Synthesis method of eslicarbazepine acetate chiral intermediate

Abstract

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of an eslicarbazepine acetate chiral intermediate, which comprises the following steps: complexing a metal precursor and a ligand f-phamidol to prepare a catalyst, and carrying out asymmetric hydrogenation on 5, 11-dihydro-10H-dibenzo [b, f] azacycloheptane-10-ketone by using the catalyst in a reaction system of alkali and an organic solvent to obtain the eslicarbazepine acetate chiral intermediate. The method has the characteristics of low catalyst loading capacity, high conversion rate and high selectivity, the eslicarbazepine acetate chiral intermediate prepared by using the method can obtain a good effect under the condition of low catalyst dosage, and also can obtain a good effect in expanded pilot scale production, and the method which is green, environment-friendly, high in atom economy and high in selectivity is developed by using the method to prepare the eslicarbazepine acetate chiral intermediate. The invention relates to a preparation method of an S-eslicarbazepine acetate bulk drug intermediate with high market competitiveness.

Description

Technical Field

[0001] The invention relates to the field of organic chemistry and specifically discloses a method for synthesizing a chiral intermediate of eslicarbazepine acetate. Background Art

[0002] The first prior art method is to use 5,11-dihydro-10H-dibenzo[b,f]azepine f-10-one as a raw material and adopt an asymmetric hydrogenation method to synthesize (S)-10,11-dihydro-5H-dibenzo[b,f]azepine-10-ol. Although it is simple, green and pollution-free, the amount of catalyst used in this method is still relatively high, and the precious metal iridium is used as the complex metal. The catalyst accounts for a relatively high proportion in the production cost. Only a small-scale test of gram level has been carried out, and the catalytic effect after the pilot test cannot be evaluated. In addition, the advantage in market competition is not obvious.

[0003] The second prior art method is to use oxcarbazepine as a raw material and adopt a transfer hydrogenation method to synthesize S-licarbazepine. The steps are short, the conditions are mild, and the chemical purity and optical purity of the product are high. However, the raw material oxcarbazepine is expensive, and the amount of transfer hydrogenation catalyst is higher than that of asymmetric hydrogenation. The residual level of ruthenium metal in the product will be high and difficult to remove, which is not suitable for use as an active pharmaceutical ingredient (API). In addition, transfer hydrogenation will use a large amount of triethylamine and formic acid, and more three wastes will be produced, the atom economy is low, and there is a potential risk of explosion. In view of the good drug prospects of licarbazepine, it is necessary to develop a catalyst with good selectivity, low catalyst dosage, high reaction conversion rate, green environmental protection, and high atom economy to synthesize licarbazepine. Summary of the invention

[0004] In view of the problems existing in the prior art, the first aspect of the present invention provides a method for synthesizing a chiral intermediate of eslicarbazepine acetate, characterized in that it comprises:

[0005] Compound AK-1 is mixed with a catalyst, a base, and an organic solvent to form a reaction system, and pressurized under a hydrogen atmosphere to obtain compound AK-2.

[0006] The reaction formula is as follows:

[0007]

[0008] The catalyst is obtained by complexing the ligand f-phamidol with a transition metal precursor, and the ligand structural formula of the catalyst is:

[0009]

[0010] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0011] In a specific embodiment of the first aspect of the present invention, the base is selected from Lewis bases.

[0012] In a specific embodiment of the first aspect of the present invention, the organic solvent is selected from one of alcohol, DCM, PhMe, CHCl3, THF, DCE or a mixture thereof.

[0013] In a specific embodiment of the first aspect of the present invention, the organic solvent is selected from alcohol selected from methanol, ethanol, isopropanol or a combination thereof.

[0014] In a specific embodiment of the first aspect of the present invention, the base is selected from an organic base or an inorganic base.

[0015] In a specific embodiment of the first aspect of the present invention, the base is selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium phosphate.

[0016] In a specific embodiment of the first aspect of the present invention, the metal precursor is selected from one or a combination of [Ir(NBD)Cl]2, [Ir(COD)Cl]2, and [Ir(C2H4)2Cl]2.

[0017] In a specific embodiment of the first aspect of the present invention, the hydrogen pressure is greater than 2 MPa, in some embodiments the hydrogen pressure is 3 MPa, in some embodiments the hydrogen pressure is 4 MPa, in some embodiments the hydrogen pressure is 5 MPa, and in some embodiments the hydrogen pressure is 6 MPa.

[0018] In a specific embodiment of the first aspect of the present invention, the reaction temperature is greater than 25°C, in some embodiments the reaction temperature is 30°C, in some embodiments the reaction temperature is 35°C, in some embodiments the reaction temperature is 40°C, and in some embodiments the reaction temperature is 45°C.

[0019] In a specific embodiment of the first aspect of the present invention, the reaction temperature is greater than 25-75° C., and the hydrogen pressure is 2-6 MPa.

[0020] In a specific embodiment of the first aspect of the present invention, the molar ratio of the substrate AK-1 to the catalyst is 7500 to 100000. In some embodiments, the molar ratio of the substrate AK-1 to the catalyst is 7500. In some embodiments, the molar ratio of the substrate AK-1 to the catalyst is 10000. In some embodiments, the molar ratio of the substrate AK-1 to the catalyst is 20000. In some embodiments, the molar ratio of the substrate AK-1 to the catalyst is 40000. In some embodiments, the molar ratio of the substrate AK-1 to the catalyst is 60000. In some embodiments, the molar ratio of the substrate AK-1 to the catalyst is 100000.

[0021] In a specific embodiment of the first aspect of the present invention, the molar ratio of the base to the compound AK-1 is 1:

[0022] (10-25), in some embodiments, the molar ratio of the base to the compound AK-1 is 1:15, in some embodiments, the molar ratio of the base to the compound AK-1 is 1:20, and in some embodiments, the molar ratio of the base to the compound AK-1 is 1:25.

[0023] In a specific embodiment of the first aspect of the present invention, the volume ratio of the organic solvent to compound AK-1 is (5-10):1. In some embodiments, the volume ratio of the organic solvent to compound AK-1 is 5.0:1. In some embodiments, the volume ratio of the organic solvent to compound AK-1 is 7.5:1. In some embodiments, the volume ratio of the organic solvent to compound AK-1 is 10.0:1.

[0024] In a specific embodiment of the first aspect of the present invention, the catalyst is synthesized in situ in the reaction system.

[0025] In the present invention, 1 mol of the catalyst is configured as follows: 1 mol of the metal precursor (e.g. [Ir(COD)Cl]2,

[0026] [Ir(NBD)Cl]2, [Ir(C2H4)2Cl]2) and 2.1 mol of a ligand (f-phamidol, any one of L1 to L6) are mixed in an organic solvent (eg isopropanol) to obtain 2 mol of a catalyst.

[0027] In some embodiments of the present invention, the room temperature is 40-10°C, in some embodiments the room temperature is 15-35°C, in some embodiments the room temperature is 20-30°C, and in some embodiments the room temperature is 25°C.

[0028] In the present invention, S / C (substrate / catalyst ratio) is the ratio of the molar amount of substrate AK-1 to the molar amount of catalyst.

[0029] The reagents used in the embodiments of the present invention were purchased from Xilong, Aladdin, Sinopharm Shanghai Test, etc.

[0030] Advantages of the present invention:

[0031] The invention provides a method for asymmetric hydrogenation of 5,11-dihydro-10H-dibenzo[b,f]azepan-10-one. The method has the characteristics of high efficiency, high selectivity, low catalyst dosage and high reaction conversion rate. The catalyst structure of the invention is novel, and the catalyst dosage is 1 / 7500 to 1 / 100000 of the substrate, which greatly reduces the catalyst dosage and cost, has high atom economy, and obtains (S)-10,11-dihydro-5H-dibenzo[b,f]azepine-10-ol with high yield and high enantioselectivity, which is used for preparing eslicarbazepine acetate chiral intermediates, and the intermediates are scaled up to pilot production, thereby developing a green, environmentally friendly, highly atom-economical and market-competitive S-eslicarbazepine acetate raw material preparation route. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Chiral spectrum of AK-2 racemate;

[0033] Figure 2 Chiral purity spectrum of AK-2 in Group 9 of Example 1;

[0034] Figure 3 HPLC purity spectrum of AK-2 in Group 9 of Example 1; DETAILED DESCRIPTION

[0035] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0036]

[0037] Under an inert gas atmosphere, the catalyst dosage was calculated according to the substrate / catalyst ratio (S / C) in Table 1, and the metal precursor [Ir(COD)Cl]2 and f-phamidol were dissolved in 5-15 mL of isopropanol solution at a molar ratio of 1:2.1, and stirred at room temperature for 2 h until completely dissolved to obtain a configured catalyst, and stirred at room temperature for 2 h until completely dissolved to obtain a catalyst, and the weighed AK-1 and sodium tert-butoxide (5 mol%) shown in Table 1 were added to the reaction vessel, and the in-situ configured catalyst was added. The solvent isopropanol was added and dissolved and stirred for 1 h. The volume ratio of AK-1 to isopropanol solvent was 1:(5-7.5), and the oxygen content (<150 ppm) was tested after replacing argon (4-5 MPa) three times, and then replaced hydrogen (4-5 MPa) three times. The pressure was filled to 5.0 MPa for the last time, stirring was turned on, and the temperature was raised to 65°C. After reaching the time shown in Table 1, stop heating, return to room temperature, slowly drop the prepared ammonium chloride aqueous solution into the reaction solution, and measure the pH of the reaction solution (6-8 is acceptable). Concentrate the organic phase under reduced pressure, cool the residue to 0°C, slowly drop 5 times the volume of 0°C ice water relative to the substrate, stir for 2h after the addition, filter under reduced pressure, wash the filter cake with water, dry the filter cake at 50°C with forced air for 12h, weigh and calculate the yield, and send it for related substance detection and chiral purity detection, and obtain Table 1.

[0038] Table 1 Experimental results of different substrate / catalyst ratios

[0039]

[0040] Embodiment 2:

[0041]

[0042] Under an inert gas atmosphere, the catalyst dosage was calculated with a substrate / catalyst ratio (S / C) of 7500. The metal precursor [Ir(COD)Cl]2 and f-phamidol were dissolved in 5 mL of the solvent shown in Table 2, and stirred at room temperature for 2 h until completely dissolved to obtain the configured catalyst. 15.0 g of AK-1 and sodium tert-butoxide (5 mol%) were added to the reaction vessel. The configured catalyst was added to the reaction vessel, and the same solvent used to configure the catalyst was added. The volume ratio of AK-1 to the solvent was 1:7.5. The mixture was dissolved and stirred. After replacing argon (4-5 MPa) three times, the oxygen content (<150 ppm) was tested, and then hydrogen (4-5 MPa) was replaced three times. The pressure was filled to 5.0 MPa for the last time, stirring was turned on, the temperature was raised to 65 ° C, the reaction was stopped after 12 h, the temperature was restored to room temperature, the configured ammonium chloride aqueous solution was slowly added dropwise to the reaction solution, and the pH of the reaction solution was measured (6-8 was qualified). The organic phase was concentrated under reduced pressure, and the residue was cooled to 0°C. Five times the volume of 0°C ice water relative to the substrate was slowly added dropwise. After the addition was complete, the mixture was stirred for 2 h. The mixture was filtered under reduced pressure and the filter cake was washed with water. The filter cake was dried at 50°C for 12 h and then weighed to calculate the yield. The cake was then sent for related substance detection and chiral purity detection. The results are shown in Table 2.

[0043] Table 2 Screening of reaction solvents

[0044]

[0045] Embodiment 3:

[0046]

[0047] Under an inert gas atmosphere, 0.0048 mmol of the metal precursor [Ir(COD)Cl]2 and 0.010 mmol of the ligand shown in Table 3 were dissolved in 5 mL of isopropanol solution and stirred for 2 h to dissolve to obtain a catalyst. 15.0 g of AK-1, sodium tert-butoxide (5 mol%) and the catalyst prepared above were added to the reaction vessel, and isopropanol was added to dissolve and stirred for 1 h. The volume ratio of AK-1 to isopropanol solvent was 1:7.5. The solution was stirred and the oxygen content (<150

[0048] ppm), and then replace hydrogen three times (4-5MPa), and finally pressurize to 5.0MPa, start stirring, raise the temperature to 65℃, react for 12h, stop heating, return to room temperature, slowly add the prepared ammonium chloride aqueous solution to the reaction liquid, and measure the pH of the reaction liquid (6-8 is qualified). Concentrate the organic phase under reduced pressure, cool the residue to 0℃, slowly add 0℃ ice water with a volume of 5 times that of the substrate, stir for 2h after adding, filter under reduced pressure, wash the filter cake with water, and dry the filter cake at 50℃ with air.

[0049] After 12 hours, the product was weighed and the yield was calculated, and the product was sent for related substance detection and chiral purity detection, as shown in Table 3.

[0050] Table 3 Screening of ligand skeletons based on S / C=7500 transformation number

[0051]

[0052] Embodiment 3:

[0053]

[0054] Under an inert gas atmosphere, the catalyst dosage was calculated with a substrate / catalyst ratio (S / C) of 7500. The metal precursor and ligand f-phamidol shown in Table 4 were dissolved in 5 mL of isopropanol solution and stirred for 2 h to dissolve. The catalyst was prepared. 15.0 g of AK-1 and sodium tert-butoxide (5 mol%) and the prepared catalyst were added to the reaction vessel. The isopropanol solvent was added and dissolved and stirred. The volume ratio of AK-1 to isopropanol solvent was 1:7.5. After replacing argon (4-5 MPa) three times, the oxygen content (<150 ppm) was tested. Hydrogen (4-5 MPa) was replaced three times. The pressure was filled to 5.0 MPa for the last time. Stirring was started and the temperature was raised to 65 ° C. After reacting for 12 h, heating was stopped and the temperature was restored to room temperature. The prepared ammonium chloride aqueous solution was slowly added dropwise to the reaction solution, and the pH of the reaction solution was measured (6-8 was qualified). The organic phase was concentrated under reduced pressure, the residue was cooled to 0°C, and 0°C ice water in a volume 5 times that of the substrate was slowly added dropwise. After the addition was completed, the mixture was stirred for 2 hours, filtered under reduced pressure, and the filter cake was washed with water. The filter cake was dried at 50°C for 12 hours, and then weighed to calculate the yield. The cake was also sent for related substance detection and chiral purity detection, as shown in Table 4.

[0055] Table 4 Screening of different metal precursors

[0056]

[0057] Embodiment 4:

[0058]

[0059] Under an inert gas atmosphere, 0.0718 mmol of metal precursor [Ir(COD)Cl]2 and 0.151 mmol of ligand f-phamidol were dissolved in 15 mL of isopropanol solution, stirred for 2 hours to dissolve, and the catalyst was prepared. 3 kg of AK-1 and sodium tert-butoxide (5 mol%), the catalyst prepared above, and isopropanol solvent were added to the reaction vessel. The feed volume ratio of AK-1 to isopropanol solvent was 1:5. Dissolve and stir, replace argon (4-5 MPa) three times and then test the oxygen content (<150 ppm), replace hydrogen (1-6 MPa) three times, and release hydrogen three times. After the three replacements, pressurize to the pressure shown in Table 5 for the last time, start stirring, heat to 65 ° C, start sampling to detect the HPLC purity of the product (≥95% is qualified), and sample once every 4 hours. Stop heating after 36 hours, return to room temperature, slowly add the prepared ammonium chloride aqueous solution to the reaction solution, and measure the pH of the reaction solution (6-8 is qualified). The organic phase was concentrated under reduced pressure, the residue was cooled to 0°C, and 0°C ice water in a volume 5 times that of the substrate was slowly added dropwise. After the addition was completed, the mixture was stirred for 2 hours, filtered under reduced pressure, and the filter cake was washed with water. The filter cake was dried at 50°C for 12 hours, and then weighed to calculate the yield. The cake was also sent for related substance detection and chiral purity detection, as shown in Table 5.

[0060] Table 5 Effect of hydrogen pressure

[0061]

[0062] Embodiment 5:

[0063]

[0064] Under an inert gas atmosphere, 0.0048 mmol of metal precursor [Ir(COD)Cl]2 and 0.010 mmol of ligand f-phamidol were dissolved in 5 mL of isopropanol solution and stirred for 2 h to dissolve to prepare a catalyst. 15.0 g of AK-1 and sodium tert-butoxide (5 mol%) were added to the reaction vessel. The above-prepared catalyst was added with isopropanol solvent. The volume ratio of AK-1 to isopropanol solution was 1:5. The mixture was dissolved and stirred. After replacing argon (4-5 MPa) three times, the oxygen content (<150 ppm) was tested. Hydrogen (4-5 MPa) was replaced three times. The pressure was filled to 5.0 MPa for the last time. Stirring was started. The temperature was raised to the temperature shown in Table 6. After reacting for 12 h, heating was stopped and the mixture was returned to room temperature. After returning to room temperature, the prepared ammonium chloride aqueous solution was slowly added dropwise to the reaction solution. The pH value of the reaction solution was measured (6-8 was acceptable). The organic phase was concentrated under reduced pressure, the residue was cooled to 0°C, and 0°C ice water in a volume 5 times that of the substrate was slowly added dropwise. After the addition was completed, the mixture was stirred for 2 hours, filtered under reduced pressure, and the filter cake was washed with water. The filter cake was dried at 50°C for 12 hours, and then weighed to calculate the yield. The cake was also sent for related substance detection and chiral purity detection, as shown in Table 6.

[0065] Table 6 Temperature screening

[0066]

[0067]

[0068] Embodiment 6:

[0069]

[0070] Under an inert gas atmosphere, the catalyst dosage was calculated with a substrate / catalyst ratio (S / C) of 7500. The metal precursor [Ir(COD)Cl]2 and the ligand f-phamidol were dissolved in 5 mL of isopropanol solution and stirred for 2 h to dissolve. The catalyst was prepared. 15.0 g of AK-1 and the base shown in Table 7 were added to the reaction vessel, and the prepared catalyst was added. The solvent isopropanol was added and dissolved and stirred for 1 h. The volume ratio of AK-1 to isopropanol solvent was 1:7.5. After replacing argon (4-5 MPa) three times, the oxygen content (<150 ppm) was tested, and then hydrogen (4-5 MPa) was replaced three times. The pressure was filled to 5.0 MPa for the last time, stirring was turned on, and the temperature was raised to 65 ° C. After 12 h, heating was stopped and the temperature was restored to room temperature. The prepared ammonium chloride aqueous solution was slowly added dropwise to the reaction solution, and the pH of the reaction solution was measured (6-8 was qualified). The organic phase was concentrated under reduced pressure, the residue was cooled to 0°C, and 0°C ice water in a volume 5 times that of the substrate was slowly added dropwise. After the addition was completed, the mixture was stirred for 2 hours, filtered under reduced pressure, and the filter cake was washed with water. The filter cake was dried at 50°C for 12 hours, and then weighed to calculate the yield. The cake was also sent for related substance detection and chiral purity detection, as shown in Table 7.

[0071] Table 7 Alkali screening

[0072]

[0073] In Table 7, “ / ” represents no investment

[0074] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral intermediate of eslicarbazepine acetate, characterized in that: include: Compound AK-1 is mixed with a catalyst, a base, and an organic solvent to form a reaction system, and pressurized under a hydrogen atmosphere to obtain compound AK-2. The reaction formula is as follows: The catalyst is obtained by complexing the ligand f-phamidol with a transition metal precursor, and the ligand structural formula of the catalyst is: The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

2. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to claim 1, characterized in that: The base is selected from Lewis bases, and / or the organic solvent is selected from one of alcohols, DCM, PhMe, CHCl3, THF, DCE or a mixture thereof.

3. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to claim 1, characterized in that: The organic solvent is selected from alcohol selected from methanol, ethanol, isopropanol or a combination thereof, and / or the base is selected from organic bases or inorganic bases.

4. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to claim 1, characterized in that: The base is selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium phosphate, and / or the metal precursor is selected from one or a combination of [Ir(NBD)Cl]2, [Ir(COD)Cl]2, and [Ir(C2H4)2Cl]2.

5. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to any one of claims 1 to 4, characterized in that: The hydrogen pressure is greater than 2 MPa, and / or the reaction temperature is greater than 25°C.

6. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to any one of claims 1 to 4, characterized in that: The reaction temperature is greater than 25-75° C., and / or the hydrogen pressure is 2-6 MPa.

7. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to any one of claims 1 to 4, characterized in that: The molar ratio of the substrate AK-1 to the catalyst is 7500-100000.

8. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to any one of claims 1 to 4, characterized in that: The molar ratio of the base to the compound AK-1 is 1:(10-25), preferably 1:

20.

9. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to any one of claims 1 to 8, characterized in that: The volume ratio of the organic solvent to the compound AK-1 is (5-10):

1.

10. The method for synthesizing the chiral intermediate of eslicarbazepine acetate according to any one of claims 1 to 9, characterized in that: The catalyst is synthesized in situ in the reaction system.

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