[ CAS No. 277756-45-3 ] {[proInfo.proName]}

Name: 277756-45-3|1-(Trifluoromethyl)cyclobutanecarboxylic acid|98%
Brand: Ambeed
SKU: A103627
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Quality Control of [ 277756-45-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 277756-45-3 ]

SDS Specification

Alternatived Products of [ 277756-45-3 ]

Product Details of [ 277756-45-3 ]

CAS No. :	277756-45-3	MDL No. :	MFCD03425197
Formula :	C₆H₇F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HYRCPSRIIWIESW-UHFFFAOYSA-N
M.W :	168.11	Pubchem ID :	2782838
Synonyms :

Calculated chemistry of [ 277756-45-3 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	30.54
TPSA :	37.3 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) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.21
Log Po/w (XLOGP3) :	1.72
Log Po/w (WLOGP) :	3.06
Log Po/w (MLOGP) :	1.4
Log Po/w (SILICOS-IT) :	1.81
Consensus Log Po/w :	1.84

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.83
Solubility :	2.46 mg/ml ; 0.0147 mol/l
Class :	Very soluble
Log S (Ali) :	-2.12
Solubility :	1.28 mg/ml ; 0.0076 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.23
Solubility :	9.88 mg/ml ; 0.0587 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 277756-45-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 277756-45-3 ]

* 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 [ 277756-45-3 ]
Downstream synthetic route of [ 277756-45-3 ]

[ 277756-45-3 ] Synthesis Path-Upstream 1~2

1
[ 5445-51-2 ]
[ 277756-45-3 ]

Reference： [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 141 - 146

2
[ 3779-29-1 ]
[ 277756-45-3 ]

Reference： [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 141 - 146

[ 277756-45-3 ] Synthesis Path-Downstream 1~88

1
[ 277756-45-3 ]
[ 1033538-21-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; In dichloromethane; at 20℃; for 1h;	l-Chloro-N,N,2-trimethyl-l-propenylamine (332 mg, 2.5 mmol) was added to a solution of l-(trifluoromethyl)cyclobutanecarboxylic acid (418 mg, 2.5 mmol) in methylene chloride (3 mL) and the reaction left to stir at rt for 1 h to afford a acyl chloride solution. Ethylmagnesium EPO <DP n="126"/>bromide (3 M in diethyl ether) (0.46 mL, 1.4 mmol) was added to a solution of 4-iodo-N,N- dimethyl-2-[2-(4-pyridin-2-ylphenyl)ethyl]-lH-imidazole-l -sulfonamide (600 mg, 1.2 mmol) in methylene chloride (12 mL) at it After stirring at rt for 30 min, CuCN-2LiCl (1 M in THF; 1.37 mL, 1.37 mmol) was added followed by the above acyl chloride solution, and the reaction was stirred for 2 hr. The reaction mixture was diluted with methylene chloride and poured into half saturated aqueous ammonium chloride. The aqueous phase was extracted with methylene chloride, and the extracts were dried (sodium sulfate) and concentrated in vacuo. Chromatography of the resulting residue over silica gel eluting with 40-100percent ethyl acetate/hexane afforded N,N-dimethyl-2-[2-(4-pyridin-2-ylphenyl)ethyl]-4- { [ 1 -(trifluoromethyl)- cyclobutyljcarbonyl} - lH-imidazole- 1 -sulfonamide.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane;	Compound 1-243[00517] To a solution of l-(trifluoromethyl)cyclobutanecarboxylic acid (18 equiv) in dichloromethane was added oxalyl chloride (16 equiv) and catalytic N,N- dimethylformamide. Once gas evolution ceased, this crude reaction mixture was added portion- wise to a suspension of Compound 1-107 (1 equiv) in dichloromethane/pyridine (2:1) until complete consumption of starting material was observed by LS/MS. Purification via silica gel chromatography (0-10percent methanol in dichloromethane) following an aqueous ammonium chloride and dichloromethane workup provided the desired compound as a white solid (74percent).1H NMR (400 MHz, CD3OD) delta 8.76 (d, IH), 8.16 (s, IH), 7.44 (s, IH), 7.29-7.24 (m, IH), 7.11-7.06 (m, IH), 7.03 (t, IH), 6.87-6.81 (m, 2H), 5.96 (s, 2H), 2.85-2.77 (m, 2H), 2.58-2.51 (m, 2H), 2.14-1.97 (m, 2H).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h;	To a 0 °C solution of 1-trifluoromethyl-l-cyclobutylcarboxylic acid (1.50 g, 8.92 mmol) in DCM (15 mL) was added oxalyl chloride (1.50 g, 11.82 mmol) followed by catalytic amount of DMF. The reaction mixture was stirred at RT for 1 h. The solvent from the reaction mixture was completely evaporated. In a different flask, a suspension of semicarbazide hydrochloride (1.50 g, 13.45 mmol) in water (15mL) was treated with NaHC03 (1.50 g, 17.86 mmol) and stirred at RT for 30 minutes till a clear solution forms. To this solution was added the above acid chloride dissolved in EtOAc (20 mL) and the resultant mixture was stirred at RT over night. The organic layer was separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were concentrated and the residue was treated with sodium hydroxide (1.50 g, 37.5 mmol) in water (15 mL), heated at 100 °C for 3 h, and stirred for 20 h at RT. The reaction mixture was acidified with cone. HCl to pH 1 and stirrred at RT for 1 h. The reaction mixture was concentrated to a small volume under high vacuum and diluted with MeOH. The separted solids were filtered and washed with methanol. The filtrate was evaporated and further dried by azeotropic distillation from toluene to provide 5-(l- (trifluoromethyl)cyclobutyl)-2,4-dihydro-3H-l ,2,4-triazol-3-one (1.05 g, 57percent) as a light brownish residue, sutiable for use without further purification.

Reference： [1]Patent: WO2008/51405,2008,A1 .Location in patent: Page/Page column 124-125
[2]Patent: WO2012/3405,2012,A1 .Location in patent: Page/Page column 278
[3]Patent: WO2014/145023,2014,A1 .Location in patent: Paragraph 0390

2
[ 98-59-9 ]
[ 277756-45-3 ]
[ 1038404-00-0 ]

Yield	Reaction Conditions	Operation in experiment
68%		[0374] Toluene-4-sulfonic acid l-trifluoromethyl-cyclobutylmethyl ester(90); 1-Tpifluoromethyl-cyclobutanecarboxylic acid (89) (1 5 g, 8 93 mmol) was dissolved in anhydrous Et2O (I5 mL) The solution was chilled to 0 0C A 2M solution of LAH in THF (5 mL, 10 mmol) was added dropwise to the stirring solution The mixture stirred at 0 0C for 30 mm and at room temperature for 3 h The excess LAH was quenched by the careful addition of water (20 mL) The mixture was diluted with Et2O (20 mL) and washed with IM HCl (25 mL) The aqueous layer <n="175"/>was back extracted with Et2psi (2 x 15 mL) The combined organic extracts were dried over MgSpsi4 and filtered Tpiethylamine (1 63 mL, 11 6 mmol), 4-methyl- benzenesulfonyl chloride (1 87 g, 9 82 mmol) and dimethyl-pypidin-4-yl-amine (0 893 g) were added to the ether solution The mixture stirred at room temperature for 16h Only starting materials were observed The mixture was concentrated under partial vacuum to afford a thick oil The oil was dissolved in CH2CI2 (50 mL) and stirred at 45 0C for 16 h The mixture was diluted with CH2Cl2 (50 mL), washed with IM HCl (25 mL), aqueous saturated NaHCpsi3 (25 mL), brine (25 mL) and passed through a plug of silica gel The filtrate was concentrated in vacuo to afford the desired product, toluene-4-sulfonic acid l-trifluoromethyl-cyclobutylmethyl ester (90) (1 86 g, 6 mmol, 68 percent), as a clear oil 1H NMR (400 MHz, DMSO-rf6) delta 1 81 - 1 97 (m, 4H), 2 11 - 2 22 (m, 2H), 2 42 (s, 3H), 426 (s, 2H), 748 (d, 2H, J = 8 4 Hz), 7 80 (d, 2H, J= 7 7 Hz)

Reference： [1]Patent: WO2008/82725,2008,A1 .Location in patent: Page/Page column 173-174

3
4-hydroxymethylphenoxymethyl polystyrene resin [ No CAS ]
[ 277756-45-3 ]
C₁₃H₁₃F₃NO₃Pol [ No CAS ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 638 - 643

4
[ 936019-95-3 ]
[ 277756-45-3 ]
[ 936018-09-6 ]

Yield	Reaction Conditions	Operation in experiment
53%		Example 1-26General Procedure (A)1-Trifluoromethyl-cyclobutanecarboxylic Acid Methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzyl]-amide To a solution of 1-trifluoromethyl-cyclobutanecarboxylic acid (33.6 mg, 0.2 mmol) in THF (5 mL) was added with stirring HOBt (27 mg, 0.2 mmol) followed by EDAC (38 mg, 0.2 mmol) and the mixture was stirred for 30 min. at ambient temperature. To the resulting mixture was added (4-methylaminomethyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (50 mg, 0.17 mmol, Example 1) and DIPEA (35 muL, 0.2 mmol). The reaction mixture was stirred for 16 h. at ambient temperature. The solvent was evaporated and the residue purified using preparative HPLC (Method Z4): Amount isolated=40 mg (53percent) of the title compound as an oil.1H NMR (400 MHz, CDCl3) delta 0.94 (d, 3H), 1.04 (d, 3H), 1.13 (d, 3H), 1.17-1.60 (m, 4.5H), 1.75-1.90 (m, 2H), 2.10 (m, 1H), 2.24 (m, 0.5H), 2.55 (m, 2H), 2.73 (m, 2H), 2.83+2.86 (2.x.s, 3H, rotamers), 3.15 (d, 0.5H), 3.26 (t, 1H), 3.60 (d, 0.5H), 3.98 (bs, 0.5H), 4.46 (bs, 0.5H), 4.63 (m, 2H), 7.29 (m, 2H), 7.40 (t, 2H).HPLC-MS (Method Z1): m/z=451 (M+1); tr=2.18 min.

Reference： [1]Patent: US2009/124598,2009,A1 .Location in patent: Page/Page column 37

5
[ 939427-07-3 ]
[ 277756-45-3 ]
(S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(1-(trifluoromethyl)cyclobutyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		To a solution of <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (54 mg, 0.354 mmol) in toluene (0.9 mL) was added TEA (35.5 mg, 0.354 mmol), followed by DPPA (76.4 muL, 0.354 mmol). The reaction mixture was heated at 90° C. for 2 h, then allowed to cool to room temperature. (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (51 mg, 0.117 mmol) was added and the reaction mixture was stirred for 4.5 hr at room temperature. The reaction mixture was concentrated and purified first by ISCO chromatography (12 g column) using hexanes/EtOAc (0-30percent over 18 min) and then by preparative HPLC Shimadzu-AXIA column, 30.x.100 mm eluting with 40-100percent MeOH (90percent in H2O, 0.1percent TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. 1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(1-(trifluoromethyl)cyclobutyl)urea was isolated as a white solid (49 mg, 69percent yield). LCMS: RT=4.10 min [M+H] 608.15 (LCMS Method 1); NMR: 400 MHz 1H (CDCl3) 8.25 ppm, 1H, d, J=2.5 Hz; 7.66 ppm, 1H, dd, J=8.6, 2.5 Hz; 7.14 ppm, 7H, m; 6.86 ppm, 1H, d, J=8.8 Hz; 6.61 ppm, 2H, d, J=7.1 Hz; 5.86 ppm, 1H, t, J=53 Hz; 4.73 ppm, 1H, s; 4.39 ppm, 1H, d, J=12.9 Hz; 3.52 ppm, 1H, d, J=12.9 Hz; 2.47 ppm, 2H, m; 2.27 ppm, 2H, m; 1.97 ppm, 2H, m.

Reference： [1]Patent: US2007/161685,2007,A1 .Location in patent: Page/Page column 454-455

6
[ 6638-79-5 ]
[ 277756-45-3 ]
[ 1211521-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In dichloromethane;	HATU (14.9 g, 39.3 mmol, 1.1 equiv) and N,O-dimethylhydroxylamine hydrochloride (3.9 g, 39.3 mmol, 1.1 equiv) were charged into a round-bottomed flask containing 200 mL dichloromethane. Triethylamine (14.9 mL, 107 mmol, 3.0 equiv) was added, and then a solution of <strong>[277756-45-3](1-trifluoromethyl)cyclobutanecarboxylic acid</strong> (6.0 g, 35.7 mmol, 1.0 equiv) in DCM (25 mL) was added. The reaction was stirred at room temperature until complete consumption of the carboxylic acid. The solution was concentrated in vacuo to remove volatiles and the residue was partitioned between DCM (200 mL) and saturated NH4Cl (100 mL). The aqueous was extract with DCM (200 mL) and the combined organics were dried over Na2SO4 and then concentrated. The crude was purified by silica gel chromatography to afford the product (5.64 g, 27 mmol, 75percent yield) as colorless oil.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1893 - 1901
[2]Patent: US2011/20278,2011,A1 .Location in patent: Page/Page column 111

7
[ 277756-45-3 ]
[ 371917-16-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃;	1-Trifluoromethyl-cyclobutanecarboxylic acid (5.0 g, 30. mmol) was dissolved in diethyl ether (60 mL) and cooled to 0 "C. Lithium aluminum hydride (38.66 mL, 1M in diethyl ether) was added dropwise and the solution was allowed to warm to room temperature overnight. The reaction solution was cooled to 0 °C with stirring, and sodium sulfate decahydrate was added, which resulted in gradual evolution of gas. Portionwise addition was continued until no more bubbling was observed at room temperature. The reaction solution was then filtered over a bed of Celite, washing with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.44 g of a mixture containing the desired product and some diethyl ether residue (36percent by NMR integration). This afforded 1-trifluoromethyl-cyclobutyl-methanol (3.46 g, 78percent) as a colorless oil. H NMR (250MHz, CDC13) delta (ppm): 3.82 (s, 2H), 2.39-2.14 (m, 2H), 2.10-1.85 (m, 4H).
78%	With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃;	1-Trifluoromethyl-cyclobutanecarboxylic acid (5.0 g, 30. mmol) was dissolved in diethyl ether (60 mL) and cooled to 0 C. Lithium aluminum hydride (38.66 mL, 1 M in diethyl ether) was added dropwise, and the solution was allowed to warm to room temperature overnight. The reaction solution was cooled to 0 C with stirring, and sodium sulfate decahydrate was added, which resulted in gradual evolution of gas. Portionwise addition was continued until no more bubbling was observed at room temperature. The reaction solution was then filtered over a bed of Celite, washing with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.44 g of a mixture containing the desired product and some diethyl ether residue (36percent by NMR integration). This afforded 1-trifluoromethyl-cyclobutyl-methanol (3.46 g, 78percent) as a colorless oil.1H NMR (250 MHz, CDCl3) delta (ppm): 3.82 (s, 2H), 2.39-2.14 (m, 2H), 2.10-1.85 (m, 4H).
		To an ice -cooled solution of l-(trifluoromethyl)cyclobutanecarboxylic acid (1.1 g, 6.54 mmol) in Et20 (15 mL), 2 M Lithium aluminum hydride in THF (5 mL, 10.00 mmol) was added slowly. After stirring for 1 h under ice-cooling, the mixture was allowed to warm to room temperature. After 18 h, the mixture was quenched with wet Et20 and then, 20 mL of 2 M HC1 was added. The mixture was transferred into a separatory funnel and extracted four times with ca. 100 mL Et20. Combined organic phases were dried over MgS04, filtered, and concentrated to give the title compound (ca. 37percent pure, 1.96 g, 4.71 mmol, 71.9 percent yield) as a colorless liquid (which still contained ca. 27percent THF and ca. 36percent Et20). lU NMR (400 MHz, CDC13) delta ppm 1.67 (m, 1H), 1.96-2.05 (m, 4H), 2.24-2.32 (m, 2H), 3.81-3.82 (d, J = 6.1 Hz, 2H).

With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 1h;Inert atmosphere;

Step 1: Synthesis of ( 1 -(trifluoromethyl)cyclobutyl)methanol:To a stirred solution of Lithium aluminium hydride (2.7 g) in dry ether (80 ml), l-(trifluoromethyl)cyclobutanecarboxylic acid (6 g) was added at 0 °C under N2 atmosphere and the reaction mixture was stirred for about 1 h at 0 °C. After completion of the reaction (monitored by .H- NMR), the reaction mixture was quenched by cautious addition of water (1 ml), 15 percent aq. NaOH solution (1 ml) and again water (3 ml), with stirring continued for 30 min. The reaction mixture was filtered and cake was washed with ether twice. Due to volatile nature of the compound, only half of the ether volume was reduced on hot water both using without any vacuum and next reaction was proceeded as such. 1H NMR (CDC13, 300 MHz): delta 3.81 (s, 2H), 2.30- 2.26 (m, 2H), 2.06- 1.91 (m, 4H), 1.71 (br s, 1H); ES Mass: (M- H) 152.95.

Reference： [1]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00328; 00329
[2]Patent: WO2018/107100,2018,A1 .Location in patent: Page/Page column 156; 157
[3]Patent: WO2011/127051,2011,A1 .Location in patent: Page/Page column 215; 216
[4]Patent: WO2012/25857,2012,A1 .Location in patent: Page/Page column 43-44

8
[ 277756-45-3 ]
[ 1338556-65-2 ]

Reference： [1]Patent: WO2011/127051,2011,A1

9
[ 277756-45-3 ]
2-(methylsulfonyl)-5-((1r,4r)-4-(1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yloxy)cyclohexyloxy)pyrazine [ No CAS ]

Reference： [1]Patent: WO2011/127051,2011,A1

10
[ 277756-45-3 ]
[ 1354043-34-7 ]

Reference： [1]Patent: WO2012/3405,2012,A1

11
[ 67-56-1 ]
[ 277756-45-3 ]
[ 1188909-22-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1082 - 1105

12
[ 277756-45-3 ]
[ 1188909-23-0 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1082 - 1105

13
[ 277756-45-3 ]
[ 1188909-21-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1082 - 1105

14
[ 277756-45-3 ]
[ 1188909-24-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1082 - 1105

15
[ 277756-45-3 ]
[ 1188909-25-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1082 - 1105

16
[ 277756-45-3 ]
[ 1038404-00-0 ]

Reference： [1]Patent: WO2012/25857,2012,A1

17
[ 277756-45-3 ]
[ 1360569-33-0 ]

Reference： [1]Patent: WO2012/25857,2012,A1

18
[ 277756-45-3 ]
[ 1360569-36-3 ]

Reference： [1]Patent: WO2012/25857,2012,A1

19
[ 277756-45-3 ]
[ 1360569-35-2 ]

Reference： [1]Patent: WO2012/25857,2012,A1

20
[ 277756-45-3 ]
[ 1360569-44-3 ]

Reference： [1]Patent: WO2012/25857,2012,A1

21
[ 277756-45-3 ]
[ 1360569-43-2 ]

Reference： [1]Patent: WO2012/25857,2012,A1

22
[ 277756-45-3 ]
[ 1360568-93-9 ]

Reference： [1]Patent: WO2012/25857,2012,A1

23
[ 277756-45-3 ]
[ 1360568-94-0 ]

Reference： [1]Patent: WO2012/25857,2012,A1

24
[ 277756-45-3 ]
[ 1360568-95-1 ]

Reference： [1]Patent: WO2012/25857,2012,A1

25
[ 277756-45-3 ]
[ 1360569-06-7 ]

Reference： [1]Patent: WO2012/25857,2012,A1

26
[ 277756-45-3 ]
[ 1360569-07-8 ]

Reference： [1]Patent: WO2012/25857,2012,A1

27
[ 277756-45-3 ]
[ 1360569-08-9 ]

Reference： [1]Patent: WO2012/25857,2012,A1

28
[ 277756-45-3 ]
[ 75-65-0 ]
[ 1268883-16-4 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; triethylamine; at 20℃; for 48h;4A Molecular sieve; Inert atmosphere; Reflux;	Step A: Preparation of l-(Trifluoromethyl)cyclobutanamine Hydrochloride.l-(Trifluoromethyl)cyclobutanecarboxylic acid (1 g, 5.95 mmol) and triethylamine (0.912 mL, 6.54 mmol) in anhydrous teri-butanol (20 mL) was stirred at room temperature in the presence of 4A molecular sieves powder. To the mixture was added diphenylphosphorazidate (1.801 g, 6.54 mmol). The reaction mixture was refluxed under N2 for 2 days, filtered, then concentrated in vacuo. The oily residue was stirred in ether, ether layer was isolated. The procedure was repeated three times. The combined organics were washed with 5percent citric acid, saturated aqueous NaHC03 twice, brine, dried over anhydrous Na2S04, and concentrated to give tert-b tyl l-(trifluoromethyl)cyclobutylcarbamate (713 mg) as a white solid. The solid was dissolved in 1.25 N HC1 in methanol solution (10 mL), stirred at 50 °C overnight, and concentrated to give the title compound (493 mg). .H NMR (400 MHz, DMSO- d6) delta 1.87-1.97 (m, 1H), 2.04-2.15 (m, 1H), 2.44-2.50 (m, 4H), 9.40 (br, 3H).

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 1309 - 1313
[2]Patent: WO2012/116279,2012,A1 .Location in patent: Page/Page column 102

29
C₂₇H₃₁F₄N₃O₄ [ No CAS ]
[ 277756-45-3 ]
C₂₈H₂₈F₇N₃O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3640 - 3645

30
1-(4'-(piperidin-4-ylmethoxy)biphenyl-4-yl)ethanone hydrochloride [ No CAS ]
[ 277756-45-3 ]
1-(4'-((1-(1-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-yl)methoxy)biphenyl-4-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 3h;	1-(4'-(piperidin-4-ylmethoxy)biphenyl-4-yl)ethanone hydrochloride (380 mg, 1.10 mmol), <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (185 mg, 1.10 mmol), EDC (421 mg, 2.20 mmol) and HOBt (270 mg, 2.20 mmol) were dissolved in DMF 6 mL. DIPEA (284 mg, 2.20 mmol) was added thereto, and the reaction was performed at 60 °C for 3 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (40 - 50 percent EtOAc / hexane) to yield the title compound as yellow solid (350 mg, 69percent).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 78

31
1-(4-(5-(piperidin-4-ylmethoxy)pyridine-2-yl)phenyl)ethanone hydrochloride [ No CAS ]
[ 277756-45-3 ]
1-(4-(5-((1-(1-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-yl)methoxy)pyridine-2-yl)phenyl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 24h;	1-(4-(5-(piperidin-4-ylmethoxy)pyridine-2-yl)phenyl)ethanone hydrochloride (250 mg, 0.72 mmol), <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (145 mg, 0.87 mmol), EDC (276 mg, 1.44 mmol) and HOBt (195 mg, 1.44 mmol) were dissolved in DMF 2 mL. DIPEA (186 mg, 1.44 mmol) was added thereto. At 50 °C, the reaction was performed for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (40-50 percent EtOAc/hexane) to yield the title compound as white solid (158 mg, 47percent).
47%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 24h;	1-(4-(5-(piperidin-4-ylmethoxy)pyridine-2-yl)phenyl)ethanone hydrochloride (250 mg, 0.72 mmol), <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (145 mg, 0.87 mmol), EDC (276 mg, 1.44 mmol) and HOBt (195 mg, 1.44 mmol) were dissolved in DMF 2 mL. DIPEA (186 mg, 1.44 mmol) was added thereto. At 50° C., the reaction was performed for a day. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (40-50percent EtOAchexane) to yield the title compound as white solid (158 mg, 47percent).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 79; 80
[2]Patent: US2015/166480,2015,A1 .Location in patent: Paragraph 0707

32
2'-fluoro-4'-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride [ No CAS ]
[ 277756-45-3 ]
2'-fluoro-4'-((1-(1-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-yl)methoxy)biphenyl-4-yl 1-(trifluoromethyl)cyclobutanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%		2'-fluoro-4'-(piperidin-4-ylmethoxy)biphenyl-4-ol hydrochloride (1.5 g, 4.44 mmol), <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (1.12 g, 6.66 mmol) and BOP (3.93 g, 8.88 mmol) were dissolved in DMF 6 mL. After stirring for 10 minutes at room temperature, TEA (1.35 g, 13.32 mmol) was added thereto, following with stirring at 50 °C for 8 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous brine solution, dried over MgSO4, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (40 g ISCO silica gel cartridge, EtOAc/hexane) to yield the title compound as white solid (580 mg, 29percent).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 201

33
[ 1126-09-6 ]
[ 277756-45-3 ]
ethyl 1-(1-(trifluoromethyl)cyclobutanecarbonyl)piperidin-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h;	<strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (500 mg, 2.97 mmol), ethyl piperidin-4-carboxylate (514 mg, 3.27 mmol), EDC (1.14 g, 5.94 mmol) and HOBt (803 mg, 5.95 mmol) were dissolved in CH2Cl2 10 mL. DIPEA (1.05 mL, 5.95 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH4Cl aqueous solution, and extracted with EtOAc. The extracted organic layer was dried over MgSO4, and then filtered. The filtrate was purified by silica gel column chromatography (10-30percent EtOAchexane) to yield the title compound as colorless oil (850 mg, 93percent)
82%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h;	1-(trifiuoromethyl)cyclobutanecarboxylic acid (500 mg, 2.97 mmol), ethyl piperidin-4-carboxylate (514 mg, 3.27 mmol), EDC (1.14 g, 5.94 mmol) and HOBt (803 mg, 5.95 mmol) was dissolved in CH2Cl2 10 mL. DIPEA (1.05 mL, 5.95 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH4CI aqueous solution, and extracted with EtOAc. The organic layer was dried over MgSO4, and then filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 percent EtOAc/hexane) to yield the title compound as colorless oil (750 mg, 82percent).
82%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h;	l-(Trifluoromethyl)cyclobutanecarboxylic acid (0.50 g, 2.97 mmol), ethyl piperidin-4- carboxylate (0.51 g, 3.27 mmol), EDC (1.14 g, 5.94 mmol), and HOBt (0.80 mg, 5.95 mmol) were dissolved in CH2C12 (10 mL). DIPEA (1.05 mL, 5.95 mmol) was added thereto. They are reacted at room temperature for 8 hours. To the reaction mixture, saturated NH4C1 aqueous solution and EtOAc were added, And then, the organic layer was extracted from there. The extracted organic lay was dried with MgS04, and filtered. The obtained filtrate was purified by silica gel column chromatography (10-70 percent EtOAc/hexane) to obtain the desired compound (0.75 g, 82percent) as colorless oil .

Reference： [1]Patent: US2015/166480,2015,A1 .Location in patent: Paragraph 1136
[2]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 68
[3]Patent: WO2015/80446,2015,A1 .Location in patent: Page/Page column 24

34
[ 277756-45-3 ]
4-(6-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine-3-yl)benzoic acid [ No CAS ]

Reference： [1]Patent: WO2015/80446,2015,A1
[2]Patent: US2015/166480,2015,A1
[3]Patent: WO2013/187646,2013,A1

35
[ 277756-45-3 ]
methyl 4-(6-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine-3-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2015/80446,2015,A1
[2]Patent: US2015/166480,2015,A1
[3]Patent: WO2013/187646,2013,A1

36
[ 277756-45-3 ]
1-(4'-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-yl)ethanone [ No CAS ]

Reference： [1]Patent: US2015/166480,2015,A1
[2]Patent: WO2013/187646,2013,A1

37
[ 277756-45-3 ]
1-(4'-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)biphenyl-4-yl)ethanol [ No CAS ]

Reference： [1]Patent: US2015/166480,2015,A1
[2]Patent: WO2013/187646,2013,A1

38
[ 277756-45-3 ]
1-(4-(5-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine-2-yl)phenyl)ethanone [ No CAS ]

Reference： [1]Patent: US2015/166480,2015,A1
[2]Patent: WO2013/187646,2013,A1

39
[ 277756-45-3 ]
1-(4-(5-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine-2-yl)phenyl)ethanol [ No CAS ]

Reference： [1]Patent: US2015/166480,2015,A1
[2]Patent: WO2013/187646,2013,A1

40
[ 277756-45-3 ]
5-(4-(methylsulfonyl)phenyl)-2-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine [ No CAS ]

Reference： [1]Patent: US2015/166480,2015,A1
[2]Patent: WO2013/187646,2013,A1

41
[ 277756-45-3 ]
(1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2015/80446,2015,A1
[2]Patent: US2015/166480,2015,A1
[3]Patent: WO2013/187646,2013,A1

42
[ 277756-45-3 ]
5-bromo-2-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)methoxy)pyridine [ No CAS ]

Reference： [1]Patent: WO2015/80446,2015,A1
[2]Patent: US2015/166480,2015,A1
[3]Patent: WO2013/187646,2013,A1

43
[ 277756-45-3 ]
[ 1263101-85-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1893 - 1901

44
[ 277756-45-3 ]
[ 1263101-86-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1893 - 1901

45
[ 277756-45-3 ]
5-(1-(trifluoromethyl)cyclobutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Reference： [1]Patent: WO2014/145023,2014,A1

46
[ 277756-45-3 ]
1-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2014/145023,2014,A1

47
[ 277756-45-3 ]
1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2014/145023,2014,A1

48
4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide [ No CAS ]
[ 3315-16-0 ]
[ 277756-45-3 ]
N-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		Example 72 A solution of 1-trifluoromethyl-cyclobutane-1-carboxylic acid (0.413 g, 2.457 mmol) in DCM (8 mL) was treated with oxalyl chloride (0.179 mL, 2.047 mmol) and DMF (1 drop), stirred for at RT for 2 h, treated with silver cyanate (0.982 g, 6.55 mmol), stirred at RT for 1 h, treated with a solution of 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (0.2 g, 0.819 mmol) and DIEA (0.858 mL, 4.91 mmol) in dioxane (8 mL) and stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth and washed with EtOAc. The filtrate was washed with satd. NaHCO3, water, then brine and the combined aqueous washes were back-extracted with EtOAc. The combined organics were dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford N-methyl-4-((6-(3-(1-(trifluoromethyl)cyclobutanecarbonyl)ureido)pyridin-3-yl)oxy)picolinamide (0.259 g, 72percent). 1H NMR (400 MHz, DMSO-d6): delta 11.16 (br s, 1H), 10.87 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.32 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.81 (dd, J=9.0, 2.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.19 (dd, J=5.6, 2.7 Hz, 1H), 2.78 (d, J=4.8 Hz, 3H), 2.67 (t, J=10.5 Hz, 2H), 2.41 (m, 2H), 1.90-1.87 (m, 2H); MS (ESI) m/z: 438.2 (M+H+).

Reference： [1]Patent: US2014/275016,2014,A1 .Location in patent: Paragraph 0364

49
N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)acetamide [ No CAS ]
[ 3315-16-0 ]
[ 277756-45-3 ]
N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		Example 25 A solution of <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (0.250 g, 1.487 mmol) in DCM (10 mL) was treated with oxalyl chloride (0.180 g, 1.418 mmol) followed by a catalytic amount of DMF and stirred at RT for 1 h. The mixture was treated with silver cyanate (0.250 g, 1.668 mmol), stirred at RT for 2 h, treated with Example A2 (0.200 g, 0.819 mmol) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth, rinsed well with DCM, then THF and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide (140 mg, 37percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 11.14 (br s, 1H), 10.84 (s, 1H), 10.56 (s, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 2.70 (m, 2H), 2.42 (m, 2H), 2.03 (s, 3H), 1.90 (m, 2H); MS (ESI) m/z: 438.1 (M+H+).

Reference： [1]Patent: US2014/275016,2014,A1 .Location in patent: Paragraph 0302

50
[ 1225278-36-3 ]
[ 3315-16-0 ]
[ 277756-45-3 ]
N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		Example 101 A solution of <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (0.250 g, 1.487 mmol) in DCM (10 mL) was treated with oxalyl chloride (0.180 g, 1.418 mmol) followed by a catalytic amount of DMF and stirred at RT for 1 h. The mixture was treated with silver cyanate (0.250 g, 1.668 mmol), stirred at RT for 2 h, treated with Example A2 (0.200 g, 0.748 mmol) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth, rinsed well with DCM, then THF and the filtrate was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide (175 mg, 51%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): delta 11.34 (br s, 1H), 10.84 (s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.25 (s, 1H), 8.05 (br d, J=9.0 Hz, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.68 (m, 2H), 2.41 (m, 2H), 1.97-1.83 (m, 2H); MS (ESI) m/z: 461.1 (M+H+).

Reference： [1]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0543

51
6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine [ No CAS ]
[ 3315-16-0 ]
[ 277756-45-3 ]
N-((6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		Example 102 A solution of <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (0.250 g, 1.487 mmol) in DCM (10 mL) was treated with oxalyl chloride (0.180 g, 1.418 mmol) followed by a catalytic amount of DMF and stirred at RT for 1 h. The mixture was treated with silver cyanate (0.250 g, 1.668 mmol), stirred at RT for 2 h, treated with Example A6 (0.200 g, 0.711 mmol) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth, rinsed well with DCM, then THF and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-((6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide (200 mg, 56percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 11.14 (br s, 1H), 10.78 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.87 (br s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.68 (m, 2H), 2.42 (m, 2H), 2.27 (s, 3H), 1.98-1.82 (m, 2H); MS (ESI) m/z: 475.1 (M+H+).

Reference： [1]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0544

52
4-((4-bromophenoxy)methyl)piperidine hydrochloride [ No CAS ]
[ 277756-45-3 ]
(4-((4-bromophenoxy)methyl)piperidin-1-yl)(1-(trifluoromethyl)cyclobutyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;	4-((4-Bromophenoxy)methyl)piperidine hydrochloride (2.00 g, 6.52 mmol) was dissolved in CH2C12 (40 mL), and then EDC (2.50 g, 13.05 mmol), HOBt (1.76 g, 13.05 mmol), DIPEA (2.31 mL, 13.05 mmol), l-(trifluoromethyl)cyclobutane carboxylic acid (1.09 g, 6.52 mmol) was added thereto. The mixture was stirred at the room temperature for 12 hours. From the reaction mixture, the solvent was removed under reduced pressure. To the obtained concentrate, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHC03 aqueous solution, dried with anhydrous MgS04, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc/hexane = 1 / 4) to obtain white solid (2.10 g, 76percent).

Reference： [1]Patent: WO2015/80446,2015,A1 .Location in patent: Page/Page column 22

53
4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate [ No CAS ]
[ 277756-45-3 ]
(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin-1-yl)(1-(trifluoromethyl)cyclobutyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 10h;	4-((4?-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate [the product of synthesis step 5 of compound 431; 140 mg, 0.37 mmol], <strong>[277756-45-3]1-(trifluoromethyl)cyclobutanecarboxylic acid</strong> (92 mg, 0.55 mmol), EDC (141 mg, 0.73 mmol) and HOBt (99 mg, 0.73 mmol) were dissolved in DMF 2 mL, and then DIPEA (95 mg, 0.73 mmol) was added thereto. At 60° C., the reaction was performed for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50-60percent EtOAchexane) to yield the title compound as white solid (105 mg, 57percent)

Reference： [1]Patent: US2015/166480,2015,A1 .Location in patent: Paragraph 0643

54
4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate [ No CAS ]
[ 277756-45-3 ]
4-((4’-(methylsulfonyl)biphenyl-4-yloxy)methyl)-1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidine [ No CAS ]