Preparation method of 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidylamine dihydrochloride

Abstract

The invention provides a preparation method of 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidylamine dihydrochloride, which comprises the following steps: taking a compound (III) as an initial raw material, generating a compound (IV) under the action of a reducing agent, reacting the compound (IV) with dimethyl sulfate to generate a compound (V), and salifying the compound (V) with hydrogen chloride gas to generate a compound (VI). The synthesis method disclosed by the invention is mild in reaction condition, simple and convenient in post-treatment procedure, high in production efficiency, high in product purity and yield, low in industrial production cost and capable of realizing industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride. Background Art

[0002] 4-Methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine is an important pharmaceutical intermediate used in the synthesis of sufentanil and the like. When prepared as a hydrochloride and stored, it has high stability.

[0003]

[0004] Patent document CN102127007A discloses a method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine:

[0005]

[0006] The above-mentioned process for synthesizing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine has the following problems:

[0007] (1) Using lithium aluminum hydride as a reducing agent results in many side reactions (such as decarboxylation and debenzylation), low product purity, and low yield;

[0008] (2) Using lithium aluminum hydride as a reducing agent has poor thermal stability, is flammable and explosive, and poses a great safety hazard;

[0009] (3) Tetrahydrofuran is used as the reaction solvent, and an extraction process is required in the post-processing. Not only is the post-processing procedure complicated, but it is also inconvenient to recycle and reuse the solvent.

[0010] In summary, developing a method for synthesizing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride with mild process conditions, simple operation procedures, few side reactions, high safety, and the ability to obtain high yield and high purity is a technical problem that needs to be solved urgently. Summary of the Invention

[0011] The present invention provides a method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride. The method uses red aluminum as a reducing agent and 2-methyltetrahydrofuran as a reaction solvent. This method reduces the occurrence of side reactions in the preparation method and improves the purity and yield of the product. Furthermore, the method eliminates the extraction process, simplifies the process, and facilitates solvent recovery and reuse, making it more suitable for industrial continuous production.

[0012] The present invention provides a method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride, which comprises the following steps:

[0013] Step 1: Compound (III) is subjected to reduction reaction with red aluminum in 2-methyltetrahydrofuran to obtain a mixed solution of compound (IV);

[0014]

[0015] Step 2: reacting the mixture of compound (IV) with dimethyl sulfate in the presence of potassium tert-butoxide to obtain a mixture of compound (V);

[0016]

[0017] Step 3: introducing hydrogen chloride gas into the mixed solution of compound (V) to generate compound (VI);

[0018]

[0019] In some embodiments, the reaction temperature of the reduction reaction in step 1 is 25°C to 90°C, preferably 50°C to 87°C, and more preferably 75°C to 85°C.

[0020] In one embodiment, the reaction temperature of the reduction reaction in step 1 is 80°C.

[0021] In some embodiments, the molar ratio of red aluminum to the compound (III) in step 1 is 2:1 to 6:1, preferably 3:1 to 5:1, and more preferably 3:1 to 3.5:1. In an exemplary embodiment, the molar ratio of red aluminum to the compound (III) in step 1 is 3.2:1 to 3.5:1; in another exemplary embodiment, the molar ratio of red aluminum to the compound (III) is 3.0:1; in another exemplary embodiment, the molar ratio of red aluminum to the compound (III) is 3.1:1; in another exemplary embodiment, the molar ratio of red aluminum to the compound (III) is 3.2:1; in another exemplary embodiment, the molar ratio of red aluminum to the compound (III) is 3.3:1; in yet another exemplary embodiment, the molar ratio of red aluminum to the compound (III) is 3.4:1; and in yet another exemplary embodiment, the molar ratio of red aluminum to the compound (III) is 3.5:1.

[0022] In other embodiments, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) in step 1 is 5:1 to 10:1, ml:g. In an exemplary embodiment, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 5:1 to 7:1, ml:g; in another exemplary embodiment, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 5:1, ml:g; in another exemplary embodiment, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 6:1, ml:g; in another exemplary embodiment, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 7:1, ml:g.

[0023] In other embodiments, the reaction time of the reduction reaction in step 1 is 1 hour to 12 hours; in an exemplary embodiment, the reaction time of the reduction reaction is 1.5 hours to 6 hours; in an exemplary embodiment, the reaction time of the reduction reaction is 1.8 hours to 4 hours; in an exemplary embodiment, the reaction time of the reduction reaction is 2 hours, 2.5 hours, 3 hours or 4 hours.

[0024] In other embodiments, the molar ratio of potassium tert-butoxide to the compound (IV) in step 2 is 2:1 to 3:1; in one exemplary embodiment, the molar ratio of potassium tert-butoxide to the compound (IV) is 2:1; in another exemplary embodiment, the molar ratio of potassium tert-butoxide to the compound (IV) is 3:1.

[0025] In other embodiments, the molar ratio of dimethyl sulfate to the compound (IV) in step 2 is 1.5:1 to 2:1; in an exemplary embodiment, the molar ratio of dimethyl sulfate to the compound (IV) is 1.6:1.

[0026] In other embodiments, the reaction temperature of the reaction in step 2, i.e., the methyl etherification reaction, is 10°C to 50°C; in an exemplary embodiment, the reaction temperature of the methyl etherification reaction is 20°C to 40°C; in an exemplary embodiment, the reaction temperature of the methyl etherification reaction is 30°C.

[0027] In other embodiments, the reaction time of the reaction in step 2, i.e., the methyl etherification reaction, is 1 to 5 hours; in one exemplary embodiment, the reaction time of the methyl etherification reaction is 2 to 5 hours; in one exemplary embodiment, the reaction time of the methyl etherification reaction is 2 hours.

[0028] Furthermore, the present invention provides a method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride, which comprises the following steps:

[0029]

[0030] Step 1: Compound (III) is subjected to a reduction reaction with red aluminum in 2-methyltetrahydrofuran to obtain a mixed solution of compound (IV);

[0031] Step 2: reacting the mixture of compound (IV) with dimethyl sulfate in the presence of potassium tert-butoxide to obtain a mixture of compound (V);

[0032] Step 3: introducing hydrogen chloride gas into the mixed solution of compound (V) to generate compound (VI);

[0033] in,

[0034] In step 1, the molar ratio of red aluminum to the compound (III) is 3.5:1; and / or

[0035] In step 1, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 10:1; and / or

[0036] In step 2, the molar ratio of potassium tert-butoxide to the compound (IV) is 3:1; and / or

[0037] In step 2, the molar ratio of dimethyl sulfate to the compound (IV) is 1.6:1.

[0038] In an exemplary embodiment, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) in step 1 is 10:1; the molar ratio of potassium tert-butoxide to the compound (IV) in step 2 is 3:1; and the molar ratio of dimethyl sulfate to the compound (IV) in step 2 is 1.6:1.

[0039] Compared with the prior art, the beneficial effects achieved by the present invention include: using red aluminum as a reducing agent and selecting 2-methyltetrahydrofuran as a reaction solvent, on the one hand, reducing side reactions and significantly improving product purity and yield; on the other hand, eliminating the extraction process and simplifying the process procedure, making it very suitable for large-scale industrial production.

[0040] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. Other advantages of the present application can be realized and obtained by the solutions described in the description and the drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The accompanying drawings are used to provide an understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application and do not constitute a limitation on the technical solution of the present application.

[0042] Figure 1HPLC chromatogram for determining the conversion rate of compound (III) in Example 6;

[0043] Figure 2 HPLC chromatogram for determining the conversion rate of compound (IV) in Example 6;

[0044] Figure 3 HPLC chromatogram for determining the purity of compound (V) in Example 6. DETAILED DESCRIPTION

[0045] The application will be further described in conjunction with the following examples, but is not limited thereto, any equivalent replacement in the art according to the disclosure of the application shall fall within the protection scope of the application.

[0046] The detection in the examples of the application is completed by high performance liquid chromatography, and the specific chromatographic conditions are as follows:

[0047] Chromatographic conditions for the reduction post control detection:

[0048] Chromatographic column: YMC Triart C18 (100 mm x 4.6 mm, 3 μm)

[0049] Mobile phase A: 5 g / L ammonium carbonate in tetrahydrofuran / water (10:90) (for reduction reaction determination); or 5 g / L ammonium carbonate in tetrahydrofuran / water (15:85) (for methanolysis reaction determination)

[0050] Mobile phase B: acetonitrile

[0051] Flow rate: 1.5 mL / min

[0052] Column temperature: 30°C

[0053] Injection volume: 20 μL

[0054] Detection wavelength: 220 nm

[0055] Elution gradient:

[0056] Time / min Mobile phase A % Mobile phase B % 0 90 10 15 40 60 20 40 60 25 90 10 30 90 10

[0057] Example 1: Experiment of different reducing agents and reaction solvents

[0058]

[0059] Weigh 6 portions of 10 g of compound (III) each and mix with 100 mL of reaction solvent. Control the temperature below 20°C and add the reducing agent dropwise to carry out the above-mentioned reduction reaction (for the 3rd, 6th, and 9th groups of experiments, N,N-carbonyldiimidazole-activated compound (III) must be added before adding the reducing agent to activate compound (III)). HPLC control detection is stopped until the reaction of compound (III) is completely completed (for the 7th and 8th groups of experiments, the solubility of compound (III) in toluene is very low. After overnight reaction, the detection shows that most of compound (III) still does not participate in the reaction). Then cool to room temperature, add 2M sodium hydroxide solution dropwise to quench the reaction, separate the liquids, and dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain compound (IV) (for the 1st to 3rd groups of experiments, separation is difficult after quenching, and ethyl acetate must be added for extraction before separation). The experimental data results are shown in the following table:

[0060]

[0061] Conclusion: (1) For the reducing agent, compared with the lithium aluminum hydride and sodium borohydride reducing agent system, the use of red aluminum as the reducing agent simplifies the operation procedure, significantly shortens the reaction time, and significantly improves the product purity and yield; (2) For the reaction solvent, the use of 2-methyltetrahydrofuran not only simplifies the process procedure, but also avoids the loss of the product in the post-processing procedure, improves the yield, and significantly improves the product purity. At the same time, the solvent is also easy to recycle and reuse.

[0062] Example 2

[0063]

[0064] Weigh 3 portions of 100g of compound (III) separately, add 1000mL of 2-methyltetrahydrofuran, add red aluminum (70wt% toluene solution) as a reducing agent dropwise below 20°C, and after the addition is complete, raise the temperature to 80°C and reflux to carry out the above reduction reaction. The test is stopped when the HPLC control test shows that all the reaction of compound (III) is complete. Cool to room temperature, add 2M sodium hydroxide solution dropwise to quench the reaction, separate the liquids, and dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain compound (IV). The following 4 groups of experiments were carried out respectively:

[0065] Group Red aluminum (70 wt% solution in toluene) Reaction time Yield Purity 1 134 mL 10h 94％ 97.63％ 2 268 mL 2h 94％ 98.11％ 3 286 mL 2h 98％ 98.77％ 4 313 mL 2h 100％ 99.76％ 5 447 mL 2h 100％ 99.79％

[0066] Conclusion: When the molar ratio of reduction and compound (III) is in the range of 3:1 to 3.5:1, the reaction time is shortened and the product yield and purity are significantly improved.

[0067] Example 3

[0068]

[0069] Three 10g portions of compound (III) were weighed and added to the reaction solvent, 2-methyltetrahydrofuran. 3.5eq of red aluminum (70wt% solution in toluene) was added dropwise at below 20°C. The mixture was heated and refluxed for 2h. HPLC control showed that compound (III) had fully reacted in the second and third experiments, while the first experiment showed that most of compound (III) had not reacted. The mixture was cooled to room temperature and quenched by the addition of 2M sodium hydroxide solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (IV).

[0070] Group 2-methyltetrahydrofuran Yield Purity 1 10 mL NA NA 2 50 mL 92％ 98.91％ 3 100 mL 100％ 99.72％

[0071] Conclusion: When the mass volume ratio of compound (III) to 2-methyltetrahydrofuran was 1:1 (g:ml), compound (III) had poor solubility in the solvent, low reaction efficiency, and low product yield and purity. At mass volume ratios of 1:5 and 1:10, compound (III) reacted completely within 2 hours, and the resulting product had comparable purity. Furthermore, the inventors discovered that when the mass volume ratio was 1:5, the reaction solution obtained after completion of the reaction became turbid, making separation difficult, and the yield of the resulting product was significantly lower than that obtained when the mass volume ratio was 1:10.

[0072] Example 4

[0073]

[0074] Three portions (10 g each) of compound (III) were weighed and added to each of them with 100 mL of 2-methyltetrahydrofuran. 3.5 eq (equivalent) of red aluminum (70 wt% in toluene) was added dropwise at a temperature below 20°C to carry out the above reduction reaction (reaction temperature and reaction time are as follows). HPLC analysis showed that compound (III) had fully reacted. The temperature was lowered to room temperature, and 2 M sodium hydroxide solution was added dropwise to quench the reaction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (IV).

[0075] Group Reaction temperature Reaction time Yield Purity 1 25℃ 10h 100％ 99.37％ 2 50℃ 4h 100％ 98.78％ 3 80℃ 2h 100％ 99.36％

[0076] Conclusion: Under the premise of ensuring experimental safety, during the reduction reaction of compound (III) under the action of reducing agent red aluminum, the higher the temperature, the higher the reaction efficiency and the shorter the time.

[0077] Example 5

[0078]

[0079] Weigh 4 portions of potassium tert-butoxide and add 500 mL of 2-methyltetrahydrofuran to each portion. Cool to 0-8°C, then dropwise add a mixed solution of 87.5 g of compound (IV) and 500 mL of 2-methyltetrahydrofuran. Stir at 30°C for 1 hour. Add 59.5 g of dimethyl sulfate dropwise, and react at 30°C until HPLC control indicates that compound (IV) has fully reacted. Stop the experiment. Add water dropwise to quench the reaction, separate the liquids, and dry, filter, and concentrate the organic phase to obtain compound (V).

[0080] Group Potassium tert-butoxide Reaction time Yield Purity 1 57g Overnight 85％ 85.73％ 2 75.6g 5h 97.5％ 95.12％ 3 114g 2h 98.7％ 95.69％ 4 152g 2h 90.2％ 75.12％

[0081] Conclusion: Under the same reaction conditions, when the molar ratio of potassium tert-butoxide to compound (IV) is in the range of 2:1 to 3:1, the reaction efficiency is higher, and the product purity and yield are also significantly improved.

[0082] Example 6 Synthesis of 4-(methoxymethyl)-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride (Compound (VI))

[0083] Synthesis of 4-(anilino)-1-(phenylmethyl)-4-piperidinol (Compound (IV))

[0084]

[0085] 1.0 kg of compound (III) and 10 L of 2-methyltetrahydrofuran were added to a reactor and stirred. The temperature in the reactor was controlled at 0-20 ° C. 3.3 kg of red aluminum (70 wt% toluene solution) was weighed and added to a dropping bottle. The red aluminum solution was added dropwise, and the internal temperature was controlled at 10-30 ° C. After the addition was completed, the temperature was raised to 80 ° C for reflux reaction. The HPLC control test was performed until the reaction of compound (III) was completed. The total reaction time was 2 h. The temperature was lowered to room temperature, 2 M sodium hydroxide solution was added dropwise for quenching, and the solution of compound (IV) was obtained by separation, drying over anhydrous sodium sulfate, and filtration for the next reaction.

[0086] Synthesis of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine (Compound (V))

[0087]

[0088] 5 L of 2-methyltetrahydrofuran and 0.725 kg of potassium tert-butoxide were added to a reaction kettle and stirred. The temperature of the liquid was controlled at 0-10°C. The compound (IV) solution obtained above was then added to the reaction kettle with stirring. After the addition, the internal temperature was controlled at 30°C and stirred for 1 hour. 651 g of dimethyl sulfate was weighed and added to the reaction kettle with stirring. The reaction was terminated by HPLC monitoring until the complete reaction of compound (IV) was complete. The total reaction time was 2 hours. Purified water was then added to quench the reaction. The solution was separated, dried, and filtered to obtain a compound (V) solution, which was used directly in the next reaction.

[0089] Synthesis of 4-(Methoxymethyl)-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride (Compound (VI))

[0090]

[0091] 11L of the compound (V) solution obtained in the previous step was added to the reactor and stirred. The temperature in the reactor was lowered to 5°C to 15°C for reaction. The cylinder was opened and hydrogen chloride gas was introduced for 40 minutes. The pH of the reaction solution was measured to be <2. The cylinder was closed and nitrogen gas was switched. Stirring was continued for 0.5 hours, and the pH of the solution was re-measured to be <2. Stirring was continued for 1 hour. After the reaction was completed, the filter cake was washed with ethanol and then placed in a hot 60 mbar vacuum drying oven at 55-65°C under reduced pressure to obtain compound (VI) (purity: 99.77%, total yield: 75%).

[0092] Example 7 Three batches of confirmation test

[0093] Three batches of compound (VI) 4-(methoxymethyl)-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride obtained by the synthesis method of Example 6 were weighed and tested for related substances, residual solvents, purity, etc. The test results are shown in Table 1 below.

[0094] Table 1. Three batches of validation experimental data

[0095]

[0096] Conclusion: From the test data in Table 1, it can be seen that the related substances and residual solvents of 4-(methoxymethyl)-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride obtained by the preparation method of the present invention do not exceed the standard and the purity is also high.

[0097] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride, characterized in that: The preparation method comprises the following steps: Step 1: Compound (III) is subjected to a reduction reaction with red aluminum in 2-methyltetrahydrofuran to obtain a mixed solution of compound (IV); Step 2: reacting the mixture of compound (IV) with dimethyl sulfate in the presence of potassium tert-butoxide to obtain a mixture of compound (V); Step 3: Add hydrogen chloride gas to the mixture of compound (V) to generate compound (VI) 2. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to claim 1, wherein In step 1, the molar ratio of red aluminum to the compound (III) is 2:1 to 6:1, preferably 3:1 to 5:1, more preferably 3:1 to 3.5:1, or 3.0:1, 3.1:1, 3.2:1, 3.3:1, 3.4:1 or 3.5:

1.

3. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to claim 1, wherein In step 1, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 5:1 to 10:1, ml:g, or 5:1, 6:1, 7:1, 8:1, 9:1 or 10:

1.

4. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to claim 1, wherein The reaction temperature of the reduction reaction in step 1 is 25°C to 90°C, preferably 50°C to 87°C, more preferably 75°C to 85°C, or 80°C.

5. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to claim 1, wherein The reaction time of the reduction reaction in step 1 is 1 to 12 hours, preferably 1.5 to 6 hours, more preferably 1.8 to 4 hours, or 2 hours, 2.5 hours, 3 hours or 4 hours.

6. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to any one of claims 1 to 5, characterized in that: In step 2, the molar ratio of potassium tert-butoxide to the compound (IV) is 2:1 to 3:

1.

7. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to any one of claims 1 to 5, characterized in that: The molar ratio of dimethyl sulfate to the compound (IV) is 1.5:1 to 2:

1.

8. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to any one of claims 1 to 5, characterized in that: The reaction temperature of the reaction in step 2 is 10°C to 50°C, preferably 20°C to 40°C, more preferably 30°C; and / or the reaction time of the reaction in step 2 is 1 to 5 hours, preferably 2-5 hours, more preferably 2 hours.

9. A method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride, characterized in that: The preparation method comprises the following steps: Step 1: Compound (III) is subjected to reduction reaction with red aluminum in 2-methyltetrahydrofuran to obtain a mixed solution of compound (IV); Step 2: reacting the mixture of compound (IV) with dimethyl sulfate in the presence of potassium tert-butoxide to obtain a mixture of compound (V); Step 3: introducing hydrogen chloride gas into the mixed solution of compound (V) to generate compound (VI); in, In step 1, the molar ratio of red aluminum to the compound (III) is 3.5:1; and / or In step 1, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 10:1; and / or In step 2, the molar ratio of potassium tert-butoxide to the compound (IV) is 3:1; and / or In step 2, the molar ratio of dimethyl sulfate to the compound (IV) is 1.6:

1.

10. The method for preparing 4-methoxymethyl-N-phenyl-1-benzyl-4-piperidinamine dihydrochloride according to claim 9, characterized in that: In step 1, the molar ratio of red aluminum to the compound (III) is 3.5:1; In step 1, the volume mass ratio of 2-methyltetrahydrofuran to the compound (III) is 10:1; In step 2, the molar ratio of potassium tert-butoxide to the compound (IV) is 3:1; and In step 2, the molar ratio of dimethyl sulfate to the compound (IV) is 1.6:1.

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