[ CAS No. 848488-91-5 ] {[proInfo.proName]}

Name: 848488-91-5|(R)-tert-Butyl 2-carbamoylpiperidine-1-carboxylate|98%
Brand: Ambeed
SKU: A256180
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Quality Control of [ 848488-91-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 848488-91-5 ]

CAS No. :	848488-91-5	MDL No. :	MFCD03840195
Formula :	C₁₁H₂₀N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KIFYKONQFFJILQ-MRVPVSSYSA-N
M.W :	228.29	Pubchem ID :	7145549
Synonyms :

Calculated chemistry of [ 848488-91-5 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	64.31
TPSA :	72.63 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.17
Log Po/w (XLOGP3) :	0.41
Log Po/w (WLOGP) :	0.88
Log Po/w (MLOGP) :	0.62
Log Po/w (SILICOS-IT) :	0.26
Consensus Log Po/w :	0.87

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.25
Solubility :	12.8 mg/ml ; 0.0563 mol/l
Class :	Very soluble
Log S (Ali) :	-1.5
Solubility :	7.19 mg/ml ; 0.0315 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.87
Solubility :	30.7 mg/ml ; 0.135 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.7

Safety of [ 848488-91-5 ]

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 [ 848488-91-5 ]

* 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 [ 848488-91-5 ]
Downstream synthetic route of [ 848488-91-5 ]

[ 848488-91-5 ] Synthesis Path-Upstream 1~2

1
[ 28697-17-8 ]
[ 848488-91-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 18 h;	Step B. tert-Butyl (2R)-2-(aminocarbonyl)piperidine-1-carboxylate; HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)- 1 -(tert- butoxycarbonyl) piperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 °C. The mixture was stirred for 18 h at room temperature, diluted with H20 (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10percent Na2C03 solution (2x30 mL), brine (2x30 mL) and dried with Na2S04. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) g, 100 percent) as a white solid. (at)H NMR(400 MHz, CDCl3) No. 1.46 (s, 9 H), 1.63 (m, 2 H), 2.22 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 3 H), 4.01 (m, 1 H), 4.71 (m, 1 H), 6.46 (s broad, 2 H). MS (ESI) (M+H) (at)= 228.92
99%	Stage #1: With triethylamine; methyl chloroformate In tetrahydrofuran at 0℃; Stage #2: With ammonia In tetrahydrofuran; water at 0 - 20℃; for 4 h;	a) 1, 1-Dimethylethyl (2/tO-2-(aminocarbonyI)-1-piporidinecarboxylalc. To a cold (0°C) solution of fe/iS-1-iUl, 1-dimethylethy^oxy]carbonyl]-2-piperidinecarboxylic acid(1.0 g, 4.36 mmol) in THF (20 ml) was added triethylamine (0.60 mL, 4,36 rnmol)followed by slow addition of methyl chloroform ate (0.34 mL, 4,36 rnmol). After a fewminutes a suspension had formed, To this mixture was added concentrated NI-LiOH(1.5 mL) and the solution was allowed to warm to rt as the bath warmed and stirredfor a total of 4 h. The mixture was concentrated in vacuo and the residue was takenup in EtOAc, The organic layer was washed with citric acid, bicard and then brine,dried over NasSO-i. Filtration and concentration gave 1, 1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (3 .0 g, 99percent). ¹H NMR (CDCl₃) δ 6,03(br, 1 H), 5.45 (br, 1 H), 4.77 (br, 1 H), 4.06 (br, 1 H), 2.82 (m, 1 H), 2.29 (m, 1 H),1.67- 1.43 (m, 13 H),
89%	With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 1.5 h;	Example 1; 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone; The title compound was prepared as illustrated in scheme 1, steps 1 to 5.; Step 1. A suspension of ammonium chloride (3.44 g, 64 mmol) in N,N-dimethylacetamide (150 mL) under argon was treated with diisopropylethylamine (13.44 g, 17.7 mL, 104 mmol). A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.10 g, 22 mmol) was added, followed by TBTU (10.11 g, 31 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate (850 mL) and washed several times with water (5*50 mL) and finally with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.54 g, 89percent) as a white solid, MS (ISP): 229.0 (M+H)^+..

Reference： [1] Patent: WO2005/115986, 2005, A1, . Location in patent: Page/Page column 103
[2] Patent: WO2006/116764, 2006, A1, . Location in patent: Page/Page column 121; 151
[3] Patent: US2008/300279, 2008, A1, . Location in patent: Page/Page column 9
[4] ACS Infectious Diseases, 2018, vol. 4, # 7, p. 1130 - 1145

2
[ 848488-91-5 ]
[ 940000-26-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; trifluoroacetic anhydride In tetrahydrofuran at 0℃; for 1 h;	b) 1, 1-Dimethylethyl (2R)-2-cyano-1-piporidinecarboxylate. To a cold (0 °C) solutionof 1,1-dimethylethyl (2J?)-2-(aminocarbonyl)-1-piperidinecarboxylate (269 mg, 1.17mmol) in THF (10 mL) was added triethylamme (0,33 mL, 2.34 mmol) and thentrifluoroacetic anhydride (0.17 mL, 1 J 7 mmol). The mixture was stirred at 0 °C for1 h and concentrated in vacuo. The residue was taken up in EtOAc and washedsuccessively with sodium bicarbonate, 0,5 NHCl and brine. The organics were driedover NasSO-j, filtered and concentrated to give 1, 1-dimethylethyl(2/i?)-2-cyano-1-piperidinecarboxylate (255 mg, 99percent) as a crystalline solid uponstanding, ¹H NMR (CDCl₃) δ 5.23 (br, 1 H), 4.05 (br, 1 H), 2.93 (br, 1 H), 1,93- 1.39 (m,6 H), 1.46 (s, 9 H).

Reference： [1] Patent: WO2006/116764, 2006, A1, . Location in patent: Page/Page column 121; 151

[ 848488-91-5 ] Synthesis Path-Downstream 1~32

1
[ 28697-17-8 ]
[ 848488-91-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 18.0h;	Step B. tert-Butyl (2R)-2-(aminocarbonyl)piperidine-1-carboxylate; HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)- 1 -(tert- butoxycarbonyl) piperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 C. The mixture was stirred for 18 h at room temperature, diluted with H20 (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10% Na2C03 solution (2x30 mL), brine (2x30 mL) and dried with Na2S04. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) g, 100 %) as a white solid. (at)H NMR(400 MHz, CDCl3) No. 1.46 (s, 9 H), 1.63 (m, 2 H), 2.22 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 3 H), 4.01 (m, 1 H), 4.71 (m, 1 H), 6.46 (s broad, 2 H). MS (ESI) (M+H) (at)= 228.92
99%		a) 1, 1-Dimethylethyl (2/tO-2-(aminocarbonyI)-1-piporidinecarboxylalc. To a cold (0C) solution of fe/iS-1-iUl, 1-dimethylethy^oxy]carbonyl]-2-piperidinecarboxylic acid(1.0 g, 4.36 mmol) in THF (20 ml) was added triethylamine (0.60 mL, 4,36 rnmol)followed by slow addition of methyl chloroform ate (0.34 mL, 4,36 rnmol). After a fewminutes a suspension had formed, To this mixture was added concentrated NI-LiOH(1.5 mL) and the solution was allowed to warm to rt as the bath warmed and stirredfor a total of 4 h. The mixture was concentrated in vacuo and the residue was takenup in EtOAc, The organic layer was washed with citric acid, bicard and then brine,dried over NasSO-i. Filtration and concentration gave 1, 1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (3 .0 g, 99%). 1H NMR (CDCl3) δ 6,03(br, 1 H), 5.45 (br, 1 H), 4.77 (br, 1 H), 4.06 (br, 1 H), 2.82 (m, 1 H), 2.29 (m, 1 H),1.67- 1.43 (m, 13 H),
94%	With ammonium chloride; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 15.0h;	(R)-1-(tert-Butoxycarbonyl)piperidine-2-carboxylic acid (0.500 g, 2.18 mmol) and ammonium chloride (0.700 g, 13.1 mmol) were suspended in DMF (10 mL), and HATU (1.24 g, 3.27 mmol) and diisopropylethylamine (1.14 mL, 6.54 mmol) were added at 0 C. After stirring the reaction mixture at room temperature for 15 hours, distilled water was added to the reaction mixture and the aqueous layer was extracted with diethyl ether. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=60/40 to 30/70) to obtain the title compound (hereinafter referred to as the compound of Reference Example 13) (0.467 g, 2.05 mmol, 94%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 1.42-1.68 (m, 5H), 1.48 (s, 9H), 2.28-2.30 (m, 1H), 2.79-2.85 (m, 1H), 4.05 (brs, 1H), 4.78 (brs, 1H), 5.44 (brs, 1H), 6.03 (brs, 1H). ESI-MS: m/z=251(M+Na)+.

89%

With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; for 1.5h;

Example 1; 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone; The title compound was prepared as illustrated in scheme 1, steps 1 to 5.; Step 1. A suspension of ammonium chloride (3.44 g, 64 mmol) in N,N-dimethylacetamide (150 mL) under argon was treated with diisopropylethylamine (13.44 g, 17.7 mL, 104 mmol). A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.10 g, 22 mmol) was added, followed by TBTU (10.11 g, 31 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate (850 mL) and washed several times with water (5*50 mL) and finally with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.54 g, 89%) as a white solid, MS (ISP): 229.0 (M+H)+..

Reference： [1]Patent: WO2005/115986,2005,A1 .Location in patent: Page/Page column 103
[2]Patent: WO2006/116764,2006,A1 .Location in patent: Page/Page column 121; 151
[3]Patent: US2020/392107,2020,A1 .Location in patent: Paragraph 0318-0321
[4]Patent: US2008/300279,2008,A1 .Location in patent: Page/Page column 9
[5]ACS Infectious Diseases,2018,vol. 4,p. 1130 - 1145

2
[ 848488-91-5 ]
[ 870970-82-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; at 20.0℃; for 4.0h;	Step C. (2R)-Piperidine-2-carboxamide; tert-Butyl (2R)-2-(aminocarbonyl)piperidine-1-carboxylate (2.28 g, 10 mmol) was treated with 4 NHCI in dioxane (60 mL, 240 mmol) for 4 h at room temperature. After evaporation of the solvent, the title compound was washed with ether and dried in vacuo (HCl salt, 1.65 g, 100 %). 1H NMR (400 MHz, DMSO-D6) No. 1.36 1.81 (m, 5 H), 2.11 (m, 1 H), 2.77 - 2.97 (m, 1 H), 3.16 (m, 1 H), 3.67 (m, 1 H), 7.54 (s, 1 H), 7.94 (s, 1 H), 8.61 (s, 1 H), 9.22 (s, 1 H).

Reference： [1]Patent: WO2005/115986,2005,A1 .Location in patent: Page/Page column 103-104

3
[ 848488-91-5 ]
[ 940000-26-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; trifluoroacetic anhydride; In tetrahydrofuran; for 1.0h;	b) 1, 1-Dimethylethyl (2R)-2-cyano-1-piporidinecarboxylate. To a cold (0 °C) solutionof 1,1-dimethylethyl (2J?)-2-(aminocarbonyl)-1-piperidinecarboxylate (269 mg, 1.17mmol) in THF (10 mL) was added triethylamme (0,33 mL, 2.34 mmol) and thentrifluoroacetic anhydride (0.17 mL, 1 J 7 mmol). The mixture was stirred at 0 °C for1 h and concentrated in vacuo. The residue was taken up in EtOAc and washedsuccessively with sodium bicarbonate, 0,5 NHCl and brine. The organics were driedover NasSO-j, filtered and concentrated to give 1, 1-dimethylethyl(2/i?)-2-cyano-1-piperidinecarboxylate (255 mg, 99percent) as a crystalline solid uponstanding, 1H NMR (CDCl3) delta 5.23 (br, 1 H), 4.05 (br, 1 H), 2.93 (br, 1 H), 1,93- 1.39 (m,6 H), 1.46 (s, 9 H).

Reference： [1]Patent: WO2006/116764,2006,A1 .Location in patent: Page/Page column 121; 151

4
[ 848488-91-5 ]
[ 1089729-72-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	With Lawessons reagent; In 1,4-dioxane; at 20℃;	Step 2. A solution of <strong>[848488-91-5](R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.31 g, 6 mmol) in dioxane (20 mL) was treated under argon with Lawesson's reagent (1.16 g, 3 mmol). The mixture was stirred at room temperature overnight. The volatiles were evaporated and the resulting white solid purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (0.74 g, 47%), MS (ISP): 245.4 (M+H)+..

Reference： [1]Patent: US2008/300279,2008,A1 .Location in patent: Page/Page column 9
[2]ACS Infectious Diseases,2018,vol. 4,p. 1130 - 1145

5
[ 848488-91-5 ]
[ 1089729-31-6 ]