1209780-71-1|tert-Butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate| Ambeed

Structure of 1209780-71-1

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Quality Control of [ 1209780-71-1 ] Purity: 97% SDS Specification

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Product Details of [ 1209780-71-1 ]

CAS No. :	1209780-71-1
Formula :	C₁₀H₁₇F₂NO₃
M.W :	237.24
SMILES Code :	O=C(N1CC(F)(F)C(O)CC1)OC(C)(C)C
MDL No. :	MFCD16250751
InChI Key :	GISYXRBCSOIMTM-UHFFFAOYSA-N
Pubchem ID :	56932106

Safety of [ 1209780-71-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1209780-71-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	0
Fraction Csp3	0.9
Num. rotatable bonds	3
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	57.89
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.43
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.08
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.15
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.6

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.93
Solubility	2.78 mg/ml ; 0.0117 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.95
Solubility	2.69 mg/ml ; 0.0113 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.25
Solubility	13.2 mg/ml ; 0.0558 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.82 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.88

Application In Synthesis of [ 1209780-71-1 ]

* 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 [ 1209780-71-1 ]

[ 1209780-71-1 ] Synthesis Path-Downstream 1~35

1
[ 1067914-83-3 ]
[ 1209780-71-1 ]

Yield	Reaction Conditions	Operation in experiment
		tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-l-carboxylate (3.10 g, 12.2 mmol) was dissolved in 95% EtOH (50 mL) and the solution was treated with sodium borohydride (2.32 g, 61.2 mmol) and stirred at ambient temperature for 3 hours. The reaction was treated dropwise with 3N HCl until vigorous gas evolution ceased, then stirred at ambient temperature for 20 minutes (pH of the mixture was 3-4 at this point). The reaction was neutralized with saturated NaHCCh and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the desired product as a white solid (1.39 g).

References: [1]Patent: WO2010/22076,2010,A1 .Location in patent: Page/Page column 114; 115.

2
[ 1209780-71-1 ]
[ 1209780-70-0 ]
[ 1209780-72-2 ]

Yield	Reaction Conditions	Operation in experiment
		tert-Butyl 3,3-difluoro-4- hydroxypiperidine-1-carboxylate (0.0706 g, 0.298 mmol) was treated with 1 M KOtBu in THF (0.283 mL, 0.283 mmol) and stirred for 15 minutes. The solution was treated with 2- ([l,2,4]triazolo[4,3-a]pyridin-3-yl)-6,8-difluoroquinoline (0.042 g, 0.149 mmol) and DMF (0.80 mL) then the mixture was stirred at ambient temperature for 16 hours. The mixture was directly chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/ethyl acetate. The desired product was collected and concentrated to a colorless oil, (72 mg). MS APCI (+) m/z 500.0 (M+l) detected.

References: [1]Patent: WO2010/22076,2010,A1 .Location in patent: Page/Page column 115.

3
[ 24424-99-5 ]
[ 1239596-54-3 ]
[ 1209780-71-1 ]

Yield	Reaction Conditions	Operation in experiment
82.1%	In dichloromethane; at 20℃; for 12h;Inert atmosphere;	To a solution of B7 (250 mg, 1.8 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (392 mg, 1.8 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 hours. Water was added to the solution and the mixture was extracted with dichloromethane (20 mL). The organic phase was dried over sodium sulfate, filtered, concentrated in vacuo and washed with n-hexane to give the product B8 as a white solid (350 mg, yield 82.1%). 1H NMR (400 MHz, DMSO-d6) 5ppm: 5.76 (d, J = 5.4 Hz, 1H), 4.02 - 3.66 (m, 2H), 3.68 - 3.44 (m, 2H), 3.29 (s, 1H), 1.75 (ddd, J = 11.3, 7.6, 3.8 Hz, 1H), 1.70 - 1.50 (m, 1H), 1.40 (s, 8H)
	In dichloromethane; at 20℃; for 2h;Inert atmosphere;	ferf-Butyl 3,3-difluoro-4-hydroxypiperidine-1 -carboxylate:In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3,3-difluoropiperidin-4-ol (700 mg, 5.10 mmol) in dry CH2CI2 (50 ml.) was added Boc20 (1 .1 1 g, 5.10 mmol). The reaction mixture was stirred at rt for 2 h. Water was then added, the layers separated and the aq. layer extracted with CH2CI2 (3x). The combined org. extracts were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 08: tR = 0.69 min; [M-CH3+H]+ = 223.30.
	In dichloromethane; at 20℃; for 2h;Inert atmosphere;	tert-Butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3,3-difluoropiperidin-4-ol (700 mg, 5.10 mmol) in dry CH2Cl2 (50 mL) was added Boc2O (1.11 g, 5.10 mmol). The reaction mixture was stirred at rt for 2 h. Water was then added, the layers separated and the aq. layer extracted with CH2Cl2 (3*). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 08: tR=0.69 min; [M-CH3+H]+=223.30.

	In dichloromethane; at 20℃; for 2h;Inert atmosphere;	In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3,3-difluoropiperidin-4-ol (700 mg, 5.10 mmol) in dry CH2CI2 (50 ml_) was added Boc20 (1.1 1 g, 5.10 mmol). The reaction mixture was stirred at rt for 2 h. Water was then added, the layers separated and the aq. layer extracted with CH2CI2 (3x). The combined org. extracts were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 08: tR = 0.69 min; [M-CH3+H]+ = 223.30.
	With triethylamine; In tetrahydrofuran; at 20℃; for 16h;	To a suspension of 3,3-difluoropiperidin-4-ol (1g; 5.76mmol) in THF (5ml_) was added triethylamine (0.86 mL; 6.34 mmol) followed by Boc anhydride (1.32g; 6.05mmol), and the mixture was stirred at RT for 16h. The reaction mixture was then diluted with water (100 mL) and extraxted with EtOAc (3x 50 mL), the organic layer was washed with 1N HCI (2 x 30 mL), brine, dried over anhydrous Na2S04, and concentrated to provide the desired product as a white solid . 1H NMR (400 MHz, DMSO-cfe) delta 5.73 (d, J= 5.4 Hz, 1H), 3.91 - 3.63 (m, 2H), 3.61 -3.41 (m, 2H), 3.29 (d, J=4.8Hz, 1H), 1.75 (ddt, J= 15.3, 7.7, 3.8 Hz, 1H), 1.56 (dtt, J= 11.0, 7.0, 3.1 Hz, 1 H), 1 .40 (s, 9H). M/Z (M+H) = 182.1 .

References: [1]Patent: EP3438107,2019,A1 .Location in patent: Paragraph 0165; 0172.
[2]Patent: WO2019/214634,2019,A1 .Location in patent: Page/Page column 78.
[3]Patent: WO2012/66488,2012,A2 .Location in patent: Page/Page column 64.
[4]Patent: US2013/231319,2013,A1 .Location in patent: Paragraph 0559.
[5]Patent: WO2013/171694,2013,A1 .Location in patent: Page/Page column 30.
[6]Patent: WO2018/229683,2018,A1 .Location in patent: Page/Page column 45-46.

4
[ 1067914-81-1 ]
[ 1209780-71-1 ]

References: [1]Patent: WO2012/66488,2012,A2 .
[2]Patent: US2013/231319,2013,A1 .
[3]Patent: WO2013/171694,2013,A1 .
[4]Patent: EP3438107,2019,A1 .

5
[ 1209780-71-1 ]
[ 1215071-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	With Dess-Martin periodane; In dichloromethane; at 20℃;Inert atmosphere; cooling with ice;	ferf-Butyl 4-(2-ethoxy-2-oxoethylidene)-3,3-difluoropiperidine-1 -carboxylate: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of ferf-butyl 3,3-difluoro-4-hydroxypiperidine-1- carboxylate (2.40 g, 10.00 mmol) in dry CH2CI2 (50 ml.) was added a solution of Dess- Martin periodinane (50 ml. of a 15% solution in CH2CI2, 24.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHC03 (50 ml.) was then added followed by 10% aq. Na2S03 (50 ml_). The mixture was stirred at rt for 1 h, the layers separated and the aq. layer extracted with CH2CI2 (3x). The combined org. extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The crude residue was redissolved in CH2CI2 (30 ml.) and stirred in the presence of molecular sieves for 24 h, filtered and concentrated under reduced pressure to give ferf-butyl 3,3-difluoro-4- oxopiperidine-1 -carboxylate as a yellow solid. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to NaH (45 mg, 1 .12 mmol, 60% dispersion in oil washed with heptane) was added a solution of triethyl phosphonoacetate (262 mg, 1.17 mmol) in dry THF (10 ml.) at 0 C. The reaction mixture was stirred at 0 C for 30 min. Molecular sieves were then added followed by a solution of ferf-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (220 mg, 0.93 mmol) in THF (5 ml_). The reaction mixture was stirred at 0 C for 30 min and at rt for 1 h. Water was then added and the mixture extracted with EA (3x). The combined org. extracts were dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (mixture of E and Z isomers). LC-MS- conditions 08: tR = 0.88 and 0.93 min; [M-CH3+H]+ = 291.27.
	With Dess-Martin periodane; In dichloromethane; at 20℃;Inert atmosphere;	tert-Butyl 4-(2-ethoxy-2-oxoethylidene)-3,3-difluoropiperidine-1-carboxylate In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of <strong>[1209780-71-1]tert-butyl <strong>[1209780-71-1]3,3-difluoro-4-hydroxypiperidine-1-carboxylate</strong></strong> (2.40 g, 10.00 mmol) in dry CH2Cl2 (50 mL) was added a solution of Dess-Martin periodinane (50 mL of a 15% solution in CH2Cl2, 24.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHCO3 (50 mL) was then added followed by 10% aq. Na2SO3 (50 mL). The mixture was stirred at rt for 1 h, the layers separated and the aq. layer extracted with CH2Cl2 (3*). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was redissolved in CH2Cl2 (30 mL) and stirred in the presence of molecular sieves for 24 h, filtered and concentrated under reduced pressure to give tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate as a yellow solid.
	With Dess-Martin periodane; In dichloromethane; at 20℃;Inert atmosphere;	In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of terf-butyl 3,3-difluoro-4-hydroxypiperidine-1 - carboxylate (2.40 g, 10.00 mmol) in dry CH2CI2 (50 mL) was added a solution of Dess- Martin periodinane (50 mL of a 15% solution in CH2CI2, 24.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHC03 (50 mL) was then added followed by 10% aq. Na2S03 (50 mL). The mixture was stirred at rt for 1 h, the layers separated and the aq. layer extracted with CH2CI2 (3x). The combined org. extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The crude residue was redissolved in CH2CI2 (30 mL) and stirred in the presence of molecular sieves for 24 h, filtered, and concentrated under reduced pressure to give feri-butyl 3,3-difluoro-4- oxopiperidine-1 -carboxylate as a yellow solid.

References: [1]Patent: WO2012/66488,2012,A2 .Location in patent: Page/Page column 63-64.
[2]Patent: US2013/231319,2013,A1 .Location in patent: Paragraph 0557.
[3]Patent: WO2013/171694,2013,A1 .Location in patent: Page/Page column 30.

6
[ 1209780-71-1 ]
[ 1334415-93-8 ]

References: [1]Patent: WO2012/66488,2012,A2 .
[2]Patent: US2013/231319,2013,A1 .

7
[ 1209780-71-1 ]
[ 1334412-95-1 ]

References: [1]Patent: WO2012/66488,2012,A2 .
[2]Patent: US2013/231319,2013,A1 .

8
[ 1209780-71-1 ]
[ 1378026-49-3 ]

References: [1]Patent: WO2012/66488,2012,A2 .
[2]Patent: US2013/231319,2013,A1 .

9
[ 1239596-53-2 ]
[ 1209780-71-1 ]

References: [1]Patent: WO2012/66488,2012,A2 .
[2]Patent: US2013/231319,2013,A1 .
[3]Patent: WO2013/171694,2013,A1 .
[4]Patent: EP3438107,2019,A1 .

10
[ 1209780-71-1 ]
[ 1067914-82-2 ]

References: [1]Patent: WO2013/171694,2013,A1 .

11
[ 1209780-71-1 ]
(±)-tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2013/171694,2013,A1 .

12
[ 1209780-71-1 ]
C₂₈H₃₅BrF₃N₃O₄ [ No CAS ]

References: [1]Patent: WO2013/171694,2013,A1 .

13
[ 1209780-71-1 ]
(1S,2R,3R,4R)-N²-(4-bromo-2-fluorobenzyl)-N³-(3,3-difluoropiperidin-4-yl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide [ No CAS ]

References: [1]Patent: WO2013/171694,2013,A1 .

14
[ 1209780-71-1 ]
2-fluoro-5-(6-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzonitrile [ No CAS ]
tert-butyl 4-(2-cyano-4-(6-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenoxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of a racemic mixture tert-butyl 3,3-difluoro-4-hydroxypiperidine-1- carboxylate (97 mgs, 0.41 mmol) in 2-Me-THF (9 mL) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide solution (1.0 M, 0.4 mL, 0.41 mmol) was added in a single portion and the mixture was stirred at 0 C for 40 minutes, and then 2-fluoro-5-(6-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzonitrile (100 mgs, 0.21 mmol) was added. The mixture was stirred at 60 C for 1 hr. After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure to yield the crude tert-butyl 4- (2-cyano-4-(6-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)phenoxy)-3,3-difluoropiperidine-1-carboxylate which was dissolved in DCM (3 mL) and TFA was added (2 mL). The resulting solution was stirred st rt for 16h. The mixture was then concentrated and purified by reverse phase chromatography to give the title compound as TFA salt. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33F2N7O3 as (M+H)+ 602.7 found: 602.2; 1H NM (400 MHz, DMSO-d6) delta 12.79 (s, 1 H), 10.15 (s, 1 H), 8.81 (s, 1 H), 8.68 - 8.48 (m, 2H), 7.75 - 7.60 (m, 3H), 7.47 - 7.45 (m, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 5.49 - 5.41 (m, 1 H), 4.91 - 4.85 (m, 2H), 4.52 - 4.43 (m, 1 H), 3.93 (s, 3H), 3.86 - 3.74 (m, 2H), 3.64 - 3.55 (m, 6H), 3.35 - 3.22 (m, 2H), 3.30 - 3.20 (m, 4H), 2.41 - 2.15 (m, 2H).

References: [1]Patent: WO2015/187684,2015,A1 .Location in patent: Page/Page column 202.

15
[ 4858-85-9 ]
[ 1209780-71-1 ]
tert-butyl 4-((3-chloropyrazin-2-yl)oxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
440 mg		A) tert-butyl 4-((3-chloropyrazin-2-yl)oxy)-3,3-difluoropiperidine-1-carboxylate To a mixture of <strong>[1209780-71-1]tert-butyl <strong>[1209780-71-1]3,3-difluoro-4-hydroxypiperidine-1-carboxylate</strong></strong> (400 mg) and DMF (6.0 mL) was added sodium hydride (88 mg) at 0 C., and the mixture was stirred for 15 min. To the mixture was added 2,3-dichloropyrazine (250 mg), and the mixture was stirred overnight at room temperature. The mixture was poured into saturated sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (440 mg). 1H NMR (300 MHz, CDCl3) delta 1.39-1.52 (9H, m), 1.90-2.29 (2H, m), 3.39 (1H, m), 3.56-3.91 (2H, m), 3.91-4.28 (1H, m), 5.60 (1H, m), 8.02 (2H, s).

References: [1]Patent: US2016/24049,2016,A1 .Location in patent: Paragraph 0774; 0775.

16
[ 1209780-71-1 ]
2-((3,3-difluoropiperidin-4-yl)oxy)-3-(pyridin-4-yl)pyrazine [ No CAS ]

References: [1]Patent: US2016/24049,2016,A1 .

17
[ 1209780-71-1 ]
2-(3,3-difluoro-4-((3-(pyridin-4-yl)pyrazin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylacetamide [ No CAS ]

References: [1]Patent: US2016/24049,2016,A1 .

18
[ 1209780-71-1 ]
[ 179897-89-3 ]
tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of NaH (8.35 g, 208.0 mmol, 60.0% purity, 1.1 eq) in DMF (225 mL) was added a solution of compound Z9 (45.0 g, 190.0 mmol, 1 eq) in DMF (90 mL) at 0 C and the mixture was stirred at 0 C for 0.5 h. A solution of compound 1A (37.9 g, 190.0 mmol, 1 eq) in DMF (45 mL) was added dropwise and the mixture was stirred at 25 C for 0.5 h. The reaction mixture was poured into aqueous saturated NH4C1 (500 mL), extracted with ethyl acetate (800 mL x 2). The organic phase was washed with water (300 mL x 2), brine (300 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a crude product. The crude product was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/l, 1/2) to afford compound Z10 (79.0 g, 177.0 mmol, 93.3% yield, 93.5% purity) as an yellow oil. LCMS: RT = 0.994 min, MS[M+Na]+ = 439.0; NMR:, CDC13 400MHz. delta 7.69 (d, / = 3.6 Hz, 1H), 7.65 (dd, J = 3.6, 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.65 (dd, J = 3.2, 6.4 Hz, 1H), 4.38 - 4.13 (m, 1H), 4.05 - 3.84 (m, 1H), 3.76 - 3.51 (m, 1H), 3.48 - 3.22 (m, 1H), 2.14 - 2.05 (m, 2H), 1.48 (s, 9H).

References: [1]Patent: WO2019/79373,2019,A1 .Location in patent: Paragraph 00561; 00380.

19
[ 1209780-71-1 ]
2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile [ No CAS ]
tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)phenoxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step-1: <strong>[1209780-71-1]tert-butyl <strong>[1209780-71-1]3,3-difluoro-4-hydroxypiperidine-1-carboxylate</strong></strong> (154 mg, 0.46 mmol) was added Me-THF (9 mL) under argon atmosphere and cooled at 0 C. To well stirred solution was added potassium tert-butoxide (73 mg) at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile (200 mg, 0.46 mmol) and warmed to room temperature over 10 min. The reaction was heated at 80 C. overnight. The reaction was cooled to RT and diluted with DCM, quenched with water (5-8 mL) and the mixture was adsorbed on silica gel, the solvent concentrated to dryness. The crude product was purified by flash column chromatography on silica gel to afford tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)phenoxy)-3,3-difluoropiperidine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38F2N8O4: 649.3. found: 649.2

References: [1]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 0659.

20
[ 1209780-71-1 ]
[ 1401310-80-2 ]
[ 530-62-1 ]
tert-butyl 4-((((5-chloro-3-(3-ethylureido)isoquinolin-8-yl)-methyl)carbamoyl)oxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3755 - 3775.

21
[ 1209780-71-1 ]
tert-butyl 4-(4-aminophenoxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

References: [1]Patent: US2017/183342,2017,A1 .

22
[ 1209780-71-1 ]
tert-butyl 3,3-difluoro-4-phenoxypiperidine-1-carboxylate [ No CAS ]

References: [1]Patent: US2017/183342,2017,A1 .

23
[ 1209780-71-1 ]
3,3-difluoro-4-phenoxypiperidine [ No CAS ]

References: [1]Patent: US2017/183342,2017,A1 .

24
[ 1209780-71-1 ]
methyl 2-cyano-6-(3,3-difluoro-4-phenoxypiperidin-1-yl)-5-methylnicotinate [ No CAS ]

References: [1]Patent: US2017/183342,2017,A1 .

25
[ 1209780-71-1 ]
2-(3,3-difluoro-4-phenoxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ No CAS ]

References: [1]Patent: US2017/183342,2017,A1 .

26
[ 1209780-71-1 ]
[ 350-46-9 ]
tert-butyl 3,3-difluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 50℃; for 5h;Inert atmosphere;	To a solution of <strong>[1209780-71-1]tert-butyl <strong>[1209780-71-1]3,3-difluoro-4-hydroxypiperidine-1-carboxylate</strong></strong> (800 mg, 3.37 mmol) in THF (8 mL) was added potassium 2-methylpropan-2-olate (757 mg, 6.74 mmol). A solution of 1-fluoro-4-nitrobenzene (523 mg, 3.71 mmol) in DMF (1 mL) was added to the mixture, the reaction was stirred at 50 C. for 5 h under an atmosphere of N2(g). Upon completion the reaction was concentrated and the residue was purified by silica gel chromatography (10/1 petroleum ether/EtOAc) to give the title compound.

References: [1]Patent: US2017/183342,2017,A1 .Location in patent: Paragraph 0283.

27
[ 403-54-3 ]
[ 1209780-71-1 ]
tert-butyl 4-(3-cyanophenoxy)-3.3-difluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 50℃; for 1h;	To a solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-l -carboxylate (50 mg, 0.211 mmol) in THF (2 mL) was added potassium 2-methylpropan-2-olate (23.65 mg, 0.211 mmol). A solution of 3-fluorobenzonitrile (38.3 mg, 0.316 mmol) in DMF (0.5 mL) was added to the mixture and the resulting mixture was stirred at 50 C for 1 h. The reaction was quenched with water (2 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 m x 3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (50: 1 to 1 : 1 petroleum ether: EtOAc) to give the title compound.

References: [1]Patent: WO2018/118734,2018,A1 .Location in patent: Page/Page column 63.

28
[ 403-54-3 ]
[ 1209780-71-1 ]
3-((3,3-difluoropiperidin-4-yl)oxy)benzonitrile [ No CAS ]

References: [1]Patent: WO2018/118734,2018,A1 .

29
[ 1209780-71-1 ]
Racemic tert-butyl 4-(2-carbamoyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]