[ CAS No. 150008-24-5 ] {[proInfo.proName]}

Name: 150008-24-5|tert-Butyl 4-(hydroxyimino)piperidine-1-carboxylate|98%
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Quality Control of [ 150008-24-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 150008-24-5 ]

CAS No. :	150008-24-5	MDL No. :	MFCD09953970
Formula :	C₁₀H₁₈N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LDLQTMSUZKHEHY-UHFFFAOYSA-N
M.W :	214.26	Pubchem ID :	15462924
Synonyms :

Calculated chemistry of [ 150008-24-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	61.01
TPSA :	62.13 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) :	-7.02 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.41
Log Po/w (XLOGP3) :	0.82
Log Po/w (WLOGP) :	1.47
Log Po/w (MLOGP) :	0.74
Log Po/w (SILICOS-IT) :	0.86
Consensus Log Po/w :	1.26

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.49
Solubility :	6.98 mg/ml ; 0.0326 mol/l
Class :	Very soluble
Log S (Ali) :	-1.71
Solubility :	4.21 mg/ml ; 0.0196 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.97
Solubility :	23.0 mg/ml ; 0.107 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.42

Safety of [ 150008-24-5 ]

Signal Word:	Danger	Class:	4.1
Precautionary Statements:	P280-P210-P240-P264-P270-P301+P310-P330-P370+P378-P403+P233-P405-P501	UN#:	1325
Hazard Statements:	H228-H302-H317-H319-H341-H351	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 150008-24-5 ]

* 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 [ 150008-24-5 ]
Downstream synthetic route of [ 150008-24-5 ]

[ 150008-24-5 ] Synthesis Path-Upstream 1~5

1
[ 150008-24-5 ]
[ 190900-21-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In tetrahydrofuran; ethyl acetate at 70℃; Inert atmosphere	To a solution of ketoxime (0.01 mol) in THF (10 mL) was added T3P (15 mol percent, 50percent soln in EtOAc) and the resulting reaction mixture was stirred at reflux for 1-4 h under nitrogen atmosphere. When the reaction was completed as confirmed by TLC, the solvent was removed under vacuum and the residue was diluted with water (20 mL). The product was extracted with ethyl acetate (2 .x. 20 mL) and the combined organic phase was washed with saturated NaHCO₃ solution (1 .x. 10 mL) and brine. The organic phase was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure to afford the desired amides in good purity.
48%	Stage #1: With sodium carbonate In water; acetone for 0.0833333 h; Stage #2: With p-toluenesulfonyl chloride In water; acetone at 20℃;	To a solution of intermediate I-49 (11 g, 50 mmol, 1.0 eq) in acetone (60 mL) was added a solution of Na₂CO₃(16 g, 150 mmol, 3.0 eq) in water (80 mL) and the reaction mixture was stirred for 5 minutes. A solution of p-toluenesulfonyl chloride (14 g, 75 mmol, 1.5 eq) in acetone (20 mL) was added slowly and the reaction mixture was stirred at room temperature for 3 hours. Excess solvent was removed by evaporation, water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO₄, the solids were removed by filtration and the filtrate was concentrated by evaporation. The crude reaction product was purified by silica gel column chromatography to give intermediate I-50 (5.0 g, 48percent). MS (ESI): m/z 159.1 (M+H⁺).

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1074 - 1077
[2] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 108
[3] Patent: WO2006/56877, 2006, A2, . Location in patent: Page/Page column 24
[4] Tetrahedron Letters, 2009, vol. 50, # 2, p. 148 - 151

2
[ 150008-24-5 ]
[ 190900-21-1 ]

Reference： [1] Patent: EP1477490, 2004, A1, . Location in patent: Page 109

3
[ 79099-07-3 ]
[ 150008-24-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydroxylamine hydrochloride; sodium acetate In methanol; waterReflux	All of the oxime substrates used in this investigation were synthesized in quantitative yields by refluxing a mixture of 1 equiv of the corresponding ketones or aldehydes, 1.6 equiv of hydroxylamine hydrochloride, and 2.0 equiv of sodium acetate in aqueous methanol.
100%	With hydroxylamine hydrochloride; sodium acetate In ethanol; water	To a solution of tert-butyl 4-piperidinone carboxylate in ethanol (400 mL), hydroxylamine hydrochloride (29.34 g) and sodium acetate (34.64 g) were added, and stirred at 100°C for seven hours. The reaction mixture was cooled to room temperature, and the filtrate obtained by filtering off the solid was concentrated under reduced pressure. Water was added to the residue, and extracted twice with ethyl acetate. The combined organic layer was washed in a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried on anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, dried under vacuum to obtain a title compound (quantitative yield) as a white solid compound. ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 1.46 (s, 9H), 2.27 (m, 2H), 2.49 (m, 2H), 3.36-3.52 (m, 4H), 10.50 (s, 1H).
96%	Stage #1: With hydroxylamine hydrochloride; sodium acetate In ethanol at 20℃; for 1 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	Hydroxylamine hydrochloride (2.50 g, 36.0 mmol) was added to a solution of l-Boc-4-piperidone (6.10 g, 30.0 mmol) and sodium acetate (2.95 g, 36.0 mmol) in ethanol (60 ml) and the whole was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (120 ml) and washed with saturated aqueous NaHCO₃ (30 ml) and brine, dried over MgSO₄ and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate/n-hexane to give tert-butyl 4- (hydroxyimino)piperidine-1-carboxylate (6.18 g, 96 percent) as a white solid.

65%

With hydroxylamine hydrochloride In pyridine at 65℃; for 1 h;

To a solution of N-t-butoxycarbonyl-4-piperidone 1 (15 g, 75.3 mmol) in pyridine (50 mL) was added hydroxylamine .bul. HCl (5.23 g, 75.3 mmol). The mixture was heated in an oil bath at 65 °C for 1 h. After cooling, pyridine was removed under reduced pressure and the residue was dried under high vacuum overnight to give a solid. To this solid was added water (100 mL) and the mixture was sonicated. The precipitate was filtered and washed with water then dried under high vacuum to give the oxime derivative of compound 1 (10.5 g, 65percent); FAB MS [M+1]⁺ 215.3. The oxime (10 g, 46.67 mmol) was dissolved in absolute EtOH (100 mL) followed by the addition of Raney Ni (29 g, washed with absolute EtOH). The mixture was hydrogenated in a Parr shaker at 50 psi overnight. After reaction was complete, the Raney Ni was filtered off (caution; risk of fire) and the filtrate was concentrated to give compound 2 (9.2 g, 46 mmol,98percent yield) as an oil which solidified under high vacuum drying. FAB MS [M+1]⁺ 201.3. To a solution of the bromoacetamide derivative 3 (3.0g,6.2 mmol) (prepared in Example 3) in CH₂Cl₂ (62 mL) at -10 °C were added Huenig's base (1.2 mL, 6.82 mmol) and compound 2 (2.48 g, 12.39 mmol). The solution was gradually warmed to RT overnight. After reaction was complete, CH₂Cl₂ (300 mL) was added and the mixture was washed with brine (100 mL, 3x), dried over MgSO₄ and filtered. The filtrate was evaporated to dryness to give a light yellow solid which was purified by flash chromatography on silica gel (200 g), eluting with 5percent [NH₄OH/MeOH (1:9)] /CH₂Cl₂ to give a 71percent yield of the title compound 4 as a white solid (2.66 g, 4.4 mmol), m.p. 78-81 °C; FAB MS [M+1]⁺³⁵Cl 603.1; Calcd. for C₃₁H₄₀N₄O₄Cl₂, C, 61.69; H, 6.68; N,9.28; Cl,11.74. Found: C, 61.33; H, 6.94; N, 9.17; Cl, 11.27.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2942 - 2945
[2] Tetrahedron Letters, 2010, vol. 51, # 24, p. 3216 - 3217
[3] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1074 - 1077
[4] Patent: EP1477490, 2004, A1, . Location in patent: Page 109
[5] Patent: WO2008/150447, 2008, A1, . Location in patent: Page/Page column 206
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 983 - 988
[7] Patent: EP937069, 2006, B1, . Location in patent: Page/Page column 46-47
[8] Patent: WO2006/56877, 2006, A2, . Location in patent: Page/Page column 23-24
[9] Tetrahedron Letters, 2009, vol. 50, # 2, p. 148 - 151
[10] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 108
[11] Patent: WO2017/156177, 2017, A1, . Location in patent: Paragraph 00318
[12] Patent: WO2006/105056, 2006, A2, . Location in patent: Page/Page column 16-17

4
[ 79099-07-3 ]
[ 497-19-8 ]
[ 150008-24-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With hydroxylamine hydrochloride In methanol	a N-tert-Butoxycarbonyl-4-piperidone oxime To a stirred suspension of hydroxylamine hydrochloride (0.84 g, 12.0 mmol) in methanol (10 mL) at 0° C. was added solid Na₂ CO₃ (0.64 g, 6.0 mmol). The mixture was stirred for ca. 5 min. N-t-Boc-4-piperidone (1.99 g, 10.0 mmol) was added and the mixture was stirred for ca 2 h. The reaction mixture was concentrated in vacuo to ca. half its original volume, then diluted with saturated NaHCO₃ (100 mL) and extracted with CHCl₃ (4*50 mL). The combined organic layers were dried over Na₂ SO₄, filtered, and concentrated in vacuo to yield 1.86 g (87percent) of the desired product as a tan solid. MS (ES+) m/z 215.0 [M+H]⁺.

Reference： [1] Patent: US6077857, 2000, A,

5
[ 79099-07-3 ]
[ 150008-24-5 ]

Reference： [1] Patent: US5276041, 1994, A,

[ 150008-24-5 ] Synthesis Path-Downstream 1~90

1
2-chloro-1,3-dimethyl imidazolium chloride [ No CAS ]
[ 150008-24-5 ]
[ 190900-21-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 4-(hydroxyimino)piperidinone carboxylate (32.70 g) in acetonitrile (250 mL), 2-chloro-1,3-dimethylimidazolynium chloride (30.96 g) was added, to which triethylamine (51 mL) was added dropwise at room temperature over 20 minutes. After dropwise addition, it was further stirred at room temperature for 30 minutes, and then water (50 mL) was added and stirred overnight. After the reaction mixture was diluted with ethyl acetate, the organic layer was separated. The organic layer was washed in 0.1 mol/L hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, and then dried on anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, dried under vacuum to obtain a crude title compound as a brown semi-solid compound. The product was used in the subsequent reaction without further purification.

Reference： [1]Patent: EP1477490,2004,A1 .Location in patent: Page 109

2
[ 79099-07-3 ]
[ 150008-24-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydroxylamine hydrochloride; sodium acetate; In methanol; water;Reflux;	All of the oxime substrates used in this investigation were synthesized in quantitative yields by refluxing a mixture of 1 equiv of the corresponding ketones or aldehydes, 1.6 equiv of hydroxylamine hydrochloride, and 2.0 equiv of sodium acetate in aqueous methanol.
100%	With hydroxylamine hydrochloride; sodium acetate; In ethanol; water;	To a solution of tert-butyl 4-piperidinone carboxylate in ethanol (400 mL), hydroxylamine hydrochloride (29.34 g) and sodium acetate (34.64 g) were added, and stirred at 100C for seven hours. The reaction mixture was cooled to room temperature, and the filtrate obtained by filtering off the solid was concentrated under reduced pressure. Water was added to the residue, and extracted twice with ethyl acetate. The combined organic layer was washed in a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried on anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, dried under vacuum to obtain a title compound (quantitative yield) as a white solid compound. 1H-NMR (400 MHz, DMSO-d6) delta(ppm): 1.46 (s, 9H), 2.27 (m, 2H), 2.49 (m, 2H), 3.36-3.52 (m, 4H), 10.50 (s, 1H).
96%		Hydroxylamine hydrochloride (2.50 g, 36.0 mmol) was added to a solution of l-Boc-4-piperidone (6.10 g, 30.0 mmol) and sodium acetate (2.95 g, 36.0 mmol) in ethanol (60 ml) and the whole was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (120 ml) and washed with saturated aqueous NaHCO3 (30 ml) and brine, dried over MgSO4 and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate/n-hexane to give tert-butyl 4- (hydroxyimino)piperidine-1-carboxylate (6.18 g, 96 %) as a white solid.

65%	With hydroxylamine hydrochloride; In pyridine; at 65℃; for 1h;	To a solution of N-t-butoxycarbonyl-4-piperidone 1 (15 g, 75.3 mmol) in pyridine (50 mL) was added hydroxylamine ? HCl (5.23 g, 75.3 mmol). The mixture was heated in an oil bath at 65 C for 1 h. After cooling, pyridine was removed under reduced pressure and the residue was dried under high vacuum overnight to give a solid. To this solid was added water (100 mL) and the mixture was sonicated. The precipitate was filtered and washed with water then dried under high vacuum to give the oxime derivative of compound 1 (10.5 g, 65%); FAB MS [M+1]+ 215.3. The oxime (10 g, 46.67 mmol) was dissolved in absolute EtOH (100 mL) followed by the addition of Raney Ni (29 g, washed with absolute EtOH). The mixture was hydrogenated in a Parr shaker at 50 psi overnight. After reaction was complete, the Raney Ni was filtered off (caution; risk of fire) and the filtrate was concentrated to give compound 2 (9.2 g, 46 mmol,98% yield) as an oil which solidified under high vacuum drying. FAB MS [M+1]+ 201.3. To a solution of the bromoacetamide derivative 3 (3.0g,6.2 mmol) (prepared in Example 3) in CH2Cl2 (62 mL) at -10 C were added Huenig's base (1.2 mL, 6.82 mmol) and compound 2 (2.48 g, 12.39 mmol). The solution was gradually warmed to RT overnight. After reaction was complete, CH2Cl2 (300 mL) was added and the mixture was washed with brine (100 mL, 3x), dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give a light yellow solid which was purified by flash chromatography on silica gel (200 g), eluting with 5% [NH4OH/MeOH (1:9)] /CH2Cl2 to give a 71% yield of the title compound 4 as a white solid (2.66 g, 4.4 mmol), m.p. 78-81 C; FAB MS [M+1]+35Cl 603.1; Calcd. for C31H40N4O4Cl2, C, 61.69; H, 6.68; N,9.28; Cl,11.74. Found: C, 61.33; H, 6.94; N, 9.17; Cl, 11.27.
46.4%	With hydroxylamine hydrochloride; sodium acetate; In ethanol; at 90℃; for 12h;	To a stirred solution of tert-butyl 4-oxopiperidine-1 -carboxylate (10.00 g, 0.0502 mol) in ethanol (100 mL) hydroxylamine hydrochloride (6.98 g, 0.100 mol) and CH3COONa (8.23 g, 0.100 mol) were added, then heated to 90 C for 12 h under nitrogen atmosphere. After completion of the reaction by LCMS, the reaction mixture was concentrated and to the crude material water (100 mL) was added followed by extraction by using dichloromethane (250 mL).The organic layer was concentrated and the crude product was purified by silica gel column (Biotage) using 18- 30% of ethyl acetate in pet ether to obtain tert-butyl-4-(hydroxyimino)piperidine-1-carboxylate (5 g, 46.4 %) as a white solid. (0830) MS: 159.1 (M+H)+- t-butyl (0831) 1H-NMR (400 MHz, DMSO- 6) d = 10.45 (s, 1 H), 3.33-3.36 (m, 4H), 2.42-2.44 (m, 2H), 2.20- 2.22 (m, 2H), 1.41 (s, 9H).
	With hydroxylamine hydrochloride; In pyridine; at 20℃;Molecular sieve;	To a solution of /ert-butyl 4-oxopiperidine-l-carboxylate (50 g, 251 mmol) in pyridine (500 mL) is added molecular sieves (50 g) and the mixture is stirred at room temperature for 10 minutes, followed by the addition of NH2OH HCl (30.25 g, 427 mmol). The resulting reaction is stirred at room temperature overnight, and the reaction mixture filtered through a pad of celite to remove the molecular sieves. The filtrate is diluted with water, the layers separated and the aqueous phase extracted with more ethyl acetate. The combined organic phases are washed with brine, dried over EPO <DP n="25"/>MgSO4, filtered, and concentrated in vacuo to provide the title compound. This material is used in the next step without further purification.1H NMR (300 MHz, DMSO-ddelta): 1.52 (s, 9H), 2.36 (t, J=6.0 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 3.50-3.58 (m, 4H).
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; at 100℃; for 7h;	To a solution of I-48 (50 g, 0.25 mol, 1.0 eq) in ethanol (300 mL) hydroxylamine hydrochloride (35 g, 0.50 mol, 2.0 eq) was added followed by sodium acetate (41 g, 0.50 mol, 2.0 eq) and the reaction mixture was stirred at 100 C. for 7 hours. Solids were removed by filtration and the filtrate was concentrated by evaporation. Water was added to the residue; the reaction mixture was extracted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The combined organic layers were dried on anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated to give intermediate I-49 (54 g, 100%) as white solid that was used in the following step without further purification. MS (ESI): m/z 159.1 (M+H+).
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 15℃; for 2h;	To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100 mmol) and sodium acetate (9.88 g, 120 mmol) in a mixture of ethanol (160 mL) and water (40 mL) was added hydroxylamine hydrochloride (8.37 g, 120 mmol) and the reaction mixture was stirred at 15 C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo, and 300 mL water and 300 mL dichloromethane was added. The aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound. 1H NMR (300MHz, CDCl3) delta = 8.71 (br. s., 1H), 3.55 (q, J = 6.8 Hz, 4H), 2.63 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 2H), 1.49 (s, 9H).
	With hydroxylamine hydrochloride; triethylamine; In ethanol; at 0 - 20℃; for 6h;Heating / reflux;	Example 2 Synthesis of Compound 191 EPO <DP n="18"/>A solution of 5.8 g (0.31 mol) of N-t-Boc-piperidone in 80 ml of ethanol was cooled to O0C on an ice bath. To this was added 5.2 ml (0.04 mol) of TEA then 2.6 g (0.37 mol) of solid hydroxylamine HCl. The mixture was warmed to room temperature and then heated to reflux temperature for 6 h. The solvent was removed and the solid was partitioned between saturated aqueous ammonium chloride and ethyl acetate (100 ml each). The aqueous layer was extracted with a second portion of ethyl acetate (100 ml) and the combined extract was dried over sodium sulfate. The solvent was removed at reduced pressure to afford 6.0 g of a white solid. The solid was dissolved in 60 ml of methanol and then hydrogenated over 5% Rhodium on Alumina (0.6 g) at 5O0C. After the uptake of hydrogen ceased, the catalyst was filtered and the solvent removed to afford 5.5 g (98%) of reactant 5. The NMR spectrum was consistent with the proposed structure.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945
[2]Tetrahedron Letters,2010,vol. 51,p. 3216 - 3217
[3]Tetrahedron Letters,2011,vol. 52,p. 1074 - 1077
[4]Patent: EP1477490,2004,A1 .Location in patent: Page 109
[5]Patent: WO2008/150447,2008,A1 .Location in patent: Page/Page column 206
[6]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 983 - 988
[7]Patent: EP937069,2006,B1 .Location in patent: Page/Page column 46-47
[8]Patent: WO2019/134978,2019,A1 .Location in patent: Page/Page column 124
[9]Patent: WO2006/56877,2006,A2 .Location in patent: Page/Page column 23-24
[10]Tetrahedron Letters,2009,vol. 50,p. 148 - 151
[11]Patent: US2010/204214,2010,A1 .Location in patent: Page/Page column 108
[12]Patent: WO2017/156177,2017,A1 .Location in patent: Paragraph 00318
[13]Patent: WO2006/105056,2006,A2 .Location in patent: Page/Page column 16-17

3
[ 150008-24-5 ]
[ 190900-21-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 70℃;Inert atmosphere;	To a solution of ketoxime (0.01 mol) in THF (10 mL) was added T3P (15 mol percent, 50percent soln in EtOAc) and the resulting reaction mixture was stirred at reflux for 1-4 h under nitrogen atmosphere. When the reaction was completed as confirmed by TLC, the solvent was removed under vacuum and the residue was diluted with water (20 mL). The product was extracted with ethyl acetate (2 .x. 20 mL) and the combined organic phase was washed with saturated NaHCO3 solution (1 .x. 10 mL) and brine. The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford the desired amides in good purity.
48%		To a solution of intermediate I-49 (11 g, 50 mmol, 1.0 eq) in acetone (60 mL) was added a solution of Na2CO3 (16 g, 150 mmol, 3.0 eq) in water (80 mL) and the reaction mixture was stirred for 5 minutes. A solution of p-toluenesulfonyl chloride (14 g, 75 mmol, 1.5 eq) in acetone (20 mL) was added slowly and the reaction mixture was stirred at room temperature for 3 hours. Excess solvent was removed by evaporation, water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The crude reaction product was purified by silica gel column chromatography to give intermediate I-50 (5.0 g, 48percent). MS (ESI): m/z 159.1 (M+H+).
		To a solution of tert-butyl 4-(hydroxyimino)piperidine-l-carboxylate (1 O g, 4.67 mmol) in acetone (20 mL) is added a solution OfNa2CO3 (1.48 g, 14 mmol) in water (20 mL), and the mixture is stirred for 5 minutes, then a solution of p- toluenesulfonyl chloride (1.33 g, 7 mmol) in acetone (5 mL) is added slowly. The reaction is stirred at room temperature for 3h, then the acetone is removed in vacuo, water is added, and the solution extracted with dichloromethane. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by chromatography (6percent MeOH in dichloromethane) to afford the title compound.1H NMR (300 MHz, DMSO-ds): 1.41 (s, 9H), 2.40 (m, 2H), 3.09 (m, 2H), 3.39-3.44 (m, 4H), 7.62 (m, IH).

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1074 - 1077
[2]Patent: US2010/204214,2010,A1 .Location in patent: Page/Page column 108
[3]Patent: WO2006/56877,2006,A2 .Location in patent: Page/Page column 24
[4]Tetrahedron Letters,2009,vol. 50,p. 148 - 151

4
[ 150008-24-5 ]
[ 87120-72-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen;Raney nickel; In ethanol; under 2585.81 Torr;	To a solution of N-t-butoxycarbonyl-4-piperidone 1 (15 g, 75.3 mmol) in pyridine (50 mL) was added hydroxylamine ? HCl (5.23 g, 75.3 mmol). The mixture was heated in an oil bath at 65 C for 1 h. After cooling, pyridine was removed under reduced pressure and the residue was dried under high vacuum overnight to give a solid. To this solid was added water (100 mL) and the mixture was sonicated. The precipitate was filtered and washed with water then dried under high vacuum to give the oxime derivative of compound 1 (10.5 g, 65%); FAB MS [M+1]+ 215.3. The oxime (10 g, 46.67 mmol) was dissolved in absolute EtOH (100 mL) followed by the addition of Raney Ni (29 g, washed with absolute EtOH). The mixture was hydrogenated in a Parr shaker at 50 psi overnight. After reaction was complete, the Raney Ni was filtered off (caution; risk of fire) and the filtrate was concentrated to give compound 2 (9.2 g, 46 mmol,98% yield) as an oil which solidified under high vacuum drying. FAB MS [M+1]+ 201.3. To a solution of the bromoacetamide derivative 3 (3.0g,6.2 mmol) (prepared in Example 3) in CH2Cl2 (62 mL) at -10 C were added Huenig's base (1.2 mL, 6.82 mmol) and compound 2 (2.48 g, 12.39 mmol). The solution was gradually warmed to RT overnight. After reaction was complete, CH2Cl2 (300 mL) was added and the mixture was washed with brine (100 mL, 3x), dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give a light yellow solid which was purified by flash chromatography on silica gel (200 g), eluting with 5% [NH4OH/MeOH (1:9)] /CH2Cl2 to give a 71% yield of the title compound 4 as a white solid (2.66 g, 4.4 mmol), m.p. 78-81 C; FAB MS [M+1]+35Cl 603.1; Calcd. for C31H40N4O4Cl2, C, 61.69; H, 6.68; N,9.28; Cl,11.74. Found: C, 61.33; H, 6.94; N, 9.17; Cl, 11.27.
	With hydrogen;5% rhodium on activated aluminium oxide; In methanol; at 50℃;	Example 2 Synthesis of Compound 191 EPO <DP n="18"/>A solution of 5.8 g (0.31 mol) of N-t-Boc-piperidone in 80 ml of ethanol was cooled to O0C on an ice bath. To this was added 5.2 ml (0.04 mol) of TEA then 2.6 g (0.37 mol) of solid hydroxylamine HCl. The mixture was warmed to room temperature and then heated to reflux temperature for 6 h. The solvent was removed and the solid was partitioned between saturated aqueous ammonium chloride and ethyl acetate (100 ml each). The aqueous layer was extracted with a second portion of ethyl acetate (100 ml) and the combined extract was dried over sodium sulfate. The solvent was removed at reduced pressure to afford 6.0 g of a white solid. The solid was dissolved in 60 ml of methanol and then hydrogenated over 5% Rhodium on Alumina (0.6 g) at 5O0C. After the uptake of hydrogen ceased, the catalyst was filtered and the solvent removed to afford 5.5 g (98%) of reactant 5. The NMR spectrum was consistent with the proposed structure.

Reference： [1]Patent: EP937069,2006,B1 .Location in patent: Page/Page column 46-47
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 983 - 988
[3]Patent: WO2006/105056,2006,A2 .Location in patent: Page/Page column 16-17

5
[ 79099-07-3 ]
[ 497-19-8 ]
[ 150008-24-5 ]

Yield	Reaction Conditions	Operation in experiment
1.86 g (87%)	With hydroxylamine hydrochloride; In methanol;	a N-tert-Butoxycarbonyl-4-piperidone oxime To a stirred suspension of hydroxylamine hydrochloride (0.84 g, 12.0 mmol) in methanol (10 mL) at 0 C. was added solid Na2 CO3 (0.64 g, 6.0 mmol). The mixture was stirred for ca. 5 min. N-t-Boc-4-piperidone (1.99 g, 10.0 mmol) was added and the mixture was stirred for ca 2 h. The reaction mixture was concentrated in vacuo to ca. half its original volume, then diluted with saturated NaHCO3 (100 mL) and extracted with CHCl3 (4*50 mL). The combined organic layers were dried over Na2 SO4, filtered, and concentrated in vacuo to yield 1.86 g (87%) of the desired product as a tan solid. MS (ES+) m/z 215.0 [M+H]+.

Reference： [1]Patent: US6077857,2000,A

6
[ 79099-07-3 ]
4-hydroxyiminopiperidine trifluoroacetate [ No CAS ]
[ 150008-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; chloroform; hydroxylamine hydrochloride;	REFERENCE EXAMPLE 1 4-hydroxyiminopiperidine trifluoroacetate The above identified compound can be prepared in accordance with the following formulas. STR13 15.5 g (77.6 mmol) of N-Boc-4-piperidone was refluxed for one hour in methanol in the presence of 7.0 g (100.8 mmol) of hydroxylamine hydrochloride and 14.1 ml (100.8 mmol) of triethylamine. Then, methanol was distilled off, and the residue was thoroughly washed with water in chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 10.6 g of N-Boc-4-hydroxyiminopiperidine as white powder. Melting point: 92-93 C. MS(M/Z): 114(M+ --Boc), 97(--OH), 85, 69, 56 1 H-NMR delta(CDCl3): 1.48(9H,s), 2.32-2.37(2H,m), 2.60-2.64(2H,m), 3.50-3.57(4H,m).

Reference： [1]Patent: US5276041,1994,A

7
[ 150008-24-5 ]
[ 1195-45-5 ]
[ 1092464-56-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine; In tetrahydrofuran; at 0℃; for 4.16667h;	A solution of 4-fluorophenylisocyanate (775 mg, 5.65 mmol) in tetrahydrofuran (20 ml) was added to a solution of tert-butyl 4-(hydroxyimino)piperidine-1- carboxylate (1.00 g, 4.67 mmol) and triethylamine (0.783 ml, 5.65 mmol) in tetrahydrofuran (30 ml) at 0C over 10 minutes and stirred at 0C for 4 hours. The mixture was concentrated in vacuo and the residual solid was recrystallized from ethyl acetate/n-hexane to give tert- butyl 4-(4-fluorophenylcarbamoyloxyimino)piperidine-1-carboxylate (1.57 g, 96 %) as a white solid.

Reference： [1]Patent: WO2008/150447,2008,A1 .Location in patent: Page/Page column 206

8
[ 150008-24-5 ]
[ 372-48-5 ]
[ 1095264-39-3 ]

Yield	Reaction Conditions	Operation in experiment
23%		tert-Butyl 4-oxo-3-(2-oxo-1,2-dihydropyridin-3-yl)piperidine-1-carboxylate Potassium tert-butoxide (1.22 g, 10.8 mmol) were added to <strong>[150008-24-5]tert-butyl 4-(hydroxyimino)piperidine-1-carboxylate</strong> (2.11 g, 9.85 mmol) in DMF (10 mL) at 0 C. under argon. The resulting suspension was stirred for 20 mins. 2-Fluoropyridine (0.85 mL, 9.85 mmol) was added to the reaction mixture and the resulting solution was stirred at 80 C. for 21 hours. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (250 mL). The organic layers were combined and washed with brine (250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. Flash column chromatography (silica, gradient 5 to 100% EtOAc in isohexane) yielded tert-butyl 4-oxo-3-(2-oxo-1,2-dihydropyridin-3-yl)piperidine-1-carboxylate (0.654 g, 23%) as a cream solid. MS (+ve ESI): 293 (M+H)+ 1H NMR (400.13 MHz, CDCl3) delta 1.50 (9H, s), 2.64 (2H, s), 3.41 (1H, s), 3.48 (2H, t), 3.73 (1H, s), 4.26 (2H, s), 6.26 (1H, t), 7.24-7.27 (1H, m), 7.30-7.32 (1H, m)
		To a suspension of sodium hydride (0.268 g, 7.00 mmol) in DMF (3 ml_) the title compound from Step A above (0.500 g, 2.33 mmol) was added drop wise (dissolved in DMF 5 mL) at 0 (0833) C, then stirred at room temperature for 60 min. After that 2-fluoropyridine (0.340 g, 3.50 mmol) was added dropwise at 0 C (dissolved in DMF 2 mL) and then stirred at room temperature for 3 h. After completion of the reaction by TLC, the reaction mixture was quenched with ice water followed by extraction using ethyl acetate (30 mL). The organic layer was separated, dried over sodium sulphate, filtered and then concentrated to obtain tert-butyl 4-oxo-3-(2-oxo-1 ,2-dihydropyridin-3-yl)piperidine-1-carboxylate (300 mg, crude) as a pale brown solid. The crude product was taken as such for next step. (0834) MS: 293.2 (M+H)+.

Reference： [1]Patent: US2009/12077,2009,A1 .Location in patent: Page/Page column 31
[2]Patent: WO2019/134978,2019,A1 .Location in patent: Page/Page column 124; 125

9
[ 446-48-0 ]
[ 150008-24-5 ]
[ 1229313-22-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

10
[ 150008-24-5 ]
[ 57825-30-6 ]
[ 1229313-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

11
[ 150008-24-5 ]
[ 823-78-9 ]
[ 1229313-27-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

12
[ 150008-24-5 ]
[ 100-39-0 ]
[ 1219625-85-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

13
[ 150008-24-5 ]
[ 73789-86-3 ]
C₂₀H₃₀N₂O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

14
[ 150008-24-5 ]
[ 611-17-6 ]
[ 1229313-13-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

15
[ 150008-24-5 ]
[ 2746-25-0 ]
[ 1229313-33-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

16
[ 150008-24-5 ]
[ 622-95-7 ]
[ 224178-71-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

17
[ 150008-24-5 ]
[ 589-15-1 ]
[ 1229313-28-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

18
[ 150008-24-5 ]
[ 89-92-9 ]
[ 1229313-38-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

19
[ 150008-24-5 ]
[ 456-41-7 ]
[ 1229313-23-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

20
[ 150008-24-5 ]
[ 766-80-3 ]
[ 1229313-15-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

21
[ 150008-24-5 ]
[ 459-46-1 ]
[ 1229313-25-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

22
[ 150008-24-5 ]
[ 874-98-6 ]
[ 1229313-31-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

23
[ 150008-24-5 ]
[ 17201-43-3 ]
[ 1229313-19-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

24
[ 150008-24-5 ]
[ 20443-99-6 ]
[ 1229313-18-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

25
[ 150008-24-5 ]
[ 18880-04-1 ]
[ 1229313-30-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

26
[ 150008-24-5 ]
[ 3958-57-4 ]
[ 1229313-10-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

27
[ 150008-24-5 ]
[ 100-11-8 ]
[ 1229313-11-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

28
[ 150008-24-5 ]
[ 3433-80-5 ]
[ 1229313-26-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2942 - 2945

29
[ 150008-24-5 ]
[ 1228630-89-4 ]

Yield	Reaction Conditions	Operation in experiment
	With urea hydrogen peroxide adduct; sodium hydrogencarbonate; trifluoroacetic anhydride; In acetonitrile; at 0 - 70℃; for 0.5h;	To a solution of urea hydrogen peroxide (24.5 g, 261 mmol) in acetonitrile (90 mL) was added a solution of trifluoroacetic anhydride (39.2 g, 186 mmol) in acetonitrile (90 mL) dropwise and the reaction was stirred at 0 C for 2 hrs. This solution was added dropwise to a mixture of (Z/E)-<strong>[150008-24-5]tert-butyl 4-hydroxyiminopiperidine-1-carboxylate</strong> (16.0 g, 74.6 mmol) and saturated sodium bicarbonate (31.3 g, 373 mmol) in acetonitrile (150 mL) with stirring at 70 C and the reaction mixture was stirred at 70 C for 0.5 hr. On completion, the reaction mixture was cooled to 25 C and 50 mL of saturated aqueous solution of sodium sulfite was added. Then the reaction mixture was concentrated in vacuo to remove acetonitrile and 300 mL water and 300 mL ethyl acetate was added. The aqueous phase was extracted with ethyl acetate (3 × 300 mL). The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound.1H NMR (400MHz, CDCl3) delta = 4.52 (tt, J = 4.3, 10.1 Hz, 1H), 4.05 (br. s., 2H), 3.01 (t, J = 11.4 Hz, 2H), 2.23 (dd, J = 3.6, 13.0 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.48 (s, 9H).

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 3216 - 3217
[2]Patent: WO2017/156177,2017,A1 .Location in patent: Paragraph 00319

30
[ 150008-24-5 ]
C₂₁H₃₅N₃O₃ [ No CAS ]