[ CAS No. 632352-56-8 ] {[proInfo.proName]}

Name: 632352-56-8|tert-Butyl 4-oxo-3-phenylpiperidine-1-carboxylate|97%
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SKU: A114233
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Quality Control of [ 632352-56-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 632352-56-8 ]

SDS Specification

Alternatived Products of [ 632352-56-8 ]

Product Details of [ 632352-56-8 ]

CAS No. :	632352-56-8	MDL No. :	MFCD08669341
Formula :	C₁₆H₂₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SIZBVZFDWNCKJM-UHFFFAOYSA-N
M.W :	275.34	Pubchem ID :	23643714
Synonyms :

Calculated chemistry of [ 632352-56-8 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	81.28
TPSA :	46.61 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.85
Log Po/w (XLOGP3) :	2.26
Log Po/w (WLOGP) :	2.6
Log Po/w (MLOGP) :	2.1
Log Po/w (SILICOS-IT) :	2.47
Consensus Log Po/w :	2.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.93
Solubility :	0.324 mg/ml ; 0.00118 mol/l
Class :	Soluble
Log S (Ali) :	-2.88
Solubility :	0.367 mg/ml ; 0.00133 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.68
Solubility :	0.0578 mg/ml ; 0.00021 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.78

Safety of [ 632352-56-8 ]

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 [ 632352-56-8 ]

* 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 [ 632352-56-8 ]
Downstream synthetic route of [ 632352-56-8 ]

[ 632352-56-8 ] Synthesis Path-Upstream 1~6

1
[ 76041-09-3 ]
[ 24424-99-5 ]
[ 632352-56-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine In acetonitrile at 20℃; for 14 h;	To a solution of the compound (3.47 g) obtained in Process 4 and Et₃N (2.76 ml) in acetonitrile (50 ml), di-tert-butyl dicarbonate (6.55 g) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10percent citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 4-oxo-3-phenylpiperidine-1-carboxylic acid tert-butyl ester as white powder (3.90 g, 71percent). The obtained product was used in the next process without further purification.

Reference： [1] European Journal of Organic Chemistry, 2007, # 26, p. 4376 - 4382
[2] Patent: EP1553084, 2005, A1, . Location in patent: Page/Page column 44

2
[ 910875-39-7 ]
[ 24424-99-5 ]
[ 632352-56-8 ]

Yield	Reaction Conditions	Operation in experiment
5.46 g	With triethylamine In acetonitrile for 14 h;	The obtained powder of crude 7 (5.00 g, 23.6 mmol) was dissolved in a mixture of CH₃CN (100 mL) and Et₃N (4.94 mL, 35.4 mmol) and then di-tert-butoxycarbonate (7.73 g, 35.4 mmol) was slowly added thereto. After stirring for 14 h, the reaction mixture was concentrated in vacuo, and then the residue was dissolved in EtOAc and H₂O. The organic layer was washed with aqueous NH₄Cl and brine, dried and concentrated to provide 8 (5.46 g, 84percent) as white solids. ¹H NMR (CDCl₃) δ: 1.50 (9H, s), 2.57 (2H, t, J = 6.1 Hz), 3.45-3.74 (3H, m), 4.10-4.40 (2H, m), 7.15-7.21 (2H, m), 7.28-7.41 (3H, m).

Reference： [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446

3
[ 591-50-4 ]
[ 79099-07-3 ]
[ 632352-56-8 ]

Reference： [1] Journal of the American Chemical Society, 2014, vol. 136, # 14, p. 5225 - 5228

4
[ 446302-83-6 ]
[ 632352-56-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446

5
[ 1384264-55-4 ]
[ 632352-56-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446

6
[ 1345345-81-4 ]
[ 632352-56-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446

[ 632352-56-8 ] Synthesis Path-Downstream 1~88

1
[ 76041-09-3 ]
[ 24424-99-5 ]
[ 632352-56-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine; In acetonitrile; at 20℃; for 14h;	To a solution of the compound (3.47 g) obtained in Process 4 and Et3N (2.76 ml) in acetonitrile (50 ml), di-tert-butyl dicarbonate (6.55 g) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 4-oxo-3-phenylpiperidine-1-carboxylic acid tert-butyl ester as white powder (3.90 g, 71%). The obtained product was used in the next process without further purification.

Reference： [1]European Journal of Organic Chemistry,2007,p. 4376 - 4382
[2]Patent: EP1553084,2005,A1 .Location in patent: Page/Page column 44

2
[ 632352-56-8 ]
[ 2627-86-3 ]
(+)-cis-tert-butyl 4-amino-3-phenylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of the compound (60.6 g) obtained in Process 5 of Reference Example 1, (S)-1-phenylethylamine (40 g), aluminium chloride (1.5 g) in toluene (750 ml) was stirred at reflux temperature for 8 hours under argon air flow. The reaction solution was azeotropically dehydrated and reacted in Dean-Stark reflux tube with adding toluene (1000 ml). The reaction solution was concentrated under reduced pressure. Raney nickel (110 g, water contained) was washed with ethanol, and then a solution thereof in ethanol (500 ml) was prepared. The previous residue was added thereto, and then the reaction mixture was stirred at 25C for 62 hours under hydrogen pressure of 0.5 MPa. Raney nickel was removed by decantation, and the supernatant was concentrated under reduced pressure. To the residue was added ethyl acetate, and then the precipitated crystal was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 3 : 1) to obtain yellow oil (77 g).The obtained residue (77 g) was added to palladium carbon (5 wt%, 11.1 g) in ethanol (500 ml), and then, the reaction mixture was stirred at 45C for 13 hours under hydrogen pressure of 0.5 MPa. The palladium carbon was removed by filtration, and the filtrate was concentrated and dried. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 2 : 1 ? only ethyl acetate ? ethyl acetate : methanol = 2 : 1) to obtain the title compound as colorless powder (52.2 g). 1H-NMR (CDCl3) : delta 0.87 (1H, brs), 1.20 (1H, brs), 1.46 (9H, s), 1.61 (1H, m), 1.88 (1H, m), 2.93 (1H, m), 3.30-4.11 (5H, m), 7.00-7.52 (5H, m). [alpha]25D +103 (c 1.0, CHCl3). Optical yield: 98.3%ee

Reference： [1]Patent: EP1553084,2005,A1 .Location in patent: Page/Page column 55

3
[ 632352-56-8 ]
[ 632353-34-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; hydrogen;RuCl2[(R)-BINAP][(R,R)-DPEN]; In isopropyl alcohol; toluene; tert-butyl alcohol; at 30℃; under 5250.53 Torr; for 2.5h;	A mixture of the compound (1.51 g) obtained in Process 5 of Reference Example 1, [RuCl2[(R)-BINAP][(R,R)-DPEN]] catalyst (0.0055 g), a 1 M solution (5.5 ml) of potassium tert-butoxide in tert-butyl alcohol, 2-propanol (20 ml) and toluene (5 ml) was stirred at 30C for 2.5 hours under hydrogen atmosphere of 0.7 MPa, after the inner atmosphere was sufficiently replaced with the argon gas. To the reaction mixture, 1 N hydrochloric acid (5 ml) was added, and then the mixture was concentrated and dried under reduced pressure. The residue was disoersed in water and ethyl acetate, the organic layer was separated and washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure.

Reference： [1]Patent: EP1553084,2005,A1 .Location in patent: Page/Page column 70

4
[ 632352-56-8 ]
[ 632352-57-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With L-Selectride; In tetrahydrofuran; at -78 - 0℃; for 1h;	To a solution of the compound (9.70 g) obtained in Process 5 in THF (100 ml), a solution of 1 M L-selectride/THF (78 ml) was added at -78C, and the reaction mixture was stirred at 0C for 1 hour. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (hexane : ethyl acetate = 3 : 1) to obtain crude 4-hydroxy-3-phenylpiperidine-1-carboxylic acid tert-butyl ester (9.32 g, 95%) as colorless oil. 1H-NMR (CDCl3) : delta 1.50 (9H, s), 2.57 (2H, t, J=6.1 Hz), 3.45-3.75 (3H, m), 4.10-4.40 (2H, m), 7.15-7.21 (2H, m), 7.28-7.41 (3H, m).

Reference： [1]Patent: EP1553084,2005,A1 .Location in patent: Page/Page column 44

5
[ 632352-56-8 ]
[ 1271738-27-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 75℃; for 1h;	A mixed solution of the compound (8.82 g) obtained in Process 5 of Reference Example 1, hydroxyamine hydrochloride (6.67 g) and sodium acetate (7.88 g) in ethanol (50 ml) and water (20 ml) was stirred at 75C for 1 hour. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure to obtain 4-(hydroxyimino)-3-phenylpiperidine-1-carboxylic acid tert-butyl ester as a white paste-like material. The obtained product was used in the next process without further purification.
		To a solution of 8 (15.0 g, 54.4 mmol), concentrated HCl (13.8 mL) and sodium acetate (13.4 g, 163 mmol) in H2O (100 mL) and EtOH (150 mL) was added 50% aqueous hydroxylamine (9.70 mL, 163 mmol), and then the mixture was heated at 75 C for 2 h. The reaction mixture was concentrated in vacuo, and then the mixture was extracted with EtOAc. The extract was washed with aqueous NaHCO3 and brine, dried and concentrated to give white paste (20.8 g). The obtained product was dissolved in EtOH (150 mL) and THF (150 mL), and then Raney Ni (washed with H2O and EtOH, ca. 15 g) was added. The mixture was stirred under an atmosphere of H2 (5 atm) at 75 C for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to provide 9 as a mixture of cis and trans isomers (7.18 g, 72%) as white powder, which was used in the next step without further purification.

Reference： [1]Patent: EP1553084,2005,A1 .Location in patent: Page/Page column 44
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 6430 - 6446

7
[ 632352-56-8 ]
[ 632352-60-4 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 4 4-Amino-3-phenyl-piperidine-1-carboxylic acid tert-butyl ester. Prepared according to the General Procedures. General procedure 2 (amination): to the N-protected-3-aryl-oxopiperidine (1 mol %) in methanol was added anhydrous ammonium chloride (20 mol %) and 4 A molecular sieves (ca. 1 g/mol substrate). After stirring for 1 hour (1 h), sodium cyanoborohydride (0.6 mol %) is added and the mixture is stirred for 1 h. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is then dissolved in ethyl acetate, washed sequentially with water and brine, dried with sodium sulfate and concentrated. If necessary, purification is accomplished via silica gel chromatography.
		To a solution of (±)-tert-butyl 4-oxo-3-phenyl-piperidine-1-carboxylate (200 mg, 726 mumol, CAS 632352-56-8) in methanol (8.00 mL) was added ammonium acetate (168 mg, 2.18 mmol). The mixture solution was stirred at 25 C for 1 hr, and then sodium cyanoborohydride (137 mg, 2.18 mmol) was added. The mixture was stirred at 25 C for 11 hrs. The reaction mixture was concentrated under reduced pressure to remove methanol. The residue was diluted with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to dichloromethane : methanol = 10:1) to give the title compound.1H NMR (400 MHz, CDCl3) delta = 7.49 - 7.27 (m, 3H), 7.25 - 7.18 (m, 1H), 7.18 - 6.97 (m, 1H), 4.24 (br. s., 1H), 3.91 - 3.74 (m, 1H), 3.39 - 3.19 (m, 1H), 2.97 - 2.80 (m, 1H), 2.43 - 2.26 (m, 1H) , 1.99 - 1.82 (m, 1H), 1.51 - 1.33 (m, 9H), 1.27 - 1.20 (m, 1H).
	With ammonium acetate; sodium cyanoborohydride; In methanol; at 20℃;	Sodium cyanotrihydroborate (103 mg, 1.64 mmol) was added in 2 portions at 10 minute intervals to a solution of te/7-butyl 4-oxo-3-phenylpiperidine-l-carboxylate (430 mg, 1.56 mmol) and ammonium acetate (1204 mg, 15.62 mmol) in dry methanol (7.8 mL). The resulting solution was stirred at room temperature overnight and was then quenched with saturated aq NaHCO, (5.0 mL) and extracted with EtOAc (2 x 10 mL). The organic layers were combined and dried over anhydrous Na2S04. The solvent was removed to give the title compound as a colorless oil (420 mg, 97 % yield) which was used without further purification. ESI-MS [M+H]+ calc?d for CI6H24N202, 277.34; found [M-55], 221.1.

Reference： [1]Patent: US2006/19975,2006,A1 .Location in patent: Page/Page column 16; 18
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 6430 - 6446
[3]Patent: WO2017/156177,2017,A1 .Location in patent: Paragraph 00345
[4]Patent: WO2019/169153,2019,A1 .Location in patent: Paragraph 0392-0393

8
[ 632352-56-8 ]
[ 880094-04-2 ]
trans-N-boc-3-phenyl-4-hydroxypiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; In methanol; at 0℃; for 1h;	To N-Boc-3-phenyl-4-oxopiperidine (3.50 g, 12.7 mmol) in methanol (50 mL) at ice-bath temperature was added sodium borohydride (580 mg, 12.7 mmol). The mixture was stirred for 1 h, and concentrated under vacuum. The mixture was dissolved in methylene chloride, washed with water, dried via filtration through cotton and concentrated. Purification by silica gel chromatography eluting with 3:1 hexanes/ethyl acetate gave the title material.

Reference： [1]Patent: US2006/19975,2006,A1 .Location in patent: Page/Page column 18

9
[ 632352-56-8 ]
[ 5815-08-7 ]
[ 1172638-56-0 ]