[ CAS No. 657-36-3 ] {[proInfo.proName]}

Name: 657-36-3|4-Trifluoromethylpiperidine|97%
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SKU: A244473
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Quality Control of [ 657-36-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 657-36-3 ]

Product Details of [ 657-36-3 ]

CAS No. :	657-36-3	MDL No. :	MFCD00102068
Formula :	C₆H₁₀F₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RDRQUUWCJTYHCT-UHFFFAOYSA-N
M.W :	153.15	Pubchem ID :	136469
Synonyms :

Calculated chemistry of [ 657-36-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.75
TPSA :	12.03 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	1.65
Log Po/w (WLOGP) :	2.43
Log Po/w (MLOGP) :	1.66
Log Po/w (SILICOS-IT) :	2.07
Consensus Log Po/w :	1.92

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.76
Solubility :	2.64 mg/ml ; 0.0173 mol/l
Class :	Very soluble
Log S (Ali) :	-1.52
Solubility :	4.67 mg/ml ; 0.0305 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.96
Solubility :	1.68 mg/ml ; 0.011 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.12

Safety of [ 657-36-3 ]

Signal Word:	Danger	Class:	8,3
Precautionary Statements:	P501-P270-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405	UN#:	2734
Hazard Statements:	H302-H314-H226	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 657-36-3 ]

* 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.

Upstream synthesis route of [ 657-36-3 ]
Downstream synthetic route of [ 657-36-3 ]

[ 657-36-3 ] Synthesis Path-Upstream 1~2

1
[ 3796-24-5 ]
[ 657-36-3 ]

Yield	Reaction Conditions	Operation in experiment
49 %Chromat.	With hydrogen In tetrahydrofuran at 30℃; for 4 h; Autoclave; Glovebox	General procedure: Autoclave Par 477 equipped with PID control temperature and reservoir for kinetic measurements and HEL 24 Cat reactor for substrate scope were used as reactors for the hydrogenation reactions. In a typical experiment, the autoclave was charged in the glove-box with the desired Rh NPs (1.25 or 0.625molpercent; the catalyst concentration was calculated based on the total number of metallic Rh atoms in the surface of the NPs) and the substrate (0.124M) in THF. Molecular hydrogen was then introduced until the desired pressure was reached and the reaction was stirred for the desired reaction time at the selected temperature. At the end of the reaction, the autoclave was depressurised and the solution was filtered through silica for subsequent analysis by GC. The conversion and selectivities for each reaction product were determined by GC-FID on an Agilent Technologies 7890A spectrometer, with a HP-5 column (30m×0.25mm×0.25μm) using undecane as internal standard. TOF was defined as moles of products per mol Rh at the surface of the NPs per hour.

Reference： [1] Journal of Catalysis, 2017, vol. 354, p. 113 - 127

2
[ 383865-57-4 ]
[ 657-36-3 ]

Reference： [1] Patent: US2002/45615, 2002, A1,

[ 657-36-3 ] Synthesis Path-Downstream 1~110

1
[ 657-36-3 ]
[ 70032-25-6 ]
[ 99726-79-1 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 394 - 404

2
[ 794533-95-2 ]
[ 657-36-3 ]
1-(4-benzenesulfonyl-4-methyl-pentyl)-3-trifluoromethyl-piperidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1255 - 1258

3
[ 617716-51-5 ]
[ 657-36-3 ]
N,2-dicyclopropyl-5-methyl-6-[4-(trifluoromethyl)piperidin-1-yl]-4-pyrimidinamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1834 - 1839

4
[ 892403-92-8 ]
[ 657-36-3 ]
4-(4-methoxy-phenyl)-2-methyl-7-[3-(4-trifluoromethyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro-isoquinoline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 702 - 706

5
1-(6-chloromethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-2-one [ No CAS ]
[ 657-36-3 ]
4-[2-(4-fluoro-phenyl)-ethyl]-1-[6-(4-trifluoromethyl-piperidin-1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-piperazin-2-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 819 - 822

6
[ 657-36-3 ]
[ 1004528-38-4 ]
N-(2-(1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)-4-(trifluoromethyl)piperidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With caesium carbonate; In ethanol; at 160℃; for 0.5h;	To phenyl 2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethylcarbamate (209 mg, 0.5 mmol) were added A- (trifluoromethyl) piperidine (77 mg, 0.5 mmol), cesium carbonate (163, 0.5 mmol) and EtOH (0.5 mL) . The mixture was heated to 1600C for 30 minutes then cooled down and purified by MPLC (DCM/MeOH 97/3) to yield N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -4- (trifluoromethyl) piperidine-1-carboxamide as a white solid (78 mg, 33percent) . Crystallized from AcOEt/hexanes: 1H NMR (400 MHz, DMSO-de) delta 1.15-1.32 (m, 2H), 1.70-1.80 (m, 2H), 2.64-2.74 (m, 2H), 3.15-3.22 (m, 2H), 3.26-3.33 (m, 4H), 4.00-4.08 (m, IH), 6.70 (t, IH, J = 5.5 Hz), 7.45-7.50 (m, IH), 7.58-7.64 (m, 2H) , 7.78-7.84 (m, 2H), 8.38 (t, IH, J = 5.5 Hz), 9.05 (s, IH); m/z (APCI pos) 478.1 (100percent) [M+H] .

Reference： [1]Patent: WO2008/11130,2008,A2 .Location in patent: Page/Page column 218-219

7
[ 659731-34-7 ]
[ 657-36-3 ]
C₁₉H₁₈N₅O₂SF₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3528 - 3539

8
[ 657-36-3 ]
[ 1373219-20-5 ]
1-(4-benzenesulfonyl-3,3-dimethylbutyl)-4-trifluoromethylpiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; In methanol; for 1h;	Sodium cyanoborohydride (78 mg, 1.2 mmol) was added to a stirred solution of the crude 4-benzenesulfonyl-3,3-dimethyl-butyraldehyde (240 mg, 1 mmol) and <strong>[657-36-3]4-trifluoromethylpiperidine</strong> (321 mg, 2.1 mmol) in methanol (4 ml). The mixture was stirred for 1 hour, quenched with sat. aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica (dichloromethane:methanol) to give the title product. [0332] deltaH (360 MHz, CDCl3): 7.91 (2H, m), 7.64 (1H, m), 7.56 (2H, m), 3.11 (2H, s), 3.00 (2H, br d, J 11.9 Hz), 2.38 (2H, m), 2.07 (5H, m), 1.72 (2H, m), 1.66-1.50 (2H, m), 1.20 (6H, s); m/z (ES+) 378 (M+H)+.

Reference： [1]Patent: US2004/229864,2004,A1 .Location in patent: Page/Page column 35

9
[ 657-36-3 ]
[ 891862-96-7 ]
N-{1-[3-(1-ethyl-5-[4-(trifluoromethyl)piperidin-1-yl]methyl}-1H-pyrazol-3-yl)phenyl]-1-methylethyl}-2,2,2-trifluoroethanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; triethylamine; In 1,2-dichloro-ethane; for 4h;	Steps 1-4 of Example 1 were repeated, using ethyl hydrazine in place of methyl hydrazine, and using 3-(5-DIMETHOXYMETHYL-1-ETHYL-LH-PYRAZoL-3-YL)-BENZONITRILE from the first step. The resulting aldehyde (50 mg, 0.13 mmol) in 1, 2-DICHLOROETHANE (5 ml) was treated with 4-TRIFLUOROMETHYLPIPERIDINE (21 mg, 0. 14 mmol), triethylamine (35 5 GEL, 0.26 mmol) and sodium TRIACETOXYBOROHYDRIDE (40 MG, 0.20 mmol). The mixture was stirred for 4 h and diluted with DICHLOROMETHANE, washed with saturated aqueous sodium hydrogencarbonate, water, brine, dried (MGS04), filtered and evaporated. The crude product was purified by flash chromatography (2: 1 iso-hexane/ethyl acetate) to give a white foam (45 MG). H NMR (ppm) (CDC13) 8 1.38 (3 H, t, J = 7.2Hz), 1.82 (6 H, s), 2.55 (4 H, s), 3.39-3. 49 (2 H, q, J=8. 2 Hz), 3.58 (2 H, s), 3.74 (4 H, t, J = 4.6Hz), 4.15 (2 H, q, J = 7. 1Hz), 5. 30 (1 H, br s), 6.24 (1 H, s), 7.35 (1 H, d, J = 7.7Hz), 7. 48 (1 H, t, J = 7.7Hz), 7.55 (2 H, M). MS (MH 475.

Reference： [1]Patent: WO2004/89911,2004,A1 .Location in patent: Page 40

10
[ 800400-48-0 ]
[ 657-36-3 ]
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(4-fluorobenzyl)-2-oxo-2-(4-trifluoromethylpiperidin-1-yl)ethyl]amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 96h;	To 4-trifluoromethyl piperidine (17MG, 0. 1 LMMOL) was added a solution OF 2- (S)-[(5-chloro-1H-pyrrolo [2,3-c] pyridine-2-carbonyl) amino]-3- (4- fluorophenyl) propionic acid (EXAMPLE 228,40mg, 0. 1 LMMOL) in DMF (400muL) followed by a solution of HATU (50mg, 0. 13mmol) in DMF (400, UT) and finally a solution of DIPEA (23muL, 0. 13mmol) in DMF (200muL). The resulting mixture was stirred at rt for 96h then solvent was removed in vacuo. The crude material was purified by crystallisation from THF/petroleum ether to give the title compound as a yellow powder. (ES+) = 497.23 [M+ H] + ; RT = 3. 50min.

Reference： [1]Patent: WO2004/104001,2004,A2 .Location in patent: Page 130

11
[ 657-36-3 ]
[ 106-96-7 ]
[ 623948-94-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; In acetonitrile; at 20℃; for 10h;	In a single-necked flask,A solution of 4- (trifluoromethyl) piperidine (1.05 g, 6.86 mmol)And K2CO3 (2.00 g, 11.2 mmol)Was dissolved in MeCN (50 mL)Then 3-bromoprop-1-yne (0.62 mL, 7.19 mmol) was slowly added dropwise,Plus completed,The reaction was stirred at room temperature for 10 h.The reaction mixture was filtered,The filtrate was concentrated,The crude product was isolated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5/1)To give a colorless transparent liquid (1.20 g, 92percent).
32%	With potassium carbonate; In ethanol; at 20℃; for 20h;	4-Trifluoromethylpiperidine (2.0 g, 13 mmol) was added to a solution of propargyl bromide (80 wt. percent 5.4 g, 36 mmol) in ethanol (30 ml). Potassium carbonate (5.4 g, 39 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and the solids washed with ethyl acetate. The filtrate was evaporated in vacuo, diluted with sodium hydrogen carbonate (sat, 50 ml) and extracted with ethyl acetate (2 x 40 ml). The extracts were washed with brine, dried (MgS04) and evaporated in vacuo to provide 1-propargyl-<strong>[657-36-3]4- trifluoromethylpiperidine</strong> as a brown oil (795 mg, 32percent). (ES+) 192 ([MH] +).

Reference： [1]Patent: CN106187838,2016,A .Location in patent: Paragraph 0357; 0358; 0359
[2]Patent: WO2003/93253,2003,A1 .Location in patent: Page/Page column 17-18

12
[ 657-36-3 ]
[ 24424-99-5 ]
[ 623165-99-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In tetrahydrofuran; at 20℃; for 16h;	Triethylamine (8.0 ml), <strong>[657-36-3]4-trifluoromethylpiperidine</strong> (8. 00g) and BOC20 (12.5 g) in THF (100 ml) was stirred for 16 hours at rt. Added water (60 ml) and extracted with EtOAc (3x 50 ml). The combined organic phases were washed with brine (50 ml). Drying, concentration and column chromatography on silica eluting with 5percent EtOAc/hexane gave the BOC- protected amine (12.51 g, 95percent).

Reference： [1]Patent: WO2003/93251,2003,A1 .Location in patent: Page/Page column 35

13
[ 657-36-3 ]
C₂₀H₂₄BrF₃N₂O₂S [ No CAS ]
C₂₆H₃₃F₆N₃O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	A solution of the alcohol from Step 1 (60 mg) in dry DCM (3 ml) was cooled to-30°C. Added PBr3 (0.07 ml, 1. OM in DCM) dropwise and allowed to warm to 0°C over 1 hr. Added saturated sodium bicarbonate solution and filtered through celite, washing with DCM. The layers were separated and the organics dried (MgS04), filtered and evaporated. The crude allylic bromide was dissolved in DCM (2 ml) then <strong>[657-36-3]4- trifluoromethylpiperidine</strong> (85 mg) and DIPEA (90 mg) were added and the reaction was stirred for 16 hours at rt. Added water (10 ml) and extracted with DCM (3x 10 ml), the combined organic phases were washed with brine (20 ml), dried (MgS04), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 15percent EtOAc/hexane then dissolved in Et20/MeOH, cooled to 0°C and bubbled in HCl for 5 mins. Concentrated and triturated with Et20 to give the desired compound (HCl salt) as a white powder (55 mg, 65percent). 1H NMR (360MHz, MeOH) OH 1. 19 (2H, m), 1.76 (2H, m), 1.95 (2H, m), 2.06 (3H, s), 2.21 (2H, m), 2.45 (2H, m), 2.65 (3H, m), 3.06 (2H, m), 3.31 (2H, m), 3.50 (2H, s), 3.68 (2H, m), 3.85 (4H, m), 6.74 (1H, s), 7.13 (3H, m). MS (ES+) 566, MH+.

Reference： [1]Patent: WO2003/93251,2003,A1 .Location in patent: Page/Page column 27-28

14
[ 657-36-3 ]
C₂₀H₂₁BrF₃N₃O₃S [ No CAS ]
C₂₆H₃₀F₆N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Phosphorus tribromide (1.0 M in dichloromethane, 115 FL, 0.115 mmol) was added to a solution of the alcohol from Step 1 (100 mg, 0.23 mmol) in dry dichloromethane (2 mL) at 0°C under nitrogen. The reaction was stirred at 0°C for 30 minutes, then at room temperature for 1 hour. The reaction was recooled in an ice bath, then quenched with saturated aqueous sodium hydrogen carbonate (2 mL). The mixture was partitioned between dichloromethane and water, the layers separated and the aqueous layer extracted with dichloromethane (x2). The combined extracts were washed with brine (xl), dried (Na2SO4), filtered and evaporated to give the allylic bromide. This was used without further purification. The bromide was taken up in dry dichloromethane (1 mL) at room temperature under nitrogen. Diisopropylethylamine (200 fiL, 1.15 mmol) and <strong>[657-36-3]4-trifluoromethylpiperidine</strong> (150 mg, 1.0 mmol) were added. The solution was stirred at room temperature overnight, then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane (x2), and the combined extracts washed with brine (xl), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 2-4 4--> 6-4 8percent ethyl acetate/dichloromethane, to give the amine (55 mg, 41percent) as a colourless solid: 1H NMR (360MHz, CDC13) on 1. 29-1. 34 (2H, m), 1.67-1. 76 (4H, m), 1.84-1. 88 (2H, m), 1.98-2. 12 (3H, m), 2.22-2. 50 (2H, m), 2.74 (2H, dd, J= 16.1, 7.7), 3.01-3. 06 (2H, m), 3.20-3. 27 (4H, m), 3.43 (2H, s), 3.68 (2H, q, J= 8.7), 4.69 (1H, s), 7.02 (1H, s), 7.16 (1H, d, J= 7.9), 7.49 (1H, s), 7.59 (1H, d, J= 7.9). MS (ES+) 577, MH+.

Reference： [1]Patent: WO2003/93251,2003,A1 .Location in patent: Page/Page column 29-30

15
[ 657-36-3 ]
C₂₀H₂₃F₃N₂O₃S [ No CAS ]
C₂₅H₃₁F₆N₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With tetrakis(triphenylphosphine) palladium(0); benzoic acid; In 1,4-dioxane; for 65h;Heating / reflux;	A solution of the product of Step 1 (24 mg, 0.06 mmol), 4- trifluoromethyl piperidine (9 mg, 0.05 mmol), benzoic acid (0. 1M in dioxane, 60 pi, 0.0066 mmol) and tetrakis-triphenylphospine palladium (0) (4 mg, 5 molpercent) in dioxane (0.4 ml) was degassed and heated at reflux for 65 hours. The reaction was purified by SCX ion exchange resin eluting with ammonia (2M in methanol) to give after evaporation a pale gum. The gum was further purified by preparative TLC eluting with ethyl acetate to give a pale gum (5 mg, 15percent). 8 (iH, 360 MHz, CDC13) 1.25-1. 41 (2H, m), 1.53-2. 04 (7H, m), 2.13-2. 19 (2H, m), 2.44-2. 55 (3H, m), 2. 65-2. 72 (3H, m), 2.87-2. 91 (1H, m), 3.05 (1H, d, J = 11. 2 Hz), 3.16-3. 32 (3H, m), 3.43 (2H, s), 3.55-3. 71 (4H, m), 4.72 (1H, brs), 6.08 (1H, dd, J = 16.0 8. 9 Hz), 6.48 (1H, d, J = 16.0 Hz) and 7.04-7. 15 (3 H, m). (ES+) 582 ([MH] +).

Reference： [1]Patent: WO2003/93251,2003,A1 .Location in patent: Page/Page column 34-35

16
[ 657-36-3 ]
[ 912934-69-1 ]
(6-((2,6-dichlorophenylthio)methyl)pyridin-2-yl)(4-(trifluoromethyl)piperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 10h;	To a solution of compound 13D (0.1 mmol) in DMF (2 mL) was added <strong>[657-36-3]4-(trifluoromethyl)piperidine</strong> (0.12 mmol), PyAOP (0.1 mmol), and DIEA (0.15 mmol). The reaction was stirred vigorously for 10 h. After the DMF solvent was removed by Speed Vac, the residue was purified by Prep-HPLC to give Example 13. LC/MS m/z 449 (M+H). 1H NMR (500 MHz, CDCl3): delta 1.57 (m, 2H), 1.80 (dd, 2H), 2.23 (m, 1H), 2.78 (t, 2H), 4.14 (s, 2H), 4.35 (dd, 2H), 7.09 (m, 2H), 7.25 (d, 2H), 7.43 (d, 1H), 7.58 (t, 1H).

Reference： [1]Patent: US2006/235028,2006,A1 .Location in patent: Page/Page column 29-30

17
[ 657-36-3 ]
[ 877868-77-4 ]
1-[3-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzyl]-4-(trifluoromethyl)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 20℃;	To a solution of 3-({4-[E)-2-(2,4-difluorophenyl)vinyl]phenyl } sulfonyl)benzaldehyde (Example 50 Step 1,100 mg, 0.26 mmol) and <strong>[657-36-3]4-(trifluoromethyl)piperidine</strong> (0.04 mL, 0.28 mmol) in tetrahydrofuran (1 mL) was added triacetoxyborohydride (83 mg, 0.39 mmol) in one portion and the reaction stirred overnight at room temperature. 4N sodium hydroxide was added and the products extracted into ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution and water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25percent ethyl acetate/isohexane to yield the title compound as an oily solid which was treated with ethereal HCI to give the hydrochloride salt (96 mg, 66percent). deltaH (400 MHz, d6 DMSO): 8.26 (1 H, s), 8.03-7.95 (3 H, m), 7.89-7.83 (4 H, m), 7.71 (1 H, t, J = 7.6 Hz), 7.44-7.28 (3 H, m), 7.16 (1 H, td, J = 1.8, 8.3 Hz), 4.40 (2 H, s), 3.43-3.38 (2 H, m), 3.00-2.92 (1 H, m), 2.67-2.60 (1 H, m), 2.03-1.97 (2 H, m), 1.86-1.80 (2 H, m). m/z (ES+) 522 [MH+].

Reference： [1]Patent: WO2006/21805,2006,A1 .Location in patent: Page/Page column 50

18
[ 657-36-3 ]
[ 812694-98-7 ]
C₁₆H₁₉F₃N₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 392 - 395

19
[ 657-36-3 ]
[ 1184727-99-8 ]
[ 1184728-10-6 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5262 - 5268
[2]Patent: US2012/29018,2012,A1 .Location in patent: Page/Page column 6

20
[ 657-36-3 ]
[ 1159705-98-2 ]
[ 1159705-90-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3441 - 3444

21
[ 657-36-3 ]
[ 1187878-06-3 ]
[ 1187878-36-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4692 - 4697

22
[ 657-36-3 ]
[ 1233478-96-0 ]
[ 1233479-29-2 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure for 9-(ammomethyl)-5,10-dihydro-4H-mdeno[l,2- b]thieno[3,2-d]pyridin-4-one (29): A mixture of bromo compound (28) (100 mg, 0.3 mmol), amine (excess) in ethanol (2 ml) was refluxed for 16 hr. The solvent was evaporated and the mixture was suspended in DMF (4 ml), DMSO (0.5 ml) and TFA (2 ml) and filtered. The filtrate was purified by silica gel column and followed by reverse phase chromatography.; 5.3 Examples; The following examples were prepared according to the methods, schemes and experimental described above.; Example 47: 9-((4-(trifluoromethyl)piperidin-l-yl)methyl)-5,10-dihydro-4H- indeno[l,2-b]thieno[3,2-d]pyridin-4-one; 1H NMR (DMSO-d6): d 12.62 (bs, IH), 9.63 (bs, IH), 8.23 (s, IH), 8.16 (s, IH), 7.58 (m, 2H), 7.42 (m, IH), 4.51 (m, 2H), 4.05 (s, 2H), 3.52 (m, 2H), 3.17 (m, 2H), 2.73 (m, IH), 2.03 (m, 2H), 1.75 (m, 2H) .MS: m/z 405.20 (M-H+).

Reference： [1]Patent: WO2010/77663,2010,A2 .Location in patent: Page/Page column 77; 94-95; 99; 125-126

23
[ 657-36-3 ]
[ 1233478-98-2 ]
[ 1233479-32-7 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure for 9-(aminomethyl)-5,10-dihydro-4H-indeno[l,2- b]thieno[2,3-d]pyridin-4-one (36): A mixture of bromo compound (35) (100 mg, 0.3 mmol), amine (excess) in ethanol (2 ml) was reflux ed for 16 hr. The solvent was evaporated and the mixture was suspended in DMF (4 ml), DMSO (0.5 ml) and TFA (2 ml) and filtered. The filtrate was purified by silica gel column and followed by reverse phase chromatography.; 5.3 Examples; The following examples were prepared according to the methods, schemes and experimental described above.; Example 54: 9-((4-(trifluoromethyI)piperidin-l-yl)methyI)-5,10-dihydro-4H- indeno [ 1 ,2-b] thieno [2,3-d] py ridin-4-one; 1H NMR (DMSO-d6):d 12.59 (bs, IH), 9.53 (bs, IH). 8.13 (d, J= 2.0 Hz, IH), 7.63 (d, J= 2.0 Hz, IH), 7.49 (m, 3H), 4.51 (s, 2H), 4.05 (s, 2H), 3.58 (d, J= 8.0 Hz, 2H), 3.19 (m, 2H), 2.65 (m, IH), 2.03 (m, 2H) 1.78 (m, 2H).MS: m/z 405.2 (M-H+).

Reference： [1]Patent: WO2010/77663,2010,A2 .Location in patent: Page/Page column 77; 95; 99; 130

24
[ 657-36-3 ]
[ 1257397-40-2 ]
[ 1765-93-1 ]
[ 1257397-68-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	In 2,3,4-trifluorotoluene; at 120℃; for 0.166667h;microwave irradiation;	Step 1methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-1-yl)methyl)-3-hydroxyphenyl)acetate The mixture methyl 2-(4-formyl-3-hydroxyphenyl)acetate (intermediate 1) (930 mg, 4.79 mmol), 4-fluorophenylboronic acid (737 mg, 5.26 mmol), <strong>[657-36-3]4-trifluoromethyl-piperidine</strong> (115 mg, 7.18 mmol) in 5 mL of trifluoro-toluene was heated using microwave irradiation at 12O0C for 10 minutes. The organic solvent was then removed to give a crude product, which was purified by flash chromatography on silica (15-25percent EtOAc in hexane) to give the desired methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l- yl)methyl)-3-hydroxyphenyl)acetate as a colorless oil (1.67 g, 82percent). 1H NMR (400MHz ,DMSO-de) delta = 10.36 (s, 1 H), 7.42 (dd, J= 5.6, 8.4 Hz, 2 H), 7.22 - 7.05 (m, 3 H), 6.72 - 6.59 (m, 2 H), 4.69 (s, 1 H), 3.58 (s, 3 H), 3.51 (s, 2 H), 3.05 - 2.94 (m, 1 H), 2.81 - 2.71 (m, 1 H), 2.40 - 2.31 (m, 1 H), 2.02 - 1.86 (m, 2 H), 1.85 - 1.72 (m, 2 H), 1.59 - 1.39 (m, 2 H); LCMS m/z 426.2 [M+ 1]+.

Reference： [1]Patent: WO2010/138901,2010,A1 .Location in patent: Page/Page column 126-127
[2]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 786 - 791

25
[ 657-36-3 ]
C₃₉H₅₄O₁₁ [ No CAS ]
[ 1299470-59-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1634 - 1638

26
[ 657-36-3 ]
[ 1257397-46-8 ]
[ 1765-93-1 ]
C₂₃H₂₅F₄NO₃ [ No CAS ]