 mL / min. The reaction liquid flowing out of the reactor is collected in reaction liquid receiving tank 7. After collecting the reaction liquid for 10 min, reaction liquid receiving tank 7 is switched to reaction liquid receiving tank 8. The material in reaction liquid receiving tank 7 is filtered to obtain filter cake (compound IV) 54.8 g, which is reserved for later use. The filtrate is washed once with 50 mL of water, and the organic phase is concentrated under reduced pressure until no liquid flows out, leaving a residue of 29.7 g. 60 mL of methyl tert-butyl ether is added to the residue to prepare material C. Material C was transferred to tank 9 of the packed bed reactor. The flow rate of metering pump 10 was adjusted to 5.0 mL / min. The effluent from the packed bed reactor was then transferred to tank 1 of the microchannel reactor to continue the reaction. Every 10 minutes, the effluent from the microchannel reactor was switched and treated as described above. After the microchannel reactor had run continuously for 70 minutes, the remaining material in tank 1 was insufficient for one batch, and collection of the reaction solution was stopped. A total of 7 treatments were performed on the reaction material, yielding 362.5 g of wet compound IV, approximately 297.2 g dry, with a molar yield of approximately 60.3%.

[0027] Sodium hydroxide (50 g) was added to water (350 mL) and stirred to dissolve, preparing an alkaline solution. The wet product of compound IV (362.5 g) was added to the alkaline solution, stirred, extracted, and the aqueous phase was discarded. 35 wt% hydrochloric acid-ethanol (77.5 g) was added to the organic phase and stirred for 2 h; a large amount of solid precipitated, which was filtered and dried under vacuum at 60 °C to constant weight, yielding 198.8 g of atomoxetine hydrochloride, with a molar yield of 56.3%. HPLC analysis of atomoxetine hydrochloride was performed. Figure 4 As shown, the purity is 99.94%.

[0028] The present invention has been described in detail through the above embodiments. It should be noted that the molar yield in the embodiments is about 60% because the batch size affects the continuous reaction. Taking Example 1 as an example, the remaining residue after the mother liquor is concentrated is 84.2g. This part of the material can still be used in the racemic-resolution process, and complete conversion can increase the yield by more than 20%.

[0029] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be limited by the claims and their equivalents.

Claims

1. A method for preparing atomoxetine hydrochloride, characterized in that, Includes the following steps: ， X = F, Cl, Br, I, (1) Using compound I and compound II as starting materials, etherification reaction yields compound III, and solvent A is used to extract the reaction solution to obtain material A; (2) Prepare material B by mixing chiral resolving agent with solvent B. Input material A and material B into microchannel reactor at 5~10℃ through their respective feed pumps. Collect the reaction liquid, filter to obtain compound IV, and collect the filtrate for later use. (3) Concentrate the filtrate from step (2), add solvent C to prepare material C, input material C into a packed bed reactor filled with ruthenium catalyst for racemic reaction, and connect the outflowing reaction liquid to the storage tank of material A. (4) The compound IV prepared in step (2) was dechiralized using a base and acid was added to obtain atomoxetine hydrochloride.

2. The preparation method according to claim 1, characterized in that, In step (1), compound I and compound II undergo an etherification reaction in the presence of potassium hydroxide. The molar ratio of compound I, compound II and potassium hydroxide is 1:(1.2~1.8):(2.5~3.5). The reaction temperature in step (1) is 80~130℃.

3. The preparation method according to claim 1, characterized in that, In step (1), solvent A is one or more of toluene, ethyl acetate and methyl tert-butyl ether in any proportion; the concentration of compound III in material A is 1.5~2.0 mol / L.

4. The preparation method according to claim 1, characterized in that, In step (2), the chiral resolving agent is L-oxalic acid, L-mandelic acid or L-tartaric acid; solvent B is one or more of toluene, ethyl acetate and methyl tert-butyl ether in any proportion; the concentration of the chiral resolving agent in material B is 1.5~2.0 mol / L.

5. The preparation method according to claim 1, characterized in that, In step (2), the input flow rate of material A is 10~50 mL / min; the input flow rate of material B is 5~25 mL / min.

6. The preparation method according to claim 1, characterized in that, In step (3), solvent C is one or more of toluene, ethyl acetate and methyl tert-butyl ether in any proportion; the concentration of compound VI in material C is 1.5~2.0 mol / L.

7. The preparation method according to claim 1, characterized in that, In step (3), the flow rate of material C is 5~20 mL / min.

8. The preparation method according to claim 1, characterized in that, The alkali used in step (4) is a mixture of one or more of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate in any proportion. When using it, the alkali is dissolved in water to prepare an alkali solution of 10-20 wt%, and the molar ratio of compound IV to the alkali is 1:(1.5-2).

9. The preparation method according to claim 1, characterized in that, The acid used in step (4) is hydrogen chloride gas, hydrochloric acid methanol solution or hydrochloric acid ethanol solution. The HCl concentration in the hydrochloric acid methanol solution and hydrochloric acid ethanol solution is 20~50wt%, and the molar ratio of compound IV to HCl is 1:(1~1.1).

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