[ CAS No. 264905-39-7 ] {[proInfo.proName]}

Name: 264905-39-7|1-Boc-4-Ethylaminopiperidine|95%
Brand: Ambeed
SKU: A525598
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Quality Control of [ 264905-39-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 264905-39-7 ]

SDS Specification

Alternatived Products of [ 264905-39-7 ]

Product Details of [ 264905-39-7 ]

CAS No. :	264905-39-7	MDL No. :	MFCD06808580
Formula :	C₁₂H₂₄N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SRDSJYNZSNVSGS-UHFFFAOYSA-N
M.W :	228.33	Pubchem ID :	18374730
Synonyms :

Calculated chemistry of [ 264905-39-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.92
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	69.01
TPSA :	41.57 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) :	-6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.19
Log Po/w (XLOGP3) :	1.6
Log Po/w (WLOGP) :	1.61
Log Po/w (MLOGP) :	1.44
Log Po/w (SILICOS-IT) :	1.14
Consensus Log Po/w :	1.8

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.93
Solubility :	2.66 mg/ml ; 0.0117 mol/l
Class :	Very soluble
Log S (Ali) :	-2.08
Solubility :	1.88 mg/ml ; 0.00823 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.12
Solubility :	1.71 mg/ml ; 0.0075 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.34

Safety of [ 264905-39-7 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P273-P301+P310-P305+P351+P338	UN#:	2810
Hazard Statements:	H301-H315-H319-H335-H410	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 264905-39-7 ]

* 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.

Downstream synthetic route of [ 264905-39-7 ]

[ 264905-39-7 ] Synthesis Path-Downstream 1~49

1
[ 79099-07-3 ]
[ 75-04-7 ]
[ 264905-39-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In ethanol; water at 50℃; for 4h;	1.1 l-tert-Butoxycarbonyl-4-piperidone (15g, 75.28mmol) was dissolved in ethanol (150ml) and treated with 70% ethylamine/H2O (6.06ml, 75.29mmol), followed by 5%Pt/C JM type 117 (2.25g, 20 wt%). The reaction mixture was subjected to hydrogenation at 2bar, 50°C with stiring for 4 hours. The reaction mixture was purged with nitrogen and filtered through GF/F filter paper. The catalyst was washed with ethanol (2x 15ml). The liquors were combined and evaporated to dryness to give N-(l-tert-butoxycarbonyl-4- ρiperidinyl)ethylamine as a colourless oil (18.33g, 107%).1H ΝMR (400 MHz, CDCl3): δ 4.04 (s, 2H), 2.78 (t, 2H), 2.68 (q, 2H), 2.64 - 2.58 (m, IH), 1.84 (d, 2H), 1.48 (s, 9H), 1.29 - 1.19 (m, 2H), 1.11 (t, 3H).
99%	With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran; 1,2-dichloro-ethane at 20℃; for 24h; Inert atmosphere;
94%	Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; ethylamine With acetic acid In tetrahydrofuran for 0.0833333h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran for 24h;	22 PREPARATIVE EXAMPLE 22: Solution of ethylamin (2.0 M in THF, 20.0 mL, 20.0 MMOL) was to N-Boc-4- piperidone (3. 00G, 15.0 MMOL). Acetic acid (2.0 mL) was added, the mixture was stirred for 5 min, then NaBH (OAc) 3 (4.22 g, 20.0 MMOL) was added. The mixture was stirred under N2 for 24 hr, poured into 10 % aqueous NA2CO3 (300 mL), and extracted with CH2CI2 (3 x 50 mL). The combined extracts were dried over NA2SO4, filtered, and the solvent was evaporated. The resulting oil (3.20 g, 94 %) was used without purification. LCMS: MH+ = 229.

88%	Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; ethylamine With triethylamine; zinc(II) chloride In methanol at 60℃; for 7h; Stage #2: With sodium cyanoborohydride In methanol at 25℃; for 17h;	To Intermediate 1, tert-butyl 4-oxopiperidine-1-carboxylate (3.0 g, 15.1 mmol) in MeOH (40 mL) was added Intermediate 44, ethanamine (12.6 mL, 25.1 mmol, 2 M in THF), Et3N (4.2 mL,30.3 mmol) and ZnCI2 (0.1 g, 0.7 mmol) and the reaction mixture was stirred at 60 °C for 7 h. NaBH3CN (1.2 g, 19.6 mmol) was added portionwise and the resulting reaction mixture was stirred at 25 °C for 17 h. The solvents were removed in vacuo and the residue was partitioned between H20 (250 mL) and EtOAc (200 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL), and the combined organic phases were dried (Na2504) and the solventwas removed in vacuo. The residue was purified by column chromatography (normal basicactivated alumina, 10 to 30 % EtOAc in hexane) to give Intermediate 43, tert-butyl 4-(ethylamino)piperidine-1-carboxylate (3.0 g, 88 %) as a gum.The data for Intermediate 43 are in Table 2.
84%	With palladium on activated charcoal; hydrogen In ethanol at 20℃;	131.1 A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol), Palladiuml carbon (1 g), ethanol (50 mL) and ethanamine (2.1 mL) was stirred under an atmosphere of H2 overnight at room temperature. The solids were filtered and the filtrate was concentrated to afford 4.8 g (84%) of tert-butyl 4-(ethylamino)piperidine-1-carboxylate as a colorless oil.
	With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃;
1.7 g (97%)	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; 1,2-dichloro-ethane	1.A Step A Step A 4-(N-Ethylamino)-1-tert-butoxycarbonylpiperidine Ethylamine (10 mL, 1 M in THF, 10 mmol) and DIEA (2.3 mL, 13.4 mmol) were dissolved in 100 mL of 1,2-dichloroethane under nitrogen. A solution of 1-tert-butoxycarbonyl-4-piperidone (1.3 g, 6.7 mmol) in 100 mL of 1,2-dichloroethane was added, followed by sodium triacetoxyborohydride (4.2 g, 20 mmol). The mixture was stirred at rt under nitrogen for 14 h, then diluted with CH2Cl2. The solution was washed twice with each of 1 N NaOH and brine, dried over Na2So4 and concentrated to afford 1.7 g (97%) of the title compound.
	With sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran	R.107.1 1-tert-Butoxycarbonyl-4-(ethylamino)piperidine REFERENCE EXAMPLE 107-1 1-tert-Butoxycarbonyl-4-(ethylamino)piperidine To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (3.99 g, 20 mmol) in THF (40 mL) were added ethylamine (20 mL of a 2.0 M solution in THF, 40 mmol), acetic acid (1.15 mL, 20 mmol) and sodium triacetoxyborohydride (8.48 g, 40 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 1 N aqueous sodium hydroxide (120 mL) at 0° C. and stirred at room temperature for 30 minutes. The organic solvent was evaporated under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate (40 mL, 220 mL). The combined organic layers were washed with brine (220 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the title compound (4.54 g, 19.9 mmol, 99%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.05-1.4 (2H, m), 1.11 (3H, t, J=7.2 Hz), 1.45 (9H, s), 1.7-1.95 (2H, m), 2.5-2.9 (3H, m), 2.68 (2H, q, J=7.2 Hz), 3.9-4.2 (2H, m).
	With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 25℃;
	Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; ethylamine In methanol at 20℃; for 1h; Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 2h;	19.1 Step 1: Ethylamine (1.2 equivalent) was added to a solution of the compound 19a (1 eq.) in methanol, and stirred at room temperature for 1 hour.Sodium borohydride (1.5 eq.) was then added in portions and stirred at room temperature for 2 h.After the reaction, it was quenched with saturated ammonium chloride solution and extracted with dichloromethane.The organic layer solvent was dried to give the crude product 19b, which was used directly for next step.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2006/64221, 2006, A1 Location in patent: Page/Page column 7
[2]Xie, Weilong; Park, Sung-Woo; Jung, Hoimin; Kim, Dongwook; Baik, Mu-Hyun; Chang, Sukbok [Journal of the American Chemical Society, 2018, vol. 140, # 30, p. 9659 - 9668]
[3]Current Patent Assignee: MERCK & CO INC - WO2004/46111, 2004, A1 Location in patent: Page 30-31
[4]Current Patent Assignee: SOSEI GROUP CORPORATION - WO2017/21730, 2017, A1 Location in patent: Page/Page column 44; 52
[5]Current Patent Assignee: SANOFI - WO2015/120049, 2015, A1 Location in patent: Page/Page column 210
[6]Finke, Paul E.; Oates, Bryan; Mills, Sander G.; MacCoss, Malcolm; Malkowitz, Lorraine; Springer, Martin S.; Gould, Sandra L.; DeMartino, Julie A.; Carella, Anthony; Carver, Gwen; Holmes, Karen; Danzeisen, Renee; Hazuda, Daria; Kessler, Joseph; Lineberger, Janet; Miller, Michael; Schleif, William A.; Emini, Emilio A. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2475 - 2479]
[7]Current Patent Assignee: MERCK & CO INC - US6399619, 2002, B1
[8]Current Patent Assignee: ABBVIE INC - US6562978, 2003, B1
[9]Bourdonnec, Bertrand Le; Leister, Lara K.; Ajello, Christopher A.; Cassel, Joel A.; Seida, Pamela R.; O'Hare, Heather; Gu, Minghua; Chu, Guo-Hua; Tuthill, Paul A.; DeHaven, Robert N.; Dolle, Roland E. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 336 - 343]
[10]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - CN107814792, 2018, A Location in patent: Paragraph 0205; 0206

2
[ 75-36-5 ]
[ 264905-39-7 ]
tert-butyl 4-[acetyl(ethyl)amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 4-(N-ethylamino)-1-tert-butoxycarbonylpiperidine With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: acetyl chloride In dichloromethane at 0 - 25℃; for 8h;	To Intermediate 43, tert-butyl 4-(ethylamino)piperidine-1-carboxylate (0.20 g, 0.9 mmol) inDCM (10 mL) was added triethylamine (0.15 mL, 1.1 mmol) dropwise and the mixture wasstirred at 0 °C for 30 mi Acetyl chloride (0.09 g, 1.1 mmol) was added dropwise at 0 °C and the resulting reaction mixture was stirred at 25 °C for 8 h before removal of the solvents in vacuo. The residue was partitioned between H20 (120 mL) and EtOAc (100 mL) and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic phaseswere dried (Na2504) and the solvent removed in vacuo. The residue was purified by columnchromatography (normal basic activated alumina, 0.5 to 1 .0 % MeOH in DCM) to give tert-butyl4-[acetyl(ethyl)amino]piperidine-1-carboxylate (0.15 g, 63%) as a liquid.LCMS (Method I): mlz 271 [M+H] (ES), at 3.79 mi UV active.
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;

Reference： [1]Current Patent Assignee: SOSEI GROUP CORPORATION - WO2017/21730, 2017, A1 Location in patent: Page/Page column 44; 45; 52
[2]Finke, Paul E.; Oates, Bryan; Mills, Sander G.; MacCoss, Malcolm; Malkowitz, Lorraine; Springer, Martin S.; Gould, Sandra L.; DeMartino, Julie A.; Carella, Anthony; Carver, Gwen; Holmes, Karen; Danzeisen, Renee; Hazuda, Daria; Kessler, Joseph; Lineberger, Janet; Miller, Michael; Schleif, William A.; Emini, Emilio A. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2475 - 2479]

3
[ 624-83-9 ]
[ 264905-39-7 ]
4-(1-ethyl-3-methyl-ureido)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;

Reference： [1]Finke, Paul E.; Oates, Bryan; Mills, Sander G.; MacCoss, Malcolm; Malkowitz, Lorraine; Springer, Martin S.; Gould, Sandra L.; DeMartino, Julie A.; Carella, Anthony; Carver, Gwen; Holmes, Karen; Danzeisen, Renee; Hazuda, Daria; Kessler, Joseph; Lineberger, Janet; Miller, Michael; Schleif, William A.; Emini, Emilio A. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2475 - 2479]

4
[ 264905-39-7 ]
N-ethyl-N-(piperidin-4-yl)acetamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: DIPEA / CH₂Cl₂ / 20 °C 2: HCl / methanol / 20 °C

5
[ 264905-39-7 ]
1-ethyl-3-methyl-1-piperidin-4-yl-urea; hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: DIPEA; DMAP / CH₂Cl₂ / 20 °C 2: HCl / methanol / 20 °C

6
[ 264905-39-7 ]
N-{1-[4-(benzenesulfonyl-methyl-amino)-3-phenyl-butyl]-piperidin-4-yl}-N-ethyl-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: DIPEA / CH₂Cl₂ / 20 °C 2: HCl / methanol / 20 °C 3: DIPEA; NaBH(OAc)3 / 1,2-dichloro-ethane

7
[ 264905-39-7 ]
N-{4-[4-(1-ethyl-3-methyl-ureido)-piperidin-1-yl]-2-phenyl-butyl}-N-methyl-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: DIPEA; DMAP / CH₂Cl₂ / 20 °C 2: HCl / methanol / 20 °C 3: DIPEA; NaBH(OAc)3 / 1,2-dichloro-ethane

8
[ 696643-53-5 ]
[ 264905-39-7 ]
[ 696644-12-9 ]

Yield	Reaction Conditions	Operation in experiment
12%	Stage #1: bis(trichloromethyl) carbonate; 4-(N-ethylamino)-1-tert-butoxycarbonylpiperidine In dichloromethane for 1h; Stage #2: C₂₃H₂₆F₆N₂ With N-ethyl-N,N-diisopropylamine In dichloromethane for 168h;	24 PREPARATIVE EXAMPLE 24: Solution of the product from Preparative Example 22 (200 mg, 0.45 MMOL) in dry CH2CI2 (2 mL) was added to triphosgene (45 mg, 0.15 MMOL) under N2. The mixture was stirred for 1 hr, then solution of the product from Preparative Example (114 mg, 0.50 MMOL) and diisopropylethylamine (0.2 mL) in dry CH2CI2 (1 mL) was added and stirring was continued for 7 days. The mixture was poured into 10 % aqueous Na2CO3 (50 mL) and extracted with (5 X 10 mL). The combined extracts were dried over NA2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography using 4: 1 CH2CI2/ETOAC to give 35 mg (12 %) of a wax. LCMS: MH+ = 699.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2004/46111, 2004, A1 Location in patent: Page 31-32

Yield	Reaction Conditions	Operation in experiment
96%
85%
		52.A Step A Step A 1-t-Butyloxycarbonyl-4-ethylamino-piperidine To 5.0 g of N-Boc-4-piperidone were added 12.6 ml of titanium isopropoxide and 9.34 ml of triethylamine. This mixture was stirred for 1 hour, then 25 ml of EtOH (abs) and 1.056 g of sodium cyanoborohydride were added. The reaction was stirred for 48 hours at room temperature. EtOH and HsO were added and the reaction mixture was filtered through Celite. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane to give 3.548 g of the title compound.

10
[ 264905-39-7 ]
N-(1-tert-butoxycarbonyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 4-(methylsulfonyl)phenylacetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20 - 50℃; for 1.25h; Stage #2: 4-(N-ethylamino)-1-tert-butoxycarbonylpiperidine In tetrahydrofuran; toluene at 50℃; for 0.533333h;	1.2 A slurry of carbonyldiimidazole (1.94g, 11.98mmol) in THF (10ml) was treated with a solution of 4-methylsulphonylphenylacetic acid (2.5g, 11.68mmol) in THF (12.5ml) at ambient temperature and then heated to 5O0C. After one hour carbonyldiimidazole (0.189g, 1.17mmol) was added. After a further 15 minutes a solution of N-(-tert- butoxycarbonyl-4-piperidinyl)ethylamine (2.53g, ll.lOmmol) in toluene (10ml) was added dropwise over two minutes to the reaction mixture. After 30 minutes at 5O0C the reaction mixture was treated with IM NaOH (12.5ml) and the mixture was stired rapidly for 30 min and then allowed to cool to room temperature. The organic layer was separated and washed with aqueous citric acid (10%w/w, 10ml) and then with water (5ml). The organic layer was evaporated to dryness to afford N-(I -tert-butoxycarbonyl-4-piperidinyl)-N-ethyl- 4-methanesulfonylphenyl-acetamide as a colourless oil (4.75g, 100%). EPO 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 2H), 7.47 (d, 2H), 4.56 - 4.43 (m, 0.7H), 4.28 - 4.11 (m, 2H), 3.83 (s, 0.6H), 3.79 (s, 1.4H), 3.74 - 3.60 (m, 0.3H), 3.30 (q, 2H), 3.04 (s, 3H), 2.84 - 2.55 (m, 2H), 1.75 - 1.53 (m, 4H); 1.46 (s, 9H), 1.25 (t, 2.1H), 1.14 (t, 0.9H). On a repeat of this method the oil solidified on standing (m.pt. 138-14O0C).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2006/64221, 2006, A1 Location in patent: Page/Page column 7-8

11
benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) [ No CAS ]
[ 658-93-5 ]
[ 264905-39-7 ]
[ 301232-42-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Step A 4-(N-((<strong>[658-93-5]3,4</strong>-Difluorobenzyl)carbonyl)-N-ethylamino)piperidine trifluoroacetate <strong>[658-93-5]<strong>[658-93-5]3,4</strong>-difluorophenylacetic acid</strong> (158 mg, 0.92 mmol), 4-(N-ethylamino)-1-tert-butoxycarbonylpiperidine (231 mg, 0.10 mmol, from Example 1, Step A), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (718 mg, 1.4 mmol) and 1-hydroxybenzotriazole (124 mg, 0.92 mmol) were combined in DMF. DIEA (0.320 mL, 1.8 mmol) was added and the reaction mixture was stirred at rt for 15 h. The mixture was diluted with CH2Cl2 and washed with cold 1 N HCl, 1 N NaOH, water and brine. The organic layer was dried over Na2SO4 and concentrated. ESI-MS: 383.2 (M+H); HPLC A: 3.41 min. The residue was dissolved in 50% TFA in CH2Cl2 for 3 h, then concentrated to provide the title compound.

Reference： [1]Patent: US6399619,2002,B1

12
[ 108-48-5 ]
2-(2-chloro-4-fluorophenyl)acetic acid [ No CAS ]
[ 124-63-0 ]
[ 264905-39-7 ]
[ 301232-31-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; trifluoroacetic acid	13.A Step A Step A 4-(N-((2-Chloro-4-fluorobenzyl)carbonyl)-N-ethylamino)piperidine trifluoroacetate To a solution of (2-chloro-4-fluorophenyl)acetic acid (189 mg, 1.0 mmol) in CH2Cl2 at -2° C. was added methanesulfonyl chloride (0.093 mL, 1.2 mmol) and 2,6-lutidine (0.186 mL, 1.6 mmol). The solution was stirred at -2° C. for 1.5 h and at rt for 10 min, followed by addition of 4-(N-ethylamino)-1-tert-butoxycarbonylpiperidine (208 mg, 0.9 mmol, from Example 1, Step A) and additional 2,6-lutidine (0.093 mL, 0.8 mmol). The reaction mixture was stirred at rt for 48 h and then diluted with 5% aq. sodium bicarbonate. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2So4. The solvent was removed and the residue was redissolved in 50% TFA in CH2Cl2 for 1 h. The solution was then concentrated to afford the title compound. ESI-MS: 299.2 (M+H); HPLC A: 1.76 min.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US6399619, 2002, B1

13
[ 1129-25-5 ]
[ 264905-39-7 ]
[ 333987-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran; diethyl ether	R.107.2 1-tert-Butoxycarbonyl-4-{ethyl[4-(methylsulfanyl)phenylsulfonyl]amino}piperidine REFERENCE EXAMPLE 107-2 1-tert-Butoxycarbonyl-4-{ethyl[4-(methylsulfanyl)phenylsulfonyl]amino}piperidine To a stirred solution of the title compound of reference example 107-1 (4.54 g, 19.9 mmol) in THF (50 mL) were added triethylamine (3.05 mL, 21.9 mmol) and 4-(methylsulfanyl)benzenesulfonyl chloride (4.42 g, 19.9 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL, 25 mL). The combined organic layers were washed with 1N hydrochloric acid (310 mL), saturated aqueous sodium bicarbonate solution (210 mL), brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Diethyl ether was added to the residue, the resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to afford the title compound (6.83 g, 16.5 mmol, 83%) as a white solid. 1H NMR (CDCl3) δ 1.23 (3H, t, J=7.1 Hz), 1.3-1.7 (4H, m), 1.44 (9H, s), 2.52 (3H, s), 2.5-2.8 (2H, m), 3.21 (2H, q, J=7.1 Hz), 3.65-3.9 (1H, m), 4.0-4.25 (2H, m), 7.28 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz).

Reference： [1]Current Patent Assignee: ABBVIE INC - US6562978, 2003, B1

14
[ 264905-39-7 ]
[ 301226-17-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; potassium carbonate In hexane; dichloromethane; chloroacetonitrile	52.B Step B Step B 1-t-Butyloxycarbonyl-4-(N-cyanomethyl-N-ethylamino)-piperidine To a solution of 150 mg 1-t-butyloxycarbonyl-4-ethylamino-piperidine (from Step A) in 3 ml DCE were added 60 mg of chloroacetonitrile, 109 mg of potassium carbonate, and 11 mg of potassium iodide. The reaction was stirred at 60° C. overnight. Methylene chloride was added, and the solution was washed with 2*20 ml water, and 20 ml brine. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 20% EtOAc in hexane to give 115 mg of the title compound.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US6498161, 2002, B1

15
[ 264905-42-2 ]
[ 264905-39-7 ]
[ 264904-09-8 ]

Yield	Reaction Conditions	Operation in experiment
		18 2-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-(4-piperidinyl)acetamide (18) Example 18 2-(4-Amino-2,3,5,6-tetramethylanilino)-N-ethyl-N-(4-piperidinyl)acetamide (18) The title compound (18) was obtained from 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acid and 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner as the Example 1.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US6559146, 2003, B1

16
[ 264905-35-3 ]
[ 264905-39-7 ]
[ 264904-06-5 ]

Yield	Reaction Conditions	Operation in experiment
		15 2-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-(4-piperidinyl)propamide (15) Example 15 2-(4-Amino-2,3,5-trimethylphenoxy)-N-ethyl-N-(4-piperidinyl)propamide (15) The title compound (15) was obtained from 2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]propionic acid and 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner as the Example 1.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US6559146, 2003, B1

17
[ 264905-38-6 ]
[ 264905-39-7 ]
[ 264903-98-2 ]

Yield	Reaction Conditions	Operation in experiment
		7 2-(5-Amino-2-methoxyphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide (7) Example 7 2-(5-Amino-2-methoxyphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide (7) The title compound (7) was obtained from 2-[5-(tert-butoxycarbonylamino)-2-methoxyphenoxy]acetic acid and 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner as the Example 1.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US6559146, 2003, B1

18
[ 264905-40-0 ]
[ 264905-39-7 ]
[ 264903-99-3 ]

Yield	Reaction Conditions	Operation in experiment
		8 2-(5-Amino-4-chloro-2-methoxyphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide (8) Example 8 2-(5-Amino-4-chloro-2-methoxyphenoxy)-N-ethyl-N-(4-piperidinyl)acetamide (8) The title compound (8) was obtained from 2-[5-(tert-butoxycarbonylamino)-4-chloro-2-methoxyphenoxy]acetic acid and 1-(tert-butoxycarbonyl)-4-ethylaminopiperidine by the same manner as the Example 1.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US6559146, 2003, B1

19
[ 75-04-7 ]
[ 324769-06-4 ]
[ 264905-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethylamine; tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 1h; Stage #2: With acetic acid In tetrahydrofuran Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate	6 To a solution of ethanamine (30.0 ml, 60.0 mmol, 2M solution in THF) and fe/t-butyl 4- oxopiperidine-1 -carboxylate (30.0 ml, 60.0 mmol) in THF (30.0 ml, 15.1 mmol) was added sodium triacetoxyborohydride (6.4612 g, 30.5 mmol), and stirred at r.t. under N2. After 1 h, acetic acid (2.00 ml, 34.9 mmol) was added and the reaction mixture was stirred overnight before diluting with AcOEt (200 ml) and sat'd NaHCO3 aq. (100 ml). The aqueous layer was extracted with AcOEt and the combined organic layer was washed with sat'd NaHCO3 aq. (100 ml) and sat'd NaCl (100 ml), and dried over Na2SO4. Major portion of the product was found in the aqueous layer, so it was extracted with CH2Cl 2 and dried over Na2SO4. The solvent was removed under reduced pressure and chromatographed on silica (CH2Cl2->CH2Cl2/MeOH+2N NH3 = 10/1) to yield the desired product as a colorless liquid.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2007/67629, 2007, A1 Location in patent: Page/Page column 65

20
[ 875126-57-1 ]
[ 264905-39-7 ]
(R)-tert-butyl 4-(N-ethyl-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-chloro-1-pyrrolidinylmethylenepyrrolidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	6 To a solution of (i?)-2-(3-oxo-l-tosyl-l,2,3,4-tetrahydropyrazin-2-yl)acetic acid (0.804 g, 2.59 mmol) and tert-butyl 4-(ethylamino)piperidine-l -carboxylate (0.6477 g, 2.84 mmol) in DIPEA (0.680 ml, 3.89 mmol) and DMF (5.00 ml, 2.59 mmol) was added (l-(chloro-l- pyrrolidinylmethylene)pyrrolidiniumhexafluorophosphate) (0.9484 g, 2.85 mmol), and stirred for overnight before another portion of tert-butyl 4-(ethylamino)piperidine-l -carboxylate (0.2654 g, 1.16 mmol) was added. The reaction mixture was stirred for overnight and partitioned into AcOEt (200 ml) and sat'd NaHCO3 aq. (100 ml), and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with sat'd NaHCO3 aq. (100 ml) and sat'd NaCl aq. (100 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and chromatographed on silica (CH2Cl2 -> CH2Cl2ZMeOH = 10/1) then (CH2Cl2^AcOEt) to yield title product as an off-white solid.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2007/67629, 2007, A1 Location in patent: Page/Page column 72

21
[ 50712-67-9 ]
[ 264905-39-7 ]
[ 1009633-55-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate at 25℃;

Reference： [1]Bourdonnec, Bertrand Le; Leister, Lara K.; Ajello, Christopher A.; Cassel, Joel A.; Seida, Pamela R.; O'Hare, Heather; Gu, Minghua; Chu, Guo-Hua; Tuthill, Paul A.; DeHaven, Robert N.; Dolle, Roland E. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 336 - 343]

22
[ 87120-72-7 ]
[ 75-07-0 ]
[ 264905-39-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium tris(acetoxy)borohydride; acetic acid In ethylene dibromide at 20℃;	493.1 Step 1 11426] 4-Amino-piperidine-1 -carboxylic acid tert-butyl ester (1.58 g, 7.9 mmol) and acetaldehyde (0.417 g, 9.48 mmol) were mixed with sodium triacetoxy borohydride (3.35, 15.8 mmol) in dichloroethane containing acetic acid (1%) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2C12 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (10% methanol/90% methylene chloride/ammonium hydroxide) to yield the tert-butyl ester (0.71 g, 39%).
	Stage #1: 1-(tert-butoxycarbonyl)-4-aminopiperidine; acetaldehyde With sodium cyanoborohydride; acetic acid; triethylamine In methanol at 20℃; Molecular sieves; Stage #2: With sodium hydrogencarbonate In water	16 3.0 g (15.0 mmol) 4-Amino-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 40 ml Methanol. After adding molecular sieves, 3.0 g (30.0 mmol) Triethylamine, 9.0 g (149.8 mmol) acetic acid and 659.9 mg (15.0 mmol) acetaldehyde, a solution of 2.82 g (44.9 mmol) sodium cyanoborohydride in 2 ml of methanol was added and the reaction mixture was stirred at room temperature until complete conversion of the starting material was detected. For working up, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate-solution and water. After drying with magnesium sulfate, the solvent was removed under reduced pressure. Purification was achieved by preparative HPLC, which gave the title compound as trifluoroacetate. The product fractions were combined and brought to alkaline pH by adding sodium hydrogen carbonate(s). After evaporation of the solvent i. vac, the residue was dissolved in water and extracted three times with dichloromethane. Drying with magnesium sulfate and evaporation of the solvent gave the title compound as free base. Rt = 0.95 min (Method B). Detected mass: 229.2 (M+H+).

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings); TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2016/31908, 2016, A1 Location in patent: Paragraph 1426
[2]Current Patent Assignee: SANOFI - WO2008/77552, 2008, A1 Location in patent: Page/Page column 57-58

23
[ 264905-39-7 ]
8-(2-((1-acryloylpiperidin-4-yl)(ethyl)amino)ethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: sodium carbonate / acetonitrile / 65 °C 2: carbon tetrabromide; triphenylphosphine / dichloromethane / 2 h / 20 °C 3: potassium carbonate / acetone / 60 °C 4: acetic acid; N-chloro-succinimide; triethylamine / water / 4 h / 20 °C 5: triethylamine / <i>tert</i>-butyl alcohol / 4 h / 60 °C 6: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 7: triethylamine / dichloromethane; methanol / 4 h / 20 °C