[ CAS No. 373604-28-5 ] {[proInfo.proName]}

Name: 373604-28-5|tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate|97%
Brand: Ambeed
SKU: A160297
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Quality Control of [ 373604-28-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 373604-28-5 ]

Product Details of [ 373604-28-5 ]

CAS No. :	373604-28-5	MDL No. :	MFCD11977352
Formula :	C₁₀H₁₈FNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XRNLYXKYODGLMI-UHFFFAOYSA-N
M.W :	219.25	Pubchem ID :	42609254
Synonyms :

Calculated chemistry of [ 373604-28-5 ] Expand+

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) :	2.3
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 :	1.26

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 [ 373604-28-5 ]

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 [ 373604-28-5 ]

* 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 [ 373604-28-5 ]
Downstream synthetic route of [ 373604-28-5 ]

[ 373604-28-5 ] Synthesis Path-Upstream 1~4

1
[ 211108-50-8 ]
[ 373604-28-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium tetrahydroborate In methanol at 0 - 20℃; for 4 h;	[0600j To the solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (2.0 g, 9.2 mmol, 1.0 equiv) in MeOH (15 mL), NaBH4(525 mg, 13.8 mmol, 1.5 equiv) was slowly added at 0 °C. The reaction mixture was stirred at rt for 4 h. After diluting with water (80 mL), the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine, dried, concentrated and purified by silica gel column chromatography (petroleum ether: EtOAc = 5:1) to give tert-butyl 3 -fluoro-4-hydroxypiperidine- 1 -carboxylate (1.8 g, yield: 90percent) as a yellow solid. ESI-MS (M+H-56): 164.1.
78%	With lithium tri-sec-butyl(hydrido)borate; sodium hydroxide In tetrahydrofuran; methanol at -78 - 0℃; for 0.5 h; Inert atmosphere	A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate, 2.3 (80 g, 0.368 mol) in THF (800 mL) was treated with L-Selectride (405 mL, 0.405 mol, drop wise) at -78° C. under nitrogen atmosphere. The resulting reaction mixture was stirred for 30 min. at the same temperature, MeOH (45.1 mL, 1.105 mol) 1M NaOH (1104 mL, 1.105 mol) were added and the reaction was allowed to warm to 0° C. The reaction was quenched by drop wise addition of H₂O₂ (125.1 mL, 1.843 mol). The volatiles were removed under vacuume and diluted with water (500 mL) and methylene chloride (500 mL). After separation, the organic layer was washed brine, dried over Na₂SO₄ and concentrated in vacuum to provide the desired product tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 78percent). ¹HNMR (CDCl₃, 400 MHz): δ 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84 (m, 2H), 3.82-3.58 (m, 1H), 3.55-3.27 (m, 1H), 3.18 (brs, 1H), 2.06 (brs, 1H), 1.89-1.70 (m, 2H), 1.47 (s, 9H).
78%	Stage #1: With L-Selectride In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: With methanol; sodium hydroxide In tetrahydrofuran at -78 - 0℃;	Step-2.3: Synthesis of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4: A solution of tert-butyl 3-fluoro-4-oxopiperidine-1 -carboxylate, 2.3(80g, 0.368mol) in THF (800mL) was treated with L-Selectride (405ml_, 0.405mol, drop wise) at -78°C under nitrogen atmosphere. The resulting reaction mixture was stirred for 30 min. at the same temperature, MeOH (45.1 ml_, 1 .105mol) 1 M NaOH (1 104ml_, 1 .105mol) were added and the reaction was allowed to warm to 0 °C. The reaction was quenched by drop wise addition of H2O2 (125.1 mL, 1 .843mol). The volatiles were removed under vaccume and diluted with water (500ml_) and methylene chloride (500ml_). After separation, the organic layer was washed brine, dried over Na₂SO₄and concentrated in vacuum to provide the desired product tert-butyl 3-fluoro-4-hydroxypiperidine-1 -carboxylate, 2.4 (63g, 78percent).¹HNMR (CDCI₃, 400MHz): δ 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84 (m, 2H), 3.82-3.58 (m, 1 H), 3.55-3.27 (m, 1 H), 3.18 (brs, 1 H), 2.06 (brs, 1 H), 1 .89-1.70 (m, 2H), 1 .47 (s, 9H)

Reference： [1] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0600
[2] Patent: US2015/51209, 2015, A1, . Location in patent: Paragraph 0383; 0388; 0389
[3] Patent: WO2015/22662, 2015, A1, . Location in patent: Paragraph 00251; 00252
[4] Patent: WO2012/68440, 2012, A1, . Location in patent: Page/Page column 75
[5] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 223
[6] Patent: WO2016/142855, 2016, A2, . Location in patent: Page/Page column 50-51
[7] Patent: WO2016/203112, 2016, A1, . Location in patent: Page/Page column 59; 60
[8] Patent: WO2008/124323, 2008, A1, . Location in patent: Page/Page column 58

2
[ 211108-48-4 ]
[ 373604-28-5 ]

Reference： [1] Patent: WO2012/68440, 2012, A1,
[2] Patent: WO2013/96744, 2013, A1,
[3] Patent: WO2015/22662, 2015, A1,
[4] Patent: WO2016/203112, 2016, A1,
[5] Patent: WO2008/124323, 2008, A1,

3
[ 79099-07-3 ]
[ 373604-28-5 ]

Reference： [1] Patent: WO2012/68440, 2012, A1,
[2] Patent: WO2013/96744, 2013, A1,
[3] Patent: US2015/51209, 2015, A1,
[4] Patent: WO2015/22662, 2015, A1,
[5] Patent: WO2016/203112, 2016, A1,
[6] Patent: WO2008/124323, 2008, A1,

4
[ 373604-28-5 ]
[ 934536-10-4 ]

Reference： [1] Patent: US2015/51209, 2015, A1,
[2] Patent: WO2015/22662, 2015, A1,

[ 373604-28-5 ] Synthesis Path-Downstream 1~53

1
[ 478617-58-2 ]
[ 373604-28-5 ]
tert-butyl cis-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl)oxy]piperidine-1-carboxylate [ No CAS ]
tert-butyl trans-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl)oxy]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; at 120℃; for 72h;	INTERMEDIATE 50 tert-Butyl cis-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl) oxy] piperidine-1-carboxylate and INTERMEDIATE 51 tert-Butyl trans-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl) oxy] piperidine-1-carboxylate 7-Iodo-5-nitrobenzofuran (2.0 g, 6.9 mmol), tert-butyl 3-fluoro-4-hydroxypiperidine-1- carboxylate* (3.8 g, 17.3 mmol; mixture of cisltrans isomers), 1,10-phenanthroline (0.50 g, 2.8 mmol), Cul (0.26 g, 1.4 mmol) and Cs2C03 (4.5 g, 13.8 mmol) were heated in toluene (20 mL) at 120 C for 72 h. The reaction mixture was filtered through Celite and evaporated. The resulting diastereomers were separated by flash chromatography using heptane/EtOAc [ (4 : > (2: 1) ] to yield 255 mg of the cis-isomer and 919 mg of the trans- isomer. cis-isomer (Intermediate 50): Yield: 10%, HPLC purity = 70%, m/z = 381 (M+H) +. trans-isomer (Intermediate 51) : Yield: 35%, HPLC purity = 94%, m/z = 381 (M+H) +.

Reference： [1]Patent: WO2005/58858,2005,A1 .Location in patent: Page/Page column 125

2
[ 373604-28-5 ]
[ 124-63-0 ]
(anti)-3-fluoro-4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 14h;	Step 2B: Preparation of ftransVtert-butyl 3-fluoro-4-(methylsulfonyloxytpiperidine- 1 -carboxylate:; A solution of tert-butyl 3-fluoro-4- hydroxypiperidine-1-carboxylate (52.76 g, 241 mmol) dissolved in anhydrous methylene chloride (1 L) was cooled to 0 0C and treated with triethylamine (43.6 mL, 313 mmol) followed by methanesulfonyl chloride (20.5 mL, 265 mmol). The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCtheta3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with <n="60"/>methylene chloride. The combined organic phases were washed with IN HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexanes:EtOAc to provide the desired product (7.24 g).

Reference： [1]Patent: WO2008/124323,2008,A1 .Location in patent: Page/Page column 58-59

3
[ 211108-50-8 ]
[ 373604-28-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 4h;	[0600j To the solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (2.0 g, 9.2 mmol, 1.0 equiv) in MeOH (15 mL), NaBH4(525 mg, 13.8 mmol, 1.5 equiv) was slowly added at 0 C. The reaction mixture was stirred at rt for 4 h. After diluting with water (80 mL), the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine, dried, concentrated and purified by silica gel column chromatography (petroleum ether: EtOAc = 5:1) to give tert-butyl 3 -fluoro-4-hydroxypiperidine- 1 -carboxylate (1.8 g, yield: 90%) as a yellow solid. ESI-MS (M+H-56): 164.1.
78%	With lithium tri-sec-butyl(hydrido)borate; sodium hydroxide; In tetrahydrofuran; methanol; at -78 - 0℃; for 0.5h;Inert atmosphere;	A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate, 2.3 (80 g, 0.368 mol) in THF (800 mL) was treated with L-Selectride (405 mL, 0.405 mol, drop wise) at -78 C. under nitrogen atmosphere. The resulting reaction mixture was stirred for 30 min. at the same temperature, MeOH (45.1 mL, 1.105 mol) 1M NaOH (1104 mL, 1.105 mol) were added and the reaction was allowed to warm to 0 C. The reaction was quenched by drop wise addition of H2O2 (125.1 mL, 1.843 mol). The volatiles were removed under vacuume and diluted with water (500 mL) and methylene chloride (500 mL). After separation, the organic layer was washed brine, dried over Na2SO4 and concentrated in vacuum to provide the desired product tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 78%). 1HNMR (CDCl3, 400 MHz): delta 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84 (m, 2H), 3.82-3.58 (m, 1H), 3.55-3.27 (m, 1H), 3.18 (brs, 1H), 2.06 (brs, 1H), 1.89-1.70 (m, 2H), 1.47 (s, 9H).
78%		Step-2.3:Synthesis of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4:A solution of tert-butyl 3-fluoro-4-oxopiperidine-1 -carboxylate, 2.3(80g, 0.368mol) in THF (800mL) was treated with L-Selectride (405ml_, 0.405mol, drop wise) at -78C under nitrogen atmosphere. The resulting reaction mixture was stirred for 30 min. at the same temperature, MeOH (45.1 ml_, 1 .105mol) 1 M NaOH (1 104ml_, 1 .105mol) were added and the reaction was allowed to warm to 0 C. The reaction was quenched by drop wise addition of H2O2 (125.1 mL, 1 .843mol). The volatiles were removed under vaccume and diluted with water (500ml_) and methylene chloride (500ml_). After separation, the organic layer was washed brine, dried over Na2SO4and concentrated in vacuum to provide the desired product tert-butyl 3-fluoro-4-hydroxypiperidine-1 -carboxylate, 2.4 (63g, 78%).1HNMR (CDCI3, 400MHz): delta 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84 (m, 2H), 3.82-3.58 (m, 1 H), 3.55-3.27 (m, 1 H), 3.18 (brs, 1 H), 2.06 (brs, 1 H), 1 .89-1.70 (m, 2H), 1 .47 (s, 9H)

	With sodium tetrahydroborate; at 20℃; for 2h;	Step 3. tert-Butyl 3-fluoro-4-hydroxypiperidine-l-carboxylateOHTo a solution of tert-butyl 3-fluoro-4-oxopiperidine-l-carboxylate (3.60 g, 16.6 mmol) in methanol (20 mL) was added sodium borohydride (0.815 g, 21.5 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with water and methanol was removed in vacuo. The aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2S04 and concentrated. The crude was purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in hexanes to afforddiastereomers 1 (first to elute) (0.95 g, 26%) and diastereomers 2 (second to elute) (2.7 g, 74%). LCMS (M+H-56)+: 164.1. Step 4. tert-Butyl 4-(benzoyloxy)-3-fluoropiperidine-l-carboxylate
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 4.5h;	To a solution of Compound 3 (1 g, 4.6 mmol) in ethanol (10 mL) was added NaBHt (0.3 g, 7.8 mmol) slowly at 0 C. The reaction mixture was stirred at 0 C for 0.5 h and the stirred at room temperature for 4 hours. The reaction mixture was quenched with aqueous NH4C1 solution and extracted with AcOEt. The organic layer was dried and concentrated to give the desired product.
	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	Step-1 : Synthesis of tert-butyl 3-fluoro-4-hvdroxypiperidine-l-carboxylate. To a solution of tert-butyl 3-fluoro-4-oxopiperidine-l -carboxylate (lOg, 45.87mmol, WO2015/022662) in MeOH (200mL) was added sodiumborohydride (2.5g, 69.44mmol) lot wise at 0 C. Then the reaction mixture was allowed to stir at room temperature for lh. After completion of the reaction, the reaction mixture was concentrated under vacuum and diluted with ice-cold saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (2x50mL). The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the title compound (9.1g, crude). LCMS: m/z = 220.0 (M+H)+.
	With methanol; sodium tetrahydroborate; at 20℃; for 6h;Cooling with ice;	To an ice cold solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (2.0 g, 9.21 mmol) in MeOH (20 mL) was added sodium borohydride (0.7 g, 18.42 mmol) followed by stirring at RT for 6 h. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over sodium sulphate and (0207) concentrated under reduced pressure. The residue was purified by combi-flash to afford the title compound as white solid (diasteromers) (0.9 g, 45 % and 0.6 g, 30 %).1H NMR (400 MHz, DMSO-d6): delta 5.27 (d, J=4.9 Hz, 1H), 4.36-4.15 (m, 1H), 3.69- 3.67 (m, 2H), 3.50-3.28 (m, 1H), 3.22-3.18 (m, 2H), 1.77-1.74 (m, 1H), 1.40-1.38 (m, 10H).
		2. Preparation of N-(Tcisy3-fluoropiperidin-4-viy2-(7-f2-methoxyethoxy^ imidazori.2-alpyridin-3-yl)quinolin-8-amine; Step 2A: Preparation of tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate:; tert-Butyl S-fluoro^-oxopiperidine-l-carboxylate [van Niel, M.B.; et al.; J. Med. Chem. 1999, 42, 2087-2104] (52.27 g, 241 mmol) was dissolved in anhydrous MeOH (600 mL), cooled to 0 0C and treated in portions with sodium borohydride (37.8 g, 361 mmol) over a 15 minute period. After stirring at 0 0C for 30 minutes, the mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated ammonium chloride solution (400 mL) and EtOAc (400 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to provide the desired product as a thick oil that slowly solidified upon standing (52.7 g).

Reference： [1]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0600
[2]Patent: US2015/51209,2015,A1 .Location in patent: Paragraph 0383; 0388; 0389
[3]Patent: WO2015/22662,2015,A1 .Location in patent: Paragraph 00251; 00252
[4]Patent: WO2012/68440,2012,A1 .Location in patent: Page/Page column 75
[5]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 223
[6]Patent: WO2016/142855,2016,A2 .Location in patent: Page/Page column 50-51
[7]Patent: WO2016/203112,2016,A1 .Location in patent: Page/Page column 59; 60
[8]Patent: WO2008/124323,2008,A1 .Location in patent: Page/Page column 58

4
[ 373604-28-5 ]
[ 1145658-37-2 ]
[ 1254361-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hexamethyldisilazane; In 1,4-dioxane; at 105℃; for 4h;Inert atmosphere; Microwave irradiation;	To a hot (105 degrees Celsius) solution of 1-(6-chloropyrimidin-4-yl)-5- (methylsulfonyl)indoline (33.8 mg, 0.109 mmol) and te/t-butyl-3-fluoro-4- hydroxypiperidine-1 -carboxylate (racemic mixture of cis and trans isomers) (20 mg, 0.091 mmol) in 1.5 ml. of 1 ,4-dioxane, in a microwave vial, was added sodium bis(trimethylsilyl)amide (0.14 ml_, 1 M in tetrahydrofuran). The stirred mixture was heated at 105 degrees Celsius under a nitrogen atmosphere for 4 hours before it was cooled to room temperature and diluted with water and ethyl acetate. The organic phase was removed and washed with saturated aqueous sodium bicarbonate. The combined aqueous phases were extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (1 ml.) and purified by reversed-phase HPLC (Column: Waters XBridge Cibeta 19x100 mm, 5 micrometer; Mobile phase A: 0.03% ammonium hyroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 80% water /20% acetonitrile linear to 0% water/ 100% acetonitrile in 8.5 minutes, hold at 0% water / 100% acetonitrile to 10.0 minutes. Flow: 25mL/min. Purification in this way provided 17 mg of fe/t-Butyl 3-fluoro- 4-({6-[5-(methylsulfonyl)-2,3-dihydro-1 H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1- carboxylate. LCMS (M+H)): 493.0

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 96

5
[ 373604-28-5 ]
[ 1254360-63-8 ]
[ 1254361-18-6 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium bis(trimethylsilyl)amide (0.24 ml_, 1 M in tetrahydrofuran) was added drop-wise to a solution of te/t-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (48 mg, 0.22 mmol) in tetrahydrofuran (1 mL) at room temperature. The mixture was stirred for 5 minutes, before it was added drop-wise to a stirred solution of methyl 1-(6-chloro-5- methylpyrimidin-4-yl)indoline-5-carboxylate (60 mg, 0.2 mmol) in tetrahydrofuran (1 mL) at 60 degrees Celsius. The reaction mixture was stirred at 60 degrees Celsius for 2 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude 1-(6-(1-(te/t-butoxycarbonyl)-3-fluoropiperidin-4- yloxy)-5-methylpyrimidin-4-yl)indoline-5-carboxylic acid was used in the next step without purification.

Reference： [1]Patent: WO2010/128414,2010,A1 .Location in patent: Page/Page column 101

6
[ 373604-28-5 ]
5-methyl-4-nitro-1H-pyrazole [ No CAS ]
[ 1374829-32-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2h;	Alternatively, (S)-tert-butyl 3 -(3 -methyl-4-nitro- lH-pyrazol- 1 -yl)pyrrolidine- 1 - carboxylate (049-3) and (S)-tert-butyl 3-(5-methyl-4-nitro-lH-pyrazol-l-yl)pyrrolidine-l- carboxylate or related analogs, such as tert-butyl 3-fluoro-4-(3-methyl-4-nitro-lH-pyrazol-l- yl)piperidine-l -carboxylate, can be prepared by the following procedure: To a solution of 5- methyl-4-nitro-lH-pyrazole (0.99 g, 7.8 mmol), tert-butyl 3-fluoro-4-hydroxypiperidine-l- carboxylate (1.7 g, 7.8 mmol) and triphenylphosphine (2.3 g, 8.5 mmol) in THF (8 mL) was added diisopropyl azodicarboxylate (2 g, 9.3 mmol). The reaction was stirred at room temperature for 2 hours before being diluted with water and extracted with EtOAc (4x). The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography to give tert-butyl 3-fluoro-4-(3-methyl-4- nitro-lH-pyrazol-l-yl)piperidine-l -carboxylate (2.25 g, 88%).

Reference： [1]Patent: WO2012/62783,2012,A1 .Location in patent: Page/Page column 76

7
[ 373604-28-5 ]
[ 98-88-4 ]
tert-butyl 4-(benzoyloxy)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 4. tert-Butyl 4-(benzoyloxy)-3-fluoropiperidine-l-carboxylateTo a solution of tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate(diastereomers 1, 0.95 g, 4.3 mmol) in THF (10.0 mL) at 0 C was added sodium hydride (60% in mineral oil, 0.260 g, 6.50 mmol). After stirring for 0.5 hour, benzoyl chloride (0.604 mL, 5.20 mmol) was added and stirred for 2 hours. The reaction was quenched with 1 N HCl and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified with silica gel column to give the desired product as oil (0.80 g, 57%>). Diasteromers 2 from last step was converted to the desired product using same condition in 63%> yield. LCMS (M+Na)+: 346.1.

Reference： [1]Patent: WO2012/68440,2012,A1 .Location in patent: Page/Page column 76

8
[ 211108-48-4 ]
[ 373604-28-5 ]

Reference： [1]Patent: WO2012/68440,2012,A1
[2]Patent: WO2013/96744,2013,A1
[3]Patent: WO2015/22662,2015,A1
[4]Patent: WO2016/203112,2016,A1
[5]Patent: WO2008/124323,2008,A1

9
[ 373604-28-5 ]
3-fluoropiperidin-4-yl benzoate [ No CAS ]

Reference： [1]Patent: WO2012/68440,2012,A1

10
[ 373604-28-5 ]
1-((R)-3-cyano-2-hydroxypropyl)-3-fluoropiperidin-4-yl benzoate [ No CAS ]

Reference： [1]Patent: WO2012/68440,2012,A1

11
[ 79099-07-3 ]
[ 373604-28-5 ]

Reference： [1]Patent: WO2012/68440,2012,A1
[2]Patent: WO2013/96744,2013,A1
[3]Patent: US2015/51209,2015,A1
[4]Patent: WO2015/22662,2015,A1
[5]Patent: WO2016/203112,2016,A1
[6]Patent: WO2008/124323,2008,A1

12
[ 373604-28-5 ]
[ 934536-10-4 ]

Reference： [1]Patent: US2015/51209,2015,A1
[2]Patent: WO2015/22662,2015,A1

13
[ 373604-28-5 ]
[ 446-52-6 ]
[ 1445803-93-9 ]

Yield	Reaction Conditions	Operation in experiment
66%		NaH (55-65%; 44 mg; 1.09 mmol; 1.2 eq.) was added to a solution of 3-fluoro-4-hydroxy- piperidine-1 -carboxylic acid tert-butyl ester (200 mg; 0.91 mmol; 1 eq.) in THF (15 mL) and the resulting mixture was stirred at room temperature for 15 minutes whereupon 2- fluoro-benzaldehyde (113 mg; 0.91 mmol; 1 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours then at 60C for a further 4 hours. NaH (44 mg; 1.09 mmol; 1.2 eq.) was added and the resulting mixture was stirred at 60C for 2 hours. The solution was diluted with brine extracted with EA (2x). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM then EtOAc) afforded the title compound (196 mg, 66%) as a yellow oil. H NMR (DMSO-d6) delta 10.38 (s, 1H), 7.74-7.62 (m, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 7.12 (t, J = 7.6 Hz, 1H), 5.08-4.80 (m, 2H), 4.16-3.98 (m, 1 H), 3.94-3.78 (m, 1 H), 3.42-2.95 (m, 2H), 1.96-1.83 (m, 2H), 1.40 (s, 9H).

Reference： [1]Patent: WO2013/91773,2013,A1 .Location in patent: Page/Page column 66

14
[ 373604-28-5 ]
[ 446-52-6 ]
[ 1445803-94-0 ]

Reference： [1]Patent: WO2013/91773,2013,A1

15
[ 373604-28-5 ]
[ 373604-29-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h;	To a solution of compound 4 (0.6 g, 2.7 mmol) in anhydrous DCM (4 mL) was added TFA (4 mL) at 0C. The formed mixture was stirred for 2 h, and concentrated to give the desired product which was used for the next step (600 mg, 100%).

Reference： [1]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 223; 224

16
[ 373604-28-5 ]
C₁₈H₁₅F₅N₂O₄S [ No CAS ]
C₁₈H₁₅F₅N₂O₄S [ No CAS ]

Reference： [1]Patent: WO2013/96744,2013,A1

17
[ 373604-28-5 ]
C₂₀H₂₂ClFN₂O₄S [ No CAS ]
C₂₀H₂₂ClFN₂O₄S [ No CAS ]

Reference： [1]Patent: WO2013/96744,2013,A1

18
[ 373604-28-5 ]
[ 98-59-9 ]
[ 1450879-65-8 ]
[ 1450879-66-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;	Step-6.1:Synthesis of tert-butyl (3S,4R)-3-fluoro-4-(tosyloxy)piperidine-1-carboxylate, 4.3-1Tert-butyl 3-fluoro-4-hydroxypiperidine-1 -carboxylate, 2.4 (6g, 0.0273mol) in anhydrous DCM (100 ml_) was treated with triethylamine (5.6g , 0.055mol) and DMAP (0.35g, 0.029 mol) followed by p-toluene sulfonyl chloride (5.7g, 0.03mol) at 0 C under nitrogen atmosphere. The resulting mixture was allowed slowly to ambient temperature and stirred for 16h. The reaction mixture was poured into ice water, separated the organic layer, washed with saturated NaHC03, brine solution, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (10-30% EtOAc /hexane), as the second eluted product 4.2-2, 4.1 g (major product, mixture of two enantiomers). HPLC (ZORBAX XDB): 98.35% at rt 5.3 min. Chiral HPLC: [(LUX AMYLOSE 5micron 2(250x4.60mm), Hexane : EtOH (50:50)] shows two peaks at 7.27 min (Peak-1 : 49.19% at rt) and at 1 1 .406 min (Peak-2: 49.61 % at rt).1 .6 g of the cis-isomer 4.2.2 was separated by chiral HPLC (column LUX AMYLOSE -2, flow rate: 20ml/min, Solvent: n-Hexane/Ethanol (60:40)) and 0.7 g of the 3S.4R- isomer 4.3-1 and 0.75 g of the 3R,4S-isomer 4.3-2 were obtained. Peak-1 , 4.3-1 :1HNMR (400MHz, CDCI3): delta 7.81 -7.79 (d, 2H), 7.35-7.33 (d, 2H), 4.83 -4.52 (m, 2H), 4.05-3.55(m, 2H), 3.50-3.05 (m, 2H), 2.44 (s, 3H), 2.07-2.05 (m, 1 H), 1 .71 -1 .68 (m, 1 H), 1 .43 (s, 9H); LCMS: 96.00%, m/z 274.1 (M-Boc+1 ); HPLC: 99.62%.Peak-2, 4.3-2:1H NMR (400MHz, CDCI3): delta 7.81 -7.79 (d, 2H), 7.35-7.33 (d, 2H), 4.83 -4.52 (m, 2H), 4.05-3.55(m, 2H), 3.50-3.05 (m, 2H), 2.44 (s, 3H), 2.07-2.05 (m, 1 H), 1 .71 -1.68 (m, 1 H), 1 .43 (s, 9H); LCMS: 94.48.0%, m/z 274 (M-Boc+1 ); HPLC: 97.64%.

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 8892 - 8897
[2]Patent: WO2015/22662,2015,A1 .Location in patent: Paragraph 00270

19
[ 373604-28-5 ]
tert-butyl 4-azido-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/51209,2015,A1
[2]Patent: WO2015/22662,2015,A1

20
[ 373604-28-5 ]
[ 350-46-9 ]
tert-butyl 3-fluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.6%		To a solution of tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate (10.07 g, 46 mmol, 1 eq.) in DMA (200 mL) cooled at 0 C was added NaH (3.7 g, 92 mmol, 2 eq.) in small portions and the resulting mixture was stirred at 0 C for 30 min.Then l-fluoro-4- nitrobenzene (4.9 mL, 46 mmol, 1 eq.) was added slowly and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (1000 mL), extracted with EA (3x200 mL) and the organic layers were combined, washed with brine (600 mL), dried over anhydrous Na2S04, concentrated and purified via column chromatography (PE/EA=2/1) to afford tert- butyl 3-fluoro-4-(4-nitrophenoxy)piperidine-l-carboxylate (8.7 g, 55.6%) as a yellow solid.
214 mg	With potassium tert-butylate; In tetrahydrofuran;Cooling with ice; Reflux;	Potassium tert-butoxide (202 mg) was added to a mixture containing 4-fluoronitrobenzene (141 mg), <strong>[373604-28-5]tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate</strong> (commercially available from Ark Pharm, Inc, 219 mg)and THF (10 mL) under ice cooling, and the mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, ethyl acetate was then added thereto, and washing with a saturated sodium bicarbonate aqueous solution was performed. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure, and thereby a yellow solid (214 mg) containing tert-butyl 3-fluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate was obtained.

Reference： [1]Patent: WO2015/27222,2015,A2 .Location in patent: Paragraph 0396
[2]Patent: US2019/337926,2019,A1 .Location in patent: Paragraph 0638

21
[ 373604-28-5 ]
[ 934536-09-1 ]

Reference： [1]Patent: US2015/51209,2015,A1

22
[ 373604-28-5 ]
tert-butyl (3S,4S)-4-azido-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/51209,2015,A1
[2]Patent: WO2015/22662,2015,A1

23
[ 373604-28-5 ]
(3R,4R)-tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/51209,2015,A1
[2]Patent: WO2015/22662,2015,A1

24
[ 373604-28-5 ]
(3S,4S)-tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/51209,2015,A1
[2]Patent: WO2015/22662,2015,A1

25
[ 373604-28-5 ]
[ 1260612-08-5 ]