Preparation method of CETP inhibitor Obicetrapib (AMG-899)

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a preparation method of a CETP inhibitor Obicterapib. The invention provides three preparation schemes. According to the scheme I, 2-phenyl pentenoate and (R)-N-(1-phenethyl)-4-(trifluoromethyl) aniline are subjected to a reaction, and a target compound Obicterapib is prepared through hydrolysis, cyclization, acylation, asymmetric chiral amine and other multi-step reactions; according to the second scheme, 4-halogenated benzotrifluoride reacts with (R)-3-amino valeronitrile, then nitrile hydrolysis is carried out, the product reacts with ethyl chloroformate, bis (trifluoromethyl) benzyl bromide, bis (pinacolato) diboron and ethyl 4-bromobutyrate, and finally hydrolysis is carried out to prepare the target compound Obictapib. According to the third scheme, (R)-3-(4-trifluoromethyl-phenyl amino)-valeric acid is substituted by amino to obtain a compound (R)-3-[4-(trifluoromethyl) phenyl amino]-valeric acid amide, then the compound (R)-3-[4-(trifluoromethyl) phenyl amino]-valeric acid amide reacts with ethyl chloroformate, bis (trifluoromethyl) benzyl bromide, bis (pinacolato) diboron, ethyl 4-bromobutyrate and 5-bromine-2-chloropyrimidine, and finally hydrolysis is conducted to prepare the target compound Obictapib.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemical synthesis and relates to a new preparation method of CETP inhibitor Obicetrapib (AMG-899) Background Art

[0002] Risk factors for atherosclerotic cardiovascular disease (ASCVD) are associated with plasma lipoprotein cholesterol concentrations, and the number of low-density lipoprotein (LDL) and other apolipoprotein B (apoB)-containing particles has been identified as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Even with the maximum dose of statin therapy, many people still fail to reduce their LDL-C levels to the target range. They need other treatment options to further reduce their LDL-C levels. The activity of cholesteryl ester transfer protein (CETP) and its inhibition can regulate cholesterol concentrations. Cholesteryl ester transfer protein is a hydrophobic glycoprotein with 476 amino acid residues and a molecular weight of approximately 53 kDa. As a member of the lipid transporter family, CETP plays a key role in reverse cholesterol transport (RCT) by regulating the transfer of cholesteryl esters (CE) and triglycerides (TG) between high-density lipoprotein (HDL) and apolipoprotein B-100 (apoB-100). Genomic studies have shown that single nucleotide polymorphisms (SNPs) that lack CETP activity are associated with increased and decreased concentrations of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), respectively. In addition, CETP increases brain cholesterol content. Therefore, inhibition of CETP has become a strategy to reduce atherosclerotic cardiovascular disease (ASCVD) by affecting plasma high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations.

[0003] Currently, some CETP inhibitors have been developed and used as ASCVD treatments. The first-generation CETP inhibitors (torcetrapib, dalcetrapib) mainly increase HDL-C or have off-target effects. The new-generation CETP inhibitors (anacetrapib, evacetrapib) can also effectively reduce LDL-C and apolipoprotein B, and their safety has been proven. Anacetrapib is the first CETP inhibitor proven to effectively reduce the risk of ASCVD. In addition, CETP inhibitors can also reduce the risk of new-onset diabetes, improve glucose tolerance and insulin sensitivity. The latest generation of CETP inhibitors, obicetrapib, is designed to reduce low-density lipoprotein cholesterol and apolipoprotein B. It can significantly reduce LDL-C by up to 45% and is about to enter the Phase III development stage. It may become the first CETP inhibitor as an add-on therapy for patients who do not reach the specified low-density lipoprotein target. Summary of the invention

[0004] In view of the above situation, the preparation of CETP inhibitor Obicetrapib (AMG-899) is very important. The inventors have invented three preparation methods of CETP inhibitor Obicetrapib (AMG-899) through experimental research. The compound of the present invention is prepared by the following three routes:

[0005] Solution 1

[0006]

[0007] The specific steps of this synthesis scheme are:

[0008] 1) reacting phenyl 2-pentenoate with (R)-N-(1-phenylethyl)-4-(trifluoromethyl)aniline to obtain the compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)phenyl pentanoate;

[0009] 2) Hydrolysis under alkaline conditions to obtain the compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)pentanoic acid

[0010] 3) Compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)pentanoic acid is intramolecularly cyclized to obtain compound (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one;

[0011] 4) The compound obtained in step 3) is reacted with ethyl chloroformate to obtain compound (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester

[0012] 5) The compound obtained in step 4) is subjected to aldehyde-ketone condensation with (R)-tert-butylsulfenamide to obtain the compound (R,E)-4-(((S)-tert-butylsulfonylimide)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester

[0013] 6) After sodium borohydride reduction, the compound (R, E)-4-(((S)-tert-butylsulfonylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester was obtained

[0014] 7) After removing the tert-butylsulfonyl protecting group, the compound (2R, 4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester was obtained.

[0015] 8) The compound obtained in step 7) is reacted with 5-bromo-2-chloropyrimidine, bis(trifluoromethyl)benzyl bromide, biboronic acid pinacol ester, and ethyl 4-bromobutyrate to obtain compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

[0016] 9) Hydrolyzing the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester to obtain the target compound Obicetrapib (AMG-899)

[0017] Solution 2

[0018]

[0019] X can be Cl or Br among the halogens;

[0020] The specific steps of this synthesis scheme are:

[0021] 1) 4-Halogenated trifluorotoluene reacts with (R)-3-aminovaleronitrile to obtain the compound (3R)-3-(4-trifluoromethylphenylamino)valeronitrile

[0022] 2) Hydrolysis of the nitrile group to obtain compound (3R)-3-[(4-trifluoromethylphenyl)amino]pentanamide

[0023] 3) The compound obtained in step 2) is reacted with ethyl chloroformate, bis(trifluoromethyl)benzyl bromide, biboric acid pinacol ester, and ethyl 4-bromobutyrate to obtain the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

[0024] 4) Finally, the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is hydrolyzed to obtain the target compound Obicetrapib (AMG-899)

[0025] Option 3

[0026]

[0027] The specific steps of this synthesis scheme are:

[0028] 1) (R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid is substituted with amino to obtain compound (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide

[0029] 2) The compound obtained in step 1) is reacted with ethyl chloroformate, bis(trifluoromethyl)benzyl bromide, biboric acid pinacol ester, ethyl 4-bromobutyrate, and 5-bromo-2-chloropyrimidine to obtain the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester

[0030] 3) Finally, the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl][5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is hydrolyzed to obtain the target compound Obicetrapib (AMG-899) Specific embodiments

[0031] The present invention is further described below by way of examples, but the contents of the present invention are not limited thereby.

[0032] Example 1

[0033]

[0034] Step A

[0035] Under the protection of inert gas, n-butyl lithium (2.5M in hexanes, 6.0mL, 15mmol) was added dropwise to a solution of (R)-N-(1-phenylethyl)-4-(trifluoromethyl)aniline (3.6g, 13.62mmol) in THF (50mL) at -78°C. After stirring for 30min, a solution of 2-pentenoic acid phenyl ester (2.4g, 13.62mmol) in THF (10mL) was added dropwise to the reaction solution. The mixture was reacted at -78°C for 2h, and a saturated ammonium chloride solution (50mL) was added to the reaction solution. The mixture was naturally heated to room temperature and extracted with ether three times. The organic phase was washed with saturated brine, separated, and the organic layer was concentrated. The compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)pentanoic acid phenyl ester (2.7g, yield 45%) was obtained by column purification. LC-MS (ESI): m / z = 441.2 [M+H] + .

[0036] Step B

[0037] NaOH (0.8 g, 20.0 mmol) was added to a solution of (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)phenylpentanoate (2.20 g, 5.0 mmol) in CH 2 Cl 2 / MeOH (20mL / 5mL) solution, stirred at room temperature for 2h, concentrated the reaction solution under reduced pressure, adjusted the pH to 1 with 1N HCl, and extracted with DCM. Combine the organic layers and dry them over anhydrous sodium sulfate, concentrate to obtain a residue, and use the crude product directly in the next step. LC-MS (ESI): m / z=365.4[M+H] + .

[0038] Step C

[0039] PPA (8 mL) was added to the residue from the previous step, and the reaction mixture was stirred at 100°C for 16 h, cooled to room temperature, and the reaction mixture was adjusted to pH = 14 with 10% NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by column to obtain compound (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one (1.95 g, yield 40%). LC-MS (ESI): m / z = 243.2 [M+H] + .

[0040] Step D

[0041] Add ethyl chloroformate (550 mg, 5 mmol) and 5 ml of dichloromethane to the reaction flask and stir evenly. Cool the reaction solution to 0°C, slowly add (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one (1.2 g, 4.64 mmol) dissolved in 5 ml of dichloromethane, and control the system temperature at 0-5°C; after the addition is complete, slowly add (702 mg, 7 mmol) of triethylamine, and control the system temperature at 5-10°C. After the addition, stir at room temperature (25±5°C) for 1 h. After the reaction is completed, add 1 mL of water to the reaction solution to quench the reaction, stir for 5 minutes, and stand for separation to obtain an organic layer. The organic phase was washed with 1 mol / L hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated and passed through a column to obtain (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (1.35 g, yield 90%). LC-MS (ESI): m / z = 315.3 [M+H] + .

[0042] Step E

[0043] The compound (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (1.8 g, 5.71 mmol) and (R)-tert-butylsulfenamide (2.08 g, 17.13 mmol) were dissolved in 22 mL of tetrahydrofuran, ethyl titanate (8.39 mL, 40 mmol) was added, and the temperature was raised to 65°C and stirred for 48 h. After cooling to room temperature, ethyl acetate and water were added, stirred for 15 minutes, and the obtained solid was filtered out. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a crude product (R, E)-4-(((S)-tert-butylsulfonyl imide)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester, which was used directly in the next step. LC-MS (ESI): m / z=418.5[M+H] + .

[0044] Step F

[0045] The compound (R,E)-4-(((S)-tert-butylsulfonyl imide)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (1.26 g, 3 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to -45°C. Sodium borohydride (0.17 g, 4.5 mmol) was added and the mixture was naturally returned to room temperature and stirred for 18 hours. Ice water was added to quench the mixture and the mixture was extracted with dichloromethane. The obtained organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain the compound (R,E)-4-(((S)-tert-butylsulfonylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (0.57 g, yield 45%). LC-MS (ESI): m / z=420.5[M+H] + .

[0046] Step G

[0047] The compound (R, E)-4-(((S)-tert-butylsulfonamido)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (0.50 mg, 1.20 mmol) was dissolved in 1 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse preparative column to obtain the compound (2R, 4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (0.34 g, yield 90%). LC-MS (ESI): m / z=316.3 [M+H] + .

[0048] Step H

[0049] Dissolve (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (0.35 g, 1.10 mmol) and 5-bromo-2-chloropyrimidine (0.43 g, 2.20 mmol) in 5 mL DMF, and stir the reaction solution at 150°C for 5 h. Cool to room temperature, add saturated sodium bicarbonate solution and ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify the residue by column to obtain the compound (2R,4S)-4-(5-bromopyrimidin-2-yl)amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.36 g, yield 70%). LC-MS (ESI): m / z=473.3[M+H] + .

[0050] Step I

[0051] (2R, 4S)-4-(5-bromopyrimidin-2-yl)amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.2 g) was dissolved in N, N-dimethylformamide (20 mL), sodium hydride (62.7%, 223 mg) was added under ice-water bath conditions, and the mixture was stirred at room temperature for 30 minutes. 3,5-bistrifluoromethylbenzyl bromide (1.3 mL) was added to the mixture under ice-water bath conditions, and the mixture was stirred at room temperature for 1 hour. Saturated brine and ethyl acetate were added to the mixture, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel; hexane: ethyl acetate = 10: 1) to give (2R, 4S)-4-{[3,5-ditrifluoromethylbenzyl(5-bromopyrimidin-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.56 g, yield 80%). LC-MS (ESI): m / z = 699.4 [M+H] + .

[0052] Step J

[0053] In N 2Under the protection of 5-bromopyrimidin-2-yl, (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidin-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (18.9 g, 27 mmol), biboric acid pinacol ester (8.3 g, 32.7 mmol), tris(dibenzylideneacetone)dipalladium (0.25 g, 0.27 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.26 g, 0.55 mmol) and potassium acetate (5.4 g, 5 4.5mmol) was added to 1,4-dioxane (100mL), heated to 80℃ and stirred for 3h; then cooled to room temperature, the reaction solution was washed with water until neutral, the organic phases were combined, dried, filtered, and the solvent was removed under reduced pressure; the crude product was recrystallized and purified using ethyl acetate / petroleum ether (volume ratio of 1:3) to obtain (2R,4S)-4-((3,5-ditrifluoromethylbenzyl)(5-boronic acid pyrimidin-2-yl)amino)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinolinone-1(2H)-carboxylic acid ethyl ester (15.7g, yield 78%). LC-MS (ESI): m / z=746.5[M+H] + .

[0054] Step K

[0055] (2R, 4S) -4- ((3, 5-bis (trifluoromethyl) benzyl) (5-boronic acid pyrimidin-2-yl) amino) -2-ethyl -6- trifluoromethyl -3, 4- dihydroquinolinone -1 (2H) -carboxylic acid ethyl ester was dissolved in tetrahydrofuran (10 mL), and 30% aqueous hydrogen peroxide solution (3.5 mL) was added dropwise thereto under ice cooling. One hour thereafter, a saturated aqueous sodium thiosulfate solution was added to the mixture, and the excess hydrogen peroxide was consumed. The mixture was separated into water and ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (2R, 4S) -4- { [3, 5-bis (trifluoromethyl) benzyl] - (5-hydroxypyrimidin-2-yl)} amino -2-ethyl -6- trifluoromethyl -3, 4- dihydroquinoline -1 (2H) -carboxylic acid ethyl ester (8.69 g, yield 65%). LC-MS (ESI): m / z = 636.5 [M+H] + .

[0056] Step L

[0057] Ethyl (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.22 g, 0.34 mmol) and ethyl 4-bromobutyrate (70.2 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (5 ml), potassium carbonate (1.69 g) was added thereto, and the mixture was stirred overnight at 45° C. Ethyl acetate and water were added to the mixture, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.25 g, yield 96%). LC-MS (ESI): m / z=750.7 [M+H] + .

[0058] Step M

[0059] (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonyl-propoxy)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.24 g, 0.32 mmol) was dissolved in ethanol (5 ml), and 2N aqueous sodium hydroxide solution (13 ml) was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 1N aqueous hydrochloric acid solution were added to the residue, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the target compound Obicetrapib (AMG-899) (0.22 g, yield 97%). LC-MS (ESI): m / z=722.6[M+H] + .1HNMR (400MHz, CDCl 3 )δppm 0.73(t,3H),1.32(t,3H),1.42-1.52(m,2H),1.69-1.76(m,1H),2.12(quin,2H),2.29(ddd,1H),2.59(t,2H),4.03(t,2H),4.15-4.5 2(m,4H),5.49(d,1H),5.96(d,1H),7.01(s,1H),7.50(d,1H),7.62(d,1H),7.71(br.s.,2H),7.76(s,1H),8.11(s,2H),9.60(s,1H).

[0060] Example 2

[0061]

[0062] Step A

[0063] A mixture of 4-bromotrifluorobenzoic acid (231 mg, 1.03 mmol), cesium carbonate (500 mg, 1.53 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (4.4 mg, 0.01 mmol), phenylboronic acid (1.86 mg, 0.015 mmol), (R)-3-aminopentanenitrile (98 mg, 1 mmol) and palladium acetate (1.8 mg, 0.008 mmol) was added to dry toluene (4 ml). The solution was completely degassed and filled with argon, and then heated to 80 ° C for 4 hours. The reaction mixture was cooled to room temperature and filtered through a celite pad. The solid was rinsed with toluene, and the filtrate was collected and concentrated. Purification by column chromatography gave compound (3R)-3-(4-trifluoromethylphenylamino)pentanenitrile (193 mg, yield 80%). LC-MS (ESI): m / z=242.2[M+H] + .

[0064] Step B

[0065] 90% sulfuric acid (0.42 ml, 4.43 mmol) was slowly added to a toluene (2 ml) solution of (3R)-3-(4-trifluoromethylphenylamino)pentanenitrile (190 mg, 0.785 mmol), and the mixture was stirred at 35°C for 10 hours, then the solution was cooled to room temperature and alkalized to pH 11-12 with 20% sodium hydroxide. The mixture was extracted with isopropyl ether, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give (3R)-3-[(4-trifluoromethylphenyl)amino]pentaneamide (163 mg, yield 80%). LC-MS (ESI): m / z=260.3[M+H] + .

[0066] Step C

[0067] (3R)-3-[(4-trifluoromethylphenyl)amino]pentanamide (260 mg, 1.00 mmol), Cs 2 CO 3 (456mg, 1.40mmol), Xantphos (87mg, 0.15mmol), Pd 2 (dba) 3(46 mg, 0.050 mmol), 5-bromo-2-chloropyrimidine (231 mg, 1.20 mmol) and 1,4-dioxane (2 ml), the mixture was sparged with nitrogen for 3 minutes, stirred at 100°C for 16 hours, and then cooled to room temperature. The residue was diluted with dichloromethane, filtered through celite and concentrated. The crude product was purified by column chromatography to give compound (R)-N-(5-bromopyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide (375 mg, yield 90%). LC-MS (ESI): m / z=417.2 [M+H] + .

[0068] Step D

[0069] PPA (8 mL) was added to the compound (R)-N-(5-bromopyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide, and the reaction mixture was stirred at 100°C for 16 h, cooled to room temperature, and the reaction mixture was adjusted to pH = 14 with 10% NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by column to obtain the compound (2R, 4S)-4-(5-bromopyrimidin-2-yl)amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (1.95 g, yield 40%). LC-MS (ESI): m / z = 401.2 [M+H] + .

[0070] Step E

[0071] Add ethyl chloroformate (550 mg, 5 mmol) and 5 ml of dichloromethane to the reaction flask and stir evenly. Cool the reaction solution to 0°C, slowly add (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one (1.9 g, 4.64 mmol) dissolved in 5 ml of dichloromethane, and control the system temperature at 0-5°C; after the addition is complete, slowly add (702 mg, 7 mmol) of triethylamine, and control the system temperature at 5-10°C. After the addition, stir at room temperature (25±5°C) for 1 h. After the reaction is completed, add 1 mL of water to the reaction solution to quench the reaction, stir for 5 minutes, and stand for separation to obtain an organic layer. The organic phase was washed with 1 mol / L hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated and passed through a column to obtain (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (2 g, yield 92%). LC-MS (ESI): m / z = 473.3 [M+H] + .

[0072] The next five steps were carried out in the same manner as in Example 1 to prepare the target compound Obicetrapib (AMG-899).

[0073] Example 3

[0074]

[0075] Step A

[0076] To (R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid (200 mg, 0.76 mmol) was added (2 g, 16.8 mmol) of thionyl chloride and stirred at room temperature for 1 hour. After concentration, the reaction solution was dissolved in tetrahydrofuran (1.5 mL) and mixed with 28% aqueous ammonia solution (3.0 g). The resulting solution was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The residue obtained after concentrating the organic layer and drying it with magnesium sulfate was crystallized from ethyl acetate / hexane to give (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide (148 mg, yield 75%). LC-MS (ESI): m / z=260.3[M+H] + .

[0077] Step B

[0078] (R)-3-[4-(Trifluoromethyl)phenylamino]-pentanamide (286 mg, 1.10 mmol) and 5-bromo-2-chloropyrimidine (0.47 g, 2.20 mmol) were dissolved in 5 mL DMF, and the reaction solution was stirred at 150°C for 5 h. After cooling to room temperature, saturated sodium bicarbonate solution and ethyl acetate were added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain compound (R)-N-(5-bromopyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide (321 mg, yield 70%). LC-MS (ESI): m / z=417.2[M+H] + .

[0079] Step C

[0080] In N 2Under the protection of 1% paraffin, (R)-N-(5-bromopyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide (11 g, 27 mmol), bipyrimidinyl borate (8.3 g, 32.7 mmol), tris(dibenzylideneacetone)dipalladium (0.25 g, 0.27 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.26 g, 0.55 mmol) and potassium acetate (5.4 g, 54.5mmol) was added to 1,4-dioxane (100mL), heated to 80℃ and stirred for 3h; then cooled to room temperature, the reaction solution was washed with water until neutral, the organic phases were combined, dried, filtered, and the solvent was removed under reduced pressure; the crude product was recrystallized and purified using ethyl acetate / petroleum ether to obtain (R)-N-(5-boronic acid ester pyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide (9.4g, yield 75%). LC-MS (ESI): m / z=464.3[M+H] + .

[0081] Step D

[0082] (R)-N-(5-boronic acid pyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide was dissolved in tetrahydrofuran (10 mL), and 30% aqueous hydrogen peroxide solution (3.5 mL) was added dropwise thereto under ice cooling. One hour thereafter, saturated aqueous sodium thiosulfate solution was added to the mixture, and excess hydrogen peroxide was consumed. The mixture was separated into water and ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (R)-N-(5-hydroxypyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide (4.6 g, yield 65%). LC-MS (ESI): m / z=354.3[M+H] + .

[0083] Step E

[0084] (R)-N-(5-hydroxypyrimidin-2-yl)-3-((4-(trifluoromethyl)phenyl)amino)pentanamide (0.12 g, 0.34 mmol) and ethyl 4-bromobutyrate (74.6 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (5 ml), potassium carbonate (1.69 g) was added thereto, and the mixture was stirred at 45° C. overnight. Ethyl acetate and water were added to the mixture, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give ethyl (R)-4-((2-(3-((4-(trifluoromethyl)phenyl)amino)pentanamido)pyrimidin-5-yl)oxy)butanoate. LC-MS (ESI): m / z=468.5[M+H]+ .

[0085] Step F

[0086] PPA (8 mL) was added to the compound (R)-4-((2-(3-((4-(trifluoromethyl)phenyl)amino)pentanamido)pyrimidin-5-yl)oxy)butanoic acid ethyl ester, and the reaction mixture was stirred at 100°C for 16 h, cooled to room temperature, and the reaction mixture was adjusted to pH = 14 with 10% NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried, and concentrated. The residue was purified by column to obtain the compound 5-(3-ethoxycarbonylpropoxy)-pyrimidine-2-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline. LC-MS (ESI): m / z = 452.5 [M+H] + .

[0087] Step G

[0088] Add ethyl chloroformate (550 mg, 5 mmol) and 5 ml of dichloromethane to the reaction flask and stir evenly. Cool the reaction solution to 0°C and slowly add (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one (2.1 g, 4.64 mmol) dissolved in 5 ml of dichloromethane. Control the system temperature at 0-5°C. After the addition is complete, slowly add (702 mg, 7 mmol) of triethylamine. Control the system temperature at 5-10°C. After the addition is complete, stir at room temperature (25±5°C) for 1 h. After the reaction is completed, add 1 mL of water to the reaction solution to quench the reaction. Stir for 5 minutes and let stand to separate the liquid to obtain an organic layer. The organic phase was washed with 1 mol / L hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated and passed through a column to obtain (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (2.2 g, yield 92%). LC-MS (ESI): m / z = 524.6 [M+H] + .

[0089] Step H

[0090] Ethyl (2R, 4S)-4-((5-(4-ethoxycarbonylpropoxy)pyrimidin-2-yl)amino)-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate (2.2 g) was dissolved in N, N-dimethylformamide (20 mL), sodium hydride (62.7%, 223 mg) was added under ice-water bath conditions, and the mixture was stirred at room temperature for 30 minutes. 3,5-bistrifluoromethylbenzyl bromide (1.3 mL) was added to the mixture under ice-water bath conditions, and the mixture was stirred at room temperature for 1 hour. Saturated brine and ethyl acetate were added to the mixture, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.4 g, yield 75%). LC-MS (ESI): m / z=750.7 [M+H] + .

[0091] The final step was to prepare the target compound Obicetrapib (AMG-899) using the same method as in Example 1.

[0092] The above examples are only used to illustrate the embodiments of the present invention, but the present invention is not limited to the above examples. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected, and the scope of the present invention to be protected is defined by the claims and their equivalents.

Claims

1. A method for preparing a CETP inhibitor Obicetrapib (AMG-899), It is characterized in that There are three synthesis schemes. The specific steps of scheme 1 are: (1) reacting phenyl 2-pentenoate with (R)-N-(1-phenylethyl)-4-(trifluoromethyl)aniline to obtain the compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)phenyl pentanoate; (2) Hydrolysis under alkaline conditions to obtain the compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)pentanoic acid (3) the compound (R)-3-(((R)-1-phenylethyl)(4-trifluoromethylphenyl)amino)pentanoic acid undergoes intramolecular cyclization to obtain the compound (R)-2-ethyl-6-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one; (4) The compound obtained in step 3) is reacted with ethyl chloroformate to obtain compound (R)-2-ethyl-4-oxo-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (5) The compound obtained in step 4) is subjected to an aldehyde-ketone condensation reaction with (R)-tert-butylsulfenamide to obtain the compound (R,E)-4-(((S)-tert-butylsulfonylimido)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester (6) After sodium borohydride reduction, the compound (R, E)-4-(((S)-tert-butylsulfonylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester was obtained. (7) After removing the tert-butylsulfonyl protecting group, the compound (2R, 4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydroquinoline-1(2H)-carboxylic acid ethyl ester was obtained. (8) The compound obtained in step 7) is reacted with 5-bromo-2-chloropyrimidine, bis(trifluoromethyl)benzyl bromide, bipyrimidine, and ethyl 4-bromobutyrate to obtain the compound (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (9) Hydrolyzing the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester to obtain the target compound Obicetrapib (AMG-899) The specific steps of Scheme 2 are as follows: (1) 4-halotrifluorotoluene reacts with (R)-3-aminovaleronitrile to obtain compound (3R)-3-(4-trifluoromethylphenylamino)valeronitrile (2) Hydrolysis of the nitrile group to obtain the compound (3R)-3-[(4-trifluoromethylphenyl)amino]pentanamide (3) The compound obtained in step 2) is reacted with ethyl chloroformate, bis(trifluoromethyl)benzyl bromide, bipyrimidine borate, and ethyl 4-bromobutyrate to obtain the compound (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (4) Finally, the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl][5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is hydrolyzed to obtain the target compound Obicetrapib (AMG-899) The specific steps of Scheme 3 are as follows: (1) (R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid is substituted by amino group to obtain compound (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide (2) The compound obtained in step 1) is reacted with ethyl chloroformate, bis(trifluoromethyl)benzyl bromide, bipyrimidine, ethyl 4-bromobutyrate, and 5-bromo-2-chloropyrimidine to obtain the compound (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3) Finally, the compound (2R, 4S)-4-{[3,5-bis(trifluoromethyl)benzyl][5-(3-ethoxycarbonylpropoxy)-pyrimidin-2-yl]-}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is hydrolyzed to obtain the target compound Obicetrapib (AMG-899).

2. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (1) of scheme 1, the reaction time is selected from 0-72 hours, and the reaction solvent is selected from one or more of dimethylformamide, dimethyl sulfoxide, chloroform, and tetrahydrofuran. Purification can be selected from column, slurry, Prep-TLC, Prep-HPLC or recrystallization.

3. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In steps (2) and (9) of scheme 1, step (4) of scheme 2, and step (3) of scheme 3, the base is selected from one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, the solvent used is selected from one or more of tetrahydrofuran, methanol, ethanol, and water, the molar ratio of the compound to the base is 1:4, the reaction temperature is selected from 10°C-50°C, the reaction time is selected from 0-24h, and the purification can be selected from column, slurry, Prep-TLC, Prep-HPLC or recrystallization.

4. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (3) of scheme 1 and scheme 2 and scheme 3, a cyclization reaction occurs under the action of a base, and the base used is selected from one of sodium hydride, sodium hydroxide, potassium hydride, potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine or N,N-diisopropylethylamine; the reaction solvent is selected from one of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether; the molar ratio of the compound to the base is 1:2-1:5, the temperature is selected from 50-240°C, and the reaction time is 6-24h.

5. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In the condensation reaction with ethyl chloroformate in step (4) of scheme 1 and scheme 2 and scheme 3, the acid-binding agent is selected from one of pyridine or triethylamine, 4-dimethylaminopyridine or N,N-diisopropylethylamine; the acid-binding agent is added at a low temperature of -10-10°C, and the molar ratio of the compound, ethyl chloroformate and the acid-binding agent is 1:1.2:1.5-1:2:

3. Purification can be selected from column, pulping, Prep-TLC, Prep-HPLC or recrystallization.

6. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (5) of scheme 1, the amine providing reagent is selected from one or more of S-tert-butylsulfenamide, R-tert-butylsulfenamide or a mixture thereof; the reaction temperature is selected from 20-240°C, and the reaction time is selected from 0.5-72h. The solvent used is selected from one or more of toluene, carbon tetrachloride, chlorobenzene, diphenyl ether, n-hexane, n-heptane, n-pentane, petroleum ether, benzene, THF, 2-Me-THF, DME, MTBE, ether, butyl ether, isopropyl ether, DMA, DMSO, etc. The auxiliary reagent used can be selected from one or both of ethyl titanate or isopropyl titanate. The product is selected from the crude product and used downward, and the purification can be selected from column, slurrying, Prep-TLC, Prep-HPLC or recrystallization.

7. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (6) of scheme 1, the reaction temperature is selected from -78-150°C, and the reaction time is selected from 0-72h. The solvent used is selected from one or more of toluene, carbon tetrachloride, chlorobenzene, diphenyl ether, n-hexane, n-heptane, n-pentane, petroleum ether, benzene, THF, 2-Me-THF, DME, MTBE, ether, butyl ether, isopropyl ether, DMA, DMSO, water, methanol, ethanol, isopropanol, etc. The reducing agent used can be selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride, lithium aluminum tetrahydride, lithium borohydride, zinc borohydride, and lithium borohydride. Lewis acid is added or not, preferably not Lewis acid. The product is selected from the crude product and used downward, and purification can be selected from column, pulping, Prep-TLC, Prep-HPLC or recrystallization.

8. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (7) of step 1, the reaction temperature is selected from 10-200° C., the reaction time is selected from 0-72 h, and the solvent is selected from DCM, 1,2-dichloroethane, chlorobenzene, acetonitrile, THF, 2-MeTHF, DMF, DME, 1,4-dioxane, H 2 O, NMP, DMAC, DMSO, one or more, the acid used is selected from one or two of trifluoroacetic acid and hydrochloric acid, and the equivalent of the acid is selected from ≥1eq. The product is selected from the crude product for further use, and the purification can be selected from column, slurry, Prep-TLC, Prep-HPLC or recrystallization.

9. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (8) of scheme 1 and scheme 2 and scheme 3, the reaction is respectively carried out with 5-bromo-2-chloropyrimidine and bistrifluoromethylbenzyl bromide, the reaction temperature is selected from 10-200°C, the time is selected from 0-72h, and the solvent is selected from one or more of N,N-dimethylformamide (DMF), dichloromethane, etc. The alkali agent is selected from one or more of sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium hydride, etc. Purification can be performed by washing the filter cake, filtering through a column, slurrying or recrystallization.

10. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that Step (8) of Scheme 1 and the reaction with diboric acid pinacol ester in Scheme 2 and Scheme 3, the reaction temperature is selected from 10-200°C, the reaction time is selected from 0-72h, and the solvent is selected from ether, acetonitrile, THF, DMF, DME, 1,4-dioxane, H 2 O, NMP, DMA, DMSO, benzene, toluene or two thereof. The catalyst used in the reaction can be selected from bis(triphenylphosphine)-palladium dichloride, bis(triphenylphosphine)ferrocenepalladium dichloride, bis(triphenylphosphine)ferrocenepalladium dichloride dichloromethane complex, Pd 2 (dba) 3 、pd(dppe)Cl 2 One or more of the compounds, 0.01%-20% (M / M molar ratio), the base used in the reaction is selected from triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, CsCO 3 , KOAc, NaOAc, K 2 CO 3 , tBuOK, tBuONa. 1-10 times the amount used (M / M molar ratio). Purification can be selected from column, slurry, Prep-TLC, Prep-HPLC or recrystallization.

11. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (8) of scheme 1 and scheme 2 and scheme 3, in the reaction with ethyl 4-bromobutyrate, the base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium tert-amyl alcohol, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate and dipotassium hydrogen phosphate. In some preferred embodiments, the base is selected from potassium bicarbonate and potassium carbonate. The solvent is selected from one or more of 1-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF) and N,N-dimethylaniline (DMA), the reaction temperature is selected from 60-130°C, and the purification can be selected from column, pulping, Prep-TLC, Prep-HPLC or recrystallization.

12. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (1) of scheme 2, the halogen substituent in the raw material 4-halotrifluorotoluene is independently selected from one of Cl and Br, the reaction temperature is selected from 10-200°C, the reaction time is selected from 0-72h, and the solvent is selected from one or more of N,N-dimethylformamide (DMF), dichloromethane, toluene, etc. The alkaline agent is selected from one or more of sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium hydride, cesium carbonate, etc., and purification can be selected from washing the filter cake during filtration, column, pulping or recrystallization.

13. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (2) of scheme 2, the reaction temperature is generally carried out at room temperature. The time is selected from 0-72 hours, the catalyst is selected from an acidic catalyst and a basic catalyst, specifically one of concentrated sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, etc., and the solvent is selected from ether, acetonitrile, THF, DMF, DME, 1,4-dioxane, H 2 One or more of O, NMP, DMA, DMSO, benzene, toluene, chlorobenzene, diphenyl ether, xylene, DCM, 1,2-dichloroethane. Purification can be selected from column, slurry, Prep-TLC, Prep-HPLC or recrystallization.

14. A method for preparing the CETP inhibitor Obicetrapib (AMG-899) according to claim 1, It is characterized in that In step (1) of scheme 3, the reaction temperature is selected from 20-120° C., the reaction time is selected from 0-72 h, and the solvent is selected from one or more of tetrahydrofuran (THF), dimethylformamide (DMA), methanol, ethanol, N,N-dimethylformamide (DMF) or other organic solvents.

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