A process for the synthesis of an eslicarbazepine acetate chiral intermediate

Abstract

The application relates to the technical field of organic synthesis, in particular to a synthesis method of eslicarbazepine acetate chiral intermediate, a catalyst is prepared by complexing a metal precursor and a ligand f-phamidol, and the catalyst is used for asymmetric hydrogenation of 5,11-dihydro-10H-dibenzo[b,f]azepin-10-one in a reaction system of alkali and an organic solvent; the method has the characteristics of low catalyst loading, high conversion rate and selectivity; the method is used for manufacturing eslicarbazepine acetate chiral intermediate, and good effects can be obtained under the condition of low catalyst consumption, and good effects can also be obtained in large-scale pilot production; the method develops a green and environment-friendly, high-atomic-economicity and market-competitive eslicarbazepine acetate raw material intermediate manufacturing method.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, and specifically discloses a synthesis method of eslicarbazepine acetate chiral intermediate. BACKGROUND

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

[0003] The second prior art method is to use oxcarbazepine as a raw material, and use transfer hydrogenation to synynthetize 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, the catalyst dosage is higher in transfer hydrogenation than in asymmetric hydrogenation, the residual level of ruthenium metal in the product will be high and difficult to remove, and it is not suitable for use as an active pharmaceutical ingredient (API). In addition, a large amount of triethylamine and formic acid will be used in transfer hydrogenation, a large amount of waste will be produced, the atom economy is low, and there is a potential explosion risk. In view of the good drug prospect of eslicarbazepine, 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 eslicarbazepine. SUMMARY

[0004] In view of the problems in the prior art, the first aspect of the present application provides a synthesis method of eslicarbazepine acetate chiral intermediate, characterized in that the method comprises the following steps:

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

[0006] The reaction formula is as follows:

[0007]

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

[0009]

[0010] The marked carbon atom is in R configuration, S configuration, or achiral carbon atom.

[0011] In embodiments of the first aspect of the application, the base is selected from a Lewis base.

[0012] In embodiments of the first aspect of the application, the organic solvent is selected from one or a combination of alcohol, DCM, PhMe, CHCl3, THF, DCE.

[0013] In embodiments of the first aspect of the application, the organic solvent is selected from alcohol selected from one or a combination of methanol, ethanol, isopropanol.

[0014] In embodiments of the first aspect of the application, the base is selected from an organic base or an inorganic base.

[0015] In embodiments of the first aspect of the application, 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, sodium phosphate.

[0016] In embodiments of the first aspect of the application, the metal precursor is selected from one or a combination of [Ir(NBD)Cl]2, [Ir(COD)Cl]2, [Ir(C2H4)2Cl]2.

[0017] In embodiments of the first aspect of the application, 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, in some embodiments the hydrogen pressure is 6 MPa.

[0018] In embodiments of the first aspect of the application, 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, in some embodiments the reaction temperature is 45 °C.

[0019] In embodiments of the first aspect of the application, the reaction temperature is greater than 25-75 °C, and simultaneously, the hydrogen pressure is 2-6 MPa.

[0020] In embodiments of the first aspect of the application, the molar ratio of substrate AK-1 to catalyst is 7500-100000, in some embodiments the molar ratio of substrate AK-1 to catalyst is 7500, in some embodiments the molar ratio of substrate AK-1 to catalyst is 10000, in some embodiments the molar ratio of substrate AK-1 to catalyst is 20000, in some embodiments the molar ratio of substrate AK-1 to catalyst is 40000, in some embodiments the molar ratio of substrate AK-1 to catalyst is 60000, in some embodiments the molar ratio of substrate AK-1 to catalyst is 100000.

[0021] In specific embodiments of the first aspect of the application, the molar ratio of the base to compound AK-1 is 1: 10, in some embodiments the molar ratio of the base to compound AK-1 is 1: 15, in some embodiments the molar ratio of the base to compound AK-1 is 1: 20, in some embodiments the molar ratio of the base to compound AK-1 is 1: 25.

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

[0023] In specific embodiments of the first aspect of the application, 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 specific embodiments of the first aspect of the application, the catalyst is synthesized in situ in the reaction system.

[0025] In the present application, 1 mol of catalyst is configured by mixing 1 mol of metal precursor (for example, [Ir(COD)Cl]2, [Ir(NBD)Cl]2, [Ir(C2H4)2Cl]2) with 2.1 mol of ligand (any one of f-phamidol, L1-L6) in an organic solvent (for example, isopropyl alcohol) to obtain 2 mol of catalyst.

[0026] In the present application, 1 mol of catalyst is configured by mixing 1 mol of metal precursor (for example, [Ir(COD)Cl]2, [Ir(NBD)Cl]2, [Ir(C2H4)2Cl]2) with 2.1 mol of ligand (any one of f-phamidol, L1-L6) in an organic solvent (for example, isopropyl alcohol) to obtain 2 mol of catalyst.

[0027] In the present application, in some embodiments, 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, in some embodiments the room temperature is 25°C.

[0028] In the present application, 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 each embodiment of the present application are purchased from Xilong, Aladdin, and National Medicine Shanghai Test, etc.

[0030] Advantages of the present application:

[0031] The application provides a method for asymmetric hydrogenation of 5,11-dihydro-10H-dibenzo[b,f]azepin-10-one, which has the characteristics of high efficiency and high selectivity, low catalyst consumption and high reaction conversion rate, the catalyst structure is novel, the catalyst consumption is 1 / 7500-1 / 100000 of the substrate, the catalyst consumption and cost are greatly reduced, the atomic economy is high, (S)-10,11-dihydro-5H-dibenzo[b,f]azepin-10-ol is obtained in a high yield and high enantioselectivity, is used for manufacturing eslicarbazepine acetate chiral intermediate, and is scaled up to pilot production, a green and environment-friendly, high-atomic-economy and market-competitive preparation method of S-eslicarbazepine acetate bulk drug is developed. BRIEF DESCRIPTION OF DRAWINGS

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

[0033] Figure 2 Chiral purity spectrum of AK-2 in example 1 group 9;

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

[0035] In order for those skilled in the art to better understand the technical solutions of the present application, some non-limiting examples are further disclosed below to further illustrate the present application.

[0036]

[0037] Under inert gas atmosphere, the catalyst was prepared by dissolving the metal precursor [Ir(COD)Cl]2 and f-phamidol in 5-15 mL isopropyl alcohol solution with the molar ratio of 1:2.1, stirring at room temperature for 2 h until complete dissolution, and then stirring at room temperature for 2 h until complete dissolution. The reaction vessel was charged with the AK-1 and sodium tert-butoxide (5 mol%) shown in Table 1, and the in-situ prepared catalyst was added. The solvent isopropyl alcohol was added to dissolve and stir for 1 h. The volume ratio of AK-1 to isopropyl alcohol was 1:(5-7.5). The reaction vessel was replaced with argon (4-5 MPa) for three times to test the oxygen content (<150 ppm), and then replaced with hydrogen (4-5 MPa) for three times. The pressure was finally increased to 5.0 MPa, and the stirring was started. The temperature was increased to 65°C. After reaching the time shown in Table 1, the heating was stopped, and the temperature was restored to room temperature. The prepared ammonium chloride aqueous solution was slowly added 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 5 times the volume of 0°C ice water was slowly added. After the addition was completed, the stirring was continued for 2 h. The filter cake was washed with water, and the filter cake was dried at 50°C for 12 h. The yield was calculated by weighing, and the related substance detection and chiral purity detection were performed to obtain Table 1.

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

[0039]

[0040] Example 2:

[0041]

[0042] Under inert gas atmosphere, 0.0048 mmol of metal precursor [Ir(COD)Cl]2 and 0.010 mmol of ligand shown in Table 3 were dissolved in 5 mL of isopropanol solution, stirred for 2 h to dissolve, to prepare the catalyst, 15.0 g of AK-1, sodium tert-butoxide (5 mol%) and the prepared catalyst were added to the reaction vessel, isopropanol was added to dissolve and stir for 1 h, the volume ratio of AK-1 to isopropanol solvent was 1:7.5, and the stirring was carried out, three times of argon replacement (4-5 MPa) was carried out, and the oxygen content was tested (<150 ppm), three times of hydrogen replacement (4-5 MPa) was carried out, the last time was pressurized to 5.0 MPa, the stirring was started, the temperature was increased to 65°C, after 12 h of reaction, the heating was stopped, and the temperature was restored to room temperature, the prepared ammonium chloride aqueous solution was slowly added 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, 5 times the volume of 0°C ice water relative to the substrate was slowly added, after the addition was completed, the stirring was carried out for 2 h, the filter cake was washed with water, and the filter cake was dried at 50°C under air flow for 12 h, the yield was calculated by weighing, and the related substance detection and chiral purity detection were carried out, and Table 3 was obtained.

[0043] Table 2: Screening of reaction solvents

[0044]

[0045] Example 3:

[0046]

[0047] Under inert gas atmosphere, 0.0048 mmol of metal precursor [Ir(COD)Cl]2 and 0.010 mmol of ligand shown in Table 3 were dissolved in 5 mL of isopropanol solution, stirred for 2 h to dissolve, to prepare the catalyst, 15.0 g of AK-1, sodium tert-butoxide (5 mol%) and the prepared catalyst were added to the reaction vessel, isopropanol was added to dissolve and stir for 1 h, the volume ratio of AK-1 to isopropanol solvent was 1:7.5, and the stirring was carried out, three times of argon replacement (4-5 MPa) was carried out, and the oxygen content was tested (<150 ppm), three times of hydrogen replacement (4-5 MPa) was carried out, the last time was pressurized to 5.0 MPa, the stirring was started, the temperature was increased to 65°C, after 12 h of reaction, the heating was stopped, and the temperature was restored to room temperature, the prepared ammonium chloride aqueous solution was slowly added 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, 5 times the volume of 0°C ice water relative to the substrate was slowly added, after the addition was completed, the stirring was carried out for 2 h, the filter cake was washed with water, and the filter cake was dried at 50°C under air flow for 12 h, the yield was calculated by weighing, and the related substance detection and chiral purity detection were carried out, and Table 3 was obtained.

[0048] ppm), three times of hydrogen replacement (4-5 MPa) was carried out, the last time was pressurized to 5.0 MPa, the stirring was started, the temperature was increased to 65°C, after 12 h of reaction, the heating was stopped, and the temperature was restored to room temperature, the prepared ammonium chloride aqueous solution was slowly added 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, 5 times the volume of 0°C ice water relative to the substrate was slowly added, after the addition was completed, the stirring was carried out for 2 h, the filter cake was washed with water, and the filter cake was dried at 50°C under air flow for 12 h, the yield was calculated by weighing, and the related substance detection and chiral purity detection were carried out, and Table 3 was obtained.

[0049] 12h later, the yield was calculated by weighing, and the related substance and chiral purity were detected, as shown in Table 3.

[0050] Table 3 screening of ligand skeleton based on S / C = 7500 conversion

[0051]

[0052] Example 3:

[0053]

[0054] The metal precursor and ligand f-phamidol shown in Table 4 were dissolved in 5 mL of isopropyl alcohol solution under an inert gas atmosphere, stirred for 2 h to dissolve, and the catalyst was prepared. 15.0 g of AK-1 and sodium tert-butoxide (5 mol%) were added to the reaction vessel, and the prepared catalyst was added. Isopropyl alcohol solvent was added for dissolution and stirring. The volume ratio of AK-1 to isopropyl alcohol solvent was 1:7.5. After three times of argon replacement (4-5 MPa), the oxygen content was tested (<150 ppm). Then three times of hydrogen replacement (4-5 MPa) was carried out. Finally, the pressure was increased to 5.0 MPa, and the stirring was started. The temperature was increased to 65°C, and the reaction was carried out for 12 h. After the reaction, the heating was stopped, and the temperature was restored to room temperature. The prepared ammonium chloride aqueous solution was slowly added dropwise to the reaction liquid, and the pH of the reaction liquid was measured (6-8 was qualified). The organic phase was concentrated under reduced pressure, and the residue was cooled to 0°C. 5 times the volume of 0°C ice water relative to the substrate was slowly added dropwise. After the addition was completed, the stirring was carried out for 2 h. The filter cake was washed with water, and the filter cake was dried at 50°C for 12 h. The yield was calculated by weighing, and the related substance and chiral purity were detected, as shown in Table 4.

[0055] Table 4 screening of different metal precursors

[0056]

[0057] Example 4:

[0058]

[0059] Under 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 h to dissolve, and the catalyst was prepared. 3 Kg of AK-1 and sodium tert-butoxide (5 mol%) were added to the reaction vessel, and the previously prepared catalyst was added to isopropanol solvent. The volume ratio of AK-1 to isopropanol solvent was 1:5, and dissolution stirring was performed. After three times of argon replacement (4-5 MPa), the oxygen content was tested (<150 ppm), and then three times of hydrogen replacement (1-6 MPa) was performed. After three times of replacement to release hydrogen, the last time was pressurized to the pressure shown in Table 5, stirring was started, the temperature was raised to 65°C, and sampling for product HPLC purity (≥95% was qualified) was started. Sampling was performed every 4 h. After 36 h, heating was stopped, and the temperature was returned to room temperature. An ammonium chloride aqueous solution was slowly added 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, 0°C ice water was slowly added to the substrate at a volume of 5 times, stirring was performed for 2 h after the addition was completed, the filter cake was washed with water, and the filter cake was dried at 50°C for 12 h. The yield was calculated by weighing, and the related substance detection and chiral purity detection were performed, as shown in Table 5.

[0060] Table 5 Influence of hydrogen pressure

[0061]

[0062] Example 5:

[0063]

[0064] Under 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 h to dissolve, and the catalyst was prepared. 3 Kg of AK-1 and sodium tert-butoxide (5 mol%) were added to the reaction vessel, and the previously prepared catalyst was added to isopropanol solvent. The volume ratio of AK-1 to isopropanol solvent was 1:5, and dissolution stirring was performed. After three times of argon replacement (4-5 MPa), the oxygen content was tested (<150 ppm), and then three times of hydrogen replacement (1-6 MPa) was performed. After three times of replacement to release hydrogen, the last time was pressurized to the pressure shown in Table 5, stirring was started, the temperature was raised to 65°C, and sampling for product HPLC purity (≥95% was qualified) was started. Sampling was performed every 4 h. After 36 h, heating was stopped, and the temperature was returned to room temperature. An ammonium chloride aqueous solution was slowly added 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, 0°C ice water was slowly added to the substrate at a volume of 5 times, stirring was performed for 2 h after the addition was completed, the filter cake was washed with water, and the filter cake was dried at 50°C for 12 h. The yield was calculated by weighing, and the related substance detection and chiral purity detection were performed, as shown in Table 5.

[0065] Table 6 Temperature screening

[0066]

[0067]

[0068] Example 6:

[0069]

[0070] The metal precursor [Ir(COD)Cl]2and ligand f-phamidol were dissolved in 5 mL of isopropyl alcohol solution, stirred for 2 h to dissolve, and 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 isopropyl alcohol solvent was added and stirred for 1 h. The volume ratio of AK-1 to isopropyl alcohol solvent was 1:7.5. After three times of argon replacement (4-5 MPa), the oxygen content was tested (<150 ppm). Then, three times of hydrogen replacement (4-5 MPa) was performed. Finally, the pressure was increased to 5.0 MPa, and the stirring was started. The temperature was increased to 65°C, and after 12 h, the heating was stopped, and the temperature was returned to room temperature. The prepared ammonium chloride aqueous solution was slowly added to the reaction liquid, and the pH of the reaction liquid was measured (6-8 was qualified). The organic phase was concentrated under reduced pressure, and the residue was cooled to 0°C. A volume of 0°C ice water (5 times the volume of the substrate) was slowly added, and after the addition was completed, the stirring was continued for 2 h. The filter cake was washed with water, and the filter cake was dried at 50°C for 12 h. The yield was calculated by weighing, and the related substance detection and chiral purity detection were performed, as shown in Table 7.

[0071] Table 7 Base screening

[0072]

[0073] In Table 7, " / " represents not added

[0074] The above describes the preferred embodiments of the present application, but the present application is not limited to the specific details in the above embodiments. Within the technical concept of the present application, various simple modifications can be made to the technical solutions of the present application, and these simple modifications all belong to the protection scope of the present application.

Claims

1. A process for the synthesis of a chiral intermediate of eslicarbazepine acetate characterized in that, The application relates to a method for synthesizing compound AK-2. The reaction formula is as follows: The catalyst is obtained by complexing a ligand f-phamidol with a transition metal precursor, and the structural formula of the ligand of the catalyst is as follows: ； The transition metal precursor is selected from one of [Ir(NBD)Cl]2, [Ir(COD)Cl]2 and [Ir(C2H4)2Cl]2. ； The * marked carbon atom is S configuration; The organic solvent is selected from i one of PrOH, PhMe, THF; The base is selected from any one of potassium tert-butoxide, sodium methoxide and cesium carbonate. The pressure of the hydrogen gas is greater than 2 MPa.

2. The process for the synthesis of eslicarbazepine acetate chiral intermediate according to claim 1, characterized in that, The temperature of the reaction is greater than 25 DEG C.

3. The process for the synthesis of eslicarbazepine acetate chiral intermediate according to any one of claims 1 to 2, characterized in that, The temperature of the reaction is 25-75 DEG C.

4. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, The pressure of the hydrogen gas is 2-6 MPa.

5. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, The feeding molar ratio of the compound AK-1 to the catalyst is 7500-100000.

6. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, The feeding molar ratio of the base to the compound AK-1 is 1: (10-25).

7. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, The feeding molar ratio of the base to the compound AK-1 is 1:

20.

8. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, The volume ratio of the organic solvent to the compound AK-1 is (5-10):

1.

9. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, The catalyst is synthesized in situ in the reaction system.

10. The process for the synthesis of eslicarbazepine acetate chiral intermediate as claimed in claim 1, wherein, ​

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