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[ CAS No. 120278-07-1 ] {[proInfo.proName]}

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Quality Control of [ 120278-07-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 120278-07-1 ]

CAS No. :	120278-07-1	MDL No. :	MFCD05863884
Formula :	C₁₃H₁₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YYIQGSYCCNQAGV-UHFFFAOYSA-N
M.W :	234.29	Pubchem ID :	17846640
Synonyms :

Calculated chemistry of [ 120278-07-1 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	69.33
TPSA :	55.56 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) :	-6.85 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.48
Log Po/w (XLOGP3) :	1.24
Log Po/w (WLOGP) :	1.21
Log Po/w (MLOGP) :	1.41
Log Po/w (SILICOS-IT) :	1.14
Consensus Log Po/w :	1.5

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.07
Solubility :	1.99 mg/ml ; 0.00849 mol/l
Class :	Soluble
Log S (Ali) :	-2.0
Solubility :	2.32 mg/ml ; 0.00989 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.63
Solubility :	0.545 mg/ml ; 0.00233 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.61

Safety of [ 120278-07-1 ]

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

Application In Synthesis of [ 120278-07-1 ]

* 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 [ 120278-07-1 ]
Downstream synthetic route of [ 120278-07-1 ]

[ 120278-07-1 ] Synthesis Path-Upstream 1~4

1
[ 159874-20-1 ]
[ 120278-07-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With hydrogenchloride In tetrahydrofuran; water at 30 - 55℃; Stage #2: With sodium hydroxide In tetrahydrofuran; dichloromethane; water at 10 - 25℃;	4_(N-BOC amino)-CBz piperidine (24.4 kg 73.42 mol), THF (65 kg) and 5 M HCl (23.0 kg, 110.13 mol) were combined and heated to 30 -35 ⁰C for ~2 hours, and then at 55⁰C overnight. After cooling the reaction mixture to 10⁰C, dichloromethane (97 kg) and 1OM NaOH (7.97 kg, 145.12 mol) were added, while keeping the temperature at < 25°C. The phases were separated and the organic phase was washed with 25 wt percent NaCl solution (27.5 kg). The <n="66"/>washed organic phase was distilled at atmospheric pressure to a volume of 70 L. Dichloromethane (162 kg) was then added, and the mixture was concentrated by distillation to a volume of 120L to give the title product as a solution in DCM (17.2 kg. 100percent.). lH NMR (CDCI3) 7.33 (5H, m), 5.14 (2H, s), 4.14 (2 H, br s), 2.87 (3H, m), 1.83 (2H, m), 1.66 (3H, m) and 1.28 (2H, m).

Reference： [1] Patent: WO2009/91856, 2009, A2, . Location in patent: Page/Page column 63-64

2
[ 169814-97-5 ]
[ 120278-07-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrazine In ethanol for 0.5 h; Heating / reflux	A mixture of phenylmethyl 4-(l,3-dioxo- l,3-dihydro-2H-isoindol-2-yl)-l -piperidinecarboxylate (1.5 g, 4.11 mmoles) and 25percent hydrazine hydrate (10.0 mL) in ethanol (20 mL) was heated under reflux for 30 minutes. The mixture was evaporated, re-diluted with ethanol and re-evaporated to a solid. The solid was slurried in diethyl ether, collected, washed with diethyl ether and the filtrate evaporated to give the title compound as an oil (quant.) 1η NMR (400 MHz, CHLOROFORM-,/) δ ppm 7.25 - 7.45 (m, 5 H), 5.14 (s, 2 H), 4.89 - 5.07 (m, 1 H), 3.18 - 3.42 (m, 2 H), 2.76 - 2.95 (m, 2 H), 1.74 - 1.94 (m, 2 H), 1.51 - 1.68 (m, 2 H), 1.28 (d, J=6.06 Hz, 2 H).

Reference： [1] Patent: WO2007/150011, 2007, A2, . Location in patent: Page/Page column 105

3
[ 95798-23-5 ]
[ 120278-07-1 ]

Reference： [1] Patent: WO2007/150011, 2007, A2,

4
[ 120278-07-1 ]
[ 1174020-64-4 ]

Reference： [1] Organic Letters, 2011, vol. 13, # 20, p. 5480 - 5483

[ 120278-07-1 ] Synthesis Path-Downstream 1~88

1
[ 120278-07-1 ]
[ 959680-20-7 ]
benzyl 4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 125℃; for 48h;	2-Chloro-5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidine (Method 8; 10 g, 39.4 mmol), DIPEA (15.4 ml, 86.7 nimol) and benzyl 4-aminopiperidine-l -carboxylate (11.0 g, 47.2 mmol) were added to DMA (200 ml) and heated at 125C for 2 days. The reaction mixture was evaporated to dryness, water (100 ml) added and the reaction extracted with DCM (3 X 150 ml), dried and the solvent removed in vacuo to yield a yellow solid. This was dissolved in DCM, propan-2-ol added and then the DCM slowly evaporated to yield a solid. This was filtered and washed with ether, the process was repeated with the filtrate to get two additional batches which were combined to give the title compound as an off-white solid (13.75g). nuMR (400.132 MHz, CDCl3) 1.38-1.48 (m, 2H), 1.55 (d, 6H), 2.03-2.06 (m, 2H), <n="89"/>2.60 (s, 3H), 3.00 (t, 2H), 3.85-3.94 (m, IH), 4.13-4.16 (m, 2H), 4.90 (d, IH), 5.14 (s, 2H), 5.54 (septet, IH), 7.29-7.37 (m, 5H), 7.52 (d, IH), 8.15 (d, IH); MH+ 453.

Reference： [1]Patent: WO2007/138268,2007,A1 .Location in patent: Page/Page column 87-88

2
[ 120278-07-1 ]
[ 4023-00-1 ]
[ 959793-10-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		Benzyl 4-aminopiperidine-l -carboxylate (25 g, 106.7 mmol), pyrazole-1- carboximidamide (31.3 g, 213.4 mmol) and TEA (30 ml) were dissolved in MeCN (500 ml) and heated at 60C overnight. After 18 hrs, solvents were evaporated. The resultant orange residue was partitioned between saturated aq NaHCO3 (500 ml) and DCM (500 ml). The DCM layer was separated and the fine precipitate contained within it was collected by filtration then washed with a little DCM and dried under vacuum to yield a white solid. (30.8 g, 100%). NMR (400.132 MHz) 1.31 (m, 2H), 1.82 (m, 2H), 2.96 (m, 2H), 3.57 (m, IH), 3.92 (m, 2H), 5.08 (s, 2H), 7.35 (m, 5H), 7.96 (s, 2H).
100%		Benzyl 4-aminopiperidine-l -carboxylate (20 g, 85.5 mmol) and TEA (24 ml, 171 mmol) were dissolved in acetonitrile (300 ml), then lH-pyrazole-1-carboxamide (25 g, 171 mmol) was added and the reaction was heated at 650C for 16 hrs. The reaction mixture was then evaporated to dryness and quenched with sat. aq. sodium carbonate (200 ml), extracted with DCM (3 X 150 ml), combined organics dried and the solvent removed in vacuo to yield a orange solid. Acetonitrile (100 ml) was added and stirred at 65C for 20 mins, the resulting slurry was cooled and filtered to give the title compound as a colourless solid. NMR (400.132 MHz) 1.27-1.36 (m, 2H), 1.81-1.83 (m, 2H), 3.18-3.55 (m, 3H), 3.93 (d, 2H), 5.08 (s, 2H), 7.30-7.41 (m, 5H), 7.60-8.55 (brs, 4H); MH+ 277.

Reference： [1]Patent: WO2007/138268,2007,A1 .Location in patent: Page/Page column 109
[2]Patent: WO2007/138268,2007,A1 .Location in patent: Page/Page column 114

3
[ 169814-97-5 ]
[ 120278-07-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrazine; In ethanol; for 0.5h;Heating / reflux;	A mixture of phenylmethyl 4-(l,3-dioxo- l,3-dihydro-2H-isoindol-2-yl)-l -piperidinecarboxylate (1.5 g, 4.11 mmoles) and 25% hydrazine hydrate (10.0 mL) in ethanol (20 mL) was heated under reflux for 30 minutes. The mixture was evaporated, re-diluted with ethanol and re-evaporated to a solid. The solid was slurried in diethyl ether, collected, washed with diethyl ether and the filtrate evaporated to give the title compound as an oil (quant.) 1eta NMR (400 MHz, CHLOROFORM-,/) delta ppm 7.25 - 7.45 (m, 5 H), 5.14 (s, 2 H), 4.89 - 5.07 (m, 1 H), 3.18 - 3.42 (m, 2 H), 2.76 - 2.95 (m, 2 H), 1.74 - 1.94 (m, 2 H), 1.51 - 1.68 (m, 2 H), 1.28 (d, J=6.06 Hz, 2 H).

Reference： [1]Patent: WO2007/150011,2007,A2 .Location in patent: Page/Page column 105

4
[ 120278-07-1 ]
[ 946822-60-2 ]
benzyl 4-[[4-[(6-cyclopentyl-2-methyl-3-oxo-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-9-yl)amino]-3-methoxy-benzoyl]amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 18 - 25℃; for 3h;	4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 111, 350 mg, 0.85 mmol), Benzyl 4-aminopiperidine-1-carboxylate (ABCR, 219 mg, 0.94 mmol), HATU (388 mg, 1.02 mmol) and DIPEA (445 uL, 2.55 mmol) and DMF (5 mL) were combined and stirred at room temperature for 3 hours. Solvent was evaporated and the residues partitioned between DCM (2 mL) and sat. aq. Bicarb. (2 mL), gravity filtered through a PTFE cup and solvents evaporated. The residue was taken up in DCM and purified on silica eluting with a gradient of 0-5% MeOH/DCM. Fractions containing product were combined and evaporated. To give the title compound as an orange solid.1H NMR (400.132 MHz, CDCl3) delta1.38 (m, 2H), 1.62 (m, 6H), 1.97 (m, 4H), 2.60 (m, 2H), 2.94 (m, 2H), 3.22 (s, 3H), 3.62 (m, 2H), 3.91 (s, 3H), 4.11 (m, 3H), 4.83 (m, 1H), 5.07 (s, 2H), 5.82 (d, 1H), 7.14 (m, 1H), 7.27 (m, 5H), 7.34 (d, 1H), 7.61 (s, 1H), 7.87 (s, 1H), 8.44 (d, 1H); MS m/z 628 [M+H]+.

Reference： [1]Patent: US2008/9482,2008,A1 .Location in patent: Page/Page column 31

5
[ 120278-07-1 ]
[ 68282-53-1 ]
Benzyl 4-[(4-methylimidazol-5-yl)methylamino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 0 - 20℃;Cooling with ice;	Benzyl 4-aminopiperidine-1-carboxylate (10 g), 4-methylimidazole-5-carbaldehyde (4.7 g) and acetic acid (3.0 mL) were dissolved in 1,2-dichloroethane (100 mL), sodium triacetoxyborohydride (13.6 g) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was poured into an aqueous potassium carbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to obtain the title compound (8.0 g, 57%) as an oil. NMR (200 MHz, CDCl3) delta: 1.23-1.38 (2H, m), 1.85-1.95 (2H, m), 2.19 (3H, s), 2.64-2.74 (1H, m), 2.83-2.95 (2H, m), 3.72 (2H, s), 4.07-4.18 (2H, m), 5.12 (2H, s), 7.28-7.37 (5H, m), 7.44 (1H, s).

Reference： [1]Patent: EP1564213,2005,A1 .Location in patent: Page/Page column 56

6
[ 120278-07-1 ]
[ 1457-58-5 ]
Benzyl 4-[(2-methyl-1H-imidazol-4-yl)carbonyl]amino}piperidin-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; for 12h;	WSC (4.0 g), HOBt (3.2 g) and triethylamine (3.8 mL) were added to a solution of <strong>[120278-07-1]benzyl 4-aminopiperidine-1-carboxylate</strong> (3.3 g) and 2-methyl-1H-imidazole-4-carboxylic acid (2.0 g) in acetonitrile (50 mL) and stirred for 12 hours. The reaction solution was concentrated and the residue was dissolved in chloroform and an aqueous saturated sodium bicarbonate solution. A chloroform layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain the title compound (2.4 g, 49%) as colorless powder. NMR (300 MHz, CDCl3) delta: 1.41-1.56 (2H, m), 1.93-2.06 (3H, m), 2.40 (3H, s), 2.92-3.07 (2H, m), 4.06-4.21 (2H, m), 5.14 (2H, s), 7.07 (1H, d, J = 8.3), 7.30-7.42 (5H, m), 10.92 (1H, br)

Reference： [1]Patent: EP1564213,2005,A1 .Location in patent: Page/Page column 81

7
[ 120278-07-1 ]
[ 22809-37-6 ]
C₁₉H₂₇BrN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃; for 2h;	Example 9; 1- (1-{(2S)-3-[(6-Chloronaphthalen-2-yl)sulfonyl]-2- hydroxypropanoyl} piperidin-4-yl)azepan-2-one; 9a) Benzyl 4-(2-oxoazepan-1-yl)piperidin-1-carboxylate; To a solution of <strong>[120278-07-1]benzyl 4-aminopiperidin-1-carboxylate</strong> (1.7 g) and triethylamine (1.1 mL) in THF (40 mL) was added dropwise 5-bromohexanoyl chloride (1.1 mL), and the mixture was stirred at 0C for 2 hours. The solvent was distilled off under reduced pressure and the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with an aqueous 5% citric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (40 mL), and cooled at 0C, sodium hydride (60% in oil; 0.60 g) was added thereto, and the mixture was stirred at 0C for one hour, at room temperature for one hour and at 80C for 15 hours. The solvent was distilled off under reduced pressure, the residue was diluted with water, and the solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2/1 to 5/1) to obtain the title compound (0.25 g, 10%) as a yellow oil. NMR (CDC13) 5: 1.52-1.69 (10H, m), 2.52-2.55 (2H, m), 2.80- 2.90 (2H, m), 3.20-3.24 (2H, m), 4.25 (2H, br), 4.63-4.72 (lH, m), 5.13 (2H, s), 7.26-7.37 (5H, m).

Reference： [1]Patent: WO2005/113504,2005,A1 .Location in patent: Page/Page column 90-91

8
[ 120278-07-1 ]
[ 849547-72-4 ]
Benzyl 4-((((2Z)-5-(ethoxycarbonyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h;	Ethyl (2Z)-4-bromomethyl-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylate (3.0 g) obtained in Example 13) as a synthetic intermediate and <strong>[120278-07-1]benzyl 4-aminopiperidine-1-carboxylate</strong> (3.3 g) were dissolved in DMF (50 mL). Potassium carbonate (3.8 g) was added thereto, and the mixture was mixed at 70C for 4 hours. The solvent was distilled off, and the residue was poured into water. The mixture was then extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (3.1 g) as pale yellow crystals. NMR (CDCl3) delta: 1.22-1.46 (2H, m), 1.33 (3H, t, J = 7.4), 1.62-1.99 (3H, m), 2.61-2.82 (1H, m), 2.86-3.00 (1H, m), 3.01 (3H, s), 3.42 (3H, s) , 4.05 (2H, s), 4.05-4.14 (2H, m) , 4.25 (2H, q, J = 7.4), 5.12 (2H, s), 7.34-7.37 (5H, m) .

Reference： [1]Patent: EP1669352,2006,A1 .Location in patent: Page/Page column 62

Yield	Reaction Conditions	Operation in experiment
0.847 g, (85%)		C. 1-Benzyloxycarbonyl-4-phthalimidylpiperidine (1.50 g, 4.27 mmol), prepared in Example 16B, was taken up in 20 mL of ethanol. To this solution was added hydrazine monohydrate (35 mL, 700 mmol) and this mixture was heated at 100 C. for 3 h. Brine solution (40 mL) and 10% aq. K2 CO3 (60 mL) were added and the mixture was extracted with 5% MeOH/CHCl3 (3*). The combined extracts were washed with 2N aq. HCl, 2N aq. NaOH, brine solution, dried over Na2 SO4 and concentrated to give 0.847 g, (85%) of 4-amino-1-benzyloxycarbonylpiperidine. ?1[H]-NMR(CDCl3) consistent with structure.

10
[ 120278-07-1 ]
[ 1943-83-5 ]
[ 72349-01-0 ]

Yield	Reaction Conditions	Operation in experiment
		Method R Preparation of 1-piperidin-4-ylimidazolidin-2-one Step 1: Preparation of benzyl 4-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate; 2-Chloroethylisocyanate (2.23 g) was added to a solution of <strong>[120278-07-1]benzyl 4-aminopiperidine-1-carboxylate</strong> (5 g) (CAS 120278-07-1) in THF (100 ml) and the mixture was stirred at room temperature for 1 hour. Lithium bis(trimethylsilyl)amide (21 ml of 1M solution in THF) was added and stirring was continued for 16 hours. The clear solution was evaporated to dryness and the residue was dissolved in dichloromethane (50 ml) and the solution was washed with 2M HCl (2×50 ml) and dried. The residue obtained on evaporation of the solvent was purified by chromatography on silica eluting with a solvent gradient of 30% ethyl acetate/isohexane-ethyl acetate, yield 3.2 g.

Reference： [1]Patent: US2007/167442,2007,A1 .Location in patent: Page/Page column 44

11
[ 120278-07-1 ]
[ 582325-22-2 ]
[ 1033843-48-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h;	Benzyl 4-aminopiperidine-1-carboxylate (11 g, 46.9 mmol), EDAC (9.94 g, 51.9 mmol), NMM (20.7 mL, 189 mmol) and HOBt*H2O (7.22 g, 47 mmol) were added to a solution of 6-(3-fluorophenyl)nicotinic acid (10.2 g, 47 mmol) in dichloromethane:DMF (200 mL:2 mL). The reaction mixture was stirred at room temperature for 18 h, evaporated, and chromatographed (silica gel, ethyl acetate-hexane, 2:1). The solvent was evaporated to give tert-butyl 4-(2-(3-fluorophenyl)nicotinamido)piperidine-1-carboxylate (yield 61%, 12.7 g). LC/MS =434 observed, 434.19 expected

Reference： [1]Patent: US2008/146569,2008,A1 .Location in patent: Page/Page column 126

12
[ 120278-07-1 ]
[ 98-79-3 ]
[ 1174020-66-6 ]

Yield	Reaction Conditions	Operation in experiment
		2-Hydroxypyridine-N-oxide (81 1 g, 7.3 mol), L-pyroglutamic acid (9.43 kg, 73 mol), benzyl 4-ammopiperidine-l -carboxylate (17.1 kg in dichloromethane, volume 120 L, 73 moi) and dichloromethane (80 kg) were mixed together and aged at 200C for 10 minutes to form a thick slurry. l-(3-Dimethylammopropyl)-3-ethylcarbodiimide hydrochloride (16.8 kg, 87.6 mol) was added in portions to the slurry, while keeping temperature at <30C. The slurry was then aged at 250C for 30 minutes, after which IM hydrochloric acid (94 kg, 85.5 mol) was added. The phases were left to settle overnight and then separated, and the organic phase was then washed with 2M sodium carbonate (109 kg) and then solvent switched to acetonitrile, final volume 5OL. Toluene (88.2 kg) was added and the batch cooled to 0 0C. Di-tert-butyl dicarbonate (18.32 kg, 83.95 mol) and 4-dimethylaminopyridine (223 g, 1.83 mol) were added to the batch and the solution was warmed to 25 0C and aged overnight. The batch was then concentrated by distillation to a volume of 80 L. Additional toluene (88.2 kg) was added and the batch further concentrated to 50 L. Isopropyl acetate (30 kg) was added and the resulting slurry was aged for 10 minutes. Heptane (70 kg) was then added dropwise to the slurry over 30 minutes, and the slurry was aged for 30 minutes then filtered, washed with isopropyl acetate/heptane (22.5 kg/17.4 kg), and then dried in vacuo at 55C to afford the title product as a white solid (27.5 kg, 95.5 wt %, 82 %). lH NMR (CDCI3) 7.33 (5H, m), 6.19 (IH5 m), 5.13(2H, s), 4.48 (IH, dd), 4.15 (2H, m), 3.97 (IH, m), 2.95 (2H, m), 2.73 (IH, d tr), 4.65 (IH, m), 2.61 (IH, m), 2.18 (2H, m), 1.45 (9H, s) and 1.30 (2H. m).

Reference： [1]Patent: WO2009/91856,2009,A2 .Location in patent: Page/Page column 64
[2]Organic Letters,2011,vol. 13,p. 5480 - 5483

13
[ 159874-20-1 ]
[ 120278-07-1 ]

Yield	Reaction Conditions	Operation in experiment
100%		4_(N-BOC amino)-CBz piperidine (24.4 kg 73.42 mol), THF (65 kg) and 5 M HCl (23.0 kg, 110.13 mol) were combined and heated to 30 -35 0C for ~2 hours, and then at 550C overnight. After cooling the reaction mixture to 100C, dichloromethane (97 kg) and 1OM NaOH (7.97 kg, 145.12 mol) were added, while keeping the temperature at < 25C. The phases were separated and the organic phase was washed with 25 wt % NaCl solution (27.5 kg). The <n="66"/>washed organic phase was distilled at atmospheric pressure to a volume of 70 L. Dichloromethane (162 kg) was then added, and the mixture was concentrated by distillation to a volume of 120L to give the title product as a solution in DCM (17.2 kg. 100%.). lH NMR (CDCI3) 7.33 (5H, m), 5.14 (2H, s), 4.14 (2 H, br s), 2.87 (3H, m), 1.83 (2H, m), 1.66 (3H, m) and 1.28 (2H, m).

Reference： [1]Patent: WO2009/91856,2009,A2 .Location in patent: Page/Page column 63-64

14
[ 120278-07-1 ]
[ 1184914-44-0 ]
[ 1220700-76-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl acetamide; at 90℃; for 2h;	Step i; A mixture of ethyl 4-chloro-6-quinolin-3-yl-1 ,5-naphthyridine-3-carboxylate (compound 41) (6.0 g, 17 mmol), 4-amino-1 -N-Cbz-piperidine (compound 45) (4.1 g, 17 mmol), and potassium carbonate (4.6 g, 33 mmol) in N,N-dimethylacetamide (100 ml_) was heated to 9O0C. After 2 hours, the reaction was cooled to room temperature and filtered. The filtrate was concentrated and the residue was triturated with methanol to afford methyl 4-({1 -[(benzyloxy)carbonyl]piperidin-4-yl}amino)-6-quinolin-3-yl-1 ,5- naphthyridine-3-carboxylate (compound 46) as a cream solid (8.2 g, 90%). 1H NMR (400 MHz, DMSO-c/6) ppm 1.47 - 1.66 (m, 2 H) 2.16 - 2.29 (m, 2 H) 3.04 - 3.28 (m, 2 H) 3.90 (s, 3 H) 3.95 - 4.05 (m, 2 H) 5.10 (s, 2 H) 5.55 (br s,, 1 H) 7.23 - 7.46 (m, 5 H) 7.62 - 7.75 (m, 1 H) 7.85 (ddd, J=8.46, 6.95, 1.26 Hz, 1 H) 8.12 (d, J=9.60 Hz, 2 H) 8.35 (d, J=8.84 Hz, 1 H) 8.55 (d, J=8.84 Hz, 1 H) 8.96 (s, 1 H) 9.07 (d, J=1.77 Hz, 1 H) 9.56 (br s, 1 H) 9.65 (s, 1 H). LRMS m/z 553 (M+H)+.

Reference： [1]Patent: WO2010/38165,2010,A1 .Location in patent: Page/Page column 83

15
[ 120278-07-1 ]
[ 1137477-51-0 ]
benzyl 4-(5-bromo-2-pivalamidopyridin-4-ylamino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 210℃; for 1.5h;Microwave irradiation;	N-(5-Bromo-4-chloropyridin-2-yl)pivalamide (Synthesis 155-A) (1.08 g, 3.70 mmol), benzyl 4-aminopiperidine-i-carboxylate (1.736 g, 7.41 mmol), and triethylamine (1.041 ml_, 7.41 mmol) in NMP (7.41 ml_) in a sealed vial was heated to 210 0C by microwave irradiation for 1.5 hr. The cooled solution was diluted with MeOH and purified by ion exchange on lsolute SCX Il acidic resin eluting with MeOH then 2M NH3 in MeOH. He basic fractions were combined and volatiles were removed in vacuo. The crude product was dissolved in dichloromethane and loaded onto a Biotage silica column. Flash column chromatography eluting with a gradient of EtOAc in hexanes gave N-(5-bromo-4-(1- methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (0.536 g, 1.095 mmol, 30 %) as a clear glass.1H NMR (500 MHz, CDCI3) delta 8.03 (s, 1 H), 7.95 (s, 1 H), 7.69 (s, 1 H), 7.39-7.30 (m, 5H), 5.15 (s, 2H), 4.74 (d, 1 H, J = 7.7 Hz), 4.13 (q, 3H, J = 7.0 Hz), 3.73-3.64 (m, 1H), 3.12 (t, 2H, J = 11.5 Hz), 2.13-2.06 (m, 2H), 1.54-1.43 (m, 2H), 1.33 (s, 9H). LCMS (4) Rt = 2.48 min; m/z (ESI+) 489/491 (MH+).

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 229-230

16
[ 120278-07-1 ]
[ 1174020-67-7 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

17
[ 120278-07-1 ]
[ 1174020-15-5 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

18
[ 120278-07-1 ]
C₃₆H₅₀N₄O₈ [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

19
[ 120278-07-1 ]
[ 1401540-68-8 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

20
[ 120278-07-1 ]
[ 1174020-16-6 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

21
[ 120278-07-1 ]
[ 1174020-65-5 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

22
[ 120278-07-1 ]
[ 1174020-17-7 ]
tert-butyl (2S)-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}amino)carbonyl]-5-oxopiperidine-1-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

23
[ 120278-07-1 ]
[ 1174020-18-8 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

24
[ 120278-07-1 ]
benzyl 4-[({(2S,5R)-5-[(benzyloxy)amino]piperidin-2-yl}carbonyl)amino]piperidine-1-carboxylate tosylate [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

25
[ 120278-07-1 ]
[ 1174020-21-3 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

26
[ 120278-07-1 ]
[ 1174020-64-4 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

27
[ 120278-07-1 ]
[ 1174018-99-5 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5480 - 5483

28
[ 120278-07-1 ]
[ 1351166-35-2 ]

Reference： [1]Patent: WO2011/146335,2011,A1

29
[ 120278-07-1 ]
[ 1351167-77-5 ]
[ 1351166-38-5 ]

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30
[ 120278-07-1 ]
[ 1351166-39-6 ]

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31
[ 120278-07-1 ]
[ 1351167-57-1 ]

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32
[ 120278-07-1 ]
[ 1351168-68-7 ]

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33
[ 120278-07-1 ]
[ 1351168-69-8 ]

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[ 120278-07-1 ]
[ 1351168-70-1 ]

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35
[ 120278-07-1 ]
[ 1351167-60-6 ]

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36
[ 120278-07-1 ]
[ 1351167-62-8 ]

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37
[ 120278-07-1 ]
[ 1351168-75-6 ]

Reference： [1]Patent: WO2011/146335,2011,A1

38
[ 120278-07-1 ]
[ 1351167-66-2 ]

Reference： [1]Patent: WO2011/146335,2011,A1

39
[ 120278-07-1 ]
[ 1351168-76-7 ]

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40
[ 120278-07-1 ]
[ 1351168-77-8 ]

Reference： [1]Patent: WO2011/146335,2011,A1

41
[ 120278-07-1 ]
[ 1351167-67-3 ]

Reference： [1]Patent: WO2011/146335,2011,A1

42
[ 120278-07-1 ]
[ 1351167-68-4 ]

Reference： [1]Patent: WO2011/146335,2011,A1

43
[ 120278-07-1 ]
[ 1351167-69-5 ]

Reference： [1]Patent: WO2011/146335,2011,A1

44
[ 120278-07-1 ]
[ 1351167-70-8 ]

Reference： [1]Patent: WO2011/146335,2011,A1

45
[ 120278-07-1 ]
[ 1351168-78-9 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2012/37393,2012,A1

46
[ 120278-07-1 ]
[ 1351168-79-0 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2012/37393,2012,A1

47
[ 120278-07-1 ]
[ 1351167-41-3 ]

Reference： [1]Patent: WO2011/146335,2011,A1

48
[ 120278-07-1 ]
[ 1351167-71-9 ]

Reference： [1]Patent: WO2011/146335,2011,A1

49
[ 120278-07-1 ]
[ 1351167-88-8 ]

Reference： [1]Patent: WO2011/146335,2011,A1

50
[ 120278-07-1 ]
[ 1351167-89-9 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2012/37393,2012,A1
[3]Patent: WO2013/66869,2013,A1

51
[ 120278-07-1 ]
[ 1351167-90-2 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2012/37393,2012,A1
[3]Patent: WO2013/66869,2013,A1

52
[ 120278-07-1 ]
[ 1351167-91-3 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2012/37393,2012,A1

53
[ 120278-07-1 ]
[ 1351167-86-6 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2012/37393,2012,A1
[3]Patent: WO2013/66869,2013,A1

54
[ 120278-07-1 ]
[ 1351168-03-0 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2013/66869,2013,A1

55
[ 120278-07-1 ]
[ 1351168-04-1 ]

Reference： [1]Patent: WO2011/146335,2011,A1
[2]Patent: WO2013/66869,2013,A1

56
[ 120278-07-1 ]
[ 1351166-09-0 ]

Reference： [1]Patent: WO2011/146335,2011,A1

57
[ 120278-07-1 ]
[ 1351166-10-3 ]

Reference： [1]Patent: WO2011/146335,2011,A1

58
[ 120278-07-1 ]
[ 1351168-05-2 ]

Reference： [1]Patent: WO2011/146335,2011,A1

59
[ 120278-07-1 ]
[ 1351167-92-4 ]

Reference： [1]Patent: WO2011/146335,2011,A1

60
[ 120278-07-1 ]
[ 1351166-11-4 ]

Reference： [1]Patent: WO2011/146335,2011,A1

61
[ 120278-07-1 ]
[ 1351166-12-5 ]

Reference： [1]Patent: WO2011/146335,2011,A1

62
[ 120278-07-1 ]
[ 2488-15-5 ]
[ 1351167-87-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step A: A solution of HBTU (8.1 g, 21 mmol), (S)-2-(tert- butoxycarbonylamino)-4-(methylthio)butanoic acid (5.3 g, 21 mmol) and DIEA (8.2 mL, 47 mmol) in DMF (50 mL) was stirred at ambient temperature for 30 minutes. Benzyl 4- aminopiperidine-l-carboxylate (5.0 g, 21 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The mixture was poured into IN NaOH (500 mL) and the combined organic layers were extracted into EtOAc (500 mL). The combined organic layers were washed with IN HC1 (500 mL) and brine (500 mL). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to yield (S)-benzyl 4-(2-(tert- butoxycarbonylamino)-4-(methylthio)butanamido)piperidine-l-carboxylate (10 g, 21 mmol, 100%).
100%		[00380] Step A: A solution of HBTU (8.1 g, 21 mmol), (S)-2-(tert- butoxycarbonylamino)-4-(methylthio)butanoic acid (5.3 g, 21 mmol) and DIEA (8.2 mL, 47 mmol) in DMF (50 mL) was stirred at ambient temperature for 30 minutes. Benzyl 4- aminopiperidine- 1 -carboxylate (5.0 g, 21 mmol) was added and the mixture stirred at ambient temperature for 18 hours. The mixture was poured into 1 N NaOH (500 mL) and the organics were extracted into EtOAc (500 mL). The organic layer was washed with 1 N HC1 (500 mL) and brine (500 mL), dried over MgS04 and concentrated under vacuum to yield (S)-benzyl 4- (2-(tert-butoxycarbonylamino)-4-(methylthio)butanamido)piperidine-l -carboxylate (10 g, 21 mmol, 100%).

Reference： [1]Patent: WO2011/146335,2011,A1 .Location in patent: Page/Page column 61
[2]Patent: WO2012/37393,2012,A1 .Location in patent: Page/Page column 51; 58-59

63
[ 120278-07-1 ]
[ 1365998-61-3 ]

Reference： [1]Patent: WO2012/37393,2012,A1

64
[ 120278-07-1 ]
[ 1365998-62-4 ]

Reference： [1]Patent: WO2012/37393,2012,A1

65
[ 120278-07-1 ]
[ 1365997-96-1 ]

Reference： [1]Patent: WO2012/37393,2012,A1

66
[ 120278-07-1 ]
[ 1365998-11-3 ]

Reference： [1]Patent: WO2012/37393,2012,A1

67
[ 120278-07-1 ]
[ 1365998-24-8 ]

Reference： [1]Patent: WO2012/37393,2012,A1

68
[ 120278-07-1 ]
[ 1433881-01-6 ]

Reference： [1]Patent: WO2013/66869,2013,A1

69
[ 120278-07-1 ]
(S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(3-isobutyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)pyrrolidin-2-one trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2013/66869,2013,A1

70
[ 120278-07-1 ]
(S)-benzyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-carboxylate methiodide salt [ No CAS ]

Reference： [1]Patent: WO2013/66869,2013,A1

71
[ 120278-07-1 ]
[ 2488-15-5 ]
[ 1351167-91-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step A: A solution of HBTU (8.1 g, 21 mmol), (S)-2-(tert- butoxycarbonylamino)-4-(methylthio)butanoic acid (5.3 g, 21 mmol) and DIEA (8.2 mL, 47 mmol) in DMF (50 mL) was stirred at ambient temperature for 30 minutes. Benzyl 4- aminopiperidine-1 -carboxylate (5.0 g, 21 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The mixture was poured into IN NaOH (500 mL) and extracted into EtOAc (500 mL). The combined organic layers were washed with IN HC1 (500 mL) and brine (500 mL), dried over MgS04, filtered and concentrated in vacuo to yield (S)-benzyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin- 1 -yl)piperidine- 1 -carboxylate (10 g, 21 mmol, 100%).

Reference： [1]Patent: WO2013/66869,2013,A1 .Location in patent: Paragraph 00415

72
[ 120278-07-1 ]
[ 3303-84-2 ]
4-(3-tert-butoxycarbonylaminopropionylamino)piperidine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		N-Methylmorpholine (0.44 mL, 4.00 mmol) and HATU (1.05 g, 2.76 mmol) were added to a solution of Boc-beta-Ala-OH (0.501 g, 2.65 mmol) in DCM (24 mL) under argon and the reaction was stirred at room temperature for 30 minutes. 4-Amino-1-N-CBz-piperidine (0.588 g, 2.51 mmol) was added in one portion and the reaction stirred for 95 h. The reaction was quenched with 0.25M HC1 and extracted with DCM. The organic layer was washed with saturated NaHCOs and brine, dried over Na2SO4, filtered, and concentrated to provide 1.00 g of crude product which was carried to the next step without purification. ESI-MS m/z 406 (MH)+

Reference： [1]Patent: WO2014/151958,2014,A1 .Location in patent: Paragraph 00245

73
[ 120278-07-1 ]
[ 3303-84-2 ]
[2-(piperidin-4-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2014/151958,2014,A1

74
[ 120278-07-1 ]
4-[tert-butoxycarbonyl-(2-tert-butoxycarbonylaminoethyl)amino]piperidine-1-carboxylic acid benzyl ester [ No CAS ]

Reference： [1]Patent: WO2014/151958,2014,A1

75
[ 120278-07-1 ]
(2-tert-butoxycarbonylaminoethyl)piperidin-4-ylcarbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2014/151958,2014,A1

76
[ 120278-07-1 ]
[ 89711-08-0 ]
[ 864293-75-4 ]

Yield	Reaction Conditions	Operation in experiment
23%		A mixture of 4-amino-l-N-Cbz-piperidine (0.683 g, 2.91 mmol) and N-Boc-2- aminoacetaldehyde (0.463 g, 2.91 mmol) in methanol (12 mL) was stirred under argon at room temperature for 17 h. Sodium borohydride (0.220 g, 5.82 mmol) was added and the reaction stirred for additional 7 h. The reaction was quenched with water and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (0-100% EtOAc/hexane then 5-10% CH3OH:DCM) provided 0.250 g (23%) of product. ESI-MS m/z 378 (MH)+

Reference： [1]Patent: WO2014/151958,2014,A1 .Location in patent: Paragraph 00264

77
[ 120278-07-1 ]
benzyl 4-(5-oxo-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/99777,2015,A1

78
[ 120278-07-1 ]
benzyl 4-(1-oxido-5-oxo-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/99777,2015,A1

79
[ 120278-07-1 ]
[ 108-23-6 ]
benzyl 4-(isopropoxycarbonylamino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; toluene; at 20℃; for 2h;	Benzyl 4-aminopiperidine-1-carboxylate (100 mg) and triethylamine (190 muL) are dissolved in dichloromethane (2 mL), treated with isopropyl chloroformate (920 muL, 1 M solution in toluene) and stirred for 2 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
	With triethylamine; In dichloromethane; toluene; at 20℃; for 2h;	Benzyl 4-aminopiperidine-1 -carboxylate (100 mg) and triethylamine (190 muIota_) are dissolved in dichloromethane (2 ml_), treated with isopropyl chloroformate (920 muIota_, 1 M solution in toluene) and stirred for 2 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4CI solution. The organic phase is dried (MgS04) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1 ): tR = 1 .02 min; Mass spectrum (ESI+): m/z = 321 [M+H]+.

Reference： [1]Patent: US2015/119393,2015,A1 .Location in patent: Paragraph 0306; 0307
[2]Patent: WO2015/63011,2015,A1 .Location in patent: Page/Page column 71

80
[ 120278-07-1 ]
[ 2081-44-9 ]
[ 503-38-8 ]
benzyl 4-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Benzyl 4-aminopiperidine-1-carboxylate (100 mg) is dissolved in toluene (1 mL), treated dropwise with a solution of diphosgene (52 muL) in toluene (1 mL) and stirred for 12 hours at 80 C. Tetrahydro-2H-pyran-4-ol (41 muL) is added and the mixture is heated for 3 hours at 80 C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=363 [M+H]+.
		Benzyl 4-aminopiperidine-1 -carboxylate (100 mg) is dissolved in toluene (1 mL), treated dropwise with a solution of diphosgene (52 muIota_) in toluene (1 mL) and stirred for 12 hours at 80 C. Tetrahydro-2H-pyran-4-ol (41 mu) is added and the mixture is heated for 3 hours at 80 C. The mixture is partitioned between ethylacetate and saturated aqueous NH4CI solution. The organic phase is dried (MgS04) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1 ): tR = 0.95 min; Mass spectrum (EST): m/z = 363 [M+H]+.

Reference： [1]Patent: US2015/119393,2015,A1 .Location in patent: Paragraph 0321; 0322
[2]Patent: WO2015/63011,2015,A1 .Location in patent: Page/Page column 74; 75

81
[ 120278-07-1 ]
ethyl 2-(3-hydroxypropyl)nicotinate [ No CAS ]
ethyl 2-(3-((1-((benzyloxy)carbonyl)piperidin-4-yl)amino)propyl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5 g		A dichloromethane (10 mL) solution of DMSO (4.19 mL) was added at -65 C. to a mixture of oxalyl chloride (2.55 mL) and dichloromethane (50 mL), and the resultant mixture was stirred at the same temperature as above for 15 minutes. A dichloromethane solution (10 mL) of ethyl 2-(3-hydroxypropyl)nicotinate (4.8 g) was added to the reaction mixture, and the mixture was further stirred at the same temperature as above for 20 minutes. Triethylamine (10.4 mL) was added to the reaction mixture at -78 C., and the mixture was stirred at the same temperature as above for 25 minutes and then heated to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure. Benzyl 4-aminopiperidine-1-carboxylate (5.65 g) was added to a mixture of the obtained residue and ethanol (80 mL), and the resultant mixture was stirred at room temperature for 2 hours. Sodium borohydride (0.92 g) was added to the reaction mixture at 0 C., and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1 M hydrochloric acid, followed by extraction with dichloromethane. Then, the organic layer was washed with water and saturated saline and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/dichloromethane) to obtain the title compound (5.0 g). MS (ESI+): [M+H]+ 426.0.

Reference： [1]Patent: US2015/99777,2015,A1 .Location in patent: Paragraph 0650; 0651; 0652

82
[ 120278-07-1 ]
[ 25991-27-9 ]
methyl-1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		Benzyl 4-aminopiperidine-1-carboxylate (3.04 g, 12.98 mmol) was added to a stirred mixture of methyl 2-oxo-2H-pyran-3-carboxylate (2.00, 12.98 mmol) in DMF (50 mL) at 0 C. The reaction mixture was stirred at 0 C. A solid precipitated out of the solution. The heterogeneous mixture was stirred at 0 C for five hours then allowed to warm to room temperature. EDC (3.23 g, 16.87 mmol) was added followed by 4- Dimethylaminopyridine (0.3 96 g, 3.24 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate extract was dried over sodium sulfate, filtered and concentratedto give g crude product mixture. Chromatography over Silica Gel gave methyl 1-(1- ((benzyloxy)carbonyl)piperidin-4-yl)-2-oxo- 1 ,2-dihydropyridine-3 -carboxylate (3.3 97g, 9.2mmol, 71% yield) as a tan viscous glue.

Reference： [1]Patent: WO2015/89143,2015,A1 .Location in patent: Page/Page column 176; 177

83
[ 120278-07-1 ]
1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/89143,2015,A1

84
[ 120278-07-1 ]
benzyl-4-(3-((tert-butoxycarbonyl)amino)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/89143,2015,A1

85
[ 120278-07-1 ]
benzyl-4-(3-amino-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/89143,2015,A1

86
[ 120278-07-1 ]
benzyl-4-(3-((3-(cyclopropylcarbamoyl)-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)amino)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/89143,2015,A1

87
[ 120278-07-1 ]
N-cyclopropyl-8-((4-methoxybenzyl)(methyl)amino)-6-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/89143,2015,A1

88
[ 120278-07-1 ]
N-cyclopropyl-6-((1-(1-(4-methyl-1H-imidazole-2-carbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/89143,2015,A1

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[ 711002-74-3 ]

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Amides

[ 405057-75-2 ]

1-Cbz-4-Methylaminopieridine

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[ 711002-74-3 ]

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Amines

[ 405057-75-2 ]

1-Cbz-4-Methylaminopieridine

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Benzyl 4-aminopiperidine-1-carboxylate hydrochloride

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Related Parent Nucleus of
[ 120278-07-1 ]

Aliphatic Heterocycles

[ 405057-75-2 ]

1-Cbz-4-Methylaminopieridine

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Benzyl 4-aminopiperidine-1-carboxylate hydrochloride

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Piperidines

[ 405057-75-2 ]

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Benzyl 4-aminopiperidine-1-carboxylate hydrochloride

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(S)-Benzyl 3-aminopiperidine-1-carboxylate

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(R)-Benzyl 3-aminopiperidine-1-carboxylate

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere