[ CAS No. 373603-69-1 ] {[proInfo.proName]}

Name: 373603-69-1|4-(Trifluoromethyl)piperidin-4-ol|98%
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Product Details of [ 373603-69-1 ]

CAS No. :	373603-69-1	MDL No. :	MFCD13179174
Formula :	C₆H₁₀F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AXPLSJSIKGZOMF-UHFFFAOYSA-N
M.W :	169.14	Pubchem ID :	17951321
Synonyms :

Safety of [ 373603-69-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 373603-69-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 373603-69-1 ]

[ 373603-69-1 ] Synthesis Path-Downstream 1~37

1
[ 373603-70-4 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In methanol at 20℃; for 17h;	IP 1b. IP 1b. 4-trifluoromethylpiperidin-4-ol A suspension of 6.48 g (25.00 mmol) of 1-benzyl-4-trifluoromethylpiperidin-4-ol and 810 mg Pd/C (10%) in 100 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 17 hours. The catalyst was filtered off and the filtrate evaporated down in vacuo. Yield: 4.22 g (quant. yield); C6H10F3NO (M=169.145); calc.: molpeak (M+H)+: 170; found: molpeak (M+H)+: 17; Rf value: 0.00 (silica gel, cyc/EtOAc 2:1).
100%	With hydrogen In methanol at 20℃; for 17h;
	With palladium on activated charcoal; hydrogen In ethanol

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2005/234101, 2005, A1 Location in patent: Page/Page column 10
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2005/103002, 2005, A2 Location in patent: Page/Page column 34
[3]Ryu, Je Ho; Kim, Shinae; Han, Hye Young; Son, Hyun Joo; Lee, Hyun Jung; Shin, Young Ah; Kim, Jae-Sun; Park, Hyeung-Geun [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 695 - 700]

2
[ 373603-69-1 ]
[ 868052-24-8 ]
1-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-4-trifluoromethyl-piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 60℃; for 19h;	7.2d 65.0 mg (0.38 mmol) of 4-trifluoromethylpiperidin-4-ol and 0.13 mL (0.77 mmol) of ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) of 5-(4-chlorophenyl)-2-[4-((E)-3-chloropropenyl)phenylethynyl]pyridine in 1.7 mL of DMF and shaken for 19 hours at 60° C. The reaction mixture is filtered through an injection filter and purified by HPLC-MS. The residue is diluted with 20 mL of EtOAc and 10 mL of saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the solvent is eliminated in vacuo. It is then stirred with DIPE. Yield: 40.4 mg (42.0% of theoretical); C28H24ClF3N2O (M=496.951); calc.: molpeak (M+H)+: 497/499 (Cl); found: molpeak (M+H)+: 497/499 (Cl); retention time HPLC: 5.5 min (method B).
42%	With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 60℃; for 19h;

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2005/245529, 2005, A1 Location in patent: Page/Page column 35
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2005/103032, 2005, A2 Location in patent: Page/Page column 93; 94

3
[ 946504-83-2 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen In ethanol at 20℃;	70.2 Step 2 In a round-bottomed flask, 4-hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid benzyl ester (0.82 g, 2.7 mmol) was dissolved in EtOH (5 mL). 10% Palladium on carbon (Degussa type, 82 mg) was added and the flask was evacuated, flushed with argon, evacuated and flushed with hydrogen. The reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature overnight then filtered over Celite and rinsed with MeOH. The filtrate was concentrated to afford 0.44 g (97%) of 4-trifluoromethyl-piperidin-4-ol as a pale yellow solid.
83%	With cyclohexene In ethanol for 1h; Heating / reflux;	23.B Step B: Preparation of 4-(trifluoromethyl)piperidin-4-ol; To a stirred solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (347 g, 1.15 mole) in EtOH (1.2 L) was added Pd-C (Degussa type, 10 wt. % Pd, 50% H2O, 26.0 g, 12.2 mmol) and cyclohexene (850 mL, 8.39 mol). The mixture was heated to a gentle reflux for 1 hour resulting in a slight exotherm and the vigorous evolution of gas. Upon cooling to ambient temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The resulting residue was dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, and concentrated to give an orange solid. The crude material was crystallized from MTBE to give 160 g (83%) of product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 5.71 (br s, 1H), 2.74 (m, 4H), 2.42 (br s, 1H, overlaps DMSO), 1.53 (m, 4H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/230462, 2011, A1 Location in patent: Page/Page column 81
[2]Current Patent Assignee: PFIZER INC - US2007/197537, 2007, A1 Location in patent: Page/Page column 60

4
[ 550371-74-9 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trifluoroacetic acid; In dichloromethane; at 20℃; for 0.5h;	To a solution of tert-butyl 4-hydroxy-4-(trifiuoromethyl)piperidine- 1 - carboxylate (0.07 g, 0.26 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. Concentration and drying afforded 4-(trifluoromethyl)piperidin-4-ol (0.044 g, 100%). MS (EI) for C6Hi0F3NO: 269 (MH+).
100%	With trifluoroacetic acid; In dichloromethane; at 20℃; for 0.5h;	To a solution of tert-butyl 4-hydroxy-4-(trifluoromethyl)piperidine-l- carboxylate (0.07 g, 0.26 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. Concentration and drying afforded 4-(trifiuoromethyl)piperidin-4-ol (0.044 g, 100%). MS (EI) for
	With trifluoroacetic acid; In dichloromethane; at 25℃; for 12.0h;Inert atmosphere;	Step B: 4-(Trifluoromethyl)piperidin-4-ol Example 5A (1.6g, 5.94mmol) in trifluoroacetic acid (2mL) and dichloromethane (10mL) was reacted at 25C for 12 hours under nitrogen. The reaction mixture was evaporated under reduced pressure to give title compound.

Reference： [1]Patent: WO2010/138490,2010,A1 .Location in patent: Page/Page column 32
[2]Patent: WO2010/138487,2010,A1 .Location in patent: Page/Page column 130
[3]Patent: EP3640247,2020,A1 .Location in patent: Paragraph 0136; 0138

5
[ 19099-93-5 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0 - 30 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/230462, 2011, A1

6
[ 373603-69-1 ]
6-bromo-N-((E)-5-hydroxyadamantan-2-yl)picolinamide [ No CAS ]
N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(trifluoromethyl)-4-hydroxypiperidin-1-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In acetonitrile at 150℃; for 2h; Microwave irradiation;	37 Method B: 6-Bromo-N-((E)-5-hydroxyadamantan-2-yl)picolinamide(50 mg, 0.142 mmol) was dissolved in acetonitrile (1 ml), followed by addition of piperidine (48 mg, 0.568 mmol) and triethylamine (0.04 ml, 0.284 mmol), and then the resulting liquid was subjected to microwave irradiation at 150oC for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous ammonium chloride solution (10 ml), and extracted with MC (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (4% MeOH/MC), to obtain 32 mg of white solid (63%). The following examples were synthesized in the same method as the above example 36, by using the intermediate 9 and an appropriate amine start material.

Reference： [1]Current Patent Assignee: SK CHEMICALS CO LTD - WO2011/139107, 2011, A2 Location in patent: Page/Page column 27

7
[ 550371-74-9 ]
[ 76-05-1 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 20℃; for 0.5h;	To a solution of tert-butyl 4-hydroxy-4-(trifluoromethyl)piperidine- 1 - carboxylate (0.07 g, 0.26 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. Concentration and drying afforded 4-(trifluoromethyl)piperidin-4-ol (0.044 g, 100%). MS (EI) forC6H,oF3NO: 269 (MH+).

Reference： [1]Patent: WO2012/71509,2012,A2 .Location in patent: Page/Page column 165

8
[ 79099-07-3 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2: potassium carbonate / methanol / 12 h / 20 °C 3: dichloromethane / 0.5 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 2 h / 0 - 25 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2012/71509, 2012, A2
[2]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - EP3640247, 2020, A1

9
N-(t-butoxycarbonyl)-4-(trifluoromethyl)-4-trimethylsilyloxypiperidine [ No CAS ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 12 h / 20 °C 2: dichloromethane / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2012/71509, 2012, A2

10
[ 373603-69-1 ]
6-bromo-3-(bromomethyl)-4-chloro-2-methoxyquinoline [ No CAS ]
1-((6-bromo-4-chloro-2-methoxyquinolin-3-yl)methyl)-4-(trifluoromethyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane for 18h;	16 1-((6-Bromo-4-chloro-2-methoxyquinolin-3-yl)methyl)-4-(trifluoromethyl)piperidin-4-ol To a mixture containing 6-bromo-3-(bromomethyl)-4-chloro-2-methoxyquinoline (1.0 g, 2.7 mmol, Intermediate 15) and 4-(trifluoromethyl)piperidin-4-ol (0.70 g, 4.1 mmol) in dichloromethane (14 mL) was added N,N-diisopropylethylamine (1.5 mL, 8.7 mmol). After 18 hours, dichloromethane (100 mL) was added and the solution was washed with saturated aqueous sodium bicarbonate solution (50 mL). The washed organic solution was dried with sodium sulfate and the dried solution was filtered. Celite (8 g) was added to the filtrate and the mixture was concentrated to afford a free flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as a white solid.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/111870, 2015, A1 Location in patent: Paragraph 0387; 0388

11
[ 373603-69-1 ]
6-bromo-N-((1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl)picolinamide [ No CAS ]
C₂₂H₂₈F₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 150℃; Microwave irradiation;

Reference： [1]Ryu, Je Ho; Kim, Shinae; Han, Hye Young; Son, Hyun Joo; Lee, Hyun Jung; Shin, Young Ah; Kim, Jae-Sun; Park, Hyeung-Geun [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 695 - 700]

12
[ 3612-20-2 ]
[ 373603-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran 2: hydrogen; palladium on activated charcoal / ethanol

13
[ 690265-96-4 ]
[ 373603-69-1 ]
[ 866928-31-6 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 60℃;

Reference： [1]Müller, Stephan G.; Heckel, Armin; Kley, Jörg T.; Lehmann, Thorsten; Lustenberger, Philipp; Oost, Thorsten; Roth, Gerald J.; Rudolf, Klaus; Arndt, Kirsten; Lenter, Martin; Lotz, Ralf R.H.; Maier, Gerd-Michael; Markert, Michael; Schindler, Marcus; Stenkamp, Dirk [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3264 - 3269]

14
[ 373603-69-1 ]
5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1,2-thiazol-5-yl}amino)pyrazine-2-carboxylic acid [ No CAS ]
N-(3,4-difluorophenyl)-5-[(5-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]carbonyl}pyrazin-2-yl)amino]-3-methyl-1,2-thiazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	Stage #1: 5-({4-[(3,4-difluorophenyl)carbamoyl]-3-methyl-1,2-thiazol-5-yl}amino)pyrazine-2-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 70℃; for 2h; Stage #2: 4-trifluoromethyl-4-hydroxypiperidine In tetrahydrofuran at 70℃; for 3h;	92 N-(3,4-dif[uoropheny[)-5- [(5-f [4-hydroxy-4-(trif[uoromethy[)piperidin- 1 -yl] - carbony[lpyrazin-2-y[)amino]-3-methy[-1 ,2-thiazo[e-4-carboxamide To a solution of 5-(f4- [(3,4-difluorophenyl)carbamoyl] -3-methyl- 1 ,2-thiazol-5-yllamino)pyrazine-2-carboxylic acid [Intermediate 90] (88 mg, 0.23 mmol, 1.0eq) in 1.17 mL THF was added 1,1-carbonyldiimidazole (37 mg, 0.23 mmol, 1.0eq). The reaction mixture was stirred at 70 °C for 2 h. Then, a solution of4-(trifluoromethyl)piperidin-4-ol [CAS RN: 373603-69-1] (39 mg, 0.23 mmol, 1.0eq) in THF (0.8 mL) for 1 h was added and the reaction mixture was stirred at 70°C for 2 h. Subsequently, the reaction mixture was diluted with water and extracted three times with dichloromethane/isopropanol (4/1). The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components of the organic phase were removed invacuo and the crude product by the use of dichloromethane/methanol. Purification of this solid was conducted via preparative HPLC (Method A) to give 33 mg (27 % yield of theory) of the title compound.UPLC-MS (Method 1): R = 1.17 mm; MS (ESIneg) m/z = 541 [M-H].1H-NMR (400 MHz, DMSO-d6): ö [ppm] = 1.57-1.88 (m, 4H), 2.45 (5, 3H), 3.01 (m,1H), 3.91 (m, 1H), 4.46 (m, 1H), 6.14 (5, 1H), 7.39-7.51 (m, 2H), 7.94 (dd, 1H),8.64 (5, 1H), 8.67 (5, 1H), 10.46 (5, 1H), 11.20 (5, 1H), 1H obscured by solvent signal.

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/113927, 2015, A1 Location in patent: Page/Page column 322

15
[ 6311-35-9 ]
[ 373603-69-1 ]
(3S)-3-cyclopropyl-1-(2-((5-((4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)carbonyl)pyridin-2-yl)amino)pyridin-4-yl)-2-oxopyrrolidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 15 h / 20 °C 2: potassium carbonate; dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2’,4’, 6’-triisopropyl- 1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) / tert-Amyl alcohol / 22 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2016/159773, 2016, A1

16
[ 6311-35-9 ]
[ 373603-69-1 ]
(6-bromopyridin-3-yl)(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
650 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 15h;	62 (6-bromopyridin-3-yl) (4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)methanone To a solution of 6-bromonicotinic acid (480 mg) in ethyl acetate (10 mL) were added N,N-diisopropylethylamine (1.2 mL), 1.7 M propane phosphonic acid anhydride ethyl acetate solution (2.1 mL) and 4-(trifluoromethyl)piperidin-4-ol (400 mg), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH, hexane/ethyl acetate) to give the title compound (650 mg). MS(ESI+): [M+H]+ 352.8.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2016/159773, 2016, A1 Location in patent: Paragraph 1546-1548

17
[ 373603-69-1 ]
[ 84028-86-4 ]
(S)-methyl 2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium phosphate In ethyl acetate at 20℃; for 18h;

Reference： [1]Pryde; Marron; West; Reister; Amato; Yoger; Padilla; Turner; Swain; Cox; Skerratt; Ryckmans; Blakemore; Warmus; Gerlach [MedChemComm, 2016, vol. 7, # 11, p. 2145 - 2158]

18
[ 373603-69-1 ]
[ 93554-96-2 ]
C₁₅H₁₇F₃N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether for 18h; Reflux;

Reference： [1]Pryde; Marron; West; Reister; Amato; Yoger; Padilla; Turner; Swain; Cox; Skerratt; Ryckmans; Blakemore; Warmus; Gerlach [MedChemComm, 2016, vol. 7, # 11, p. 2145 - 2158]

19
5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carbonyl chloride [ No CAS ]
[ 373603-69-1 ]
[ 947544-70-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine at 0 - 5℃; for 0.25h;

Reference： [1]Kaplan, Alan P.; Keenan, Terence; Scott, Roderick; Zhou, Xianbo; Bourchouladze, Rusiko; McRiner, Andrew J.; Wilson, Mark E.; Romashko, Darlene; Miller, Regina; Bletsch, Matthew; Anderson, Gary; Stanley, Jennifer; Zhang, Adia; Lee, Dong; Nikpur, John [ACS Chemical Neuroscience, 2017, vol. 8, # 12, p. 2746 - 2758]

20
[ 373603-69-1 ]
2-[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 180℃; for 5h; Microwave irradiation;	28 5-(4-Chlorophenyl)-2-( { 1 -(2-chlorophenyl)-5- [4-hydroxy-4-(trifluoromethyl)piperidin- 1 -yl] -1 H-1 ,2,4-triazol-3 -yl} methyl)-4- [(2)-3,3,3 -trifluoro-2-hydroxypropyl] -2,4-dihydro-3H- 1 ,2,4-triazol-3-one A solution of 2- { [5-bromo- 1 -(2-chlorophenyl)- 1 H-i ,2,4-triazol-3 -yl]methyl} -5-(4-chlorophenyl)- 4- [(2)-3,3,3 -trifluoro-2-hydroxypropyl] -2,4-dihydro-3H- 1 ,2,4-triazol-3 -one (Example 5A, 150mg, 259 jimol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (95 jil, 540 jimol) and 4-(trifluoromethyl)piperidin-4-ol (439 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180°C under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 119 mg (69% of th.) of the title compound.LC-MS (Method 3): R = 2.10 mm; MS (ESIpos): mlz = 666.1 [M+H]1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.84-7.42 (m, 8H), 6.87 (d, 1H), 6.02 (s, 1H), 5.05-4.72(m, 2H), 4.29 (br ddd d, 1H), 4.09-3.72 (m, 2H), 3.5 1-3.19 (m, 2H, overlapping with HDO peak),3.14-2.75 (m, 2H), 1.95-1.24 (m, 4H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2019/81299, 2019, A1 Location in patent: Page/Page column 106

21
[ 373603-69-1 ]
[ 1446507-68-1 ]
4-(4-trifluoromethyl-4-hydroxypiperidin-1-yl)-6-(6-(trifluoromethyl) pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In tetrahydrofuran for 16h; Reflux;	21 Example 21 4-(4-Trifluoromethyl-4-hydroxypiperidin-1-yl)-6-(6-(trifluoromethyl) pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine 4-Chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5- triazin-2-amine (43 mg, 0.10 mmol) prepared in step 4 of Example 1 was dissolved in 5 mL of tetrahydrofuran, and 4-(trifluoromethyl)piperidin-4-ol (20 mg, 0.12 mmol) and sodium carbonate (16 mg, 0.15 mmol) were added. The mixture was heated under reflux for 16 h. The resultant solution was filtered, and the filtrate was purified by column chromatography to give the title compound. 1H NMR (500MHz, DMSO-d6): δ 10.74 (s, 1H), 8.54-8.67 (m, 3H), 8.25-8.30 (m, 1H), 8.07-8.09 (m, 1H), 7.85 -7.88 (m, 1H), 6.21 (s, 1H), 4.87-4.91 (m, 1H), 4.62-4.66 (m, 1H), 3.25-3.32 (m, 2H), 1.73-1.86 (m, 4H). ES: m/z 554.2 [M+H]+.

Reference： [1]Current Patent Assignee: NANJING SANHOME INVESTMENT GROUP CO LTD - EP3489230, 2019, A1 Location in patent: Paragraph 0126; 0127

22
[ 39856-50-3 ]
[ 373603-69-1 ]
1-(6-nitropyridin-3-yl)-4-(trifluoromethyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 10h; Inert atmosphere;	5.C Step C: Step C: 1-(6-Nitropyridin-3-yl)-4-(trifluoromethyl)piperidin-4-ol Under a protection of nitrogen, after a mixture of Example 5B (1.67g, 5.90mmol), 5-bromo-2-nitropyridine (1.32g, 6.49mmol), potassium carbonate (4.08g, 29.49mmol) in DMF (50mL) was stirred at 100°C for 10 hours, it was diluted with water (50mL).The aqueous layer was extracted with ethyl acetate (50mL*3). After the combined organic layers were washed with brine (50mLx2), dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound. 1H NMR (400MHz, DMSO-d6) δ=8.29 (d, J=3.0 Hz, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.52 (dd, J=3.0, 9.3 Hz, 1H), 6.18 (s, 1H), 4.10-4.03 (m, 2H), 3.29-3.19 (m, 2H), 1.80-1.72 (m, 4H).

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - EP3640247, 2020, A1 Location in patent: Paragraph 0136; 0139

23
[ 373603-69-1 ]
C₂₄H₂₃F₃N₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 100 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 15 h / 25 °C / 775.74 Torr 3: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / tetrahydrofuran / 4 h / 25 °C / Inert atmosphere 4: caesium carbonate; chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2’,4’, 6’-triisopropyl- 1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) / water; dimethyl sulfoxide / 10 h / 120 °C / Inert atmosphere