[ CAS No. 143900-43-0 ] {[proInfo.proName]}

Name: 143900-43-0|(R)-tert-Butyl 3-hydroxypiperidine-1-carboxylate|97%
Brand: Ambeed
SKU: A185071
Price: 5.0 USD
Availability: InStock
Rating: 93 (35 reviews)

,{[proInfo.pro_purity]}

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

DV 2D 3D

3d Animation Molecule Structure of 143900-43-0

Structure of 143900-43-0 * Storage: {[proInfo.prStorage]}

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

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 143900-43-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 143900-43-0 ]

SDS Specification

Alternatived Products of [ 143900-43-0 ]

Product Details of [ 143900-43-0 ]

CAS No. :	143900-43-0	MDL No. :	MFCD04115306
Formula :	C₁₀H₁₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UIJXHKXIOCDSEB-MRVPVSSYSA-N
M.W :	201.26	Pubchem ID :	1514398
Synonyms :		Chemical Name :	(R)-tert-Butyl 3-hydroxypiperidine-1-carboxylate

Calculated chemistry of [ 143900-43-0 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	57.75
TPSA :	49.77 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) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.41
Log Po/w (XLOGP3) :	0.98
Log Po/w (WLOGP) :	1.0
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	0.56
Consensus Log Po/w :	1.16

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.51
Solubility :	6.26 mg/ml ; 0.0311 mol/l
Class :	Very soluble
Log S (Ali) :	-1.61
Solubility :	4.9 mg/ml ; 0.0244 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.7
Solubility :	39.8 mg/ml ; 0.198 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.67

Safety of [ 143900-43-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 143900-43-0 ]

* 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 [ 143900-43-0 ]
Downstream synthetic route of [ 143900-43-0 ]

[ 143900-43-0 ] Synthesis Path-Upstream 1~5

1
[ 143900-43-0 ]
[ 98977-36-7 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 11656 - 11669

2
[ 143900-43-0 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

3
[ 124-63-0 ]
[ 143900-43-0 ]
[ 404577-34-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 0 - 20℃; for 2.5 h;	B: (R)-3-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl Ester Methanesulfonyl chloride (1.73 ml, 22.5 mmol) was added to a cooled (ice bath, 0-4° C.), stirred solution of (R)-3-hydroxy-piperidine-carboxylic acid tert-butyl ester (3.0 g, 15 mmol) and triethylamine (3.12 ml, 22.5 mmol) in dichloromethane (30 ml). Following the addition the reaction was stirred at this temperature for 30 minutes before being allowed to warm to ambient temperature. After stirring at ambient temperature for 2 hours, aqueous sodium hydrogen carbonate (50 ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (300 ml) and aqueous sodium hydrogen carbonate (300 ml) and after partitioning the organic phase was washed with water (200 ml), dried with magnesium sulphate and evaporated to dryness under reduced pressure to yield (R)-3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester as a semi-crystalline solid.24B: (R)-3-Methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester To a solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (6.51 g, 32.3 mmol) and triethylamine (6.8 ml, 1.5 mol eq) in dichloromethane (70 ml) at 0° C. was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0° C. for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester, 9.03 g (100percent). NMR (CDCl₃7.27d) m 4.73(1H), m 3.63d(2H), m 3.44d(1H), m 3.32d (1H), s 3.05d(3H), m 1.95d(2H), m 1.83d(1 H), m 1.54d(1H), s 1.46d(9H)
100%	With triethylamine In dichloromethane at 0℃; for 2 h;	24B: (f?)-3-Methanesulphonyloxypiperidine-1-carboxylic acid fe/f-butyl ester To a solution of (f?)-3-hydroxypiperidine-1-carboxylic acid terf-butyl ester (6.51 g,32.3 mmol) and triethylamine (6.8ml, 1.5 mol eq) in dichloromethane (70ml) at 0 0C was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0 0C for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (f?)-3-methanesulphonyloxypiperidine-1-carboxylic acid terf-butyl ester,9.03g (100percent). NMR (CDCI3 7.27d) m 4.73/(1 H), m 3.63/(2H), m 3.44/(1 H), m 3.32/(1 H), s 3.05/(3H), m 1.95/(2H), m 1.83/(1 H), m 1.54/(1 H), s 1.46/(9H)
97%	With triethylamine In dichloromethane at 20℃; for 2 h;	To a solution of (R)-tert-butyl 3-hydroxypiperidine-1 -carboxylate (800 mg, 4.00 mmol) andTEA (2.02 g, 20.0 mmcl) in DCM (10 mL) was added MsCl (590 mg, 5.20 mmol) at 0 °C. Thesolution was warmed to room temperature and stirred for 2 hrs. The mixture was washed with H20 (10 mL x 2) and brine (20 mL), dried over Na2SO4 and concentrated to give the desired product (1.08 g, yield 97percent) as a yellow solid.1H NMR (300 MHz, CDCI3): ö 4.70 (brs, 1H), 3.75-3.60 (m, 2H), 3.47-3.39 (m, 1H), 3.35-3.27 (m, 1 H), 3.04 (s, 3H), 2.00-1.75 (m, 3H), 1.54-1.45 (m, 1 H), 1.45 (s, 9H).

95%

With triethylamine In dichloromethane at 0 - 20℃; for 1 h;

500ml three-necked flask, (R) -1-tert-butoxycarbonyl-3-hydroxypiper prepared in Example 6 (30.2 g, 0.15 mol) was added, 180 ml of methylene chloride, triethylamine (18.2 g; 0.18 mol) 0 to 10 ° C, methanesulfonyl chloride (18.9 g, 0.165 mol) was added dropwise, and the mixture was stirred at room temperature for 1 hour.The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to give (R) -1-t-butoxycarbonyl methanesulfonic acid piperidine (39.8 g). (Yield: 95percent; LC-MS: m / e = 279.1) (Theory:41.9 g).

Reference： [1] Patent: US2007/135479, 2007, A1, . Location in patent: Page/Page column 6; 13
[2] Patent: WO2007/65916, 2007, A1, . Location in patent: Page/Page column 29
[3] MedChemComm, 2014, vol. 5, # 12, p. 1879 - 1886
[4] Patent: WO2017/12576, 2017, A1, . Location in patent: Page/Page column 185
[5] Patent: CN103864673, 2016, B, . Location in patent: Paragraph 0073-0075
[6] Patent: WO2007/65916, 2007, A1, . Location in patent: Page/Page column 13-14
[7] Patent: US2007/249672, 2007, A1, . Location in patent: Page/Page column 10
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 2215 - 2221
[9] Patent: WO2005/305, 2005, A1, . Location in patent: Page 59
[10] Patent: WO2005/20975, 2005, A2, . Location in patent: Page/Page column 235; 236
[11] Patent: WO2005/20976, 2005, A2, . Location in patent: Page/Page column 238-239
[12] Patent: WO2005/60949, 2005, A2, . Location in patent: Page/Page column 237-238
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2742 - 2746

4
[ 143900-43-0 ]
[ 404577-34-0 ]

Reference： [1] Patent: EP1320525, 2004, B1,

5
[ 330786-24-8 ]
[ 143900-43-0 ]
[ 1022150-11-3 ]

Reference： [1] Patent: CN106188062, 2016, A, . Location in patent: Paragraph 0078; 0079; 0080; 0081

[ 143900-43-0 ] Synthesis Path-Downstream 1~109

1
[ 6482-24-2 ]
[ 143900-43-0 ]
[ 956324-94-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃;	Step B The Preparation of tert-butyl (3R)-3-(2-methoxyethoxy)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-hydroxypiperidin-1-carboxylate (300 mg, 1.5 mmol) in dry DMF (5 mL) was added sodium hydride (60%, 115 mg, 3.0 mmol) at 0 C. under nitrogen and the suspension was stirred at room temperature for 30 min. 1-Bromo-2-methoxyethane (0.17 mL, 1.8 mmol) was added to the reaction mixture and stirred over night at room temperature. The reaction mixture was heated at 50 C. and Sodium hydride (60%, 58 mg, 1.5 mmol) was added, then 1-bromo-2-methoxyethane (0.17 mL, 1.8 mmol). The reaction mixture was stirred at 50 C. for 2 hours. Sodium hydride (60%, 58 mg, 1.5 mmol) was added, then 1-bromo-2-methoxyethane (0.17 mL, 1.8 mmol). The reaction was stirred at 50 C. for 2 hours and then cooled to room temperature. The reaction was quenched with water (1 mL) at 0 C. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (30 mL) and water (25 mL). The phases were separated and the aqueous was extracted with dichloromethane (2*30 ml). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (50% heptane in ethyl acetate). The product was obtained as colourless oil (328 mg, 84%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.38-1.53 (m, 4H), 1.46 (s, 9H), 1.68-1.79 (m, 1H), 1.93-2.03 (m, 1H), 2.89-3.00 (m, 2H), 3.27-3.35 (m, 1H), 3.39 (s, 3H), 3.51-3.56 (m, 2H), 3.59-3.73 (m, 2H).

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 92

2
[ 143900-43-0 ]
[ 227327-85-7 ]
C₂₈H₃₉O₄N₂Cl [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5882 - 5885

3
[ 143900-43-0 ]
[ 316353-97-6 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2001,vol. 44,p. 31 - 41

4
[ 143900-43-0 ]
(R)-1-methyl-3-piperidinyl butyrate [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2001,vol. 44,p. 31 - 41

5
[ 95-56-7 ]
[ 143900-43-0 ]
[ 444605-37-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16.5h;	The compound obtained in Step 1 (10 g, 49.68 mmol), ortho bromophenol (7.14 g, 41.4 mmol) and triphenylphosphine (19.55 g, 74.5 mmol) were placed in THF (100 mL), and the mixture was cooled to 0 C. DIAD (14.7 mL, 74.5 mmol) was added dropwise for about 30 minutes, and the mixture was warmed to r.t. and stirred for about 16 hours. The mixture was diluted with ether (500 mL) and water was added (50 mL). Then the organic portion was washed with 5N NaOH (500 mL), and the aqueous phase was extracted with ether (500 mL) and concentrated. The concentrated oil was taken up in EtOAc/hexanes and the triphenylphosphine oxide crystallized. The slurry was filtered, and the filtrate was concentrated and chromatograped on silica gel to give the product (6.65 g, 45%) as a clear oil.

Reference： [1]Patent: US2004/82590,2004,A1 .Location in patent: Page/Page column 32

6
[ 95-56-7 ]
[ 143900-43-0 ]
[ 444605-60-1 ]

Yield	Reaction Conditions	Operation in experiment
17%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16.5h;	The o-bromophenol (1.72 g, 9.92 mmol) and Boc-R-3-hydroxypiperidine (2 g, 9.92 mmol) were placed in THF (60 mL) with triphenylphosphine (3.9 g, 14.9 mmol), and the system was cooled to 0 C. DIAD (2.94 mL, 14.9 mmol) was added portion wise over 30 minutes and the mixture was warmed to r.t. and stirred for about 16 hours. The mixture was diluted with ether (200 mL) and water was added (100 mL). The mixture was washed with 5N NaOH (100 mL), extracted with ether and concentrated. Ethyl acetate/hexanes was added and the triphenylphosphine oxide was crystallized and filtered away. The residue was chromatographed on silica gel (ethyl acetate/hexanes) afforded the product (588 mg, 17%) as a clear oil. MS found: 256.0 (M-Boc)

Reference： [1]Patent: US2004/82590,2004,A1 .Location in patent: Page/Page column 34

7
[ 24424-99-5 ]
(R)-piperidin-3-ol hydrochloride [ No CAS ]
[ 143900-43-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate; In dichloromethane; water; for 21h;Product distribution / selectivity;	Step A tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate A suspension of (3R)-piperidin-3-ol hydrochloride salt (3.17 g, 0.023 mol) in CH2Cl2 (40 mL) was treated with Na2CO3 (5.13 g, 0.048 mol) dissolved in H2O (80 mL), followed by di-tert-butyl dicarbonate (5.53 g, 0.025 mol) and additional CH2Cl2 (24 mL). The resulting mixture was stirred for 21 h. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (9:1 CH2Cl2:MeOH) to provide the title compound as a colorless oil (5.07 g, quantitative). MS (M+1): 202.0. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.40-1.56 (m, 2H), 1.44 (s, 9H), 1.67-1.80 (m, 1H), 1.80-1.93 (m, 1H), 2.95-3.22 (m, 2H), 3.47 (d, J=5.1 Hz, 1H), 3.51 (br s, 1H), 3.64-3.78 (m, 2H).
79%	With sodium carbonate; In dichloromethane; water; at 20℃;Product distribution / selectivity;	Step A; The Preparation of tert-butyl (3R)-3-hydroxypiperidin-1-carboxylate; To a solution of the hydrochloric salt of (3R)-3-hydroxypiperidine (2.0 g, 14.6 mmol) in water (50 mL) and dichloromethane (40 mL) were added sodium carbonate (4.12 g, 29 mmol) and di-tert-butyl dicarbonate (3.5 g, 16 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water (50 mL) and dichloromethane (50 mL). The phases were separated and the aqueous was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (30% to 50% heptane in ethyl acetate). The product was obtained as colourless oil (2.32 g, 79%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.42-1.54 (m, 2H), 1.46 (s, 9H), 1.69-1.80 (m, 1H), 1.86-1.93 (m, 1H), 2.20-2.72 (m, 1H), 2.99-3.16 (m, 2H), 3.56 (d, J=4.49 Hz, 1H), 3.50-3.60 (d, J=1.56 Hz, 1H), 3.73-3.84 (m, 1H).
	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0 - 20℃; for 48h;	To a cooled (00C) solution comprising (R)-3-hydroxy piperidine hydrochloride (5.0 g, 36.3 mmol) in water/dioxane (200 ml of a 1:1 mixture) is added sodium hydrogen carbonate (10.7 g, 127 mmol) followed by di-t-butyl dicarbonate (9.11 g, 41.7 mmol), portionwise. The reaction mixture is allowed to warm to room temperature and stirred for 2 days. The resulting suspension is filtered through Celite filter material and washed with dioxane. The filtrate is concentrated in vacuo to remove half the solvent and then acidified to pH 3 with 2M citric acid. This solution is extracted with DCM (3 x 100 ml) and the combined organic extracts are dried (MgSO4) and concentrated in vacuo to yield the titled product as a brown oil.

	With sodium hydrogencarbonate; In methanol; at 20 - 40℃; for 1.5h;Sonication;	A: (R)-3-Hydroxy-piperidine-carboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (8.7 g, 11.6 mmol) was added to a suspension of (R)-3-hydroxypiperidine hydrochloride (5.0 g, 40.0 mmol) and sodium hydrogen carbonate (24.2 g, 29.0 mmol) in methanol (70 ml). Following the addition, the reaction was sonicated at ambient temperature for 1.5 hours during which time the temperature reached 40 C. The solvent was removed under reduced pressure and the crude material partitioned between ethyl acetate (200 ml) and water (200 ml). After separation of the layers, the organic was washed sequentially with sodium hydrogen carbonate (100 ml), water (100 ml), brine (100 ml) and water (100 ml) before being dried with magnesium sulphate and evaporated to dryness under reduced pressure. The (R)-3-hydroxy-piperidine carboxylic acid tert-butyl ester was obtained as colourless oil that solidified on standing.
	With sodium hydrogencarbonate; In methanol; at 20 - 40℃; for 1.5h;Sonicated;	A: (fiKS-Hvdroxy-piperidine-carboxylic acid fe/f-butyl esterDi-fe/t-butyl dicarbonate (8.7g, 11.6mmol) was added to a suspension of (R)-3- hydroxypiperidine hydrochloride (5.Og, 40.0mmol) and sodium hydrogen carbonate (24.2g, 29.0 mmol) in methanol (70 ml). Following the addition, the reaction was sonicated at ambient temperature for 1.5 hours during which time the temperature reached 40 C. The solvent was removed under reduced pressure and the crude material partitioned between ethyl acetate (200ml) and water (200ml). After separation of the layers, the organic was washed sequentially with sodium hydrogen carbonate (100ml), water (100ml), brine (100ml) and water (100ml) before being dried with magnesium sulphate and evaporated to dryness under reduced pressure. The (f?)-3-hydroxy- piperidine carboxylic acid te/t-butyl ester was obtained as colourless oil that solidified on standing.
	With triethylamine; In dichloromethane; at 0℃;	To a suspension of (R)-(+)-3-hydroyxpiperidine hydrochloride (1 g) in DCM (20 mL) was added Et3N (3.04 mL) followed by BOC2O (1.75 g) at 0 C. which was left over the weekend. Water (50 mL) was added and extracted with DCM (100 mL). Combined organics were washed with water (2×50 mL) then brine (50 mL), dried (Na2SO4) and concentrated. The residue was columned (flash, eluted with a gradient of 0-10% MeOH/DCM). Yield: 1.55 g. 1H-NMR (CDCl3) delta 3.74-3.69 (2H, m), 3.56-3.48 (1H, m), 3.18-3.03 (2H, m), 1.92-1.83 (1H, m), 1.79-1.71 (2H, m), 1.55-1.45 (1H, m), 1.43 (9H, s).
	With potassium carbonate; In dichloromethane; water; at 20℃;	R-piperidin-3-ol HCl salt (15 g, 109 mmol) was placed in DCM/water (500 mL of 1/1 mixture) with potassium carbonate (30.1 g, 218 mmol), and di-t-butyl dicarbonate (26.2 g, 120 mmol) was added with off gassing. The mixture was stirred at r.t. overnight and then diluted with DCM (400 mL) and washed with water (2×200 mL). The organic fraction was dried and concentrated to give white crystalline solids (23.2 g).
	With dmap; triethylamine; In dichloromethane; at 20℃; for 18.25h;	Solid ditert-butyldicarbonate (26.6g, 122mmol) was added in portions over 15 minutes to a stirred solution of (3R)-piperidin-3-ol hydrochloride (15.25g, LLLMMOL), triethylamine (30.9mL, 222mmol) and 4- (DIMETHYLAMINO)-PYRIDINE (50MG) in dry dichloromethane (300mL). After stirring for 18 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 80: 20), to give the title compound as a solid.
	With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 1.5h;	(R) -3-Hydroxypiperidine hydrochloride (6.574 g, 0.048 mol) is dissolved under stirring in aqueous 2M sodium hydroxide solution (65 ml) and cooled to 0C. A solution of di-tert-butyl dicarbonate (11.44 g, 0.525 mol) in 1,4-dioxane (65 ml) is added dropwise and the reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is extracted with chloroform (3 x 150 ml) and the combined organic layers are washed once with water and once with brine, dried over magnesium sulphate, filtered off and evaporated to dryness to give the title compound.
	With dmap; In dichloromethane; at 20℃; for 18h;	Solid DITERT-BUTYLDICARBONATE (26.6g, 122MMOL) was added in portions over 15 minutes to a stirred solution of (3R)-piperidin-3-ol hydrochloride (15. 25G, 11 LMMOL), triethylamine (30.9mL, 222mmol) and 4- (DIMETHYLAMINO)-PYRIDINE (50MG) in dry dichloromethane (300mL). After stirring for 18 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 80: 20), to give the title compound as a solid.
	With dmap; triethylamine; In dichloromethane; at 20℃; for 18.25h;	Solid DITERT-BUTYLDICARBONATE (26.6g, 122MMOL) was added in portions over 15 minutes to a stirred solution of (3R)-piperidin-3-ol hydrochloride (15. 25g, 11 LMMOL), triethylamine (30.9mL, 222mmol) and 4- (DIMETHYLAMINO)-PYRIDINE (50MG) in dry dichloromethane (300mL). After stirring for 18 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (20: 80 to 80: 20), to give the title compound as a solid.
	With dmap; triethylamine; In dichloromethane; at 20℃; for 18.25h;	Solid ditert-butyldicarbonate (26.6g, 122mmol) was added in portions over 15 minutes to a stirred solution of (3R)-piperidin-3-ol hydrochloride (15. 25g, 111mmol), triethylamine (30.9mL, 222mmol) and 4- (dimethylamino)-pyridine (50mg) in dry dichloromethane (300mL). After stirring for 18 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 80: 20), to give the title compound as a solid.
	With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 16h;	Preparation #14. (R)-3-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester To a solution of (R)-3-hydroxypiperidine hydrochloride (10.3 g, 0.075 mol) in dioxane/water (80 mL each) was added di-tert-butyldicarbonate (20 g, 0.091 mol) and sodium carbonate (19 g, 0.182 mol). The mixture was stirred at room temperature for about 16 hours. The organic solvent was removed under reduced pressure and the aqueous layer was extracted with diethyl ether (3*100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure to afford (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (15.1 g, 0.075 mol) as a colorless oil; m/z (M+H)+ 202.

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 104-105
[2]Patent: WO2004/9589,2004,A1 .Location in patent: Page/Page column 48
[3]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 91-92
[4]Patent: WO2006/66929,2006,A1 .Location in patent: Page/Page column 39
[5]Patent: US2007/135479,2007,A1 .Location in patent: Page/Page column 6
[6]Patent: WO2007/65916,2007,A1 .Location in patent: Page/Page column 13
[7]Patent: US2007/249672,2007,A1 .Location in patent: Page/Page column 10
[8]Patent: US2004/82590,2004,A1 .Location in patent: Page/Page column 32
[9]Patent: WO2005/305,2005,A1 .Location in patent: Page 59
[10]Patent: WO2005/815,2005,A2 .Location in patent: Page 33
[11]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 235
[12]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 238
[13]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 237
[14]Patent: US2006/25383,2006,A1 .Location in patent: Page/Page column 79

9
[ 143900-43-0 ]
[ 28808-26-6 ]

Yield	Reaction Conditions	Operation in experiment
		(R)-3-HYDROXYPIPERIDINE-1-CARBOXYLIC acid tert-butyl ester (10 g, 0.05 mol) is dissolved in dry THF (50 ml) and cooled to 0OC under an inert atmosphere. Lithium aluminium hydride, 1M solution in THF, (80 ML, 0.08 mol) is canulated to this solution at 0 to 5OC. After the addition the reaction mixture is warmed to room temperature and stirred over night. The reaction mixture is cooled in an ice bath and Rochelle's salt (5 g) is added and the reaction left stirring for 30 minutes. Afterwards water (10 ml) is added dropwise and the solvent evaporated. The residue is taken up in chloroform (70 ml) and isopropanol (30 ML) and stirred for 1 hour. The solid is filtered off and extracted again. The organic extracts are combined and evaporated to yield the title compound as a pale oil.

Reference： [1]Patent: WO2005/815,2005,A2 .Location in patent: Page 33

10
[ 124-63-0 ]
[ 143900-43-0 ]
[ 404577-34-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Product distribution / selectivity;	B: (R)-3-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl Ester Methanesulfonyl chloride (1.73 ml, 22.5 mmol) was added to a cooled (ice bath, 0-4 C.), stirred solution of (R)-3-hydroxy-piperidine-carboxylic acid tert-butyl ester (3.0 g, 15 mmol) and triethylamine (3.12 ml, 22.5 mmol) in dichloromethane (30 ml). Following the addition the reaction was stirred at this temperature for 30 minutes before being allowed to warm to ambient temperature. After stirring at ambient temperature for 2 hours, aqueous sodium hydrogen carbonate (50 ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (300 ml) and aqueous sodium hydrogen carbonate (300 ml) and after partitioning the organic phase was washed with water (200 ml), dried with magnesium sulphate and evaporated to dryness under reduced pressure to yield (R)-3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester as a semi-crystalline solid.24B: (R)-3-Methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester To a solution of <strong>[143900-43-0](R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester</strong> (6.51 g, 32.3 mmol) and triethylamine (6.8 ml, 1.5 mol eq) in dichloromethane (70 ml) at 0 C. was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0 C. for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester, 9.03 g (100%). NMR (CDCl3 7.27d) m 4.73(1H), m 3.63d(2H), m 3.44d(1H), m 3.32d (1H), s 3.05d(3H), m 1.95d(2H), m 1.83d(1 H), m 1.54d(1H), s 1.46d(9H)
100%	With triethylamine; In dichloromethane; at 0℃; for 2h;	24B: (f?)-3-Methanesulphonyloxypiperidine-1-carboxylic acid fe/f-butyl ester To a solution of (f?)-3-hydroxypiperidine-1-carboxylic acid terf-butyl ester (6.51 g,32.3 mmol) and triethylamine (6.8ml, 1.5 mol eq) in dichloromethane (70ml) at 0 0C was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0 0C for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (f?)-3-methanesulphonyloxypiperidine-1-carboxylic acid terf-butyl ester,9.03g (100%). NMR (CDCI3 7.27d) m 4.73/(1 H), m 3.63/(2H), m 3.44/(1 H), m 3.32/(1 H), s 3.05/(3H), m 1.95/(2H), m 1.83/(1 H), m 1.54/(1 H), s 1.46/(9H)
97%	With triethylamine; In dichloromethane; at 20℃; for 2h;	To a solution of (R)-tert-butyl 3-hydroxypiperidine-1 -carboxylate (800 mg, 4.00 mmol) andTEA (2.02 g, 20.0 mmcl) in DCM (10 mL) was added MsCl (590 mg, 5.20 mmol) at 0 C. Thesolution was warmed to room temperature and stirred for 2 hrs. The mixture was washed with H20 (10 mL x 2) and brine (20 mL), dried over Na2SO4 and concentrated to give the desired product (1.08 g, yield 97%) as a yellow solid.1H NMR (300 MHz, CDCI3): oe 4.70 (brs, 1H), 3.75-3.60 (m, 2H), 3.47-3.39 (m, 1H), 3.35-3.27 (m, 1 H), 3.04 (s, 3H), 2.00-1.75 (m, 3H), 1.54-1.45 (m, 1 H), 1.45 (s, 9H).

95%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	500ml three-necked flask, (R) -1-tert-butoxycarbonyl-3-hydroxypiper prepared in Example 6 (30.2 g, 0.15 mol) was added, 180 ml of methylene chloride, triethylamine (18.2 g; 0.18 mol) 0 to 10 C, methanesulfonyl chloride (18.9 g, 0.165 mol) was added dropwise, and the mixture was stirred at room temperature for 1 hour.The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to give (R) -1-t-butoxycarbonyl methanesulfonic acid piperidine (39.8 g). (Yield: 95%; LC-MS: m / e = 279.1) (Theory:41.9 g).
		B: (RKS-Methanesulfonyloxy-piperidine-i-carboxylic acid te/t-butyl ester Methanesulfonyl chloride (1.73ml, 22.5mmol) was added to a cooled (ice bath, 0-4 C), stirred solution of (/^-S-hydroxy-piperidine-carboxylic acid te/t-butyl ester (3.Og, 15mmol) and triethylamine (3.12ml, 22.5mmol) in dichloromethane (30ml). Following the addition the reaction was stirred at this temperature for 30 minutes before being allowed to warm to ambient temperature. After stirring at ambient temperature for 2 hours, aqueous sodium hydrogen carbonate (50ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (300ml) and aqueous sodium hydrogen carbonate (300ml) and after partitioning the organic phase was washed with water (200ml), dried with magnesium sulphate and evaporated to dryness under reduced pressure to yield (f?)-3-methanesulfonyloxypiperidine-1-carboxylic acid te/t-butyl ester as a semi-crystalline solid.
	With triethylamine; In dichloromethane; at 0℃; for 1h;	To a solution of Intermediate 2 (1 g) in DCM (10 mL) was added Et3N (1.38 mL) followed by MsCl (0.46 mL) dropwise at 0 C. After stirring at 0 C. for 1 hour the reaction was warmed to room temperature, quenched with water (10 mL) and separated. The aqueous layer was extracted with DCM (2×20 mL). Combined organics were washed with water (40 mL), a spatula of silica added, dried (NaSO4) and concentrated. Yield: 1.4148 g. 1H-NMR (CDCl3) delta 4.71 (1H, br s), 3.62 (2H, br d), 3.49-3.27 (2H, m), 3.04 (3H, s), 2.01-1.76 (3H, m), 1.79-1.71 (2H, m), 1.55-1.45 (1H, m), 1.45 (9H, s).
	With triethylamine; In dichloromethane; at 0℃; for 3.16667h;	Methanesulfonyl chloride (9.56mL, 124mmol) was added dropwise over 10 minutes to a stirred solution of 1, 1-dimethylethyl (3R)-3-HYDROXYPIPERIDINE-1-CARBOXYLATE (20.7g, 103mmol) and triethylamine (21.5mL, 154mmol) in dichloromethane (300mL) at 0C. After stirring for 3 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (20: 80 to 50 : 50), to give the title compound as an oil.
	With triethylamine; In dichloromethane; at 0℃; for 3h;	Methanesulfonyl chloride (9. 56ML, 124MMOL) was added dropwise over 10 minutes to a stirred solution of 1, 1-dimethylethyl (3R)-3-HYDROXYPIPERIDINE-1-CARBOXYLATE (20.7g, 103MMOL) and triethylamine (21. 5mL, 154mmol) in dichloromethane (300mL) at 0C. After stirring for 3 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 50: 50), to give the title compound as an oil.
	With triethylamine; In dichloromethane; at 0℃; for 3.16667h;	Methanesulfonyl chloride (9.56mL, 124mmol) was added dropwise over 10 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-HYDROXYPIPERIDINE-1-CARBOXYLATE (20.7g, 103MMOL) and triethylamine (21. 5mL, 154MMOL) in dichloromethane (300mL) at 0C. After stirring for 3 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 50: 50), to give the title compound as an oil.
	With triethylamine; In dichloromethane; at 0℃; for 3.16667h;	Methanesulfonyl chloride (9.56mL, 124mmol) was added dropwise over 10 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate (20.7g, 103mmol) and triethylamine (21.5mL, 154mmol) in dichloromethane (300mL) at 0C. After stirring for 3 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 50: 50), to give the title compound as an oil.
3.06 g	With triethylamine; In dichloromethane; at 0℃; for 3h;	A mixture oftert-butyl (R)-3-hydroxypiperidine-l-carboxylate (5.15 g, 25 mmol) and Et3N (7.6 g, 77 mmol) in DCM (50 mL) was stirred at 0 C, MsCl (5.8 g, 52 mmol) was added to solution in dropwise, keep stirred for 3 h. The solvent was washed by saturated aqueous NaHC03 (50 mL 2) then brine (50 mL), dried over Na2S04, purified by flash chromatography on silica gel (DCM: 100%) to afford product as yellow solid, 3.06 g. ESI-MS m/z 280 (MH)+.

Reference： [1]Patent: US2007/135479,2007,A1 .Location in patent: Page/Page column 6; 13
[2]Patent: WO2007/65916,2007,A1 .Location in patent: Page/Page column 29
[3]MedChemComm,2014,vol. 5,p. 1879 - 1886
[4]Patent: WO2017/12576,2017,A1 .Location in patent: Page/Page column 185
[5]Patent: CN103864673,2016,B .Location in patent: Paragraph 0073-0075
[6]Patent: WO2007/65916,2007,A1 .Location in patent: Page/Page column 13-14
[7]Patent: US2007/249672,2007,A1 .Location in patent: Page/Page column 10
[8]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2215 - 2221
[9]Patent: WO2005/305,2005,A1 .Location in patent: Page 59
[10]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 235; 236
[11]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 238-239
[12]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 237-238
[13]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2742 - 2746
[14]Patent: WO2019/232053,2019,A1 .Location in patent: Paragraph 00365

11
[ 263400-68-6 ]
[ 143900-43-0 ]
[ 848440-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 40℃; for 3h;	DIETHYLAZODICARBOXYLATE (3.73 g) was added dropwise to a mixture of tert-butyl (3R)- 3-HYDROXYPIPERIDINE-1-CARBOXYLATE (4.29 g), 4-chloro-6-methoxyquinazolin-7-ol (3.00 g) and triphenylphosphine (5.61 g) in methylene chloride (75 ml). The solution was then heated to 40C and stirred for 3 hours. After cooling the mixture was filtered and then purified by flash column chromatography eluting with ISOHEXANE/ACETONE/TRIETHYLAMINE (80/20/1) to give tert- butyl (3S)-3- [ (4-CHLORO-6-METHOXYQUINAZOLIN-7-YL) oxy] PIPERIDINE-1-CARBOXYLATE as a colourless oil (3.29 g) which was used directly

Reference： [1]Patent: WO2005/26150,2005,A1 .Location in patent: Page/Page column 104

12
[ 143900-43-0 ]
C₁₀H₁₈NO₃^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; oil; for 0.416667h;	Preparation 182 : 1,1-dimethylethyl (3R)-3-(methyloxy)piperidine-1- carboxylate To a solution of 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate (Preparation 128,1. 6 g, 7.95 MMOL) in anhydrous tetrahydrofuran (35 ml) was added sodium hydride (60% dispersion in oil, 0.32 g, 7.95 MMOL) in portions. The resulting mixture was stirred for 25 min then iodomethane (2.27 g, 16 MMOL) was added dropwise and the reaction mixture was stirred for 17 h. The reaction mixture was diluted with ethyl acetate (150 ML) and washed with brine (5% solution, 150 ML). The aqueous layer was extracted with ethyl acetate (2 x 50 mi) and the combined organic extracts were dried (MGS04) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography on silica gel (70 g) eluting with dichloromethane : methanol (100: 1 and then 50: 1) to give a yellow oil (1.68 g). The trace of iodine was removed by dissolving the product in ethyl acetate (50 mi) and washing with aqueous sodium metabisulphite (5% solution, 2 x 35 ML), water (35 ML) and aqueous sodium hydrogen carbonate (5% solution, 35 ml). The organic extracts were dried (MGS04) and concentrated in vacuo to give the desired product as a colourless oil (1.62 g).

Reference： [1]Patent: WO2004/72086,2004,A2 .Location in patent: Page 204-205

13
(3R)-piperidin-3-ol (S) camphor sulphonic acid salt [ No CAS ]
[ 24424-99-5 ]
[ 143900-43-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 0 - 20℃; for 72h;	Preparation 128: 1,1-dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate To a solution of (3R)-piperidin-3-ol. (S) camphor sulphonic acid salt (Preparation 115,5. 03 g, 15.7 MMOL) in dichloromethane (50 ML) and triethylamine (2.4 ML, 17.3 MMOL) was added at 0 C a solution of di-TEFF-butyl dicarbonate (3.8 g, 17.3 MMOL) dropwise in dichloromethane (10 ML). The reaction mixture was stirred at room temperature for 3 d, before ethyl acetate and water were added. The organic extracts were washed with brine, dried (MGS04) and concentrated in vacuo to give the title compound as a colourless oil (3.29 g, 100%).

Reference： [1]Patent: WO2004/72086,2004,A2 .Location in patent: Page 177-178

14
[ 62414-68-0 ]
[ 24424-99-5 ]
[ 143900-43-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydrogencarbonate; In ethanol;	Hydroxypiperidine 39a (3.72 g, 36.8 mmol) was dissolved in a mixture of H2O/EtOH (250 ml, 1:1, v/v). Then, NaHCO3 (15.40 g, 183.5 mmol) was added, followed by the addition of Boc2O (9.63 g, 44.1 mmol). After the reaction was completed, the mixture was filtered and the filtrate was evaporated. The crude product was then purified by flash chromatography on a silica gel using a linear gradient of 10% EtOH/CHCl3 in CHCl3. Product 41a was obtained in a 97% yield (6.70 g, 33.51 mmol) as a colorless oil.1H NMR, 13C NMR, and IR spectra were identical to those of 20a. HRMS (ESI) C10H19O3NNa (M+Na)+ calcd 224.12571, found 224.12563; [alpha]D20 +16.6 (c 0.717, EtOH).
	With triethylamine;dmap; In dichloromethane; at 20℃; for 96h;	A mixture of (R)-3-hydroxypiperidine (2.709 g, 19.7 mmol), di-t-butyl dicarbonate (4.04 g, 31.5 mmol), dichloromethane (8 mL), triethylamine (5.76 mL, 41.34 mmol) and 4-dimethylaminopyridine (241 mg, 1.97 mmol) was stirred for 4 hours and 20 minutes at room temperature. To the reaction mixture were further added di-t-butyl dicarbonate (1.516 g, 11.82 mmol), triethylamine (1.91 mL, 11.82 mmol) and 4-dimethylaminopyridine (120 mg, 0.985 mmol), followed by stirring for 4 days at room temperature. Aqueous solution of ammonium chloride was added to the reaction mixture and extraction was performed twice with diethyl ether. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give a crude product of (R)-3-hydroxypiperidine-1-carboxylic acid t-butyl ester.

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500
[2]Patent: US2005/261291,2005,A1 .Location in patent: Page/Page column 107-108
[3]Helvetica Chimica Acta,2014,vol. 97,p. 1507 - 1515

15
[ 24424-99-5 ]
[ 143900-43-0 ]

Reference： [1]Patent: CN103864673,2016,B

16
[ 34619-03-9 ]
(R)-piperidin-3-ol hydrochloride [ No CAS ]
[ 143900-43-0 ]

Yield	Reaction Conditions	Operation in experiment
6.6 g (92%)	With potassium carbonate; In tetrahydrofuran; water; ethyl acetate;	EXAMPLE 6 344738 R-3-[1-(4-chlorophenyl)cyclopropylmethoxy]-4-(3-piperidinyloxy)-1,2,5-thiadiazole (lot #M52-FBA-212). R-3-hydroxy-1-t-butoxycarbonylpiperidine. Di-t-butylcarbonate (9.5 g, 0.044 m) was added to a solution of R-3-hydroxypiperidine hydrochloride (5.0 g, 0.036 m) and potassium carbonate (12.0 g,.086 m) in 140 ml of a 50% solution of THF in water and stirred for 4 hr. EtOAc was added and the solution washed with water, dried and condensed to yield 6.6 g (92%) of R-3-hydroxy-1-t-butoxycarbonylpiperidine. 3-(N-t-Butyloxycarbonyl-3-piperidyloxy)-4-n-propylthiothiadiazole. 3 g of R-3-hydroxy-1-t-BOC-piperidine (0.015 m) was added to a stirred solution of potassium t-butoxide (1.66 g, 0.015 m) in 80 ml THF and cooled to 0-5 C.

Reference： [1]Patent: US6117883,2000,A

17
[ 104-12-1 ]
[ 143900-43-0 ]
[ 143835-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; dichloromethane;	(a) Into a solution of (R)-(-)-N-tert-butoxycarbonyl-3-piperidinol (Reference Example 2) (23 g) in dry tetrahydrofuran (20 ml) were added 4-chlorophenyl isocyanate (1.43 ml) and triethylamine (1.87 mi) successively at room temperature with stirring, and then the mixture was stirred at room temperature for 10 hours. The reaction mixture was distilled under reduced pressure to give residues which was adsorbed on ca. 20 g of silica gel with employment of 50 ml of methylene chloride and purified through column chromatography (alumina, n-hexane:ethyl acetate =5:1) to give (R)-(+)-N-tert-butoxycarbonyl-3-piperidyl 4-chlorophenylcarbamate (3.07 g) of colorless prism crystal. Melting point 160-161 C. Elementary analysis (%) for C17 H23 ClN2 O4:

Reference： [1]Patent: US5300515,1994,A

18
[ 24424-99-5 ]
[ 7087-68-5 ]
[ 143900-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sodium chloride; In methanol; dichloromethane;	Reference Example 2 (R)-(-)-N-tert-butoxycarbonyl-3-piperidinol Into a suspension of the compound (37.88 g) synthesised in the Reference Example (1) in a mixture (300 ml) of methylene chloride:methanol (1:1) were successively added diiso-propylethylamine (38.41 ml) and a solution of di-tertbutyl dicarbonate (22.91 g) in methylene chloride (50 ml) at room temperature with stirring. After stirred at room temperature for 3 hours, the mixture was distilled off under reduced pressure to give residue, which was then dissolved into methylene chloride (300 ml). This organic layer was washed twice with saturated aqueous solution of sodium hydrogen carbonate and once with saturated aqueous solution of sodium chloride to give residue. This was purified through column chromatography (silica gel, n-hexane:ethyl acetate=1:2) and further the solvent was distilled under reduced pressure (200 C./0.7 mm Hg) to give the title compound (21.03 g) as colorless oily product. Elementary analysis for C10 H19 NO3:

Reference： [1]Patent: US5300515,1994,A

19
[ 266690-49-7 ]
[ 143900-43-0 ]
[ 940890-58-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 48h;Under argon;	C: (S)-3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid te/t-butyl esterTo a solution of (f?)-3-hydroxypiperidine-1-carboxylic acid te/t-butyl ester (209 mg, 1.04 mmol), triphenylphosphine (327 mg, 1.249 mmol), 1-amino-isoquinolin-6-ol (200 mg, 1.249 mmol) in THF (4 ml) and DMF (394ul_) at 0 C, under argon, was added dropwise diethylazodicarboxylate (197 ml.) over 5 min. The mixture was then warmed to ambient temperature and stirred for 48 h. Water was then added and the mixture basified with dilute NaOH. The mixture was extracted with ethyl acetate (X3), dried (sodium sulphate) filtered and evaporated under reduced pressure to give a residue. Flash chromatography of the residue on silica (eluent: 2-10% methanol in dichloromethane with 1 % aqueous ammonia) gave (S) 3-(1-amino-isoquinolin-6- yloxy)piperidin-1-carboxylic acid te/t-butyl ester (72 mg), EI-MS: m/z = 344.1 [M+H]+.

Reference： [1]Patent: WO2007/65916,2007,A1 .Location in patent: Page/Page column 14

20
[ 143900-43-0 ]
[ 404577-34-0 ]
14-O-[(N-(3-Methyl-2-amino-buturyl-piperidin-3-yl)sulfanyl)acetyl]mutilin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; dichloromethane;	D) N-BOC-3(R)-methylsulfonyloxy-piperidine A solution of 5.08 g of N-BOC-3(R)-Hydroxy-piperidine and 8.7 g of methanesulfonic acid anhydride in 100 ml of pyridine is stirred at room temperature. Pyridine is distilled off under high vacuum and the distillation residue obtained is dissolved in CH2Cl2, which is extracted with 1N HCl. The organic phase obtained is dried and the solvent is evaporated off to dryness. The residue is purified by chromatography. 3.8 g of N-BOC-3(R)-methylsulfonyloxy-piperidine are obtained. 1H-NMR(CDCl3): 4.7(m,1H,CHOSO2CH3), 3.2-3.6(m,4H,CHN), 3.0(s,3H,CH3SO2), 1.4(m,9H,tert.butyl).

Reference： [1]Patent: EP1320525,2004,B1

21
[ 109-02-4 ]
[ 62414-68-0 ]
[ 143900-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; dichloromethane;	C) N-BOC-3(R)-Hydroxy-piperidine A suspension of 3.48 g of 3-(R)-hydroxypiperidine, 8.72 g of di-tert.butyl-dicarbonat and 4.0 g of N-metyl-morpholine in 70 ml of dioxane is stirred at room temperature. From the mixture obtained the solvent is evaporated off and the evaporation residue is dissolved in CH2Cl2 and extracted with 1N HCl. The organic phase is dried and the solvent is evaporated off. 5.08 g of N-BOC-3(R)-Hydroxy-piperidine are obtained which can be used without further puification for further reaction.

Reference： [1]Patent: EP1320525,2004,B1

22
[ 143900-43-0 ]
[ 74-88-4 ]
[ 745066-86-8 ]

Yield	Reaction Conditions	Operation in experiment
		4.1) (R)-3-Methoxy-piperidine-1-carboxylic acid tert-butyl ester (intermediate 12): <n="61"/>To commercially available (RJ-S-hydroxy-piperidine-i-carboxylic acid tert-butyl ester (4.5 g, 22.36 mmol) in 60 ml DMF at 00C was added NaH (1.3 g, 33.54 mmol, 55-65 % in mineral oil) under stirring in three portions under an argon atmosphere. After 20 min methyl iodide (4.76 g, 33.54 mmol) was added and the reaction was warmed to RT and stirred for another 3 h. After quenching with sat. aq NaHCO3-solution the mixture was extracted with ethyl acetate. The organic layer was washed with 1 N KHSO4 and brine. The organic layer was dried with MgSO4, filtered and evaporated. The crude material was purified by chromatography on silica gel. Yield: 4.6 g, 96 %

Reference： [1]Patent: WO2009/103440,2009,A1 .Location in patent: Page/Page column 58-59

23
[ 108-24-7 ]
[ 143900-43-0 ]
tert-butyl (3R)-3-acetoxypiperidine-1-carboxylate [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2008,vol. 56,p. 1310 - 1313

24
[ 18162-48-6 ]
[ 143900-43-0 ]
[ 1093216-40-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2008,vol. 56,p. 1310 - 1313

25
[ 1072-85-1 ]
[ 143900-43-0 ]
[ 444605-37-2 ]

Yield	Reaction Conditions	Operation in experiment
72%		Sodium hydride (2.99 g, 74.55 mmol) (60% in mineral oil) was slurred in DMF (20 mL) and heated to 65 C. To the slurry was added 1 (5 g, 24.85 mmol) in DMF (25 mL) dropwise over 30 minutes. The mixture was stirred at 65 C. for about an hour. Bromofluorobenzene (5.5 mL, 49.7 mmol) in DMF (5 mL) was added dropwise, and the mixture was stirred at 65 C. for about 16 hours. The reaction was diluted with water and concentrated to an oily solid, which was then extracted between water (200 mL) and 1/1 EtOAc/hexanes (200 mL). The organic layer was dried, filtered and concentrated. Chromatography gave the compound 2 (6.35 g, 72%) as a clear oil.

Reference： [1]Patent: US2004/82590,2004,A1 .Location in patent: Page/Page column 33

26
[ 2577-48-2 ]
[ 143900-43-0 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

27
[ 53912-80-4 ]
[ 143900-43-0 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

28
[ 113304-84-0 ]
[ 143900-43-0 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

29
[ 91599-79-0 ]
[ 143900-43-0 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500
[2]Patent: CN103864673,2016,B

30
[ 344-25-2 ]
[ 143900-43-0 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

31
[ 143900-43-0 ]
[ 1271240-70-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium azide; In N,N-dimethyl-formamide; at 90℃; for 12h;	Mesyl derivative 41a (9.20 g, 32.9 mmol) and sodium azide (8.56 g, 131.7 mmol) were heated to 90 C in DMF (200 ml) for 12 h. The solvent was then evaporated and the product was obtained in a 91% yield (6.77 g, 29.9 mmol) as a light yellow liquid after purification on a silica gel using a linear gradient of ethyl acetate in toluene.1H NMR, 13C NMR, and IR spectra were identical to those of 29. HRMS (ESI) C10H18O2N4Na (M+Na)+ calcd 249.1322, found 249.1320; [alpha]D20 +19.3 (c 0.302, EtOH).

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

32
[ 143900-43-0 ]
[ 1271240-81-3 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

33
[ 143900-43-0 ]
[ 1271240-90-4 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

34
[ 143900-43-0 ]
[ 1271240-99-3 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

35
[ 143900-43-0 ]
[ 1271241-02-1 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

36
[ 143900-43-0 ]
[ 1271241-05-4 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

37
[ 143900-43-0 ]
[ 1271241-08-7 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

38
[ 143900-43-0 ]
[ 1271241-11-2 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

39
[ 143900-43-0 ]
[ 1271241-15-6 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

40
[ 143900-43-0 ]
[ 625471-18-3 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

41
[ 143900-43-0 ]
[ 1332712-32-9 ]

Reference： [1]Patent: WO2011/104338,2011,A1

42
[ 143900-43-0 ]
[ 1332720-87-2 ]

Reference： [1]Patent: WO2011/104338,2011,A1

43
[ 143900-43-0 ]
[ 1332720-88-3 ]

Reference： [1]Patent: WO2011/104338,2011,A1

44
[ 446-35-5 ]
[ 143900-43-0 ]
[ 1332712-31-8 ]

Yield	Reaction Conditions	Operation in experiment
		IV.1 (R)-3-(5-Fluoro-2-nitro-phenoxy)-piperidine-1 -carboxylic acid fe/f-butyl ester (R)-3-Hydroxy-piperidine-1 -carboxylic acid te/t-butyl ester (4.7 g) in THF (60 ml) was cooled to 0C. At this temperature LiHMDS (1 M; 28.0 ml in THF) was added drop wise and the reaction m ixture was stirred for 45 minutes. Then 2,4-difluoronitro- benzene (4.1 g) in THF (1 0 ml) was added and stirring was continued for 1 6 hours. The reaction mixture was quenched with sat. aq . NH CI and concentrated in vacuo. The aqueous layer was adjusted to pH 3 with 1 0% aq . KHSO4 and extracted with DCM . The organic layer was passed through a hydrophobic frit, concentrated and purified by chromatography (silica gel, hexan/EtOAc 4/1 ).Yield: 6.7 g

Reference： [1]Patent: WO2011/104338,2011,A1 .Location in patent: Page/Page column 43-44

45
[ 143900-43-0 ]
[ 1375637-54-9 ]

Reference： [1]Patent: WO2012/64548,2012,A1

46
[ 4774-14-5 ]
[ 143900-43-0 ]
[ 1147998-31-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		Sodium hydride (225.6 g, 5.64 mol) is dispersed into THF (3 L) and the temperature is lowered to 0 - 5 C. A solution of (i?)-3-hydroxy-l-boc piperidine (891.6 g, 4.43 mol) in THF (3 L) is added over 1 h while maintaining the temperature between 0 - 5 C. The reaction is stirred for I h. 2,6-Dichloropyrazine (600 g, 4.03 mol) as a solution in THF (3 L) is added dropwise over 1.5 h maintaining the same temperature. The reaction is stirred for 2 h at 25 - 30 C, and then poured onto ice. The mixture is diluted with, water and extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate, filtered, arsd concentrated. The residual oil is triturated with 5% dichloromethane in hexane to give the product as a white solid. The solid is collected by filtration and dried to give 1538 g crude material. The crude product is retriturated with 5% dichloromethane in hexanes to give a white solid in quantitative yield. ES/MS m/'z

Reference： [1]Patent: WO2012/64548,2012,A1 .Location in patent: Page/Page column 7-8

47
[ 143900-43-0 ]
[ 1405127-88-9 ]

Reference： [1]Patent: WO2012/148775,2012,A1

48
[ 143900-43-0 ]
[ 1405127-89-0 ]

Reference： [1]Patent: WO2012/148775,2012,A1

49
[ 13091-23-1 ]
[ 143900-43-0 ]
[ 1405127-87-8 ]

Yield	Reaction Conditions	Operation in experiment
70%		To a solution of (R)-tert-butyl 3-hydroxypiperidine-l-carboxylate (1.22 g, 6.06 mmol, Astatech Inc., Bristol, PA) in DMF (15 mL) at 0 C was added NaH (60% wt. in oil) (283 mg, 7.06 mmol). The ice bath was removed, and the mixture was stirred at RT for 15 min. Solid 4-chloro-3-nitropyridine (800 mg, 5.05 mmol) was added and the resulting brown mixture was stirred at 0 C for 15 min before warming to RT. The reaction was quenched with ice and extracted with EtOAc (50 mL), washed with brine (2 x 30 mL) and dried over MgSOt, filtered and concentrated. Purification by silica gel chromatography (10-100% EtOAc in hexanes) afforded tert-butyl (3^)-3-((3-nitro-4-pyridinyl)oxy)-l- piperidinecarboxylate (1.14 g, 70%o yield) as a bright yellow crystalline solid. MS (ESI, pos. ion) m/z: 346.1 (M+Na+). .H NMR (400 MHz, CDCh) delta ppm 9.00 (1 H, s), 8.61 (1 H, d, J=5.9 Hz), 7.07 (1 H, br. s.), 4.48 - 4.59 (1 H, m), 3.76 (1 H, br. s.), 3.49 (3 H, br. s.), 2.06 (1 H, d, J=7.8 Hz), 1.94 (2 H, dd, J=11.7, 5.5 Hz), 1.41 (9 H, br. s.), 1.25 (1 H, br. s.).

Reference： [1]Patent: WO2012/148775,2012,A1 .Location in patent: Page/Page column 64; 65

50
[ 1376437-50-1 ]
[ 143900-43-0 ]
[ 1376437-51-2 ]

Yield	Reaction Conditions	Operation in experiment
21%	With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; for 18h;Inert atmosphere; Reflux;	21.2 3-[(4-[(3R)-1-(tert-Butoxycarbonyl)piperidin-3-yl]oxy}phenyl)carbonyl]-2-butylindolizine-7-carboxylate A mixture of 8.0 g (16.35 mmol) of propan-2-yl 2-butyl-3-[(4-iodophenyl)carbonyl]indolizine-7-carboxylate, 6.0 g (29.81 mmol) of <strong>[143900-43-0]tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate</strong>, 8.0 g (24.55 mmol) of Cs2CO3, 0.5 g (2.77 mmol) of 1,10-phenanthroline and 0.25 g (1.31 mmol) of CuI in 20 ml of anh. toluene is refluxed for 18 h under argon. The reaction mixture is then taken up with 200 ml of EtOAc, washed successively with 100 ml of water and 50 ml of brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure. The residue obtained is chromatographed on a silica column, elution being carried out with a cyclohexane/EtOAc gradient of 0 to 40% with respect to EtOAc. After concentration under reduced pressure, 2.45 g of (3R)-1-(Cert-butoxycarbonyl)piperidin-3-yl 3-[(4-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}phenyl)carbonyl]-2-butylindolizine-7-carboxylate are obtained in the form of a yellow powder. Yield=21%.

Reference： [1]Patent: US2013/245006,2013,A1 .Location in patent: Paragraph 0441-0443

51
[ 143900-43-0 ]
tert-butyl (R)-3-(((R)-1-(4-methoxyphenyl)ethyl)amino)-piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 11656 - 11669

52
[ 143900-43-0 ]
(±)-tert-butyl 3-(allylamino)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 11656 - 11669

53
[ 143900-43-0 ]
[ 98977-36-7 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 11656 - 11669

54
[ 143900-43-0 ]
(±)-tert-butyl 3-(dibenzylamino)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 11656 - 11669

55
[ 98977-36-7 ]
[ 143900-43-0 ]
[ 143900-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With culture of Xanthomonas fragariae (CECT 549); at 30℃; for 48h;Microbiological reaction;	General procedure: The strains selected in the secondary screening were used as biocatalysts in liquid medium for the reduction of cyclic ketones using cyclohexanone as a model substrate by adapting a methodology previously reported [28]. The microorganisms were cultured as mentioned above (see standard growth conditions), and then cyclohexanone (10mM) was added. The reaction was carried out at 30C in an orbital shaker at 180rpm for 2days. After removing the cells by centrifugation, the supernatants were extracted using ethyl acetate or diethyl ether, and the organic layers were analyzed by Gas Chromatography (GC).

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 827 - 830
[2]Tetrahedron Letters,2017,vol. 58,p. 1644 - 1650
[3]Tetrahedron Letters,2017,vol. 58,p. 1644 - 1650
[4]ChemBioChem,2018,vol. 19,p. 239 - 246
[5]Process Biochemistry,2017,vol. 58,p. 137 - 144

56
[ 102774-92-5 ]
[ 143900-43-0 ]

Reference： [1]Helvetica Chimica Acta,2014,vol. 97,p. 1507 - 1515

57
[ 6859-99-0 ]
[ 24424-99-5 ]
[ 143900-43-0 ]
[ 143900-44-1 ]

Reference： [1]Helvetica Chimica Acta,2014,vol. 97,p. 1507 - 1515

58
[ 19365-07-2 ]
[ 143900-43-0 ]