Preparation method of remegapam intermediate

Abstract

The invention provides a preparation method of a remegapam intermediate (6S, 9R)-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-9-(triisopropylsiloxy)-5H-cyclohepta [b] pyridine-5-ketone, and relates to a preparation method of a remegapam intermediate. The preparation method is characterized by comprising the following three steps: firstly, preparing a cycloheptyl pyridone compound into an enol silyl ether compound of the cycloheptyl pyridone compound; reacting the obtained silyl enol ether compound with 2, 3-difluorobromobenzene to obtain a mixture with R / S spatial configuration; the obtained mixture with the spatial configuration is converted into a target compound with a single configuration under a certain condition. Compared with the prior art, the process for preparing the remegapam intermediate is simple in step, the yield and the quality of a target product can be remarkably improved, the manufacturing cost of the target product is reduced, and the industrial application prospect is relatively high.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemistry and medicinal chemistry, and relates to a method for preparing a remegipam intermediate. More specifically, the present invention relates to a method for preparing a remegipam intermediate (6S, 9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridine-5-one. Background Art

[0002] Rimegepant is the first small molecule calcitonin gene-related peptide (CGRP) receptor antagonist with a fast-dissolving orally disintegrating tablet (ODT) formulation. It is used for the acute treatment of migraine with or without aura in adults and the preventive treatment of episodic migraine in adults. It was first approved by the US FDA in February 2020. The structure of Rimegepant is shown below:

[0003]

[0004] At present, there are two main synthetic routes for Remigipam API, which are the technical solutions disclosed by the original developer Bristol-Myers Squibb in its patents WO2011046997 and WO2012050764. In the two main synthetic process routes, both involve the synthesis of the chiral aromatic intermediate (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one, which is one of the key chiral intermediates for the synthesis of Remigipam. Its molecular structure contains two chiral centers, and the structure is shown in Formula I.

[0005]

[0006] The original Bristol-Myers Squibb Company introduced the synthesis of the intermediate (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one shown in Formula I in patent WO2009126530, as shown in Scheme 1. Under the catalysis of palladium acetate, the compound of Formula II reacts with 2,3-difluorobromobenzene to obtain the target compound of Formula I, but the reaction will also simultaneously generate the S-configuration stereoisomer of the compound of Formula I (hereinafter referred to as the compound of Formula A), and the ratio is 6:1.

[0007]

[0008] At present, the synthesis methods of the compound of formula I reported in the prior art are all based on the optimization and adjustment of the original research synthesis strategy, that is, the compound of formula II is coupled with 2,3-difluorobromobenzene under the catalysis of transition metal palladium. For example, Nanjing Aidekaiteng Biomedicine Co., Ltd. reported in patents CN116768938A and CN116640811A that the compound of formula II reacts with 2,3-difluorobromobenzene under the catalytic conditions of palladium acetate to obtain the compound of formula I, as shown in Scheme 2. This method has many post-processing steps, and the chiral purity of the obtained target product (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cycloheptyl[b]pyridine-5-one is only about 98%, and the yield of the target product is less than 80%.

[0009]

[0011] David K. Leahy et al. also introduced in the literature (Organic Letters (2012), 14 (18), 4938-4941) that the compound of formula II was subjected to α-arylation reaction under the catalysis of palladium acetate (as shown in Scheme 3), to obtain a mixture of the target product (6S, 9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one and the compound of formula A, with a yield of only 63%. In the mixed product, the ratio of compound of formula I to compound of formula A was 12:1. After further purification, the ratio of compound of formula I to compound of formula A was 40:1, but the total yield was only 56.7%.

[0012]

[0013] Patent WO2024180562 discloses another new technical scheme for preparing compounds of formula I. As shown in Scheme 4, the compound of formula II reacts with 2,3-difluorobromobenzene under a Pd(OAc)2 / RuPhos catalyst system, and after post-treatment and purification, (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cycloheptyl[b]pyridine-5-one (compound of formula I) is obtained, and its HPLC purity is greater than 98.0%, but the yield of the target product is only 63%.

[0014]

[0015] Therefore, based on the shortcomings of the existing preparation technology of the key chiral intermediate of Remegipam (6S, 9R) -6- (2, 3-difluorophenyl) -6, 7, 8, 9-tetrahydro -9- (triisopropylsilyl) -5H- cyclohepta [b] pyridine -5-one, such as low overall yield and low chiral purity, it is of great significance to develop a new preparation method with simple operation, low cost, high yield and high purity. The present invention is still based on the compound shown in formula II as a raw material, and provides a new synthesis strategy for the intermediate of Remegipam (6S, 9R) -6- (2, 3-difluorophenyl) -6, 7, 8, 9-tetrahydro -9- (triisopropylsilyl) -5H- cyclohepta [b] pyridine -5-one; in the new synthesis strategy, the yield and chiral purity of the target product are high, and it is a preparation technology suitable for industrial production. Summary of the invention

[0016] In order to solve the shortcomings of the existing technical route, the present invention provides a new preparation method of Remigipam intermediate (6S, 9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one, which specifically includes the following contents:

[0017] A method for preparing a remegipam intermediate (6S, 9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one, characterized in that it comprises the following steps:

[0018] Step 1: preparing the compound represented by formula II into its enol silyl ether compound III;

[0019] Step 2: reacting the enol silyl ether compound III obtained in step 1 with 2,3-difluorobromobenzene to prepare a mixture IV with R / S stereo configuration;

[0020] Step 3: The stereochemical mixture IV obtained in step 2 is converted into a single-structure compound of formula I under certain conditions, namely (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one;

[0021]

[0022] The preparation method described in the present invention is characterized in that: the reaction described in step 1 is carried out in an organic solvent system, a strong base is used to remove the hydrogen atom at the α position of the carbonyl group of the compound of formula II, and an enol compound is prepared in situ; the enol compound prepared in situ is then reacted with a trimethylsilyl reagent to obtain an enol silyl ether compound III;

[0023]

[0024] The preparation method described in the present invention is characterized in that: in the reaction described in step 1, the organic solvent is selected from tetrahydrofuran, a mixed solvent of tetrahydrofuran-methyl tert-butyl ether, and a mixed solvent of tetrahydrofuran-hexane.

[0025] The preparation method described in the present invention is characterized in that in the reaction described in step 1, the strong base is selected from lithium diisopropylamide and butyl lithium.

[0026] The preparation method described in the present invention is characterized in that: in the reaction described in step 1, the trimethylsilyl reagent is selected from trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, and hexamethyldisilazane; and the reaction temperature is selected from -40°C to -20°C.

[0027] The preparation method described in the present invention is characterized in that the reaction described in step 2 is carried out in an aprotic solvent, and the aprotic solvent is selected from toluene, heptane, N,N-dimethylformamide, or a mixed solvent of any two of them.

[0028] The preparation method described in the present invention is characterized in that: the reaction described in step 2 occurs under the action of a precious metal catalyst, the precious metal catalyst is selected from a palladium catalyst, a ruthenium catalyst, and a rhodium catalyst; the reaction temperature is selected from 75°C to 95°C.

[0029] The preparation method described in the present invention is characterized in that: the conversion described in step 3 is carried out in a protic solvent, and the protic solvent is selected from isopropanol, an isopropanol-water mixed solvent, ethanol, and an ethanol-water mixed solvent.

[0030] The preparation method described in the present invention is characterized in that: the conversion described in step 3 is carried out under alkaline conditions, and the base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, tetramethylguanidine, and triazabicyclo[4.4.0]dec-5-ene.

[0031] The preparation method described in the present invention is characterized in that the conversion temperature described in step 3 is between 20°C and 50°C.

[0032] In the prior art, the method of synthesizing the intermediate compound of formula I of remegipam by Pd catalysis of compound of formula II is low in activity due to the low reaction efficiency of the H atom at the α position of the carbonyl group, and the reaction of the substrate compound of formula II is incomplete, and more chiral isomers of compound of formula A are generated during the reaction, so that the purity of the d-mixed product is low, and it is difficult to precipitate during the stereo configuration conversion, thereby resulting in a low yield of the product of the target stereo configuration (compound of formula I). ​​The technical scheme described in the present invention first prepares the compound of formula II into its enol silyl ether compound III, and after the carbonyl enolization, the original H atom at the α position becomes an olefin H atom with higher activity, and the reaction activity becomes higher. Therefore, compared with the prior art, the reaction of enol silyl ether compound III is more thorough, and very few compounds of formula A are produced during the reaction, which greatly improves the yield and purity of the d-mixed product IV. The high-purity d-mixed product IV finally realizes the conversion of the stereo configuration under alkaline conditions, and can precipitate crystals with a higher yield, thereby improving the purity and yield of the target stereo configuration product (compound of formula I).

[0033] Compared with the prior art, the technical solution described in the present invention has the following advantages:

[0034] (1) The method for preparing the intermediate compound of formula I of the present invention has a high yield of up to 89.6% (the yield of the compound of formula I in the prior art is less than 80%);

[0035] (2) The preparation method described in the present invention effectively improves the purity of the intermediate compound of formula I of Remigipam to 98.3%, and the content of the isomer compound of formula A is only 1.60%. The ratio of compound of formula I to compound of formula A is 61:1, and the product quality is higher (compound of formula I to compound of formula A is 40:1 in the prior art). BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Attached Figure 1 The compound of formula III described in the present invention 1 H-NMR spectrum Attached Figure 2 The compound of formula III described in the present invention 1 C-NMR spectrum Attached Figure 3 The compound of formula IV described in the present invention 1 H-NMR spectrum Attached Figure 4 The compounds of formula I described in the present invention 1 H-NMR spectrum Attached Figure 5 The HPLC purity of the compound of formula I prepared by the technical scheme described in Organic Letters (2012), 14 (18), 4938-4941

[0038] Attached Figure 6 The HPLC purity of the compound of formula I prepared by the technical scheme described in the present invention DETAILED DESCRIPTION

[0039] The following specific embodiments are provided to enable those skilled in the art to fully understand the present invention, but are not intended to limit the present invention in any way.

[0040] In the following examples, unless otherwise specified, all temperatures are degrees Celsius; unless otherwise specified, the room temperature is 20-30°C; unless otherwise specified, various starting materials and reagents are commercially available and are used directly without further purification; unless otherwise specified, various solvents are industrial grade solvents and are used directly without further treatment; unless otherwise specified, commercial manufacturers include but are not limited to Hangzhou Chemical Reagent, Sinopharm Reagent, etc.

[0041] In the following examples, unless otherwise specified, the liquid phase purity detection method of the compound of formula I is carried out according to the following HPLC method and chromatographic conditions: chromatographic column: ACE C18-AR 4.6*150mm, 3μm or equivalent column; flow rate: 1.0mL / min; injection volume: 20μL; column temperature: 40°C; wavelength: 235nm; running time: 45min; mobile phase A: purified water; mobile phase B: acetonitrile; elution gradient: 0→15min, mobile phase A: mobile phase B=30:70; 15→25min, mobile phase A: mobile phase B=30:70→0:100; 25→35min, mobile phase A: mobile phase B=0:100; 35→37min, mobile phase A: mobile phase B=0:100→30:70; 37→45min, mobile phase A: mobile phase B=30:70. Test solution: Accurately weigh 25 mg of the test sample, dissolve it in a 25 mL volumetric flask with 60% acetonitrile water and make up to the mark, and shake well.

[0042] Example 1: Preparation of compound I by the technical scheme described in Organic Letters (2012), 14 (18), 4938-4941

[0043] 4.90g of compound II, 3.50g of 2,3-difluorobromobenzene, 135mg of palladium acetate, 175mg of tri-tert-butylphosphine tetrafluoroborate and 1.80g of sodium tert-butoxide were added to a 250mL two-necked bottle, and 15mL of toluene was added. The mixture was heated and stirred at 95°C for 4 hours. After the reaction was completed, it was cooled to 25°C, and a saturated ammonium chloride solution was added to wash the mixture twice, and water was added after concentrating under reduced pressure and filtered. The filter cake was first washed with NMP / water solution (3:1), then washed with water, and then vacuum dried at 50°C for 24 hours to obtain a mixture of 3.99g of compound I and compound A, with a yield of 60.9%.

[0044] A mixture of 3.50 g of the compound of formula I and the compound of formula A was dissolved in 20 mL of isopropanol / water solution, and 0.2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene was added, and stirred at 20°C for 48 hours. After the reaction was completed, the mixture was filtered, and the filter cake was washed with isopropanol / water solution and vacuum dried at 50°C to obtain 3.15 g of white solid compound of formula I, with a yield of 90% and a product purity of 95.9%, and 3.67% of compound of formula A, with compound of formula I: compound of formula A = 26:1.

[0045] Example 2: Preparation of compound I by the technical scheme described in Organic Letters (2012), 14 (18), 4938-4941

[0046] 5.00 g of compound II, 3.45 g of 2,3-difluorobromobenzene, 150 mg of palladium acetate, 180 mg of tri-tert-butylphosphine tetrafluoroborate and 1.70 g of sodium tert-butoxide were added to a 250 mL two-necked bottle, and 15 mL of toluene was added. The mixture was heated and stirred at 90°C for 4 hours. After the reaction was completed, it was cooled to 25°C, and a saturated ammonium chloride solution was added to wash the mixture twice, and water was added after concentrating under reduced pressure and filtered. The filter cake was first washed with NMP / water solution (3:1), then washed with water, and then vacuum dried at 50°C for 24 hours to obtain a mixture of 4.03 g of compound I and compound A, with a yield of 60.3%.

[0047] A mixture of 4.00 g of the compound of formula I and the compound of formula A was dissolved in 20 mL of isopropanol / water solution, and 0.2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene was added, and stirred at 20°C for 48 hours. After the reaction was completed, the mixture was filtered, and the filter cake was washed with isopropanol / water solution and vacuum dried at 50°C to obtain 3.62 g of white solid compound of formula I, with a yield of 90.5% and a product purity of 96.3%, and 3.29% of compound of formula A, with the ratio of compound of formula I to compound of formula A being 29:1.

[0048] Example 3: Synthesis of Compounds of Formula III

[0049]

[0050] Add 5.00g of compound II to a 250mL two-necked bottle, add 15mL of anhydrous tetrahydrofuran under argon protection, move the reaction to a -30℃ cold trap and stir, slowly drop 30mL of freshly prepared lithium diisopropylamide (LDA) into the reaction bottle with a syringe. Dissolve 3.26g of trimethylsilyl chloride in 10mL of anhydrous tetrahydrofuran, then add to the reaction bottle, stir for 30min, and move to room temperature to continue the reaction for 30min.

[0051] After the reaction was completed, the mixture was quenched with a saturated sodium bicarbonate solution, 50 mL of ethyl acetate was added to extract the layers, and the organic layer was concentrated under reduced pressure to obtain 6.70 g of a crude product of the compound of formula III. 1 H-NMR (400MHz, CD3Cl): δ8.37(dd,1H),7.96(dd,1H),7.19(m,1H),5.49(d,1H),5.20(d,1H),2.49-2.54 (m,1H),2.19-2.25(m,1H),2.00-2.24(m,1H),1.05-1.15(m,3H),1.01(d,9H),0.93(d,9H),0.2(s,9H); 1 C-NMR (101MHz, CD3Cl): δ160.4,146.5,144.3,135.4,131.2,122.2,114.6,75.9,33.5,22.3,18.1,12.4,0.36.

[0052] Example 4: Synthesis of Compounds of Formula III

[0053]

[0054] Add 4.90g of compound II to a 250mL two-necked bottle, add 20mL of anhydrous tetrahydrofuran under argon protection, move the reaction to a -35°C cold trap and stir, slowly drop 25mL of freshly prepared LDA into the reaction bottle with a syringe. Dissolve 3.15g of hexamethyldisilazane in 15mL of anhydrous methyl tert-butyl ether, then add to the reaction bottle, stir for 30min, and move to room temperature to continue the reaction for 30min.

[0055] After the reaction was completed, the mixture was quenched with a saturated sodium bicarbonate solution, 50 mL of ethyl acetate was added to extract the layers, and the organic layer was concentrated under reduced pressure to obtain 6.50 g of a crude product of the compound of formula III.

[0056] Example 5: Synthesis of Compounds of Formula III

[0057]

[0058] Add 5.20g of compound II to a 250mL two-necked bottle, add 20mL of anhydrous tetrahydrofuran under argon protection, move the reaction to a -40℃ cold trap and stir, slowly add 20mL of n-butyl lithium to the reaction bottle with a syringe. Dissolve 3.30g of trimethylsilyl trifluoromethanesulfonate in 20mL of anhydrous tetrahydrofuran, then add to the reaction bottle, stir for 30min, and move to room temperature to continue the reaction for 30min.

[0059] After the reaction was completed, the mixture was quenched with a saturated sodium bicarbonate solution, 50 mL of ethyl acetate was added to extract the layers, and the organic layer was concentrated under reduced pressure to obtain 6.75 g of a crude product of the compound of formula III.

[0060] Example 6: Synthesis of Compounds of Formula III

[0061]

[0062] Add 5.00g of compound II to a 250mL two-necked bottle, add 30mL of anhydrous tetrahydrofuran under argon protection, move the reaction to a -20℃ cold trap and stir, slowly drop 20mL of freshly prepared LDA into the reaction bottle with a syringe. Dissolve 3.00g of trimethylsilyl chloride in 20mL of hexane, then add to the reaction bottle, stir for 30min, and move to room temperature to continue the reaction for 30min.

[0063] After the reaction was completed, the mixture was quenched with a saturated sodium bicarbonate solution, 50 mL of ethyl acetate was added to extract the layers, and the organic layer was concentrated under reduced pressure to obtain 6.45 g of a crude product of the compound of formula III.

[0064] Example 7: Synthesis of Compounds of Formula III

[0065]

[0066] Add 4.95g of compound II to a 250mL two-necked bottle, add 20mL of anhydrous tetrahydrofuran under argon protection, move the reaction to a -30℃ cold trap and stir, slowly drop 25mL of freshly prepared LDA into the reaction bottle with a syringe. Dissolve 3.15g of hexamethyldisilazane in 18mL of anhydrous tetrahydrofuran-methyl tert-butyl ether mixed solvent, then add to the reaction bottle, stir for 30min, and move to room temperature to continue the reaction for 30min.

[0067] After the reaction was completed, the mixture was quenched with a saturated sodium bicarbonate solution, 50 mL of ethyl acetate was added to extract the layers, and the organic layer was concentrated under reduced pressure to obtain 6.55 g of a crude product of the compound of formula III.

[0068] Example 8: Synthesis of Compounds of Formula IV

[0069]

[0070] Add 170 mg of palladium acetate, 217 mg of tributylphosphine tetrafluoroborate and 3.60 g of sodium tert-butoxide to a 100 mL two-necked bottle, and protect with argon. Then, dissolve 6.70 g of compound III and 3.75 g of 2,3-difluorobromobenzene in 20 mL of anhydrous toluene, inject into the reaction bottle at room temperature, heat the reaction to 80 ° C, and keep the reaction for 4 hours. After the reaction is complete, add water to quench, extract with 50 mL of ethyl acetate three times, concentrate the organic layer under reduced pressure, and purify by silica gel column chromatography with dichloromethane and petroleum ether as eluents to obtain 6.20 g of compound IV with a yield of 92.4%.

[0071] Example 9: Synthesis of Compounds of Formula IV

[0072]

[0073] Add 300 mg of tetrakis(triphenylphosphine)palladium, 230 mg of tributylphosphine tetrafluoroborate and 3.45 g of sodium tert-butoxide to a 100 mL two-necked bottle, and protect with argon. Then, dissolve 6.75 g of compound III and 3.50 g of 2,3-difluorobromobenzene in 20 mL of anhydrous N,N-dimethylformamide, inject into the reaction bottle at room temperature, heat the reaction to 90 ° C, and keep the reaction for 4 hours. After the reaction is complete, add water to quench, extract with 50 mL of ethyl acetate 3 times, concentrate the organic layer under reduced pressure, and purify by silica gel column chromatography with dichloromethane and petroleum ether as eluents to obtain 5.95 g of compound IV with a yield of 90.5%.

[0074] Example 10: Synthesis of Compounds of Formula IV

[0075]

[0076] Add 150 mg of tri(triphenylphosphine)rhodium chloride, 240 mg of tributylphosphine tetrafluoroborate and 3.50 g of sodium tert-butoxide to a 100 mL two-necked bottle, and protect with argon. Then, dissolve 6.75 g of compound III and 3.75 g of 2,3-difluorobromobenzene in 20 mL of anhydrous toluene, inject into the reaction bottle at room temperature, heat the reaction to 75 ° C, and keep the reaction for 4 hours. After the reaction is complete, add water to quench, extract with 50 mL of ethyl acetate 3 times, concentrate the organic layer under reduced pressure, and purify by silica gel column chromatography with dichloromethane and petroleum ether as eluents to obtain 6.29 g of compound IV with a yield of 89.8%.

[0077] Example 11: Synthesis of Compound of Formula IV

[0078]

[0079] Add 200mg Ru / Al2O3, 230mg tributylphosphine tetrafluoroborate and 3.55g sodium tert-butoxide to a 100mL two-necked bottle, and protect with argon. Then, dissolve 6.45g of compound III and 3.45g of 2,3-difluorobromobenzene in 20mL of anhydrous toluene, inject into the reaction bottle at room temperature, heat the reaction to 90°C, and keep the reaction for 4h. After the reaction is complete, add water to quench, extract with 50mL ethyl acetate 3 times, concentrate the organic layer under reduced pressure, and purify by silica gel column chromatography with dichloromethane and petroleum ether as eluents to obtain 6.02g of compound IV with a yield of 90.2%.

[0080] Example 12: Synthesis of Compound of Formula IV

[0081]

[0082] Add 180 mg of palladium acetate, 215 mg of tributylphosphine tetrafluoroborate and 3.50 g of sodium tert-butoxide to a 100 mL two-necked bottle, and protect with argon. Then, dissolve 6.55 g of compound III and 3.55 g of 2,3-difluorobromobenzene in 20 mL of anhydrous N,N-dimethylformamide, inject into the reaction bottle at room temperature, heat the reaction to 95 ° C, and keep the reaction for 4 hours. After the reaction is complete, add water to quench, extract with 50 mL of ethyl acetate 3 times, concentrate the organic layer under reduced pressure, and purify by silica gel column chromatography with dichloromethane and petroleum ether as eluents to obtain 6.05 g of compound IV with a yield of 91.4%.

[0083] Example 13: Synthesis of Compounds of Formula I

[0084]

[0085] 2.00 g of compound IV was dissolved in 10 mL of isopropanol, and 2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added, followed by stirring at 25°C for 48 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.94 g of the target product compound I, with a yield of 97.0% and a product purity of 98.3%. The compound A was 1.60%, and the ratio of compound I to compound A was 61:1.

[0086] Example 14: Synthesis of Compounds of Formula I

[0087]

[0088] 2.00 g of compound IV was dissolved in 10 mL of isopropanol / water solution, 2 mL of DBU was added, and then stirred at 35°C for 45 h. After the reaction, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.92 g of the target product compound I, with a yield of 96.0% and a product purity of 98.0%. The ratio of compound A was 1.89%, and the ratio of compound I to compound A was 52:1.

[0089] Example 15: Synthesis of Compounds of Formula I

[0090]

[0091] 2.00 g of compound IV was dissolved in 10 mL of isopropanol / water solution, 2 mL of tetramethylguanidine (TMG) was added, and then stirred at 45°C for 46 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.93 g of the target product compound I, with a yield of 96.5% and a product purity of 97.6%, and 1.77% of the compound A, with the ratio of compound I to compound A being 55:1.

[0092] Example 16: Synthesis of Compounds of Formula I

[0093]

[0094] 2.00 g of compound IV was dissolved in 10 mL of ethanol / water solution, and 2 mL of triazabicyclo[4.4.0]dec-5-ene (TBD) was added, followed by stirring at 30°C for 42 h. After the reaction, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.90 g of the target product compound I, with a yield of 95.0% and a product purity of 97.8%, and 2.13% of the compound A, with the ratio of compound I to compound A being 46:1.

[0095] Example 17: Synthesis of Compounds of Formula I

[0096]

[0097] 2.00 g of compound IV was dissolved in 10 mL of isopropanol, and 2 mL of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) was added, followed by stirring at 40°C for 40 h. After the reaction, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.89 g of the target product compound I, with a yield of 94.5% and a product purity of 97.5%, and 2.29% of the compound A, with the ratio of compound I to compound A being 43:1.

[0098] Example 18: Synthesis of Compounds of Formula I

[0099]

[0100] 2.00 g of compound IV was dissolved in 10 mL of isopropanol / water solution, 2 mL of TBD was added, and then stirred at 35°C for 45 h. After the reaction, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.92 g of the target product compound I, with a yield of 96.0% and a product purity of 97.6%. The ratio of compound A was 2.16%, and the ratio of compound I to compound A was 45:1.

[0101] Example 19: Synthesis of Compounds of Formula I

[0102]

[0103] 2.00 g of compound IV was dissolved in 10 mL of ethanol / water solution, 2 mL of DBN was added, and then stirred at 40°C for 48 h. After the reaction, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.91 g of the target product compound I, with a yield of 95.5% and a product purity of 98.0%. The compound A was 2.07%, and the ratio of compound I to compound A was 47:1.

[0104] Example 20: Synthesis of Compounds of Formula I

[0105]

[0106] 2.00 g of compound IV was dissolved in 10 mL of isopropanol, and 2 mL of TMG was added, followed by stirring at 30°C for 45 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added to the reaction solution, filtered, and dried to obtain 1.93 g of the target product compound I, with a yield of 96.5% and a product purity of 96.9%. The content of compound A was 1.83%, and the ratio of compound I to compound A was 53:1.

[0107] The method of the present invention is described by preferred embodiments. It is obvious that persons skilled in the relevant art can make appropriate common sense adjustments, changes and combinations to the methods and applications described in the present invention where necessary within the content and scope of the present invention to implement and apply the technology of the present invention. Personnel in the art can also refer to the content of the present invention and implement it by appropriately improving the process parameters. It is particularly important to point out that all similar improvements and adjustments are obvious to those skilled in the art and should be considered to be included in the present invention.

Claims

1. A method for preparing a remegipam intermediate (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one, characterized in that: The following steps are involved: Step 1: preparing the compound represented by formula II into its enol silyl ether compound III; Step 2: reacting the enol silyl ether compound III obtained in step 1 with 2,3-difluorobromobenzene to prepare a mixture IV with R / S stereo configuration; Step 3: The stereochemical mixture IV obtained in step 2 is converted into a single-structure compound of formula I under certain conditions, namely (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-(triisopropylsilyloxy)-5H-cyclohepta[b]pyridin-5-one; 2. The preparation method according to claim 1, characterized in that: The reaction described in step 1 is carried out in an organic solvent system, and a strong base is used to remove the hydrogen atom at the α position of the carbonyl group of the compound of formula II to prepare an enol compound in situ; the enol compound prepared in situ is then reacted with a trimethylsilyl reagent to obtain an enol silyl ether compound III; 3. The preparation method as claimed in claim 1 or 2, characterized in that: In the reaction described in step 1, the organic solvent is selected from tetrahydrofuran, a mixed solvent of tetrahydrofuran-methyl tert-butyl ether, and a mixed solvent of tetrahydrofuran-hexane.

4. The preparation method according to claim 1 or 2, characterized in that: In the reaction described in step 1, the strong base is selected from lithium diisopropylamide and butyl lithium.

5. The preparation method according to claim 1 or 2, characterized in that: In the reaction described in step 1, the trimethylsilyl reagent is selected from trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, and hexamethyldisilazane; and the reaction temperature is selected from -40°C to -20°C.

6. The preparation method as claimed in claim 1, characterized in that: The reaction in step 2 is carried out in an aprotic solvent, and the aprotic solvent is selected from toluene, heptane, N,N-dimethylformamide, or a mixed solvent of any two of them.

7. The preparation method according to claim 1 or 6, characterized in that: The reaction described in step 2 occurs under the action of a noble metal catalyst, which is selected from a palladium catalyst, a ruthenium catalyst, and a rhodium catalyst; the reaction temperature is selected from 75°C to 95°C.

8. The preparation method as claimed in claim 1, characterized in that: The conversion described in step 3 is carried out in a protic solvent, and the protic solvent is selected from isopropanol, an isopropanol-water mixed solvent, ethanol, and an ethanol-water mixed solvent.

9. The preparation method according to claim 1 or 8, characterized in that: The transformation described in step 3 is carried out under alkaline conditions, and the base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, tetramethylguanidine, triazabicyclo[4.4.0]dec-5-ene.

10. The preparation method as claimed in claim 1 or 8, characterized in that: The conversion temperature described in step 3 is between 20°C and 50°C.

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