392331-66-7|1-Boc-4-(Aminomethyl)-4-hydroxypiperidine| Ambeed

Structure of 392331-66-7

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 392331-66-7 ] Purity: 95% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 392331-66-7 ]

CAS No. :	392331-66-7
Formula :	C₁₁H₂₂N₂O₃
M.W :	230.30
SMILES Code :	NCC1(CCN(CC1)C(=O)OC(C)(C)C)O
MDL No. :	MFCD11579803
InChI Key :	XYWCDAFPRBDRER-UHFFFAOYSA-N
Pubchem ID :	23396319

Safety of [ 392331-66-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 392331-66-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	0
Fraction Csp3	0.91
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	65.31
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.34
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.14
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.33
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.32
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.22
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.61

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.92
Solubility	28.0 mg/ml ; 0.121 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.0
Solubility	23.2 mg/ml ; 0.101 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.97
Solubility	24.6 mg/ml ; 0.107 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.8 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.35

Application In Synthesis of [ 392331-66-7 ]

* 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 [ 392331-66-7 ]

[ 392331-66-7 ] Synthesis Path-Downstream 1~35

1
[ 147804-30-6 ]
[ 392331-66-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With ammonium hydroxide; In methanol; at 80℃; for 16h;Sealed tube;	A 100-mL sealed tube fitted with a magnetic stir bar was charged with tert-Butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (300 mg, 1.28 mmol) and a solution of ammonium hydroxide in methanol (20 mL, 7M). The solution was stirred for 16 h at 80 C. in an oil bath and cooled to room temperature. The mixture was concentrated under vacuum to afford tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (350 mg, >95%) used without further purification. LCMS (ESI) m/z 231 [M+H].
86%	With ammonia; In methanol; at 20℃; for 12h;	To a stirred solution of tert-butyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.64 grams, 3.0 mmol, obtained in the above step) in methanol (4 mL) at room temperature, a solution of ammonia (NH3) in methanol (7M, 8 mL) was added and the reaction was stirred for12 hours. The volatiles were removed under reduced pressure to obtain the crude mass which was triturated with hexanes and ether which yielded the above titled compound (0.6 gram). Yield: 86 %.?H - NMR CDCI3 (6 ppm): 1.45 (9H, s), 1.35 - 1.60 (4H, m), 2.63 (2H, s), 3.10 - 3.25 (2H, m), 3.80 - 3.95 (2H, m).Mass (m/z): 231.5 (M+H)4.
86%	With ammonia; In methanol; at 20℃; for 12h;	To a stirred solution of N-tert butyloxycarbonyl1-oxa-6-aza-spiro[2.5]octane 21 (0.64 g, 3.0 mmols) in methanol(4.0 mL) at r.t., a solution of ammonia (NH3)in methanol (7M, 8.0 mL) was added and the reaction was stirred for 12 hours.The volatiles were removed under reduced pressure to obtain the crude masswhich was triturated with hexanes and ether which yielded the above titledcompound 22c (0.6 g) in 86% yield.1H - NMR CDCl3 (CDCl3): d 3.95 - 3.80 (m, 2H), 3.25 -3.10 (m, 2H), 2.63 (s, 2H), 1.35 - 1.60 (m, 4H), 1.45 (s, 9H). Mass (m/z): 231.5 (M+H)+. Anal. (C11H22N2O3) C, H, N

76%	With ammonia; In methanol; at 25 - 40℃; for 40h;	tert-Butyl l-Oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole) was added to methanolic ammonia solution (20 mL, 14.83 % w/v) at room temperature. Then reaction mass was stirred for 40 hours at room temperature in a closed vessel. The progress of the reaction was monitored by TLC. After completion of the reaction (TLC), the reaction mass was concentrated on rotavacuum to obtain the title compound. Yield: 0.41 gram (76%). 'H-NMR(8 ppm): 1.35 - 1.69 (16H, m), 2.61 (2H, s), 3.10 - 3.20 (2H, m), 3.81 -3.90(2H, m); Mass (m/z): 231.3 (M+H)+.
76%	With ammonia; In methanol; at 20℃; for 40h;	tert-Butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole, obtained in the step (i) of preparation 5) was added to methanolic ammonia solution (20 mL, 14.83 % w/v) at RT. Then reaction mass was stirred for 40 hours at RT in a closed vessel. The reaction mass was concentrated under vacuum to obtain the title compound. Weight: 0.41 gram (Yield: 76 %). (0385) - NMR (delta ppm): 1.35 - 1.69 (16H, m), 2.61 - 2.69 (2H, m), 3.10 - 3.20 (2H, m), 3.81 - 3.90 (2H, m); (0386) Mass (m/z): 231.3 (M+H)+ .
69%	With ammonia; In methanol; at 20℃;	Intermediate 2M: tert-butyl 4-(amiriomethyl)-4-hydroxypiperidine-1 -carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removedunder vacuum and the residue was purified by flash chromatography, silica gel, gradient dichioromethane to methanol:dichloromethane (1:4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 mm; MS:131 (M+H-100).
69%	With ammonia; In methanol; at 20℃;	A solution of intermediate 1A (10.0 g, 46.9 mmol) in ammonia (201 ml_, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
69%	With ammonia; In methanol; at 20℃;	Intermediate 2A: fert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
60.5%	With ammonia; In ethanol; water;Inert atmosphere;	A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml*3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. MS m/z (ESI): 231 [M+1]
60.5%	With ammonia; In ethanol;	A stirred solution of l-oxa-6-aza-spiro [2.5] octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol(60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml><3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane: methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. MS m/z (ESI): 231[M+1] ,
	With ammonia; In methanol; water; at 0 - 20℃; for 7h;	4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0 C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid.
	With ammonium hydroxide; In methanol; at 0 - 20℃; for 16h;	aqueous ammonia (6mL)was added to a solution of tert-butyl 1-oxa-6-azaspiro[2.5]octan-6-carboxylate (500mg, 2mmol) in methanol (4mL) at0C. The reaction solution warmed to room temperature and was stirred for 16 hours, then concentrated under reduced pressure to give a colorless oil (530mg, 2.3mmol) with a yield of 100%, which was used directly in the next step withoutpurification.

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7458 - 7461.
[2]Patent: US2016/185786,2016,A1 .Location in patent: Paragraph 0679.
[3]Patent: WO2015/92804,2015,A1 .Location in patent: Page/Page column 21.
[4]European Journal of Medicinal Chemistry,2015,vol. 103,p. 289 - 301.
[5]Patent: WO2014/147636,2014,A1 .Location in patent: Page/Page column 35; 36.
[6]Patent: WO2016/128990,2016,A1 .Location in patent: Page/Page column 36-37.
[7]Patent: WO2015/185207,2015,A1 .Location in patent: Page/Page column 173.
[8]Patent: WO2015/185208,2015,A1 .Location in patent: Page/Page column 138.
[9]Patent: WO2015/185209,2015,A1 .Location in patent: Page/Page column 78-79.
[10]Patent: US2010/4239,2010,A1 .Location in patent: Page/Page column 93.
[11]Patent: WO2007/85188,2007,A1 .Location in patent: Page/Page column 155.
[12]Patent: US2005/43334,2005,A1 .Location in patent: Page/Page column 25.
[13]Patent: EP3424928,2019,A1 .Location in patent: Paragraph 0237.
[14]Journal of Medicinal Chemistry,2020,vol. 63,p. 2434 - 2454.

2
[ 392331-66-7 ]
C₁₄H₁₆O₇ [ No CAS ]
[ 819800-94-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	Triethylamine (0.0373 mol, 5.2 ml) then ethyl chloroformate (0.0373 mol) were added dropwise at a temperature between 0C and 5C to a mixture of intermediate (8) (0.0373 mol) in DCM (100 ml) under nitrogen flow. The mixture was stirred at this temperature for 45 minutes (first mixture). Triethylamine (0.0373 mol, 5. 2ml) was added at room temperature to a mixture of intermediate (52) (0.0373 mol) in DCM (100 ml). The mixture was stirred at room temperature for 45 minutes, then added dropwise at a temperature between 0C and 5C to the first mixture. The reaction mixture was stirred at this temperature for 1 hour, then brought to room temperature, stirred for 1 hour and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CL2/CH30H/NH40H 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 12 g of intermediate (53).

References: [1]Patent: WO2005/837,2005,A1 .Location in patent: Page 29-30.

3
[ 819800-93-6 ]
[ 392331-66-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In methanol; at 14℃;	A mixture of intermediate (51) (0.058 mol) and acetic acid (12 ml) in methanol (250 ml) was hydrogenated at 14 C with palladium-on-carbon (10%, 1 G) as a catalyst. After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice/water, then alkalized with potassium hydroxide and salted out with K2CO3. This mixture was extracted twice with DCM. The separated organic layer was dried, filtered and the solvent evaporated. The residue was suspended in DIPE, filtered off, washed and dried, yielding 7.5 g of intermediate (52)
		A mixture of intermediate (64) (0.058 mol) and acetic acid (12 ml) in methanol (250 ml) was hydrogenated at 14C with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice/water, then alkalized with potassium hydroxide and salted out with K2CO3. This mixture was extracted twice with DCM. The separated organic layer was dried, filtered and the solvent evaporated. The residue was suspended in DIPE, filtered off, washed and dried, yielding 7.5 g of intermediate (65).
	With hydrogen;palladium(II) hydroxide/carbon; In ethanol; under 2068.65 Torr; for 120h;	A mixture of tert-butyl 4-hydroxy-4-(nitromethyl)piperidine-l -carboxylate (20.42 g, 78.4 mmol) and 20% palladium hydroxide on carbon (1.21 g) in ethanol (250 mL) was hydrogenated at 40 psi (2.8 x 105 Pa) for 3 d on a Parr apparatus. More 20% palladium hydroxide on carbon (1.0 g) was added and the hydrogenation was continued for 2 more days. The mixture was filtered through CELITE filter agent and the filtrate was concentrated to provide tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-l -carboxylate, which was concentrated from toluene (200 mL) to remove residual ethanol before use in the next reaction.

	With palladium 10% on activated carbon; hydrogen; acetic acid; In methanol; at 20℃;	The mixture of tert-butyl 4-hydroxy-4- (nitromethyl) piperidine-1-carboxylate (15.0 g, 0.058 mol) and acetic acid (12 mL) in methanol (180 mL) was hydrogenated at rt with palladium-on-carbon (10, 1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice water, alkalized with potassium hydroxide, extracted twice with EtOAc, dried over Na2SO4, filtered and concentrated to give tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate.
	With palladium on activated charcoal; hydrogen; acetic acid; In methanol; at 20℃;	The mixture of tert- butyl 4-hydroxy-4-(nitromethyl)piperidine-l-carboxylate (15.0 g, 0.058 mol) and acetic acid (12 mL) in methanol (180 mL) was hydrogenated at rt with palladium-on-carbon (10 %, 1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice water, alkalized with potassium hydroxide, extracted twice with EtOAc, dried over Na2S04, filtered and concentrated to give tert-butyl 4-(aminomethyl)-4- hydroxypiperidine- 1 -carboxylate.

References: [1]Patent: WO2005/837,2005,A1 .Location in patent: Page 29.
[2]Patent: WO2005/838,2005,A1 .Location in patent: Page 35.
[3]Patent: WO2006/28545,2006,A2 .Location in patent: Page/Page column 91.
[4]Patent: WO2016/65582,2016,A1 .Location in patent: Page/Page column 48.
[5]Patent: WO2016/122994,2016,A1 .Location in patent: Page/Page column 46; 47.

4
[ 908140-15-8 ]
[ 392331-66-7 ]

Yield	Reaction Conditions	Operation in experiment
59%		Step 2. tert-Butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate To a suspension of lithium alminium hydride (84 mg, 2.2 mmol) in THF (5 mL), a solution of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (200 mg, 0.88 mmol, step 1 of Example 22) in THF (1 mL) was added dropwise at 0 C. The mixture was stirred for 1 h at that temperature and Na2SO4.10H2O (400 mg) was added slowly, and the mixture was stirred for 5 h at room temperature. The mixture was filtered though a pad of Celite, washed with CH2Cl2 (20 mL*2), the filtrate was concentrated to give clear colorless oil. The residue was chromatographed on a column of silica gel eluding with CH2Cl2/MeOH/NH4OH (14:1:0.1) to give 120 mg (59%) of the title compound as white solid. 1H-NMR (CDCl3) delta: 3.98-3.75 (2H, m), 3.17 (2H, t, J=10.8 Hz), 2.56 (2H, s), 1.46 (9H, s), 1.60-1.25 (4H, m). Signals due to O and N were not observed.

References: [1]Patent: US2006/194842,2006,A1 .Location in patent: Page/Page column 39.
[2]Organic Letters,2015,vol. 17,p. 1934 - 1937.

5
acetonitrile-water [ No CAS ]
[ 392331-66-7 ]
[ 435321-22-5 ]
3-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoyl}-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethylmorpholine;; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;	(iii) 3-{3-[2-(2,4-Dichloro-Phenyl)-Ethoxy]-4-Methyl-Benzoyl}-1-Oxa-3,8-Diaza-Spiro[4.5]decane-8-carboxylic acid tert-butyl ester 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (300 mg, 0.922 mmol) and crude <strong>[392331-66-7]4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester</strong> (212.5 mg, 0.922 mmol) was dissolved in 5 ml DMF. After cooling to -15 C. HATU (386 mg, 1 mmol) and N-ethylmorpholine (318.9 mg, 2.77 mmol) were added. The mixture was stirred at 0 C. for 2 hours and at room temperature for 15 hours, evaporated and purified on RP18 (5mum) (gradient acetonitrile water 90:10 to 0:100). The fractions containing the product were evaporated and lyophilised. The product was obtained as its trifluoroacetate salt.

References: [1]Patent: US2002/198195,2002,A1 .

6
4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 392331-66-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In tetrahydrofuran;	(ii) 4-Aminomethyl-4-Hydroxy-Piperidine-1-Carboxylic Acid Tert-Butyl Ester 4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butyl ester (7.5 g) was dissolved in 100 ml of tetrahydro-furan under an argon atmosphere. A solution of lithium aluminium hydride in tetrahydro-furan (30 ml, 1 molar) was dropwise added at 0 C. After stirring for 15 hours at room temperature, a sodium hydroxide solution (20%) was slowly added under cooling. The solid was filtered after dilution with ethyl acetate and the organic layer evaporated. The crude material contains a mixture of the desired product (MS: 231.2 (M+H)+) and the corresponding trimethylsiliyl ether (MS: 303.1 (M+H)+) and was used without further purification.

References: [1]Patent: US2002/198195,2002,A1 .

7
[ 392331-66-7 ]
[ 85967-19-7 ]
[ 879514-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃;	Under a nitrogen atmosphere a solution of tert-butyl 4-(aminomethyl)-4- hydroxypiperidine-1 -carboxylate (38.9 g, 169 mmol, prepared according to Parts A and B of Example 4) in dichloromethane (420 mL) was cooled to 0 0C. Triethylamine (23.6 mL, 169 mmol) was added followed by the portionwise addition of 4-chloro-3- nitronaphthyridine (30.8 g, 147 mmol). The reaction mixture was stirred at ambient temperature overnight and then diluted with saturated aqueous sodium bicarbonate (200 mL). The layers were separated and the aqueous was extracted with dichloromethane (3 x 100 mL). The combined organics were concentrated under reduced pressure to provide a dark yellow solid. This material was triturated with saturated aqueous sodium bicarbonate, isolated by filtration, rinsed well with water, and then dried in a vacuum oven at 70 C overnight to provide 58.85 g of tert-butyl 4-hydroxy-4-[(3- nitro[l,5]naphthyridin-4-yl)amino]methyl}piperidine-l-carboxylate as a yellow solid.

References: [1]Patent: WO2006/28545,2006,A2 .Location in patent: Page/Page column 187-188.

8
[ 392331-66-7 ]
[ 39061-97-7 ]
[ 879514-18-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; In dichloromethane; for 2h;Heating / reflux;	To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidme-l -carboxylate (78.4 mmol, prepared as described above) in dichloromethane (300 mL) was added triethylamine (11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). The mixture was stirred at rt for 1 h, then heated at reflux for 1 h. The solution was transferred to a separatory funnel and extracted with water (100 mL). The organic layer was isolated and upon standing a precipitate formed. The solid was isolated by filtration and washed with dichloromethane and water and dried. Additional solid precipitated from the mother liquor and was isolated. The two yellow solids were combined and dried to yield tert- butyl 4-hydroxy-4-[(3-nitroqumolin-4-yl)amino]methyl}piperidine4 ^ (20.23 g, 82%).

References: [1]Patent: WO2006/28545,2006,A2 .Location in patent: Page/Page column 91-92.

9
[ 392331-66-7 ]
[ 26228-68-2 ]

Yield	Reaction Conditions	Operation in experiment
74%		A stirred mixture of <strong>[392331-66-7]4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester</strong> (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0~5 C. Upon completion of the addition, the mixture was stirred at 80 C. in oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 ml*3). The combined organic extracts were concentrated under reduced pressure to give 4-aminomethyl-1-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such. MS m/z (ESI): 145 [M+1]
74%		A stirred mixture of 4-aminomethyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0-~5C. Upon completion of the addition, the mixture was stirred at 80 C in oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 mlx3). The combined organic extracts were <n="157"/>concentrated under reduced pressure to give 4-aminomethyl-l-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such. MS m/z (ESI): 145[M+1]A solution of 2-carboxvmethyl

References: [1]Patent: US2010/4239,2010,A1 .Location in patent: Page/Page column 93.
[2]Patent: WO2007/85188,2007,A1 .Location in patent: Page/Page column 155-156.

10
[ 392331-66-7 ]
[ 79-04-9 ]
[ 1160247-07-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7458 - 7461.

11
[ 392331-66-7 ]
[ 1361955-58-9 ]
tert-butyl 4-hydroxy-4-((2-methoxy-6-pentadecylbenzylamino)methyl)piperidine-1-carboxylate [ No CAS ]

References: [1]Letters in drug design and discovery,2011,vol. 8,p. 626 - 632.

12
[ 392331-66-7 ]
[ 667-27-6 ]
[ 1179337-13-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	In N,N-dimethyl-formamide; for 1h;Inert atmosphere;	[00350] Preparation of 4-(but-2-ynyl)-2,2-difluoro-l-oxa-4,9- diazaspiro[5.5]undecane[00351] Step 1:To a solution of tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-l-carboxylate (3.00 g, 13.0 mmol) in N,N-dimethylformamide (30 mL) was added ethyl 2-bromo-2,2- difluoro-acetate (2.65 g, 13.0 mmol) and the reaction mixture stirred for 1 h under nitrogen. The reaction mixture was mixture diluted with ethyl acetate and water (25 mL) and brine (25 mL). The organic layer was dried over Na2S04, filtered and concentrated to provide tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4- hydroxy-piperidine- l-carboxylate (4.98 g, 12.9 mmol, 99%). NMR (400 MHz, OMSO-d6) delta 9.04 (t, J = 5.9 Hz, 1H), 4.66 (s, 1H), 3.65 (d, J = 12.7 Hz, 2H), 3.16 (d, J = 6.1 Hz, 2H), 3.02 (s, 2H), 1.38 (m, 13H).

References: [1]Patent: WO2012/125613,2012,A1 .Location in patent: Page/Page column 131-132.

13
[ 392331-66-7 ]
[ 1179337-15-5 ]

References: [1]Patent: WO2012/125613,2012,A1 .

14
[ 392331-66-7 ]
[ 1400643-40-4 ]

References: [1]Patent: WO2012/125613,2012,A1 .

15
[ 392331-66-7 ]
[ 1400643-39-1 ]

References: [1]Patent: WO2012/125613,2012,A1 .

16
[ 392331-66-7 ]
[ 1179337-14-4 ]

References: [1]Patent: WO2012/125613,2012,A1 .

17
[ 392331-66-7 ]
[ 51-36-5 ]
[ 1416984-83-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 119 - 124.

18
[ 392331-66-7 ]
[ 1416984-92-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 119 - 124.

19
[ 392331-66-7 ]
C₁₃H₁₆Cl₂N₂O₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 119 - 124.

20
[ 392331-66-7 ]
[ 1464153-65-8 ]

References: [1]Patent: WO2013/147711,2013,A1 .
[2]Patent: US2014/371199,2014,A1 .

21
[ 392331-66-7 ]
[ 1464153-66-9 ]

References: [1]Patent: WO2013/147711,2013,A1 .
[2]Patent: US2014/371199,2014,A1 .

22
[ 392331-66-7 ]
[ 1464150-55-7 ]

References: [1]Patent: WO2013/147711,2013,A1 .
[2]Patent: US2014/371199,2014,A1 .

23
[ 392331-66-7 ]
[ 383-63-1 ]
[ 1464153-64-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; In tetrahydrofuran; at 70℃; for 6h;	Step 1 : To a solution of t-butyl-4-(aminomethyl)-4-hydroxypiperidine-l-carboxylate (2.0 g, 8.69 mmol) in THF, were added DMAP (110 mg, 0.86 mmol) and ethyl 2,2,2-trifluoroacetate (1.5 g, 10.43 mmol). The reaction mixture was heated at 70 C and stirred for 6 h then was diluted with ethyl acetate. The organic layer was washed in turn with IN HCl (2x10 mL) and brine then, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, eluent n-Hexane/EtOAc 70:30) to afford tert-butyl 4- hydroxy-4-((2,2,2-trifluoroacetamido)methyl)piperidine-l-carboxylate (2.00 g, 84%) as an oil. 1H NMR (400 MHz, CDC13) delta 6.90 (bs, 1H), 3.79 (bs, 2H), 3.41 (bs, 2H), 3.25-3.18 (m, 4H), 1.57 (bs, 4H), 1.48 (s, 9H); MS (ESI) m/z 327 [C13H21F3N204+ H]+.
84%	With dmap; In tetrahydrofuran; at 70℃; for 6h;	To a solution of <strong>[392331-66-7]t-butyl-4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate</strong> (2.0 g, 8.69 mmol) in THF, were added DMAP (110 mg, 0.86 mmol) and ethyl 2,2,2-trifluoroacetate (1.5 g, 10.43 mmol). The reaction mixture was heated at 70 C. and stirred for 6 h then was diluted with ethyl acetate. The organic layer was washed in turn with 1N HCl (2*10 mL) and brine then, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, eluent n-Hexane/EtOAc 70:30) to afford tert-butyl 4-hydroxy-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate (2.00 g, 84%) as an oil. 1H NMR (400 MHz, CDCl3) delta 6.90 (bs, 1H), 3.79 (bs, 2H), 3.41 (bs, 2H), 3.25-3.18 (m, 4H), 1.57 (bs, 4H), 1.48 (s, 9H); MS (ESI) m/z 327 [C13H21F3N2O4+H]+.

References: [1]Patent: WO2013/147711,2013,A1 .Location in patent: Page/Page column 100.
[2]Patent: US2014/371199,2014,A1 .Location in patent: Paragraph 0397.

24
[ 392331-66-7 ]
5-amino-6-chloro-N-[4-hydroxy-1-(4-hydroxytetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide [ No CAS ]