[ CAS No. 63845-28-3 ] {[proInfo.proName]}

Name: 63845-28-3|2-(1-((Benzyloxy)carbonyl)piperidin-4-yl)acetic acid|95%
Brand: Ambeed
SKU: A130529
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Quality Control of [ 63845-28-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 63845-28-3 ]

SDS Specification

Alternatived Products of [ 63845-28-3 ]

Product Details of [ 63845-28-3 ]

CAS No. :	63845-28-3	MDL No. :	MFCD02179001
Formula :	C₁₅H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BUNUQMSIKUGVKD-UHFFFAOYSA-N
M.W :	277.32	Pubchem ID :	1502086
Synonyms :

Calculated chemistry of [ 63845-28-3 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.47
Num. rotatable bonds :	6
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	78.01
TPSA :	66.84 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) :	-6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.39
Log Po/w (XLOGP3) :	1.86
Log Po/w (WLOGP) :	1.98
Log Po/w (MLOGP) :	1.83
Log Po/w (SILICOS-IT) :	1.65
Consensus Log Po/w :	1.94

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.56
Solubility :	0.769 mg/ml ; 0.00277 mol/l
Class :	Soluble
Log S (Ali) :	-2.88
Solubility :	0.361 mg/ml ; 0.0013 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.76
Solubility :	0.48 mg/ml ; 0.00173 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.65

Safety of [ 63845-28-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 63845-28-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 63845-28-3 ]
Downstream synthetic route of [ 63845-28-3 ]

[ 63845-28-3 ] Synthesis Path-Upstream 1~2

1
[ 501-53-1 ]
[ 73415-84-6 ]
[ 63845-28-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide In water at 20℃; for 16 h; Cooling with ice	To prepare compound 2, a procedure published in DE 4304650 A1 was followed with modifications. 3000 mg (16.7 mmol) 2-(piperidin-4-yl) acetic acid hydrochloride (Iris Biotech, Marktredwitz, Germany) was dissolved in 46 ml of a 1 M solution of NaOH in water and cooled in an ice bath. 3350 μl benzyloxycarbonyl chloride (Cbz-Cl) (23.46 mmol, 4002 mg) were added dropwise over 5 min under stirring. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The aqueous solution was washed twice with 20 ml of diethyl ether/petroleum ether 4:1 and then acidified with 4 M HCl (aq.) to pH 1 . The product of the reaction was extracted with 3x 50 ml diisopropyl ether. The combined organic phases were dried with MgSO₄ and evaporated under reduced pressure. Compound 2 was obtained as a colorless solid (4383 mg, 15.8 mmol, 95percent). ¹H NMR (400 MHz, Chloroform-d) δ 7.40 - 7.27 (m, 5H), 5.13 (s, 2H), 4.18 (d, J = 13.3 Hz, 2H), 2.81 (t, J = 12.8 Hz, 2H), 2.29 (d, J = 7.0 Hz, 2H), 1.96 (tp, J = 11.2, 3.5 Hz, 1 H), 1.75 (d, J = 12.1 Hz, 2H), 1.30 - 1.09 (m, 2H)
60%	With sodium hydroxide In water at 0 - 20℃; for 24 h;	[00345] Intermediate 21: 2-(1 -Benzyloxycarbonyl-4-piperidyl)acetic acid [00346] 5 M NaOH (aq.) was added to a stirred solution of 2-piperidin-1-ium-4-ylacetic acidchloride (1 .OOg, 5.S7mmol) in water (4OmL) at 0 °C until pH 12 was reached. Benzyl chloroformate (0.79mL, 5.57mmol) was added dropwise to the solution. The mixture was stirred at roomtemperature for 24 hours and then the reaction mixture was extracted with Et20 (5OmL). Theaqueous fraction was acidified to pH 4 with 1 M HCI, then extracted with EtOAc (3 x 2OmL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to yield 2-Cl-Benzyloxycarbonyl-4-piperidyl)acetic acid (923mg, 3.33mmol, 60percent yield) as an off-white solid.1H NMR (DMSO-d6, 400MHz) O/ppm: 12.09 (1H, 5), 7.41-7.29 (5H, m), 5.06 (2H, 5), 4.21-4.04 (2H, m), 2.80-2.69 (2H, m), 2.15 (2H, d, J= 7.0Hz), 1.89-1.78 (1H, m), 1.73-1.64 (2H, m), 1.18-1.08 (2H,m).

Reference： [1] Patent: WO2014/125084, 2014, A1, . Location in patent: Page/Page column 33; 34
[2] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00344; 00345; 00346

2
[ 501-53-1 ]
[ 51052-78-9 ]
[ 63845-28-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With H₂; sodium hydroxide In water	A. 1-[(Phenylmethoxy)carbonyl]-4-piperidineacetic acid Platinum oxide (300 mg, Alfa) was added to a solution of pyridyl-4-acetic acid, hydrochloride (3.3 g, 19 mmol) in water (120 mL). The solution was hydrogenated at up to 50 psi of H₂ pressure for 17 hrs. The catalyst was removed by filtration through a pad of Celite and the pad was washed with more water. The stirred aqueous solution of the piperidine-4-acetic acid was cooled (0°-5° C.) and treated with 5 N aqueous NaOH solution (15 mL) to pH 12. Benzyl chloroformate (4 mL) was added dropwise to the vigorously stirred cooled solution. After one hour (maintaining the pH at 10 to 12), the reaction mixture was extracted with ether (2100 mL). The ether extracts were discarded and the aqueous layer was acidified with 2 N HCl solution (50 mL). The acidified aqueous layer was then extracted with ethyl acetate (275 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give title compound as a white solid (4.53 g, 86percent yield).

Reference： [1] Patent: US5583146, 1996, A,

[ 63845-28-3 ] Synthesis Path-Downstream 1~25

1
[ 63845-28-3 ]
[ 168050-46-2 ]
[ 168050-53-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 41 - 44

2
[ 95-54-5 ]
[ 63845-28-3 ]
4-[(2-amino-phenylcarbamoyl)-methyl]-piperidine-1-carboxylic acid benzyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 807 - 819

3
[ 63845-28-3 ]
4-(1<i>H</i>-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylic acid benzyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 807 - 819

4
[ 867162-37-6 ]
[ 63845-28-3 ]
[ 867162-98-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16.0h;	(4-({ [(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-methyl)- piperidine-1-carboxylic acid benzyl ester); [1123] (3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)-methanamine (120.00 mg, 0.35 mmol), EDC (100.64 mg, 0.53 mmol) and HOBt (47.29 mg, 0.35 mmol) were suspended in CH2C12 (2 mL) and charge with DIEA (122.00 muL, 0.70 mmol) followed by the addition of 1- N-Cbz-4-piperidineacetic acid (127.56 mg, 0.46 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with saturated NaHC03 (2 x 20 mL) and brine (2 x 20 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The crude product was purified by a 10 g Jones silica gel (wetted with 50% EtOAc/ Hexane, dried loaded onto silica, and run with 60% EtOAc/ Hexanes - 70% EtOAc/ Hexanes) affording the desired product; ¹H NMR (400 MHz, CHLOROFORM-d) 8 8.56 (1 H, d, J=2.47), 8.39 (1 H, d, J= 2.50), 8.23 (1 H, d, J= 4.77), 8.11 (2 H, d, J= 7.06), 7.85 (3 H, dd, J= 8.60, J= 8.38), 7.74 (1 H, s), 7.50 (3H, m), 7.32 (6H, m), 6.78 (1 H, d, J= 7.76), 5.10 (2 H, s), 4.11 (2 H, m), 2.75 (2 H, m), 2.21 (2 H, d, J= 7.00), 2.01 (1 H, m), 1.67 (2 H, m), 1.15 (2 H, d, J= 8.921) ; MS (ES+): m/z 605.96/606.98/608.93 (100/40/15) [MH(at)] ; HPLC: tR = 3.33 min. (OpenLynx, nonpolar_5min.).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16.0h;	(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)-methanamine (120.00 mg, 0.35 mmol), EDC (100.64 mg, 0.53 mmol) and HOBt (47.29 mg, 0.35 mmol) were suspended in CH2Cl2 use CH2C12(2 mL) and charge with DIEA (122.00 muL, 0.70 mmol) followed by the addition of l-JV-Cbz-4-piperidineacetic acid (127.56 mg, 0.46 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3 (2 x 20 mL) and brine (2 x 20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a 10 g Jones silica gel (wetted with 50% EtOAc / Hexane, dried loaded onto silica, and run with 60% EtOAc / Hexanes - > 70% EtOAc / Hexanes). The product was evaporated in vacuo which afforded the title compound; 1H NMR (400 MHz, CHLOROFORM-d) delta 8.56 (1 H, d, J=IAT), 8.39 (1 H, d, J= 2.50), 8.23 (1 H, d, J= 4.77), 8.11 (2 H, d, J= 7.06), 7.85 (3 H, dd, J= 8.60, J= 8.38), 7.74 (1 H, s), 7.50 (3H, m), 7.32 (6H, m), 6.78 (1 H, d, J= 7.76), 5.10 (2 H, s), 4.11 (2 H, m), 2.75 (2 H, m), 2.21 (2 H, d, J= 7.00), 2.01 (1 H, m), 1.67 (2 H, m), 1.15 (2 H, d, J= 8.921); MS (ES+): m/z 605.96/606.98/608.93 (100/40/15) [MH+]; HPLC: tR = 3.33 min. (OpenLynx, nonpolar_5min.).

Reference： [1]Patent: WO2005/97800,2005,A1 .Location in patent: Page/Page column 252-253
[2]Patent: WO2009/91939,2009,A1 .Location in patent: Page/Page column 66-67

5
pyridyl-4-acetic acid, hydrochloride [ No CAS ]
[ 501-53-1 ]
[ 51052-78-9 ]
[ 63845-28-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With H2; sodium hydroxide; In water;	A. 1-[(Phenylmethoxy)carbonyl]-4-piperidineacetic acid Platinum oxide (300 mg, Alfa) was added to a solution of pyridyl-4-acetic acid, hydrochloride (3.3 g, 19 mmol) in water (120 mL). The solution was hydrogenated at up to 50 psi of H2 pressure for 17 hrs. The catalyst was removed by filtration through a pad of Celite and the pad was washed with more water. The stirred aqueous solution of the piperidine-4-acetic acid was cooled (0-5 C.) and treated with 5 N aqueous NaOH solution (15 mL) to pH 12. Benzyl chloroformate (4 mL) was added dropwise to the vigorously stirred cooled solution. After one hour (maintaining the pH at 10 to 12), the reaction mixture was extracted with ether (2100 mL). The ether extracts were discarded and the aqueous layer was acidified with 2 N HCl solution (50 mL). The acidified aqueous layer was then extracted with ethyl acetate (275 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give title compound as a white solid (4.53 g, 86% yield).

Reference： [1]Patent: US5583146,1996,A

6
[ 771581-15-8 ]
[ 63845-28-3 ]
benzyl 4-(2-((3-chloropyrazin-2-yl)methylamino)-2-oxoethyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: R1-acid (1.0 eq), EDCI (1.5 eq), HOBt (1.0 eq) were taken in dry DCM, stirred at 0 oC for10 min, followed by addition of (3-chloropyrazin-2-yl)methanamine (1 eq.), the reaction wasstirred at room temperature for 3-6 h. Upon completion (monitored by thin layerchromatography), the reaction was extracted into DCM and washed with water, NaHCO3, andbrine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crudeproduct was then purified via flash chromatography over silica, eluting with a hexanes/EtOAcgradient.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 74,p. 562 - 573

7
[ 63845-28-3 ]
benzyl 4-((8-chloroimidazo[1,5-a]pyrazin-3-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 74,p. 562 - 573

8
[ 63845-28-3 ]
benzyl 4-((8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 74,p. 562 - 573

9
[ 63845-28-3 ]
benzyl 4-((8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 74,p. 562 - 573

10
[ 63845-28-3 ]
[ 1574259-00-9 ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 74,p. 562 - 573

11
[ 501-53-1 ]
[ 73415-84-6 ]
[ 63845-28-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide; In water; at 20℃; for 16h;Cooling with ice;	To prepare compound 2, a procedure published in DE 4304650 A1 was followed with modifications. 3000 mg (16.7 mmol) 2-(piperidin-4-yl) acetic acid hydrochloride (Iris Biotech, Marktredwitz, Germany) was dissolved in 46 ml of a 1 M solution of NaOH in water and cooled in an ice bath. 3350 mul benzyloxycarbonyl chloride (Cbz-Cl) (23.46 mmol, 4002 mg) were added dropwise over 5 min under stirring. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The aqueous solution was washed twice with 20 ml of diethyl ether/petroleum ether 4:1 and then acidified with 4 M HCl (aq.) to pH 1 . The product of the reaction was extracted with 3x 50 ml diisopropyl ether. The combined organic phases were dried with MgSO4 and evaporated under reduced pressure. Compound 2 was obtained as a colorless solid (4383 mg, 15.8 mmol, 95%). 1H NMR (400 MHz, Chloroform-d) delta 7.40 - 7.27 (m, 5H), 5.13 (s, 2H), 4.18 (d, J = 13.3 Hz, 2H), 2.81 (t, J = 12.8 Hz, 2H), 2.29 (d, J = 7.0 Hz, 2H), 1.96 (tp, J = 11.2, 3.5 Hz, 1 H), 1.75 (d, J = 12.1 Hz, 2H), 1.30 - 1.09 (m, 2H)
60%	With sodium hydroxide; In water; at 0 - 20℃; for 24h;pH 12.0;	[00345] Intermediate 21: 2-(1 -Benzyloxycarbonyl-4-piperidyl)acetic acid [00346] 5 M NaOH (aq.) was added to a stirred solution of 2-piperidin-1-ium-4-ylacetic acidchloride (1 .OOg, 5.S7mmol) in water (4OmL) at 0 C until pH 12 was reached. Benzyl chloroformate (0.79mL, 5.57mmol) was added dropwise to the solution. The mixture was stirred at roomtemperature for 24 hours and then the reaction mixture was extracted with Et20 (5OmL). Theaqueous fraction was acidified to pH 4 with 1 M HCI, then extracted with EtOAc (3 x 2OmL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to yield 2-Cl-Benzyloxycarbonyl-4-piperidyl)acetic acid (923mg, 3.33mmol, 60% yield) as an off-white solid.1H NMR (DMSO-d6, 400MHz) O/ppm: 12.09 (1H, 5), 7.41-7.29 (5H, m), 5.06 (2H, 5), 4.21-4.04 (2H, m), 2.80-2.69 (2H, m), 2.15 (2H, d, J= 7.0Hz), 1.89-1.78 (1H, m), 1.73-1.64 (2H, m), 1.18-1.08 (2H,m).

Reference： [1]Patent: WO2014/125084,2014,A1 .Location in patent: Page/Page column 33; 34
[2]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00344; 00345; 00346

12
[ 63845-28-3 ]
[ 1622247-27-1 ]

Reference： [1]Patent: WO2014/125084,2014,A1

13
[ 63845-28-3 ]
[ 63845-29-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; In dichloromethane; at 80℃; for 4.0h;Inert atmosphere;	502 mg (1.8 mmol) of 2-[1 -(benzyloxycarbonyl)piperidin-4-yl]acetic acid (3) were dissolved in anhydrous CH2Cl2 under argon and mixed with 10 ml SOCl2. After stirring for 4 h at 80C, the solution was directly evaporated. The residue was mixed three times with anhydrous CH2Cl2 and evaporated. The residue was further mixed three times with anhydrous toluene and evaporated in vacuo to yield 535 mg (1.8 mmol, 99%) of a white solid. The product was used in the next step without further purification.
	With oxalyl dichloride; In dichloromethane; for 1.0h;Reflux;	Step 1: (S)-benzyl 4-(2-(4-isopropyl-5,5-dimethyl-2-oxooxazolidin-3-yl)-2- oxoethyl)piperidine-l-carboxylate: A stirred solution of 2-(l-((benzyloxy)carbonyl)piperidin-4-yl)acetic acid (2.01 g, 7.25 mmol) in DCM (50 ml) was treated with oxalyl chloride (0.698 ml, 7.98 mmol). The resultant mixture was heated at reflux for 1 h, then concentrated in vacuo. The crude acid chloride was dissolved in DCM (20 ml). In a separate vessel, a stirred solution of (S)-4-isopropyl-5,5-dimethyloxazolidin- 2-one (1.14 g, 7.25 mmol) in DCM (20 ml) was cooled to -78 C and treated dropwise with n-butyllithium (2.95 ml, 7.98 mmol, 2.7 M in hexanes). The resultant solution was warmed to 0-5 C and held at this temperature for 30 min. The reaction mixture was cooled to -78 C and treated dropwise with the acid chloride solution. The resultant mixture was stirred at -78 C for 1 h, then warmed to RT and stirred for 16 h. The mixture was then quenched with saturated NH4Cl(aq) (50 ml) and the phases were partitioned and separated. The aqueous phase was extracted with EtOAc (2 x 10 ml) and the combined organic phaseswere dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (80 g cartridge, 0-40% EtOAc/isohexane), appropriate fractions were combined in MeOH and concentrated in vacuo to afford the title compound (2.23 g, 4.55 mmol, 85% purity) as a clear mobile oil. 1H NMR (400 MHz, DMSO-J6) delta 7.42 - 7.26 (m, 5H), 5.07 (s, 2H), 4.14 (d, / = 2.9 Hz, 1H), 4.04 - 3.94 (m, 2H), 2.91 (dd, / = 16.1, 6.7 Hz, 1H), 2.82 (br s, 2H), 2.74 (dd, / = 16.1, 6.8 Hz, 1H), 2.12 (pd, / = 6.9, 3.0 Hz, 1H), 2.03 - 1.90 (m, 1H), 1.76 - 1.61 (m, 2H), 1.45 (s, 3H), 1.34 (s, 3H), 1.18 - 1.04 (m, 2H), 0.93 (d, / = 7.0 Hz, 3H), 0.84 (d, / = 6.8 Hz, 3H). The compound contained 7% w/w residual EtOAc, 4% w/w residual DCM, and 2% w/w residual MeOH. This material was used in subsequent reactions without further drying.

Reference： [1]Patent: WO2014/125084,2014,A1 .Location in patent: Page/Page column 28; 30
[2]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 192; 193

14
[ 63845-28-3 ]
[ 1622247-25-9 ]

Reference： [1]Patent: WO2014/125084,2014,A1

15
[ 63845-28-3 ]
[ 1622247-26-0 ]

Reference： [1]Patent: WO2014/125084,2014,A1

16
[ 63845-28-3 ]
[ 1622247-21-5 ]

Reference： [1]Patent: WO2014/125084,2014,A1
[2]Patent: WO2014/125084,2014,A1

17
[ 67-56-1 ]
3-[2-(2-bromoacetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl)ethyl]-2-methoxybenzoic acid tert-butyl ester [ No CAS ]
[ 63845-28-3 ]
4-[2-(3-tert-butoxycarbonyl-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl)ethylcarbamoyl]methyl}piperidine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: A solution of dichloromethane (0.58 mL, 9.08 mmol) in THF (6.2 mL) under argon was cooled to -100C (MeOH, liquid N2 slush bath). n-BuLi (3.9 mL, 2.5M in hexane, 7.80 mmol) was added dropwise over 15 minutes and the reaction stirred at -100C for 30 minutes. A THF (5.7 mL) solution of 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-ylmethyl)benzoic acid tert-butyl ester (2.13 g, 5.33 mmol) was added dropwise over 15 minutes. After 10 minutes, the cooling bath was removed and the reaction stirred at 0C for 1 h. The reaction was then cooled to -78C for 30 minutes. LiHMDS (8.0 mL, 1.0M in THF, 8.0 mmol) was added dropwise over 10 minutes and the reaction allowed to slowly warm to room temperature while stirring overnight. Upon cooling to -10C, anhydrous MeOH (0.28 mL, 6.92 mmol) was added and the reaction stirred at -10C for 1 h then warmed to room temperature for 1 h. [00193] To a separate dry round bottom flask under argon containing 4-N-Boc-2-oxopiperazine-1-acetic acid (0.318 g, 1.23 mmol) and DCM (3.4 mL) was added N- methylmorpholine (0.20 mL, 1.82 mmol) and HATU (0.494 g, 1.70 mmol). DMF (1.6 mL) was added to make the reaction homogeneous. The reaction was stirred at room temperature for 3 h. A portion of the solution (-2.44 mmol) prepared above was added slowly at 0C and the reaction was gradually warmed to room temperature and stirred for 44 h. The reaction was quenched with H2O and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by a reverse phase preparative HPLC [Waters Sunfire CI 8 OBD, 5 muiotaeta, 19x50mm, 5-100% AcCN:H20 (with 0.1% TFA)] to afford 0.158 g (19%) of product. ESI-MS m/z 670 (MH)+.

Reference： [1]Patent: WO2014/151958,2014,A1 .Location in patent: Paragraph 00192; 00193; 00274

18
[ 63845-28-3 ]
(S)-benzyl 4-(2-(4-isopropyl-5,5-dimethyl-2-oxooxazolidin-3-yl)-2-oxoethyl)piperidine-1-carboxylate [ No CAS ]