[ CAS No. 1174020-40-6 ] {[proInfo.proName]}

Name: 1174020-40-6|(3S,4R)-tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate|97%
Brand: Ambeed
SKU: A192392
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Quality Control of [ 1174020-40-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1174020-40-6 ]

CAS No. :	1174020-40-6	MDL No. :	MFCD18632748
Formula :	C₁₀H₁₈FNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XRNLYXKYODGLMI-JGVFFNPUSA-N
M.W :	219.25	Pubchem ID :	40152147
Synonyms :

Calculated chemistry of [ 1174020-40-6 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	57.81
TPSA :	49.77 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) :	-6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.4
Log Po/w (XLOGP3) :	1.04
Log Po/w (WLOGP) :	1.37
Log Po/w (MLOGP) :	1.01
Log Po/w (SILICOS-IT) :	0.58
Consensus Log Po/w :	1.28

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.66
Solubility :	4.83 mg/ml ; 0.0221 mol/l
Class :	Very soluble
Log S (Ali) :	-1.68
Solubility :	4.63 mg/ml ; 0.0211 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.76
Solubility :	38.5 mg/ml ; 0.176 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.16

Safety of [ 1174020-40-6 ]

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 [ 1174020-40-6 ]

* 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 [ 1174020-40-6 ]

[ 1174020-40-6 ] Synthesis Path-Downstream 1~78

1
[ 1174020-40-6 ]
[ 1254360-87-6 ]
[ 1254361-27-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (3S,4f?)-te/t-butyl 3-fluoro-4-hydroxypiperidine-1- carboxylate (34 mg, 0.16 mmol) in tetrahydrofuran (0.5 mL) was added sodium tert- butoxide (0.17 mL, 0.17 mmol, 1 M in tetrahydrofuran) at room temperature. After 20 minutes this mixture was added to a stirred, cold (0 degrees Celsius), suspension of 5- (6-chloro-5-methylpyrimidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,2-c]pyridazine (Preparation 32) (35 mg, 0.14 mmol) in tetrahydrofuran (0.5 mL). The resulting solution was stirred at 0 degrees Celsius for 80 minutes. The cold bath was removed and the reaction was allowed to warm to room temperature. After 5.5 hours at room temperature the reaction mixture was diluted with water and brine and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine diluted with one volume of water, dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo to 60 mg of a light yellow residue. This material was purified by chromatography using 40 g of basic alumina, eluting with 20% methanol in dichloromethane. The resulting material dissolved in dimethyl sulfoxide (1 mL) and purified by reversed-phase HPLC (Column: Waters XBridge C18 19x100 mm, 5 micrometer); Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 85% water/15% acetonitrile linear to 0% water/ 100% acetonitrile in 8.5 min, hold at 0% water / 100% acetonitrile to 10.0 minutes. Flow: 25mL/min. LCMS (M+H): 431.28

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 110

2
(syn)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Yield	Reaction Conditions	Operation in experiment
	With Chiralpak AD-H; In ethanol; carbon dioxide;Resolution of racemate;	A 1 gram sample of racemic te/t-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute. The wavelength for monitoring the separation was 210 nM. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:(3S.4f?)-te/t-Butyl 3-fluoro-4-hvdroxypiperidine-1-carboxylate, enantiomer 1 (363 mg): Rf = 2.67 min (100% ee) (optical rotation in dichloromethane = +21.2 degrees)(3R4S)-fe/t-Butyl 3-fluoro-4-hvdroxypiperidine-1-carboxylate, enantiomer 2 (403 mg): R, = 2.99 min (88% ee).
	With Chiralpak AD-H column; In ethanol; carbon dioxide;Resolution of racemate;	Enantiomers of ferf-butyl-(3,4-c/s)-3-fluoro-4-hvdroxy-piperidine-1 -carboxylate A 1 gram sample of racemic te/t-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute. The wavelength for monitoring the separation was 210 nM. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:(3S,4/?)-te/t-Butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 1 (363 mg): Rf = 2.67 min (100% ee) (optical rotation in dichloromethane = +21.2 degrees) andThe absolute stereochemistry of the te/t-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate isomers was determined by making a (1 S)-(+)-camphorsulfonic acid salt of 5-(6-((3S,4f?)-3-fluoropiperidin-4-yloxy)-5-methylpyrimidin-4-yl)-1-methyl-1 , 4,5,6- tetrahydropyrrolo[3,4-c]pyrazole (see by analogy the preparation in racemic form below), prepared using enanantiomer 1 above.
	With carbon dioxide; In ethanol;Resolution of racemate;Purification / work up;	A 1 gram sample of racemic ferf-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90: 10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute. The wavelength for monitoring the separation was 210 nM. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:Compound E, Scheme 4) (3S,4/?He/f-Butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 1 (363 mg): R; = 2.67 min (100% ee) (optical rotation in dichloromethane = +21 .2 degrees) and Compound D, Scheme 4) (3 4S)-tert-Butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 2 (403 mg): Rf = 2.99 min (88% ee).

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 67-68
[2]Patent: WO2011/61679,2011,A1 .Location in patent: Page/Page column 42-43; 45
[3]Patent: WO2012/69948,2012,A1 .Location in patent: Page/Page column 83-84

3
[ 211108-48-4 ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Reference： [1]Patent: WO2011/36576,2011,A1
[2]Patent: WO2011/61679,2011,A1
[3]Patent: WO2011/61679,2011,A1
[4]Patent: WO2012/69948,2012,A1
[5]Patent: WO2013/11402,2013,A1

4
[ 211108-50-8 ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Reference： [1]Patent: WO2011/36576,2011,A1
[2]Patent: WO2011/61679,2011,A1
[3]Patent: WO2011/61679,2011,A1
[4]Patent: WO2012/69948,2012,A1
[5]Journal of Organic Chemistry,2013,vol. 78,p. 8892 - 8897
[6]Journal of Organic Chemistry,2013,vol. 78,p. 8892 - 8897
[7]Patent: WO2013/11402,2013,A1

5
[ 79099-07-3 ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Reference： [1]Patent: WO2011/36576,2011,A1
[2]Patent: WO2011/61679,2011,A1
[3]Patent: WO2011/61679,2011,A1
[4]Patent: WO2012/69948,2012,A1
[5]Patent: WO2013/11402,2013,A1

6
(syn)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Yield	Reaction Conditions	Operation in experiment
	With Chiralpak AD-H column; In ethanol; carbon dioxide;Resolution of racemate;	Step D. Enantiomers of ferf-butyl-(3,4-c/s)-3-fluoro-4-hvdroxy-piperidine-1 -carboxylateA 1 gram sample of racemic te/t-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute. The wavelength for monitoring the separation was 210 nM. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chrialpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:iert-butyl-(3,4-c/s)-3-fluoro-4-hydroxy-piperidine-1-carboxylate, enantiomer 1 (363 mg): Rf = 2.67 min (100% ee) and ieri-butyl-(3,4-c/'s)-3-fluoro-4-hydroxy-piperidine-1- carboxylate, enantiomer 2 (403 mg): Rf = 2.99 min (88% ee).

Reference： [1]Patent: WO2011/36576,2011,A1 .Location in patent: Page/Page column 39

7
[ 1208864-35-0 ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Reference： [1]Patent: WO2011/61679,2011,A1
[2]Patent: WO2012/69948,2012,A1

8
[ 1174020-40-6 ]
[ 1308277-99-7 ]
[ 1308278-00-3 ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium tert-butylate; In tetrahydrofuran; at 60℃; for 96h;	(3S.4ffl-fe/t-Butyl 4-(6-(2.3-dihvdro-1 H-imidazon .2-blDyrazol-1 -vn-5- methylpyrimidin-4-yloxy)-3-fluoropiperidine-1 -carboxylateIn a Biotage microwave vial was dissolved 1 -(6-chloro-5-methylpyrimidin-4-yl)- 2,3-dihydro-1 H-imidazo[1 ,2-b]pyrazole (Preparation 14) (105 mg, 0.446 mmol) and (3S,4f?)-tert-butyl 3-fluoro-4-hydroxycyclohexanecarboxylate (Preparation 1 ) (1 12 mg, 0.51 1 mmol) in tetrahydrofuran (4.5 ml_). The solution was heated up to 60 degrees Celsius and potassium tert-butoxide was added (0.71 ml_, 0.71 mmol). After four days, water was added and the reaction mixture was diluted with dichloromethane. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude material was purified by column chromatography on silica gel (40% to 100% ethyl acetate/heptane) to afford 100 mg (54 % yield) of the title compound as a white solid. LCMS (ES+): 419.6 (M+1 ).

Reference： [1]Patent: WO2011/61679,2011,A1 .Location in patent: Page/Page column 58

9
(anti)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 1174020-40-6 ]
[ 1174020-42-8 ]

Yield	Reaction Conditions	Operation in experiment
363 mg; 403 mg	With Chiralpak AD-H; In ethanol;Resolution of racemate;	Step D) Enantiomers of fert-butyl-(3,4-c/'s)-3-fluoro-4-hvdroxy-piperidine-1-carboxylateA 1 gram sample of racemic ieri-butyl-(3,4-c/'s)-3-fluoro-4-hydroxy-piperidine-1 - carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute. The wavelength for monitoring the separation was 210 nm. The analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute. The wavelength for monitoring the peaks was 210 nm. The following two isomers were obtained:Compound E, Scheme 1 , (3S,4f?)-fert-butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 1 (363 mg): R, = 2.67 min (100% ee); [a]D21 = +21 .2 degrees (c 0.64, dichloromethane); andCompound D, Scheme 1 , (3R4S)-tert-butyl 3-fluoro-4-hvdroxypiperidine-1 -carboxylate, enantiomer 2 (403 mg): Rf = 2.99 min (88% ee); [a]D21 = -17.8 degrees (c O.64, dichloromethane).

Reference： [1]Patent: WO2013/11402,2013,A1 .Location in patent: Page/Page column 26

10
[ 79099-07-3 ]
[ 1174020-40-6 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 8892 - 8897

11
[ 1174020-40-6 ]
[ 98-59-9 ]
[ 1450879-66-9 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 8892 - 8897

12
[ 1450879-67-0 ]
[ 1174020-40-6 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 8892 - 8897

13
[ 75291-85-9 ]
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[(5-bromo-3-carbamoylpyridin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Preparation 118tert-butyl (3S,4R)-4-[(5-bromo-3-carbamoylpyridin-2-yl)oxyl-3-fluoropiperidine- 1 -carboxylate To a solution of tert-butyl-(3S,4R)-3-fluoro-4-hydroxy-piperidine- 1 -carboxylate (WO 20131011402 Al), 3.5 g, 15.98 mmol) in DMSO (20 mL) was added potassium tert-butoxide(2.68 g, 23.97 mmol) and the mixture was stirred at room temperature for 30 minutes. 5-bromo-2-chloropyridine-3-carboxamide (Preparation 177, 2.75 g, 15.98 mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction was quenched by the addition of water (20 mL) and extracted into EtOAc (2 x 100 mL). The organic layers were combined, washed with water (2 x 50 mL), dried over sodium sulphate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with 20% EtOAc inheptanes to afford the title compound (5.00 g, 75%).1H NMR (400 MHz, DMSO-d6): O ppm 1.40 (5, 9H), 1.80-1.86 (m, 1H), 1.92-1.97 (m, 1H), 2.93-3.00 (m, 1H), 3.07-3.12 (m, 1H), 3.90-4.18 (m, 2H), 4.95-5.08 (m, 1H), 5.35-5.43 (m, 1H), 7.52(br 5, 1 H), 7.92 (br 5, 1 H), 8.27 (d, 1 H), 8.43 (d, 1 H).

Reference： [1]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 164
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 6779 - 6800

14
[ 75291-85-9 ]
[ 1174020-40-6 ]
(3S,4S)-4-[(5-bromo-3-carbamoylpyridin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		Preparation 133(35,45)-4-[(5-bromo-3-carbamoylpyridin-2-yl)oxyl-3-fluoropiperidine- 1 -carboxylate To a solution of tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine- 1 -carboxylate (WO 20131011402 Al, 605 mg, 2.76 mmol) in DMSO (4 mL) was added potassium tert-butoxide (464 mg, 4.14 mmol) and the mixture stirred at room temperature for 30 minutes. 5-bromo-2- chloronicotinamide (Preparation 177, 650 mg, 2.76 mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction was quenched by the addition of water andextracted into EtOAc. The organic layer was collected, washed with water, dried over sodiumsulphate and concentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 30% EtOAc in heptanes to afford the title compound (800 mg,69%).1H NMR (400 MHz, DMSO-d6): O ppm 1.41 (5, 9H), 1.74 (m, 1H), 2.06 (m, 1H), 3.28-3.83 (m,4H), 4.80-4.93 (m, 1H), 5.41 (m, 1H), 7.64 (br 5, 1H), 7.68-7.82 (m, 2H), 8.21 (m, 1H), 8.42 (5,1H).MS mlz 318 [M79Br-Boc+H]

Reference： [1]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 169

15
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[3-carbamoyl-5-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl]oxy}-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

16
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[(3-carbamoyl-5-{1-[(methylsulfonyl)methyl]-1H-pyrazol-4-yl}pyridin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

17
[ 1174020-40-6 ]
tert-butyl (3S,4S)-4-[2-carbamoyl-4-(1-methyl-1H-imidazol-4-yl)phenoxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

18
[ 1174020-40-6 ]
(3S,4R)-4-[2-carbamoyl-4-(1-methyl-1H-imidazol-4-yl)phenoxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

19
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[2-cyano-4-(1-methyl-1H-imidazol-4-yl)phenoxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

20
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[3-carbamoyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

21
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[4-bromo-2-carbamoylphenoxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/92610,2015,A1

22
[ 1174020-40-6 ]
[ 179897-89-3 ]
tert-butyl (3S,4R)-4-[4-bromo-2-cyanophenoxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Sealed tube;	Preparation 120tert-butyl (35,4R)-4-[4-bromo-2-cyanophenoxyl-3-fluoropiperidine- 1 -carboxylateTo a solution of tert-butyl-(35,4R)-3-fluoro-4-hydroxypiperidine- 1 -carboxylate (WO 20131011402Al, 1.00 g, 4.56 mmol) in DMF (20 mL) was added cesium carbonate (4.47 g, 13.68 mmol)followed by 5-bromo-2-fluorobenzonitrile (912 mg, 4.56 mmol) and the reaction was heated to110C for 16 hours in a sealed tube. The reaction was cooled, poured onto ice water andextracted into EtOAc twice. The combined organic layers were washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% EtOAc in heptanes to afford the title compound (1.50 g, 82%).1H NMR (400 MHz, DMSO-d6): O ppm 1.40 (5, 9H), 1.86 (m, 2H), 3.00-3.20 (m, 1H), 3.20-3.40 (m, 1H), 3.75-3.85 (m, 1H), 4.00-4.07 (m, 1H), 4.87-4.99 (m, 2H), 7.40 (d, 1H), 7.85 (dd, 1H), 8.04(s, 1H).MS mlz 301 [M-Boc81Br+H]

Reference： [1]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 165

23
[ 1174020-40-6 ]
[ 124-63-0 ]
(3S,4R)-3-fluoro-4-methanesulfonyloxypiperidine-1-carboxylic acid tert butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; at -30℃; for 2h;Inert atmosphere;	[0192] To a mixture of tert-butyl (3.V,4/)-tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate (40 g, 182.44 mmol), triethylamine (TEA) (36.92 g, 364.88 mmol, 50.79 mL) in DCM (500 mL) was added MsCl (25.08 g, 218.93 mmol, 16.94 mL) at -30C under N2. Then the mixture was stirred at -30C for 2 hours. TLC (Petroleum ether/Ethyl acetate = 1/1) showed the reactant was consumed completely and a new spot was observed. The mixture was poured into ice-water (800 mL) and extracted with DCM (300 mL x 2). The combined organic phase was dried with anhydrous Na2S04, filtered and concentrated in vacuo to give int-17 (54 g, 181.61 mmol, 99% yield) as a white solid.
98%	With triethylamine; In dichloromethane; at -30℃; for 3h;	Preparation 157(3S,4R)-3-fluoro-4-methanesulfonyloxypiperidine- 1 -carboxylic acid tert butyl ester To a solution of tert-butyl-(3S,4R)-3-fluoro-4-hydroxypiperidine- 1 -carboxylate (WO 20131011402 Al, 300 mg, 1.37 mmol) in DCM (10 mL) was added triethylamine (0.286 mL, 2.06 mmol)followed by methanesulfonyl chloride (0.128 mL, 1.64 mmol) at -30C. The reaction was stirred at this temperature for 3 hours before diluting with DCM (30 mL). The solution was washed with saturated aqueous NaHCO3 solution (10 mL), water (10 mL), brine (10 mL), dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step (400 mg, 98%).

Reference： [1]Patent: WO2020/81689,2020,A1 .Location in patent: Paragraph 0192; 0191
[2]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 178

24
[ 2075-46-9 ]
[ 1174020-40-6 ]
tert-butyl (3S,4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	To a solution of (3S, 4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (3.40 g, 15.5mmol), 4-nitro-1H-pyrazole (1.75 g, 15.5 mmol), PPh3 (6.10 g, 23.3 mmol) in THE (100 mL)was added slowly DIAD (4.71 g, 23.3 mmol) at 000. The mixture was stirred overnight at room temperature. The mixture was concentrated, the residue was dissolved in EtOAc (50 mL) and then n-hexane (100 mL) was added. The suspension was stirred vigorously for 1 hour and then filtered. The filtrate was concentrated and the crude was purified by columnchromatography on C18 (MeCN/water: 20% to 80%) to give the title compound 0209 (4.05 g,83% yield) as yellow oil.1H NMR (300 MHz, CHLOROFORM-d): 58.22 (s, 1H), 8.12 (s, 1H), 4.86-4.57 (m, 2H), 4.29-4.18 (m, 2H), 2.85 (brs, 2H), 2.28-2.12 (m, 2H), 1.48 (s, 9H).

Reference： [1]Patent: WO2015/113452,2015,A1 .Location in patent: Page/Page column 131

25
[ 1174020-40-6 ]
tert-butyl (3S,4S)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113452,2015,A1

26
[ 1174020-40-6 ]
(3S,4S)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-3-fluoropiperidine [ No CAS ]

Reference： [1]Patent: WO2015/113452,2015,A1

27
[ 1174020-40-6 ]
(3S,4S)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine [ No CAS ]

Reference： [1]Patent: WO2015/113452,2015,A1

28
[ 1174020-40-6 ]
5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-amine [ No CAS ]

Reference： [1]Patent: WO2015/113452,2015,A1

29
[ 1174020-40-6 ]
N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: WO2015/113452,2015,A1

30
[ 4548-45-2 ]
[ 1174020-40-6 ]
tert-butyl (3S,4R)-3-fluoro-4-[(5-nitropyridin-2-yl)oxy]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 5.16667h;	Sodium hydride, 60% dispersion in mineral oil (CAS-RN: 7646-69-7)(429 mg, 10.7mmol, 1.3 eq) was suspended in 20 mL THF at 0C and the reactants tert-butyl(35,4R)-3-fluoro-4-hydroxypiperidine- 1 -carboxylate (CAS-RN: 955028-88-3) (1900 mg, 8.7 mmol. 1.05 eq), which was synthesized according to Shaw et al. (JOC, 2013, 78, 8892-97.) dissolved in 10 mL THF and 2-chloro-5-nitropyridine (CASRN: 4548-45-2) (1308 mg, 8.3 mmol, 1 eq) dissolved in 10 mL THF were added. Thereaction mixture was allowed to warm up to room temperature, and then it was cooled down to 0C again for about 10 minutes and stirred for 5 h at rt. All volatile components were removed in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with brine and dryed by the use of a Whatman filter. The volatile components of the organic phasewere removed in vacuo. The final purification of this crude material was achieved via preparative MPLC (Biotage Isolera; 100 g KP cartridge: n-hexane/ethyl acetate:1:9 - 2:8) to give 2.4 g (85% yield of theory) of the title compound.1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 1.20 - 1.31 (m, 1 H), 1.40 (5, 9 H), 1.70 -1.96 (m, 2 H), 2.78 - 3.28 (m, 2 H), 3.83 - 4.03 (m, 1 H), 4.15 (5 br, 1 H), 5.31 -5.53 (m, 1 H), 7.08 (d, 1 H), 8.49 (dd, 1 H), 9.06 (d, 1 H).

Reference： [1]Patent: WO2015/113920,2015,A1 .Location in patent: Page/Page column 164

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[ 1174020-40-6 ]
tert-butyl (3S,4R)-3-fluoro-4-[(5-[(3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)oxy]piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

32
[ 1174020-40-6 ]
N-(6-[(3S,4R)-3-fluoropiperidin-4-yl]oxy}pyridin-3-yl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

33
[ 1174020-40-6 ]
N-(6-[(3S,4R)-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl]oxy}pyridin-3-yl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

34
[ 1174020-40-6 ]
N-(6-[(3S,4R)-3-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}pyridin-3-yl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

35
[ 1174020-40-6 ]
N-(6-[(3S,4R)-3-fluoro-1-(3,3,3-trifluoropropyl)piperidin-4-yl]oxy}pyridin-3-yl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

36
[ 1174020-40-6 ]
N-(6-[(3S,4R)-3-fluoro-1-propylpiperidin-4-yl]oxy}pyridin-3-yl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

37
[ 1174020-40-6 ]
N-(6-[(3S,4R)-1-butyl-3-fluoropiperidin-4-yl]oxy}pyridin-3-yl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

38
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[(5-aminopyridin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

39
[ 1174020-40-6 ]
tert-butyl (3S,4R)-4-[(5-[(5-amino-3-methyl-1,2-thiazol-4-yl)carbonyl]amino}-pyridin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

40
[ 1174020-40-6 ]
[ 77-78-1 ]
(3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

41
[ 1174020-40-6 ]
(+)-2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-ylamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

42
[ 1174020-40-6 ]
[2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl]-[2-[(R)-1-(tetrahydropyran-2-yloxy)ethyl]-1-((S)-2,2,2-trifluoro-1-methylethyl)-1H-imidazo[4,5-c]pyridin-6-yl]amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

43
[ 1174020-40-6 ]
(+)-(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

44
[ 1174020-40-6 ]
(3S,4R)-3-fluoro-1-{4-[2-[(R)-1-(tetrahydropyran-2-yloxy)ethyl]-1-((S)-2,2,2-trifluoro-1-methylethyl)-1H-imidazo[4,5-c]pyridin-6-ylamino]pyrimidin-2-yl}piperidin-4-ol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

45
[ 1174020-40-6 ]
C₆H₁₂FNO [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

46
[ 1174020-40-6 ]
(3S,4R)-3-fluoropiperidin-4-ol hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

47
[ 1174020-40-6 ]
(R)-1-[6-[2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-pyrimidin-4-ylamino]-1-((S)-2,2,2-trifluoro-1-methylethyl)-1H-imidazo[4,5-c]pyridin-2-yl]ethanol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

48
[ 1174020-40-6 ]
(3S,4R)-3-fluoro-1-{4-[2-((R)-1-hydroxyethyl)-1-((S)-2,2,2-trifluoro-1-methylethyl)-1H-imidazo[4,5-c]pyridin-6-ylamino]pyrimidin-2-yl}piperidin-4-ol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8877 - 8895

49
[ 1174020-40-6 ]
[ 62068-78-4 ]
tert-butyl (3S,4R)-4-((3-carbamoyl-6-chloropyridin-2-yl)oxy)-3-fluoropiperidine-1-carboxylate [ No CAS ]