Preparation method of viloxazine or hydrochloride thereof

Abstract

The invention discloses a preparation method of viloxazine or hydrochloride thereof, which comprises the following steps: removing benzyl from N-benzyl viloxazine to obtain viloxazine, and treating the N-benzyl viloxazine with 1-chloroethyl chloroformate to obtain the viloxazine hydrochloride. And reacting in a protic solvent to obtain the viloxazine or carrying out catalytic hydrogenation on the N-benzyl by using palladium hydroxide / carbon to obtain the viloxazine. The preparation method provided by the invention has the advantages of no catalyst poisoning phenomenon, high yield and good product purity.

Description

Technical Field

[0001] The present invention relates to a preparation method of viloxazine or its hydrochloride, and belongs to the field of pharmaceutical chemical industry. Background Art

[0002] Viloxazine sustained-release capsules are used to treat attention deficit hyperactivity disorder (ADHD) in pediatric patients aged 6-17 years. The active ingredient is viloxazine hydrochloride. The structural formula of viloxazine is shown below in Formula I:

[0003]

[0004] EP2558437B1 discloses a method for preparing viloxazine hydrochloride, comprising reacting compound A with compound B to obtain intermediate C, performing a ring-closure reaction on intermediate C to obtain N-benzylviloxazine represented by compound D, and finally removing the benzyl group by palladium-carbon reduction in the presence of hydrochloric acid to obtain viloxazine hydrochloride. The synthetic route is as follows:

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a method for preparing viloxazine or its hydrochloride, comprising removing the benzyl group from N-benzylviloxazine represented by formula D to obtain viloxazine represented by formula I, and optionally further converting it into a hydrochloride; wherein the structural formulas of N-benzylviloxazine and viloxazine are shown in formula D and formula I, respectively:

[0007]

[0008] It is characterized in that the debenzylation is selected from the following method a or method b:

[0009] Method a: Compound D is treated with 1-chloroethyl chloroformate to obtain Compound E, and Compound E is reacted in a protic solvent to obtain Viloxazine;

[0010]

[0011] Method b: Compound D is catalytically hydrogenated with palladium hydroxide / carbon to obtain viloxazine.

[0012] Furthermore, the compound represented by formula D can be obtained by referring to the method of EP2558437B1, comprising: reacting compound A with compound B to obtain intermediate C, and subjecting intermediate C to a ring-closure reaction to obtain N-benzylviloxazine represented by formula D. The synthetic route of the compound represented by formula D is as follows:

[0013]

[0014] The reaction conditions of method a can be described as follows:

[0015] The treatment of Compound D with 1-chloroethyl chloroformate to produce Compound E is preferably carried out in an aromatic hydrocarbon or halogenated hydrocarbon solvent, such as toluene, xylene, dichloromethane, or dichloroethane; more preferably toluene or xylene. The amount of solvent used is 5-20 ml / g relative to Compound D. The amount of solvent used in this step has little effect on the reaction yield.

[0016] The molar ratio of compound D to 1-chloroethyl chloroformate is 1:1-1:3, preferably 1:2-1:3.

[0017] The reaction temperature from Compound D to Compound E can be the reflux temperature of the solvent or below. When a chlorinated hydrocarbon is used, the reaction can be carried out at 0°C, room temperature, or reflux temperature. When an aromatic hydrocarbon is used, the reaction can be carried out at 50-110°C, for example, at 110°C.

[0018] The reaction time from compound D to compound E can be 2 h to 20 h. The conversion of compound D can be monitored by spot plate or HPLC. The reaction is usually complete in 2.5 h to 12 h. After the reaction is completed, the reaction solution is preferably concentrated to remove most of the solvent to obtain compound E.

[0019] Compound E can be converted to viloxazine by stirring in the presence of a protic solvent. The reaction temperature can be smoothly carried out at 0-55°C, preferably at 20-55°C.

[0020] According to one embodiment of the present invention, the protic solvent is an alcohol, preferably methanol. The amount of the solvent used is 3-10 ml / g, preferably 5-10 ml / g, relative to compound D.

[0021] The time for converting Compound E to viloxazine is usually 1-20 hours, and usually the conversion is complete in 1-2 hours.

[0022] The conditions of method b are as follows:

[0023] Compound D is catalytically hydrogenated with palladium hydroxide / carbon to obtain viloxazine. According to a specific embodiment of the present invention, the catalytic hydrogenation is carried out in a mixed solution of a lower alcohol and water, more preferably in a mixed solvent of ethanol and water. The volume ratio of the lower alcohol to water is 1:1-10:1, preferably 1:1-3:1. The amount of the solvent used for compound D is 3-20 ml / g, preferably 5-12 ml / g.

[0024] According to a specific embodiment of the present invention, the hydrogenation reaction temperature from compound D to viloxazine in method b is 20-80°C, more preferably 20-60°C;

[0025] According to a specific embodiment of the present invention, the hydrogenation reaction time from compound D to viloxazine in method b is 2-24 hours, more preferably 17-24 hours.

[0026] According to a specific embodiment of the present invention, the hydrogenation reaction pressure from compound D to viloxazine in method b is 0.1-2 MPa, more preferably 0.5 MPa-1 MPa.

[0027] According to a specific embodiment of the present invention, the feeding amount of palladium hydroxide / carbon is 1%-15% of the weight of compound D, preferably 3%-8%, for example 5%.

[0028] Method b: After the reaction is completed, the catalyst is removed by filtration, and the filtrate is concentrated to obtain viloxazine.

[0029] Once the reaction converts to viloxazine, the free base can be converted to the HCl salt using hydrochloric acid and a suitable solvent system. For example, the method disclosed in EP2558437B1 can be used, or according to a specific embodiment of the present invention, hydrochloric acid / isopropanol can be added to form the salt. Recrystallization can then be performed in an isopropanol / water / ethyl acetate (2:1:4) system, or crystallization can be performed in a primarily methanol solution to achieve better purification results.

[0030] According to the method of the present invention, the prepared viloxazine or its hydrochloride contains less than 0.1% of the morpholine hydrolysis impurity represented by formula II.

[0031]

[0032] In the present invention, when viloxazine is prepared, the morpholine hydrolysis impurities exist in the form of free base; when viloxazine hydrochloride is prepared, the morpholine hydrolysis impurities exist in the form of hydrochloride of morpholine hydrolysis impurities.

[0033] Another aspect of the present invention is to provide viloxazine or its hydrochloride, wherein the morpholine hydrolysis impurity represented by formula II is less than 0.1%.

[0034] The inventors found that during the experiment, the method for preparing viloxazine hydrochloride with reference to EP2558437B1 was used. When repeatedly attempting to debenzylate N-benzylviloxazine using Pd / C catalytic hydrogenation, the debenzylation of N-benzylviloxazine was very easy, even when using Pd / C of different specifications, and the product yield was no more than 60%. If one wants to improve the conversion rate, this can only be achieved by continuously replenishing fresh Pd / C, which is obviously economically unfeasible. The method for preparing viloxazine by debenzylation of N-benzylviloxazine provided by the present invention avoids the catalyst poisoning phenomenon, has a high product yield, and avoids the generation of impurities by hydrolysis and ring opening under acidic high temperature conditions, resulting in a high product purity. DETAILED DESCRIPTION

[0035] In order to more fully understand the present invention, the following specific examples are given, but the present invention is not limited to the following examples.

[0036] The detection conditions used in the present invention are as follows:

[0037] Viloxazine related substances and content analysis methods

[0038] This method uses reversed-phase high-performance liquid chromatography equipped with a UV detector and detection at 220 nm.

[0039] Diluent: H2O:acetonitrile = 95:5;

[0040] Blank solution: diluent;

[0041] Working reference solution: Prepare a working standard solution containing 2.0 mg / mL of viloxazine hydrochloride using diluent.

[0042] Preparation of test solution: Prepare a test solution containing 2.0 mg / mL of viloxazine hydrochloride with diluent;

[0043] Chromatographic conditions:

[0044] Instrument: High performance liquid chromatography equipped with UV and mass spectrometry detectors

[0045] Chromatographic column: ACE-Excel 3CN-ES 4.6*150mm

[0046] Aqueous mobile phase: 1.0 mL trifluoroacetic acid dissolved in 1000 mL water

[0047] Organic mobile phase: 1.0 m trifluoroacetic acid dissolved in 850 mL acetonitrile and 150 mL methanol

[0048] Detection wavelength: 220nm

[0049] Flow rate: 1.0 mL / min

[0050] Injection volume: 5 μL

[0051] Column temperature: 40°C

[0052] Collection time: 35

[0053] gradient:

[0054] Time (min) Aqueous mobile phase Organic mobile phase 0 95 5 30 30 70 35 30 70 35.1 95 5 43 95 5

[0055] In the following examples, impurities and purity were calculated based on peak area normalization.

[0056] Preparation Example: Preparation of Compound D

[0057] The compound was prepared with reference to Example 17 of EP2558437B1. The synthetic route is as follows:

[0058]

[0059] Example 1:

[0060] Add 3 g of compound D (1.0 eq) to a 100 mL reaction flask and add 30 mL of toluene, stir and dissolve. Heat to 110°C, add 3.93 g of 1-chloroethyl chloroformate (3.0 eq), react at 110°C for 2.5 h, monitor the complete conversion of D, and concentrate at 50°C. The obtained oil was added with 30 mL of methanol and stirred at 55 ° C for 1 h. The intermediate state was monitored to be completely converted into viloxazine, and the hydrolysis impurity of morpholine shown in Formula II was <0.1%. The mixture was cooled to room temperature, 1 eq 4 mol / L hydrochloric acid isopropanol solution was added, stirred for 10 min, and concentrated to obtain an oil. 12.6 mL of isopropanol and 2.6 mL of water were added, and the temperature was raised to 80 ° C to dissolve the system. The temperature was then lowered to 50 ° C and 22 mL of ethyl acetate was added. After the addition was completed, the temperature was lowered to 0 ° C and stirred for 5 h. Filtered, rinsed with ethyl acetate, and the filter cake was dried at 45 ° C to obtain 2.3 g of white viloxazine hydrochloride solid, the hydrolysis impurity of morpholine shown in Formula II was <0.1%, the purity was 99.8%, and the yield was 91.7%.

[0061] Example 2:

[0062] 3g of compound D (1.0eq) was added to a 100mL reaction flask and 30mL of toluene was added and stirred to dissolve. The temperature was raised to 110°C, 3.93g of 1-chloroethyl chloroformate (3.0eq) was added, and the reaction was continued at 110°C for 2.5h. The conversion of D was monitored to be complete, and the mixture was concentrated at 50°C. The resulting oil was added with 30mL of methanol and stirred at 20°C for 2h. The intermediate was monitored for complete conversion to viloxazine, and the morpholine hydrolysis impurity of Formula II was <0.1%. 1eq of 4mol / L hydrochloric acid in isopropanol was added, the mixture was cooled to 0°C, stirred for 5h, filtered, rinsed with ethyl acetate, and the filter cake was dried at 45°C to obtain 2.2g of a white viloxazine hydrochloride solid. The morpholine hydrolysis impurity of Formula II was <0.1%, with a purity of 99.8% and a yield of 87.7%.

[0063] Example 3:

[0064] 3 g of compound D (1.0 eq) was added to a hydrogenation kettle, 33 mL of ethanol, 15 mL of water, and 150 mg of palladium hydroxide / carbon (10%) were added. Hydrogen was passed to a pressure of 0.5 MPa and the reaction was carried out at 60° C. for 17 h. The reaction was monitored by HPLC to be complete. The morpholine hydrolysis impurity shown in Formula II was 0.5%. After filtration, 1 eq of 4M isopropanol / hydrochloric acid was added, and the filtrate was concentrated to obtain 2 g of an oily substance. 12.6 mL of isopropanol and 2.6 mL of water were added and the temperature was raised until the system became clear. The temperature was then lowered to 50° C. and 22 mL of ethyl acetate was added. After the addition was complete, the temperature was lowered to 0° C. and stirred for 5 h. The mixture was filtered and washed with ethyl acetate. The filter cake was dried at 45° C. to obtain 1.93 g of a white viloxazine hydrochloride solid. The morpholine hydrolysis impurity shown in Formula II was <0.1%, with a purity of 99.8% and a yield of 76.9%.

[0065] Example 4:

[0066] 3 g of compound D (1.0 eq) was added to a hydrogenation kettle, 33 mL of ethanol, 30 mL of water, 150 mg of palladium hydroxide / carbon (10%) was added, hydrogen was passed to 1 MPa, and the reaction was carried out at 20 ° C for 24 h. The reaction was monitored by HPLC to be complete. The morpholine hydrolysis impurity shown in Formula II was 0.3%. After filtration, 1 eq of 4M isopropanol / hydrochloric acid was added, and the filtrate was concentrated to obtain 2 g of an oily substance. 12.6 mL of isopropanol and 2.6 mL of water were added and the temperature was raised. The system was dissolved and clear. The temperature was then lowered to 50 ° C and 22 mL of ethyl acetate was added. After the addition was completed, the temperature was lowered to 0 ° C and stirred for 5 h. Filtered, washed with ethyl acetate, and the filter cake was dried at 45 ° C to obtain 1.87 g of a white viloxazine hydrochloride solid. The morpholine hydrolysis impurity shown in Formula II was <0.1%, the purity was 99.8%, and the yield was 74.6%.

[0067] Comparative Example 1: Reference EP2558437B1 Example 18

[0068] 3 g of compound D (1.0 eq) was added to a hydrogenation kettle, and 6.3 mL of ethanol, 2.94 mL of water, 2.94 mL of concentrated hydrochloric acid, and 150 mg of palladium / carbon were added. Hydrogen was passed to 0.5 MPa and the reaction was carried out at 60° C. for 18 h. HPLC monitoring showed that the remaining reaction D was 58% and the reaction was no longer continued. At the same time, 10% of the morpholine hydrolysis impurity represented by formula II was produced.

Claims

1. A method for preparing viloxazine or its hydrochloride, comprising removing the benzyl group from N-benzylviloxazine represented by D to obtain viloxazine represented by Formula I, and optionally further converting it into a hydrochloride; wherein the structural formulas of N-benzylviloxazine and viloxazine are shown in D and I respectively: It is characterized by The debenzylation is selected from the following method a or method b: Method a: Compound D is treated with 1-chloroethyl chloroformate to obtain Compound E, and Compound E is reacted in a protic solvent to obtain Viloxazine; Method b: Compound D is catalytically hydrogenated with palladium hydroxide / carbon to obtain viloxazine.

2. The method according to claim 1, characterized in that The method a is carried out in an aromatic hydrocarbon or halogenated hydrocarbon solvent, preferably toluene, xylene, dichloromethane or dichloroethane.

3. The method according to claim 1, wherein the molar ratio of compound D to 1-chloroethyl chloroformate is 1:1-1:3, preferably 1:2-1:

3.

4. The method according to claim 2, wherein the reaction solvent is an aromatic hydrocarbon, and the reaction temperature from D to E is in the range of 50-110°C, and the reaction time is 2.5h-12h.

5. The method according to claim 1, wherein the protic solvent is an alcohol solvent, preferably methanol.

6. The method according to claim 1, wherein the reaction temperature from E to viloxazine is 0-55°C, preferably 20-55°C.

7. The method according to claim 1, wherein method b is carried out in a mixed solution of lower alcohol and water, more preferably in a mixed solvent of ethanol and water.

8. method according to claim 7, the volume ratio of described lower alcohol and water is 1:1-10:1, preferably 1:1-3:

1.

9. The method according to claim 1, wherein the hydrogenation reaction temperature from compound D to viloxazine in method b is 20-80°C, more preferably 20-60°C; the reaction time is 2-24h, more preferably 17-24h; the hydrogenation reaction pressure is 0.1-2Mpa, more preferably 0.5Mpa-1Mpa; and the amount of palladium hydroxide / carbon added is 1%-15% by weight of compound D, preferably 3%-8%.

10. The method according to claim 1, wherein the synthetic route of compound D is as follows:

11. The method according to any one of claims 1 to 10, wherein the viloxazine or its hydrochloride prepared by the method contains less than 0.1% of the morpholine hydrolysis impurity represented by formula II.

12. Viloxazine or its hydrochloride, characterized in that The content of the hydrolyzed morpholine impurity represented by formula II is less than 0.1%.

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