[ CAS No. 496807-97-7 ] {[proInfo.proName]}

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2D 3D

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Quality Control of [ 496807-97-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 496807-97-7 ]

SDS Specification

Alternatived Products of [ 496807-97-7 ]

Product Details of [ 496807-97-7 ]

CAS No. :	496807-97-7	MDL No. :	MFCD03452800
Formula :	C₅H₁₀ClF₂N	Boiling Point :	No data available
Linear Structure Formula :	-	InChI Key :	LEHHIPIDKQVNEV-UHFFFAOYSA-N
M.W :	157.59	Pubchem ID :	2758349
Synonyms :

Calculated chemistry of [ 496807-97-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.86
TPSA :	12.03 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.76
Log Po/w (WLOGP) :	2.27
Log Po/w (MLOGP) :	1.49
Log Po/w (SILICOS-IT) :	1.98
Consensus Log Po/w :	1.5

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.93
Solubility :	1.87 mg/ml ; 0.0119 mol/l
Class :	Very soluble
Log S (Ali) :	-1.63
Solubility :	3.69 mg/ml ; 0.0234 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.82
Solubility :	2.39 mg/ml ; 0.0152 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 496807-97-7 ]

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

Application In Synthesis of [ 496807-97-7 ]

* 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 [ 496807-97-7 ]

[ 496807-97-7 ] Synthesis Path-Downstream 1~14

1
[ 741288-41-5 ]
[ 496807-97-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrogen;5% palladium-on-charcoal; In methanol; ethanol; for 22h;	To a solution of 1-benzyl-piperidin-3-one (1G) in CH2CI2 (LOML) is added [bis (2-methoxy- ethyl) amino] SULFER TRIFLUORIDE (1. 84mL) at 0C, and stirred for 1.5hr at room temperature. The reaction mixture is poured in aqueous NaHC03 and extracted with ethyl acetate. The organic layer is successively washed with H20 and aqueous NACI, dried over MgS04, and concentrated in vacuo. The residue is purified by column chromatography to give a colorless oil. The oil and Pd/C (5% w/w on activated carbon, 100MG) in HCI in ETOH/MEOH (50mL) is stirred for 22hr under H2 atmosphere. The reaction mixture is filtrated through celite pad. 4The filtrate is added HCI in EtOAc, then concentrated in vacuo to provide the title compound.

Reference： [1]Patent: WO2004/69256,2004,A1 .Location in patent: Page/Page column 48-49

2
E-4-(2-chloro-acetylamino)-adamantane-1-carboxylic acid methyl ester [ No CAS ]
[ 496807-97-7 ]
E-4-[2-(3,3-difluoro-piperidin-1-yl)-acetylamino]-adamantane-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of E-4-(2-chloro-acetylamino)-adamantane-1-carboxylic acid methyl ester (0.075 g, 0.26 mmoles) from Example 25B, in MeOH (1.5 mL) and DIPEA (0.05 mL, 0.29 mmoles) was treated with <strong>[496807-97-7]3,3-difluoro-piperidine hydrochloride</strong> (0.062 g, 0.39 mmoles) and stirred for 2 hours at 80 C. The cooled reaction mixture was purified on reverse phase HPLC and hydrolyzed with 3N HCl at 60 C. over 6 hours. Drying of the reaction mixture under reduced pressure provided the hydrochloride salt of the title compound as a white solid (50 mg, 52%). 1H NMR (300 MHz, DMSO-d6) delta 8.45 (m, 1H), 3.97 (bs, 2H), 3.88 (m, 1H), 3.65 (m, 2H), 3.23 (m, 2H), 2.11 (m, 2H), 1.91 (m, 11H), 1.79 (m, 2H), 1.47 (m, 2H); MS (DCI+) m/z 357 (M+H)+.

Reference： [1]Patent: US2005/245534,2005,A1 .Location in patent: Page/Page column 45

3
E-4-(2-bromo-propionylamino)-adamantane-1-carboxylic acid amide [ No CAS ]
[ 496807-97-7 ]
E-4-[2-(3,3-difluoropiperidine-1-yl)-propionylamino]-adamantane-1-carboxylic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine; In methanol; at 70℃;	A solution of E-4-(2-bromo-propionylamino)-adamantane-1-carboxylic acid amide (33 mg, 0.1 mmoles) and the hydrochloride of 3,3-difluoropiperidine (19 mg, 0.12 mmol) from Example 31B in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a white solid (18 mg, 48%). 1H NMR (400 MHz, Py-d5) delta 7.92 (d, J=7.7 Hz, 1H), 7.51 (s, 2H), 4.32 (d, J=7.7 Hz, 1H), 3.42 (q, J=7 Hz, 1H), 2.92 (q, J=10.7 Hz, 1H), 2.78 (q, J=11.6 Hz, 1H), 2.5 (m, 2H), 2.27-2.10 (m, 8H), 1.98-1.88 (m, 5H), 1.68 (m, 2H), 1.55 (m, 2H), 1.32 (d, 3H); MS (ESI+) m/z 370 (M+H)+.

Reference： [1]Patent: US2005/245534,2005,A1 .Location in patent: Page/Page column 46-47

4
[ 496807-97-7 ]
(E)-4-(2-bromo-propionylamino)-adamantane-1-carboxamide [ No CAS ]
(E)-4-[2-(3,3-difluoropiperidine-1-yl)-propionylamino]-adamantane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In methanol; at 70℃;	A solution of (E)-4-(2-bromo-propionylamino)-adamantane-1-carboxamide (33 mg, 0.1 mmoles) and the hydrochloride of 3,3-difluoropiperidine (19 mg, 0.12 mmol) from Example 31B in MeOH (0.5 mL) and DIPEA (0.1 mL) was stirred overnight at 70 C. The MeOH was removed under reduced pressure and the residue purified on reverse phase HPLC to provide the title compound as a white solid. 1H NMR (400 MHz, Py-d5) delta 7.92 (d, J=7.7 Hz, 11H), 7.51 (s, 2H), 4.32 (d, J=7.7 Hz, 1H), 3.42 (q, J=7 Hz, 1H), 2.92 (q, J=10.7 Hz, 1H), 2.78 (q, J=11.6 Hz, 1H), 2.5 (m, 2H), 2.27-2.10 (m, 8H), 1.98-1.88 (m, 5H), 1.68 (m, 2H), 1.55 (m, 2H), 1.32 (d, 3H); MS(ESI+) m/z 370 (M+H)+.

Reference： [1]Patent: US2005/277647,2005,A1 .Location in patent: Page/Page column 34

5
[ 496807-97-7 ]
[ 933796-13-5 ]
8-[(3,3-difluoropiperidin-1-yl)methyl]-3-(phenylsulfonyl)quinoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Example 27; 8-[(3,3-Difluoropiperidin-1-yl)methyl]-3-(phenylsulfonyl)quinoline hydrochloride(E27); A suspension of 3-(phenylsulfonyl)quinoline-8-carbaldehyde (D3) (45 mg, 0.15 mmol) in anhydrous dichloromethane (1 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (26 mg, 0.165 mmol) and sodium triacetoxyborohydride (37 mg, 0.175 mmol) and the mixture was stirred under argon at room temperature for 18h. The reaction mixture was then diluted with dichloromethane (30 ml) and washed with aqueous sodium bicarbonate solution (2 x 20ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.45 ml) and acetonitrile (0.45 ml) and purified by mass-directed auto-preparative chromatography using a 10 minute gradient containing water and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to a gum. This material was dissolved in ether (2 ml) and treated with 1M hydrogen chloride in ether (1 ml). The mixture was evaporated, dissolved in ether and re-evaporated to yield the title compound as a white solid (35 mg, 0.08 mmol, 53%). deltaH (CD3OD, 400MHz) 1.90-2.40 (4H, m), 3.20-3.90 (4H, m), 5.06 (2H, s), 7.61-7.72 (3H, m), 7.86 (IH, t, J = 7Hz), 8.06-8.16 (3H, m), 8.34 (1 H, dd, J = 1.2, 8.4Hz), 9.17 (1 H, d, J = 2Hz), 9.40 (1 H, d, J = 2Hz). Mass spectrum: C2IH20F2N2O2S requires 402; found 403 (MH+)

Reference： [1]Patent: WO2007/39219,2007,A1 .Location in patent: Page/Page column 44-45

6
[ 496807-97-7 ]
[ 933796-19-1 ]
8-[1-(3,3-difluoro-1-piperidinyl)ethyl]-3-(phenylsulfonyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		Example 37; 8-[1 -(3,3-Dif luoro-1 -piperidinyl)ethyl]-3-(phenylsulfonyl)quinoline (E37); A suspension of 1-[3-(phenylsulfonyl)quinolin-8-yl]ethanone (D8) (96 mg, 0.3 mmol) in anhydrous dichloromethane (2 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (52 mg, 0.33 mmol) and sodium triacetoxyborohydride (95 mg, 0.44 mmol) and the mixture was stirred under argon at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane (75 ml) and washed with aqueous sodium bicarbonate solution (2 x 50ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.90 ml) and acetonitrile (0.90 ml) and purified by mass- directed auto-preparative chromatography using a 10 minute gradient containing water EPO <DP n="52"/>and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to give the title compound as a colourless foam (14 mg, 11%). deltaH (CDCI3, 400MHz) 1.41 (3H, t, J = 7Hz), 1.70-1.89 (4H, m), 2.33-2.36 (1 H, m), 2.61- 2.78 (3H, m), 5.00 (1 H, q, J = 7Hz), 7.52-7.63 (3H, m), 7.70 (1 H, t, J = 8Hz), 7.86 (1 H, dd, J = 1.2Hz, 7Hz), 7.99-8.10 (3H, m), 8.81 (1 H, d, J = 2Hz), 9.24 (1 H1 d, J = 2Hz) Mass spectrum: C22H22F2N2O2S requires 416; found 417 (MH+)
11%	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 72h;	A suspension of l-[3-(phenylsulfonyl)quinolin-8-yl]ethanone (96 mg, 0.3 mmol) in anhydrous dichloromethane (2 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (52 mg, 0.33 mmol) and sodium triacetoxyborohydride (95 mg, 0.44 mmol) and the mixture was stirred under argon at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane (75 ml) and washed with aqueous sodium bicarbonate solution (2 x 50ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.90 ml) and acetonitrile (0.90 ml) and purified by mass-directed auto -preparative chromatography using a 10 minute gradient containing water and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to give the title compound as a colourless foam (14 mg, 11%). <n="211"/>deltaH (CDCl3, 400MHz) 1.41 (3H, t, J = 7Hz), 1.70-1.89 (4H, m), 2.33-2.36 (IH, m), 2.61-2.78 (3H, m), 5.00 (IH, q, J = 7Hz), 7.52-7.63 (3H, m), 7.70 (IH, t, J = 8Hz), 7.86 (IH, dd, J = 1.2Hz, 7Hz), 7.99-8.10 (3H, m), 8.81 (IH, d, J = 2Hz), 9.24 (IH, d, J = 2Hz) Mass spectrum: C22H22F2N2O2S requires 416; found 417 (MH+)

Reference： [1]Patent: WO2007/39219,2007,A1 .Location in patent: Page/Page column 50-51
[2]Patent: WO2008/116816,2008,A1 .Location in patent: Page/Page column 208-209

7
[ 496807-97-7 ]
[ 933796-27-1 ]
[ 933796-28-2 ]

Yield	Reaction Conditions	Operation in experiment
		Description 20; 8-[(3,3-Dif luoro-1 -piperidinyl)methyl]-3-iodoquinoline (D20); 3-lodo-delta-quinolinecarbaldehyde (D19) (2g, 7.06mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.94g, 7.77mmol) were dissolved in dichloromethane (20ml). Sodium triacetoxyborohydride (2.25g, 10.6mmol) and acetic acid (0.44ml, 7.77mmol) were added and the reaction stirred at room temperature under argon overnight. The reaction was diluted with dichloromethane, cooled and basified with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield a brown oil (2.89g). The residue was purified on the Jones Flashmaster Il with an IST SPE 7Og silica column eluting a gradient of 5-12% ethyl acetate/n-hexane over 40 minutes. This yielded the title compound as a pale yellow oil (2.27g).LC/MS [MH+] 389 consistent with molecular formula C15H15F2IN2.
	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;	3-Iodo-8-quinolinecarbaldehyde (2g, 7.06mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (0.94g, 7.77mmol) were dissolved in dichloromethane (20ml). Sodium triacetoxyborohydride (2.25g, 10.6mmol) and acetic acid (0.44ml, 7.77mmol) were added and the reaction stirred at room temperature under argon overnight. The reaction was diluted with dichloromethane, cooled and basified with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield a brown oil (2.89g). The residue was purified on the Jones Flashmaster II with an 1ST SPE 7Og silica column eluting a gradient of 5-12% ethyl acetate/«-hexane over 40 minutes. This yielded the title compound as a pale yellow oil (1.2Ig).LC/MS [MH+] 389 consistent with molecular formula Ci5H15F2IN2.

Reference： [1]Patent: WO2007/39219,2007,A1 .Location in patent: Page/Page column 32-33
[2]Patent: WO2008/116816,2008,A1 .Location in patent: Page/Page column 193

8
[ 496807-97-7 ]
[ 933796-13-5 ]
[ 933825-16-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;	A suspension of 3-(phenylsulfonyl)quinoline-8-carbaldehyde (45 mg, 0.15 mmol) in anhydrous dichloromethane (1 ml) was treated with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (26 mg, 0.165 mmol) and sodium triacetoxyborohydride (37 mg, 0.175 mmol) and the mixture was stirred under argon at room temperature for 18h. The reaction mixture was then diluted with dichloromethane (30 ml) and washed with aqueous sodium bicarbonate solution (2 x 20ml). The dichloromethane solution was dried by filtration through a hydrophobic cartridge and evaporated to a gum. This material was dissolved in a mixture of dimethylsulphoxide (0.45 ml) and acetonitrile (0.45 ml) and purified by mass-directed auto -preparative chromatography using a 10 minute gradient containing water and between 15% and 55% acetonitrile with 0.1% formic acid. Product fractions were collected and evaporated to a gum. This material was dissolved in ether (2 ml) and treated with IM hydrogen chloride in ether (1 ml). The mixture was evaporated, dissolved in ether and re-evaporated to yield the title compound as a white solid (35 mg, 0.08 mmol, 53%). <n="206"/>deltaH (CD3OD, 400MHz) 1.90-2.40 (4H, m), 3.20-3.90 (4H, m), 5.06 (2H, s), 7.61-7.72 (3H, m), 7.86 (IH, t, J = 7Hz), 8.06-8.16 (3H, m), 8.34 (IH, dd, J = 1.2, 8.4Hz), 9.17 (IH, d, J = 2Hz), 9.40 (IH, d, J = 2Hz). Mass spectrum: C2IH20F2N2O2S requires 402; found 403 (MH+)

Reference： [1]Patent: WO2008/116816,2008,A1 .Location in patent: Page/Page column 203-204

9
[ 496807-97-7 ]
[ 1111184-08-7 ]
[ 1111184-15-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In dichloromethane; at 20℃; for 2h;	Intermediate 7; 6-[(3,3-Difluoro-1 -piperidinyl)sulfonyl]-1 -[1 -(trifluoroacetyl)-4-piperidinyl]-2,3- dihydro-1H-indoleTo a solution of 1-[1-(trifluoroacetyl)-4-piperidinyl]-2,3-dihydro-1 H-indole-6-sulfonyl chloride (which may be prepared as described for Intermediate 4, 150mg, 0.38mmol) in DCM (1 OmL) was added triethylamine (132mul_, 0.95mmol) followed by 3,3- difluoropiperidine hydrochloride (71 mg, 0.45mmol). The mixture was stirred at room temperature under argon for 2 hours. It was then shaken with 1 M aqueous HCI (1OmL); the DCM layer was isolated and concentrated in vacuo. The resultant yellow oil was purified by flash chromatography on silica gel (25+S, SP4) eluting with a solvent gradient of 0 to 50% ethyl acetate/hexane to afford the title compound as a yellow oil (157mg, 86%).1H NMR (CDCI3, 400MHz): delta 1.59-1.73 (2H, m, partially obscured by H2O), 1.77-1.98 (6H, m), 2.88 (1 H, t, J=13.0), 3.01-3.12 (4H, m), 3.22-3.34 (3H, m), 3.41-3.51 (2H, m), 3.73 (1 H, tt, J=12.0, 4.0), 4.11-4.19 (1 H, m, partially obscured by EtOAc), 4.71 (1 H, m), 6.70 (1 H, d, J=1.5), 6.02 (1 H, dd, J=7.5, 1.5), 7.15 (1 H, m). Mass spectrum (ESI): C20H24F5N3O3S requires 481 ; found 482 (MH+).
86%	With triethylamine; In dichloromethane; at 20℃; for 2h;	Intermediate 6; 6-[(3,3-Difluoro-1 -piperidinyl)sulfonyl]-1 -[1 -(trifluoroacetyl)-4-piperidinyl]-2,3- dihydro-1H-indoleTo a solution of 1-[1-(trifluoroacetyl)-4-piperidinyl]-2,3-dihydro-1 H-indole-6-sulfonyl chloride (which may be prepared as described for Intermediate 4, 150mg, 0.38mmol) in DCM (1 OmL) was added triethylamine (132mul_, 0.95mmol) followed by 3,3- difluoropiperidine hydrochloride (71 mg, 0.45mmol). The mixture was stirred at room temperature under argon for 2 hours. It was then shaken with 1 M aqueous HCI (1OmL); the DCM layer was isolated and concentrated in vacuo. The resultant yellow oil was purified by flash chromatography on silica gel (25+S, SP4) eluting with a solvent gradient of 0 to 50% ethyl acetate/hexane to afford the title compound as a yellow oil (157mg, 86%).1H NMR (CDCI3, 400MHz): delta 1.59-1.73 (2H, m, partially obscured by H2O), 1.77-1.98 (6H, m), 2.88 (1 H, t, J=13.0), 3.01-3.12 (4H, m), 3.22-3.34 (3H, m), 3.41-3.51 (2H, m), 3.73 (1 H, tt, J=12.0, 4.0), 4.11-4.19 (1 H, m, partially obscured by EtOAc), 4.71 (1 H, m), 6.70 (1 H, d, J=1.5), 6.02 (1 H, dd, J=7.5, 1.5), 7.15 (1 H, m). Mass spectrum (ESI): C20H24F5N3O3S requires 481 ; found 482 (MH+).

Reference： [1]Patent: WO2009/16225,2009,A1 .Location in patent: Page/Page column 19
[2]Patent: WO2009/16227,2009,A2 .Location in patent: Page/Page column 18

10
[ 496807-97-7 ]
C₂₇H₃₀F₄N₂O₅ [ No CAS ]
C₃₂H₃₉F₆N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;	To a mixture of aldehyde 33a1 (40 mg, 0.07 mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (47 mg, 0.30 mmol) in DCM (1 mL) is added NaHB(OAc)3 (31 mg, 0.15 mmol). The mixture is stirred at RT for about 18 hours. Tetrahydrofuran (2 mL), MeOH (1 mL), NaOH (1 N, 1 mL, 1.0 mmol) and LiOH-H2O (15 mg, 0.35 mmol) are added and the mixture is stirred for 3 hours. The mixture is concentrated, taken-up in AcOH (2.5 mL), filtered then injected onto a preparative HPLC to isolate compound 1117.

Reference： [1]Patent: WO2009/18656,2009,A1 .Location in patent: Page/Page column 84

11
[ 761440-64-6 ]
[ 496807-97-7 ]
[ 1116228-93-3 ]

Yield	Reaction Conditions	Operation in experiment
68%		Step C/lntermediate B41 : 3,3-difluoro-1 '-[3-(methyloxy)-4-nitrophenyl]-1 ,4'- bipiperidine; A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (600 mg, 2.4 mmol), commercially available <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (753 mg, 4.8 mmol), acetic acid (0.20 ml_, 3.6 mmol) and triethylamine (0.33 ml_, 3.6 mmol) in 1 ,2- dichloroethane was stirred for 30 minutes. Sodium triacetoxyborohydride (615 mg, 2.9 mmol) was added. When LC/MS indicated the absence of starting material, the reaction was quenched with the addition of sat'd NaHCO3. The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 3,3-difluoro-1'-[3-(methyloxy)-4- nitrophenyl]-1 ,4'-bipiperidine (584 mg, 68%). 1H NMR (400 MHz, d6-DMSO) delta 7.84 (d, J = 9.6 Hz, 1 H), 6.55 (dd, J = 9.6 and 2.0 Hz, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 4.04 (d, J = 12.8 Hz, 1 H), 3.87 (s, 3H), 2.90 (t, J = 12.0 Hz, 2H), 2.72-2.60 (m, 3H), 2.47 (m under DMSO peak, 2H), 1.87-1.74 (m, 4H), 1.61-1.58 (m,. 2H), 1.48-1.38 (m, 2H).

Reference： [1]Patent: WO2009/20990,2009,A1 .Location in patent: Page/Page column 98

12
[ 496807-97-7 ]
[ 1138338-59-6 ]
[ 1138338-24-5 ]

Yield	Reaction Conditions	Operation in experiment
33%		Example 8a (101 mg, 0.21 mmol) was reacted with <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (2.5 eq.) as described under General Procedure K to afford the title compound (37 mg, 33%) as a clear oil. 1H NMR (300 MHz, CDCI3) delta 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.07 (t, J = 5.4 Hz, 2H), 3.97 (td, J = 6.9, 1.5 Hz, 2H), 3.83 (s, 3H), 3.05-2.83 (m, 1 H), 2.75-2.68 (m, 4H), 2.50-2.46 (m, 5H), 2.18 (s, 3H), 2.13-1.94 (m, 2H), 1.90-1.74 (m, 4H), 1.29 (d, J = 6.9 Hz, 3H). MS (ES+) m/z 528 (M + H+).; General Procedure K: Alkylation of lambda/-heterocyclesTo a solution of the lambda/-heterocycle hydrochloride salt (2.5 eq.) in anhydrous DMF (1 M) was added NaH (60% dispersion in oil, 3.0 eq.) and the reaction was stirred at room temperature for 2-3 h. To this was added the bromide (1.0 eq.) in anhydrous DMF (0.2-0.5 M) and the reaction was stirred at 50-60 0C under a N2 atmosphere until the reaction was complete by TLC (~ 16 h). The reaction was quenched with NH4CI(aq ) (sat.) and extracted with EtOAc. The organic phase was washed with water then brine, dried over MgSO4 and concentrated under vacuum.The crude residue was purified by flash chromatography.

Reference： [1]Patent: WO2009/43117,2009,A1 .Location in patent: Page/Page column 46; 67-68

13
[ 496807-97-7 ]
[ 367-80-6 ]
C₁₄H₁₆F₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 4h;	A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.), 3,3- difluoropiperidine hydrochloride (Aldrich 665517; 554.47 mg; 3.52 mmol; 1.5 eq.) and triethylamine (712.07 mg; 7.04 mmol; 3 eq.) in DMF (3 rmL) was stirred at 600C for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4CI. The organic layer was washed three times with aq. NH4CI then brine, dried over magnesium sulfate and <n="59"/>concentrated in vacuo to give a yellow oil. The oil was taken up in THF (15 ml_) and lithium hydroxide (280.86 mg; 1 1.73 mmol; 5 eq.) then water (15 ml_) were added. The reaction mixture was stirred at room temperature for 4 hours and the THF was evaporated under vaccum. The resulting solution was washed with Et2O, acidified with acetic acid and extracted twice with Et2O. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil which was crystallized from water. Filtration and drying under high vaccum afforded the title compound (630 mg, 94%) as a yellow solid. HPLC (Method A) : Rt 3.61 min (purity 99.4%). LC/MS : 286.9 (M+H)+, 284.9 (M-H)".

Reference： [1]Patent: WO2009/43890,2009,A1 .Location in patent: Page/Page column 57-58

14
[ 496807-97-7 ]
[ 1113049-90-3 ]
[ 1163691-77-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 5:; To the crude aldehyde 5a4 (2 g, 9.5 mmol) in 45 mL of DCE is added difluoropiperidine-HCI salt (1.6 g, 10.5 mmol) and triacetoxy sodium borohydride (2.8 g, 13.4 mmol). This reaction is stirred overnight at RT. The mixture is diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (10OmL). The organic phase is then dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (Combiflash, 15-40% EtOAc/Hex.) to afford 5a6 as an orange <n="65"/>oil.
	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;	To aldehyde 3a1 (2.0 g, 9.5 mmol) in 45 mL of DCE is added 3,3-difluoropiperidine- HCI salt (1.6 g, 10.5 mmol) and Na(AcO)3BH (2.8 g, 13.4 mmol). The mixture is stirred overnight at RT. The mixture is diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgS04, filtered and concentrated. The residue is purified by flash chromatography (Combiflash, 15- 40% EtOAc/Hex) to afford pyridyl chloride 3a2.

Reference： [1]Patent: WO2009/76747,2009,A1 .Location in patent: Page/Page column 63-64
[2]Patent: WO2011/32277,2011,A1 .Location in patent: Page/Page column 40

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[ CAS No. 496807-97-7 ] {[proInfo.proName]}

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[ 496807-97-7 ] Synthesis Path-Downstream 1~14

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Fluorinated Building Blocks

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Aliphatic Heterocycles

Piperidines

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