[ CAS No. 203662-51-5 ]

Name: 203662-51-5|4-Allyl-1-Boc-4-hydroxypiperidine|95%
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Product Details of [ 203662-51-5 ]

CAS No. :	203662-51-5	MDL No. :	MFCD09910310
Formula :	C₁₃H₂₃NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BWHACQPKDGMQIK-UHFFFAOYSA-N
M.W :	241.33 g/mol	Pubchem ID :	21955339
Synonyms :

Calculated chemistry of [ 203662-51-5 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.77
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	71.74
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) :	-6.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.95
Log Po/w (XLOGP3) :	1.91
Log Po/w (WLOGP) :	1.94
Log Po/w (MLOGP) :	1.6
Log Po/w (SILICOS-IT) :	1.81
Consensus Log Po/w :	2.04

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.21
Solubility :	1.49 mg/ml ; 0.00617 mol/l
Class :	Soluble
Log S (Ali) :	-2.58
Solubility :	0.637 mg/ml ; 0.00264 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.77
Solubility :	4.05 mg/ml ; 0.0168 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.49

Safety of [ 203662-51-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 203662-51-5 ]

* 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 [ 203662-51-5 ]
Downstream synthetic route of [ 203662-51-5 ]

[ 203662-51-5 ] Synthesis Path-Upstream 1~7

1
[ 79099-07-3 ]
[ 106-95-6 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
99.9%	With ammonium chloride; zinc In tetrahydrofuran; water at -10 - 40℃;	a, compound 1 ( 50g, 0.25mol) and zinc powder (49.2g, 0 . 75mol) tetrahydrofuran and ammonium chloride aqueous solution suspended (2/3,500 ml) in a mixed solution. - 10-10°C to control the temperature, to the reaction solution adding dropwisely compound 2 ( 109.3g, 0 . 90mol). The reaction slowly increase 15-40°C, to continue reaction 2-5 hours. TLC (petroleum ether/ethyl acetate = 2/1 volume ratio) display reaction is ended. The reaction solution with ethyl acetate (100mLx3). Combined with the phase, by sodium sulfate drying, filtering after concentration to obtain crude product is distilled under reduced pressure. The crude product by silica gel column (petroleum ether/ethyl acetate = 30/1 volume ratio to 10/1) to obtain colorless oily compound 3 ( 60g), yield 99.9percent.
95%	Stage #1: With ammonium chloride; zinc In tetrahydrofuran at 10℃; Industry scale Stage #2: With sulfuric acid; water In tetrahydrofuranIndustry scale Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water; <i>tert</i>-butyl alcoholIndustry scale	tert-butyl 4-allvl-4-hvdroxypiperidine-1-carboxvlate tert-butyl 4-oxopiperidine-i-carboxylate (1000 g, 5.02 mol) was dissolved in allylbromide (1080 ml_, 12.4 mol, 2.5 eq), THF (1000 ml_) and saturated ammonium chloride solution (5000 ml_). The reaction was cooled to 10 ⁰C and zinc dust (650 g, 10 mol, 2 eq) was added portion wise. After addition the reaction mixture was stirred overnight. TLC was taken (heptane/EtOAc 7:1 ) and showed full conversion. The reaction mixture was diluted with water (5 L) and acidified with 10percent H₂SO₄ to pH~6. The reaction mixture was extracted with MTBE (3x). The organic layers were combined and extracted with saturated solution of NaHCO₃, brine and evaporated to give tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1153 g, 95percent).

Reference： [1] Patent: CN105440046, 2016, A, . Location in patent: Paragraph 0006
[2] Patent: WO2010/58318, 2010, A1, . Location in patent: Page/Page column 25-26
[3] Patent: WO2014/139144, 2014, A1, . Location in patent: Page/Page column 165
[4] Patent: US2014/288081, 2014, A1, . Location in patent: Paragraph 0667; 0668; 0669
[5] Patent: WO2014/139325, 2014, A1, . Location in patent: Page/Page column 178; 179
[6] Journal of the American Chemical Society, 2015, vol. 137, # 36, p. 11586 - 11589

2
[ 79099-07-3 ]
[ 1730-25-2 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
19.08%	at 0℃; for 3 h; Inert atmosphere	1-Tert-butoxycarbonyl-4-piperidone (2.5 g, 12.55 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), allyl magnesium bromide (1M, 16.30 mL) was slowly added dropwise under nitrogen atmosphere at 0° C. over 1 h. The reaction was stirred for 2 h at 0° C. until the reaction was complete as monitored by TLC. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride (80 mL), the reaction was allowed to warm to room temperature and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous solution of sodium chloride (100 mL) once and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified with column chromatography (height: 100 mm, diameter: 50 mm, 100-200 silica gel, petroleum ether/ethyl acetate=4/1, 2/1) to afford 3-hydroxy-3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propene (750.00 mg, 3.11 mmol, yield: 19.08percent) as a yellow liquid. ¹H NMR (400 MHz, CHLOROFORM-d:) δ 5.93-5.83 (m, 1H), 5.27-5.14 (m, 2H), 3.83 (br. s., 2H), 3.18 (br. s., 2H), 2.25 (d, J=7.5 Hz, 2H), 1.61-1.50 (m, 4H), 1.48 (s, 9H).

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 48, p. 6457 - 6459
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3672 - 3683
[3] Patent: US2018/148452, 2018, A1, . Location in patent: Paragraph 0191
[4] Patent: US2012/252778, 2012, A1, . Location in patent: Paragraph 0334-0335
[5] Patent: WO2018/26371, 2018, A1, . Location in patent: Paragraph 0320

3
[ 79099-07-3 ]
[ 106-95-6 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
45%	With zinc In tetrahydrofuran	Step A 1-(t-Butoxycarbonyl)-4-(prop-2-enyl)-4-hydroxypiperidine A dry round bottom flask was purged with nitrogen and charged with 1-t-butoxycarbonyl-4-piperidinone (20 g, 100 mmol), titanocene dichloride (1.2 g, 5 mmol) and zinc dust (7.8 g, 120 mmol) in 100 mL dry THF. Allyl bromide (11.3 mL, 130 mmol) was added and the mixture was stirred for 5 h at rt. The mixture was diluted with 700 mL EtOAc, washed with 2.0 M HCl (2*200 ML), 100 mL of sat'd NaCl, dried over MgSO₄ and concentrated. Flash chromatography (650 g silica, 10/1 CH₂Cl₂/Et₂O eluant) afforded 10.9 g (45percent) of the title compound: ¹H NMR (300 MHz) δ 1.4-1.6 (13H), 2.2-2.25 (d, 2H), 3.1-3.2 (m, 2H), 3.75-3.85 (m, 2H), 5.1-5.25 (m, 2H), 5.78-5.92 (m, 1H).

Reference： [1] Patent: US6265434, 2001, B1,

4
[ 79099-07-3 ]
[ 1730-25-2 ]
[ 203662-51-5 ]

Reference： [1] Patent: US6498159, 2002, B1,

5
[ 10049-21-5 ]
[ 79099-07-3 ]
[ 1730-25-2 ]
[ 203662-51-5 ]

Reference： [1] Patent: US6518423, 2003, B1,

6
[ 203662-51-5 ]
[ 240401-09-6 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: With sodium periodate In water; <i>tert</i>-butyl alcohol at 50℃; for 0.5 h; Industry scale Stage #2: With sodium disulfite In water; <i>tert</i>-butyl alcohol at 20 - 50℃; for 59 h; Industry scale	tert-butyl (3RS)-3-hydroxy-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1153 g, 4.8 mol) was dissolved in tert-butanol (10 L) and water (4 L). To the solution sodium periodate (1124 g, 5.3 mol, 1.1 eq) was added and the mixture was stirred at 50 ⁰C for 30 minutes. At 50 ⁰C a solution of Na₂S₂O₅ (1007 g, 5.3 mol, 1.1 eq) in water (4.2 L) was added dropwise over 4 hours to the solution. After addition the reaction mixture was stirred for 7 hours at 50 ⁰C and another 48 hours at RT. The mixture was transferred to an extraction vessel and the organic layer was separated from the aqueous layer. The aqueous layer was extracted (3x) with ethyl acetate. The organic layers were combined and washed with a saturated solution of Na₂S₂O₃ (3x) to give a colorless solution. The solution was washed with brine and evaporated to give crude product (987 g, 80percent). The crude product was purified by flash chromatography (10-80percent EtOAc/Heptane) to give the title compound (287 g, 35percent). m/z 158 (MH⁺ minus Boc).

Reference： [1] Patent: WO2010/58318, 2010, A1, . Location in patent: Page/Page column 26

7
[ 203662-51-5 ]
[ 954236-44-3 ]

Reference： [1] Patent: WO2018/26371, 2018, A1,

[ 203662-51-5 ] Synthesis Path-Downstream 1~59

Yield	Reaction Conditions	Operation in experiment
		tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate The desired product was prepared by substituting allyl magnesium bromide for methyl magnesium bromide in Example 494A. MS (DCI(+)) m/e 242 (M+H)+.

2
[ 203662-51-5 ]
[ 106-95-6 ]
1,1-dimethylethyl 4-(2-propenyl)-4-(2-propenyloxy)-1-piperidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 0.833333h;	Sodium hydride (60% dispersion in mineral oil, 12 g, 0.3 mol) was added slowly to a stirred, cooled (0 C.) solution of 1,1-dimethylethyl 4-hydroxy-42-propenyl)-1-piperidinecarboxylate (Description 129, 23.1 g, 0.096 mol) in dimethylformamide (200 mL) and the mixture was stirred at 0 C. for 10 minutes. Allyl bromide (25.4 ml, 0.3 mol) was added and the mixture was stirred at 0 C. for 5 minutes, then at room temperature for 45 minutes. The mixture was cooled to 0 C. and water (200 mL) was added. The mixture was extracted with diethyl ether (2×200 mL) and the combined organic fractions were washed with water (4×200 mL) and brine (150 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (9:1), to give the title compound (5.5 g, 20%). m/z (E) 226 (M+1-C4H8).

Reference： [1]Patent: US2003/236250,2003,A1 .Location in patent: Page 130

3
ammonium chloride [ No CAS ]
[ 79099-07-3 ]
[ 1730-25-2 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether;	INTERMEDIATE EXAMPLE 21 800 ml solution of 25.0 g tert-butyl 4-oxo-1-piperidinecarboxylate in diethyl ether was cooled in ice/methanol, and 138 ml solution of allylmagnesium bromide (1 M in diethyl ether) was added dropwise thereinto. The reaction mixture was stirred for 3 hr and 10 min. The reaction solution was poured into a mixture of saturated aqueous ammonium chloride and ice. The diethyl ether layer was recovered and washed with brine. It was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and the resulting residue was purified by silica gel column chromatography to give 15.9 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate.

Reference： [1]Patent: US6498159,2002,B1

4
[ 10049-21-5 ]
[ 79099-07-3 ]
[ 1730-25-2 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether;	Example 270 4-Allyl-1-(tert-butoxycarbonyl)piperidin-4-ol Into a solution of 4.98 g of 1-(tert-butoxycarbonyl)-4-piperidone in diethyl ether (150 ml) was dropped at 0 C. in a nitrogen atmosphere 30 ml of a 1.0 M solution of allylmagnesium bromide in diethyl ether and the resulting mixture was stirred for 3 hours. Then the reaction mixture was poured into an aqueous solution of sodium dihydrogenphosphate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.12 g of the title compound as a white solid. 1H-NMR(CDCl3) delta ppm: 1.45(s, 9H), 1.54(m, 4H), 2.23(br.d, J=7 Hz, 2H), 3.15(br.s, 2H), 3.80(br.s, 2H), 5.15(ddt, J=1, 2, 16 Hz, 1H), 5.21(ddt, J=1, 2, 10 Hz, 1H), 5.86(ddt, J=7, 10, 16 Hz, 1H)

Reference： [1]Patent: US6518423,2003,B1

5
sodium metabisulfite [ No CAS ]
[ 203662-51-5 ]
[ 203662-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; ethyl acetate;	Example 271 4-(2,3-Epoxypropan-1-yl)-1-(tert-butoxycarbonyl)piperidin-4-ol To a solution of 4.115 g of <strong>[203662-51-5]4-allyl-1-(tert-butoxycarbonyl)piperidin-4-ol</strong> in dichloromethane (100 ml) were added 7.07 g of 3-chloroperbenzoic acid and 2.87 g of sodium hydrogencarbonate and the resulting mixture was heated under reflux for 24 hours. To the reaction mixture were added ethyl acetate and an aqueous solution of sodium metabisulfite and the resulting mixture was stirred for 1 hour. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/ethyl acetate) to thereby give 1.43 g of the title compound as a colorless solid. 1H-NMR(CDCl3) delta ppm: 1.45(s, 9H), 1.40-1.56(m, 5H), 1.88(dd, J=3, 14 Hz, 1H), 2.00(br.s, 1H), 2.50(dd, J=3, 6 Hz, 1H), 2.82(t, J=3 Hz, 1H), 3.14-3.27(m, 3H), 3.91(br.s, 2H)

Reference： [1]Patent: US6518423,2003,B1

6
[ 203662-51-5 ]
[ 7529-22-8 ]
[ 240401-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water; tert-butyl alcohol;	9.83 g of <strong>[203662-51-5]tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate</strong> was dissolved in 60 ml tetrahydrofuran/water (9:1), a solution (2.5 wt %, 2 ml) of osmium tetraoxide in tert-butyl alcohol and 6.68 g of N-methylmorpholine-N-oxide were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated, and the resulting residue was partitioned into ethyl acetate and water, washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give 9.11 g of tert-butyl 4-(2,3-dihydroxypropyl)-4-hydroxy-1-piperidinecarboxylate.

Reference： [1]Patent: US6498159,2002,B1

7
titanocene dichloride [ No CAS ]
[ 79099-07-3 ]
[ 106-95-6 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
10.9 g (45%)	With zinc; In tetrahydrofuran;	Step A 1-(t-Butoxycarbonyl)-4-(prop-2-enyl)-4-hydroxypiperidine A dry round bottom flask was purged with nitrogen and charged with 1-t-butoxycarbonyl-4-piperidinone (20 g, 100 mmol), titanocene dichloride (1.2 g, 5 mmol) and zinc dust (7.8 g, 120 mmol) in 100 mL dry THF. Allyl bromide (11.3 mL, 130 mmol) was added and the mixture was stirred for 5 h at rt. The mixture was diluted with 700 mL EtOAc, washed with 2.0 M HCl (2*200 ML), 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography (650 g silica, 10/1 CH2Cl2/Et2O eluant) afforded 10.9 g (45%) of the title compound: 1H NMR (300 MHz) delta 1.4-1.6 (13H), 2.2-2.25 (d, 2H), 3.1-3.2 (m, 2H), 3.75-3.85 (m, 2H), 5.1-5.25 (m, 2H), 5.78-5.92 (m, 1H).

Reference： [1]Patent: US6265434,2001,B1

8
[ 203662-51-5 ]
[ 203662-52-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With dihydrogen peroxide; potassium carbonate; In methanol; water; acetonitrile; at 60℃; for 1h;	Wherein R1 is a tert-butoxycarbonyl group. The compound of the formula II (200.0 g, 0.83 mol, 1.0 eq.), acetonitrile (170.0 g, 4.14 mol, 5.0 eq.) was dissolved in methanol (1 L), and potassium carbonate (56.6 g, 0.41 mol, 0.5 eq. The system was heated to 40 C, and a 30% by mass aqueous hydrogen peroxide solution (470.0 g, 4.14 mol, 5.0 eq.) was added dropwise, and the reaction was carried out at 60 C for 1 h. The system was cooled to 35 C, ethyl acetate (2 L), saturated brine (1 L) was added, and the layers were stirred and the organic phase was collected.The organic phase was dried, concentrated, sand-purified, and purified by column chromatography ( petroleum ether: ethyl acetate = 3:1 to 1:1) to give a compound of formula III as a colorless oil, total 156.3 g, yield 73%.
26%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;pH 8;Phosphate buffer;	4.i) 4-Hydroxy-4-oxiranylmethyl-piperidine-1-carboxylic acid tert-butyl esterA solution of 4-allyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 12.8 mmol, prepared according to J. Comb. Chem. 2002, 4, 125) in DCM and 0.3 M phosphate buffer (pH 8, 150 mL) was treated with mCPBA (3.5 g, 1.1 eq, 70%) and the mixture vigorously stirred at rt overnight. Further 3.5 g of mCPBA were added. After a total of 24 h, the phases were separated, the org. phase dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1:1 to EA) gave the desired intermediate as colourless oil (0.88 g, 26%).1H NMR (CDCl3) delta: 3.90-3.70 (m, 2H), 3.30-3.10 (m, 3H), 2.83 (dd, J=4.1, 4.9 Hz, 1H), 2.51 (dd, J=2.7, 4.9 Hz, 1H), 1.89 (dd, J=3.8, 14.5 Hz, 1H), 1.80-1.40 (m, 4H), 1.47 (s, 9H).
26%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;pH 8;Phosphate buffer;	4 i) 4-Hydroxy-4-oxiranylmethyl-piperidine-l-carboxylic acid tert-butyl esterA solution of 4-allyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (3.1g, 12.8 mmol, prepared according to J. Comb. Chem. 2002, 4, 125) in DCM and 0.3 M phosphate buffer (pH 8, 150 niL) was treated with mCPBA (3.5 g, 1.1 eq, 70%) and the mixture vigorously stirred at rt overnight. Further 3.5 g of mCPBA were added. After a total of 24 h, the phases were separated, the org. phase dried over MgSO4 and concentrated. CC(hex/EA 2:lto l :lto EA) gave the desired intermediate as colourless oil (0.88 g, 26%).1H NMR (CDCl3) delta: 3.90-3.70 (m, 2H), 3.30-3.10 (m, 3H), 2.83 (dd, ./=4.1 , 4.9 Hz, IH),2.51 (dd, J=2.7, 4.9 Hz, IH), 1.89 (dd, J=3.8, 14.5 Hz, IH), 1.80-1.40 (m, 4H), 1.47 (s,9H).

Reference： [1]Patent: CN109265389,2019,A .Location in patent: Paragraph 0026-0031; 0078-0082
[2]Patent: US2011/39823,2011,A1 .Location in patent: Page/Page column 36
[3]Patent: WO2008/126034,2008,A2 .Location in patent: Page/Page column 93
[4]Journal of the American Chemical Society,2015,vol. 137,p. 11586 - 11589

9
[ 79099-07-3 ]
[ 106-95-6 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
99.9%	With ammonium chloride; zinc; In tetrahydrofuran; water; at -10 - 40℃;	a, compound 1 ( 50g, 0.25mol) and zinc powder (49.2g, 0 . 75mol) tetrahydrofuran and ammonium chloride aqueous solution suspended (2/3,500 ml) in a mixed solution. - 10-10C to control the temperature, to the reaction solution adding dropwisely compound 2 ( 109.3g, 0 . 90mol). The reaction slowly increase 15-40C, to continue reaction 2-5 hours. TLC (petroleum ether/ethyl acetate = 2/1 volume ratio) display reaction is ended. The reaction solution with ethyl acetate (100mLx3). Combined with the phase, by sodium sulfate drying, filtering after concentration to obtain crude product is distilled under reduced pressure. The crude product by silica gel column (petroleum ether/ethyl acetate = 30/1 volume ratio to 10/1) to obtain colorless oily compound 3 ( 60g), yield 99.9%.
95%		tert-butyl 4-allvl-4-hvdroxypiperidine-1-carboxvlate tert-butyl 4-oxopiperidine-i-carboxylate (1000 g, 5.02 mol) was dissolved in allylbromide (1080 ml_, 12.4 mol, 2.5 eq), THF (1000 ml_) and saturated ammonium chloride solution (5000 ml_). The reaction was cooled to 10 0C and zinc dust (650 g, 10 mol, 2 eq) was added portion wise. After addition the reaction mixture was stirred overnight. TLC was taken (heptane/EtOAc 7:1 ) and showed full conversion. The reaction mixture was diluted with water (5 L) and acidified with 10% H2SO4 to pH~6. The reaction mixture was extracted with MTBE (3x). The organic layers were combined and extracted with saturated solution of NaHCO3, brine and evaporated to give tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1153 g, 95%).
	With ammonium chloride; zinc; In tetrahydrofuran; at 10℃;	To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (10 g, 50.2 mmol), alyl bromide (10.8 mL, 124 mmol) in THF (10 mL), and saturated ammonium chloride solution (50 mL) was added Zn dust (6.5 g, 100 mmol) portionwise below 10C. After addition was complete, the reaction mixture was stirred overnight, when TLC indicated consumption of s.m.. The reaction mixture was diluted with water (50 mL) and acidified with several drops of 10% H2SO4 to pH=6. The reaction mixture was extracted with EtOAc (3 x 200 mL). The organic layers were combined and washed with a saturated solution of NaHC03, brine and evaporated, to give the crude product which was purified by chromatography to give title compound 11B as colorless oil. 1H NMR (CHLOROFORM-d) delta: 5.77 - 5.92 (m, 1H), 5.05 - 5.21 (m, 2H), 3.76 (br. s., 2H), 3.05 - 3.22 (m, 2H), 2.21 (d, J = 7.6 Hz, 2H), 2.01 (br. s., 1H), 1.50 (dd, J = 7.2, 4.0 Hz, 3H), 1.47 (s, 1H), 1.43 (s, 9H).

	With ammonium chloride; zinc; In tetrahydrofuran; at 10℃;	To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.2 mmol), allyl bromide (10.8 mL, 124 mmol) in THF (10 mL), and saturated ammonium chloride solution (50 mL) was added Zn dust (6.5 g, 100 mmol) portionwise below 10 C. After addition was complete, the reaction mixture was stirred overnight, when TLC indicated consumption of s.m. The reaction mixture was diluted with water (50 mL) and acidified with several drops of 10% H2SO4 to pH=6. The reaction mixture was extracted with EtOAc (3×200 mL), The organic layers were combined and washed with a saturated solution of NaHCO3, brine and evaporated, to give the crude product which was purified by chromatography to give title compound 11B as colorless oil. [0669] 1H NMR (CHLOROFORM-d) delta: 5.77-5.92 (m, 1H), 5.05-5.21 (m, 2H), 3.76 (br. s., 2H), 3.05-3.22 (m, 2H), 2.21 (d, J=7.6 Hz, 2H), 2.01 (br. s., 1H), 1.50 (dd, J=7.2, 4.0 Hz, 3H), 1.47 (s, 1H), 1.43 (s, 9H).
	With ammonium chloride; zinc; In tetrahydrofuran; at 10℃;	To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (10 g, 50.2 mmol), alyl bromide (10.8 mL, 124 mmol) in THF (10 mL), and saturated ammonium chloride solution (50 mL) was added Zn dust (6.5 g, 100 mmol) portionwise below 10C. After addition was complete, the reaction mixture was stirred overnight, when TLC indicated consumption of s.m.. The reaction mixture was diluted with water (50 mL) and acidified with several drops of 10% H2SO4 to pH=6. The reaction mixture was extracted with EtOAc (3 x 200 mL). The organic layers were combined and washed with a saturated solution of NaHC03, brine and evaporated, to give the crude product which was purified by chromatography to give title compound 11B as colorless oil. 1H NMR (CHLOROFORM-d) delta: 5.77 - 5.92 (m, 1H), 5.05 - 5.21 (m, 2H), 3.76 (br. s., 2H), 3.05 - 3.22 (m, 2H), 2.21 (d, J = 7.6 Hz, 2H), 2.01 (br. s., 1H), 1.50 (dd, J = 7.2, 4.0 Hz, 3H), 1.47 (s, 1H), 1.43 (s, 9H).

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 8561 - 8565
Angew. Chem.,2019,vol. 131,p. 8649 - 8653,5
[2]Patent: CN105440046,2016,A .Location in patent: Paragraph 0006
[3]Patent: WO2010/58318,2010,A1 .Location in patent: Page/Page column 25-26
[4]Patent: WO2014/139144,2014,A1 .Location in patent: Page/Page column 165
[5]Patent: US2014/288081,2014,A1 .Location in patent: Paragraph 0667; 0668; 0669
[6]Patent: WO2014/139325,2014,A1 .Location in patent: Page/Page column 178; 179
[7]Journal of the American Chemical Society,2015,vol. 137,p. 11586 - 11589

10
[ 203662-51-5 ]
[ 240401-09-6 ]

Yield	Reaction Conditions	Operation in experiment
35%		tert-butyl (3RS)-3-hydroxy-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate <strong>[203662-51-5]tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate</strong> (1153 g, 4.8 mol) was dissolved in tert-butanol (10 L) and water (4 L). To the solution sodium periodate (1124 g, 5.3 mol, 1.1 eq) was added and the mixture was stirred at 50 0C for 30 minutes. At 50 0C a solution of Na2S2O5 (1007 g, 5.3 mol, 1.1 eq) in water (4.2 L) was added dropwise over 4 hours to the solution. After addition the reaction mixture was stirred for 7 hours at 50 0C and another 48 hours at RT. The mixture was transferred to an extraction vessel and the organic layer was separated from the aqueous layer. The aqueous layer was extracted (3x) with ethyl acetate. The organic layers were combined and washed with a saturated solution of Na2S2O3 (3x) to give a colorless solution. The solution was washed with brine and evaporated to give crude product (987 g, 80percent). The crude product was purified by flash chromatography (10-80percent EtOAc/Heptane) to give the title compound (287 g, 35percent). m/z 158 (MH+ minus Boc).

Reference： [1]Patent: WO2010/58318,2010,A1 .Location in patent: Page/Page column 26

11
[ 203662-51-5 ]
[ 1072827-13-4 ]

Reference： [1]Patent: WO2008/126034,2008,A2

12
[ 203662-51-5 ]
[ 1072827-14-5 ]

Reference： [1]Patent: WO2008/126034,2008,A2

13
[ 203662-51-5 ]
[ 1072827-15-6 ]

Reference： [1]Patent: WO2008/126034,2008,A2

14
[ 203662-51-5 ]
[ 1072825-14-9 ]

Reference： [1]Patent: WO2008/126034,2008,A2
[2]Patent: US2011/39823,2011,A1

15
[ 203662-51-5 ]
[ 1346229-46-6 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459

16
[ 203662-51-5 ]
[ 1346229-47-7 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459

17
[ 203662-51-5 ]
[ 1346229-42-2 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459

18
[ 203662-51-5 ]
tert-butyl 1-oxa-9-azaspiro[5.5]undec-3-ene-9-carboxylate [ No CAS ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 11327 - 11340

19
[ 203662-51-5 ]
[ 374795-42-3 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459

20
[ 203662-51-5 ]
[ 106-95-6 ]
tert-butyl 4-allyl-4-(allyloxy)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 11327 - 11340
[2]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459

21
[ 79099-07-3 ]
[ 1730-25-2 ]
[ 203662-51-5 ]

Yield	Reaction Conditions	Operation in experiment
19.08%	In tetrahydrofuran; at 0℃; for 3h;Inert atmosphere;	1-Tert-butoxycarbonyl-4-piperidone (2.5 g, 12.55 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), allyl magnesium bromide (1M, 16.30 mL) was slowly added dropwise under nitrogen atmosphere at 0 C. over 1 h. The reaction was stirred for 2 h at 0 C. until the reaction was complete as monitored by TLC. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride (80 mL), the reaction was allowed to warm to room temperature and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous solution of sodium chloride (100 mL) once and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified with column chromatography (height: 100 mm, diameter: 50 mm, 100-200 silica gel, petroleum ether/ethyl acetate=4/1, 2/1) to afford 3-hydroxy-3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propene (750.00 mg, 3.11 mmol, yield: 19.08%) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d:) delta 5.93-5.83 (m, 1H), 5.27-5.14 (m, 2H), 3.83 (br. s., 2H), 3.18 (br. s., 2H), 2.25 (d, J=7.5 Hz, 2H), 1.61-1.50 (m, 4H), 1.48 (s, 9H).
	In diethyl ether; at 0℃; for 1.5h;	General procedure: 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.5 mmol) was dissolved in 25 ml of diethylether and cooled to 0 C. A 1M solution of vinylmagnesiumbromide in THF (16.3 ml, 16.31 mmol) was added dropwise at 0 C. After 90 min stirring at 0 C., the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was further purified by flash chromatography (silicagel, cyclohexane/ethylacetate 4:1).
	In tetrahydrofuran; at 0℃; for 2h;	A. To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.0 g, 30.11 mmol) in THF (40 mL) was added dropwised allylmagnesium bromide (33.2 mL, 33.12 mmol). The reaction was stirred at 0 C for 2 h. saturated aqueous NH4Cl (50 mL) and EtOAc (300 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hex (100%) to hexanes (80%) and EtOAc (20%) to provide tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (5 g, 20.72 mmol) as a colorless oil.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6457 - 6459
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 3672 - 3683
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 11327 - 11340
[4]Patent: US2018/148452,2018,A1 .Location in patent: Paragraph 0191
[5]Patent: US2012/252778,2012,A1 .Location in patent: Paragraph 0334-0335
[6]Patent: WO2018/26371,2018,A1 .Location in patent: Paragraph 0320

22
[ 203662-51-5 ]
[ 1356386-52-1 ]

Reference： [1]Patent: WO2012/9217,2012,A1

23
[ 203662-51-5 ]
[ 1346229-49-9 ]

Reference： [1]Patent: WO2012/9217,2012,A1

24
[ 203662-51-5 ]
[ 1346229-43-3 ]

Reference： [1]Patent: WO2012/9217,2012,A1

25
[ 203662-51-5 ]
[ 1356385-84-6 ]

Reference： [1]Patent: WO2012/9217,2012,A1

26
[ 203662-51-5 ]
[ 1356386-54-3 ]

Reference： [1]Patent: WO2012/9217,2012,A1

27
[ 203662-51-5 ]
[ 1356386-55-4 ]

Reference： [1]Patent: WO2012/9217,2012,A1

28
[ 203662-51-5 ]
[ 1356470-45-5 ]
[ 1356470-46-6 ]

Reference： [1]Patent: WO2012/9217,2012,A1

29
[ 203662-51-5 ]
[ 4224-69-5 ]
[ 1346229-48-8 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 12. methyl l-oxa-9-azaspiro[5.5]undecane-3-carboxylate (TFA salt)Step 1. A 60% oil dispersion of sodium hydride (0.438 g, 1.2 equiv) was added to a solution of tert-butyl 4-allyM-hydroxypiperidme-1- arboxylate (2.2 g, 1 equiv) (Walters, M. A.; La, F.; Deshmukh, P.; Omecinsky, D. O. J. Comb. Chem. 2002, 4(2), 125-130) in anhydrous DMF (170 mL) and the mixture cooled to 0 *C. The mixture was warmed to room temperature over 1 hour and methyl 2-(bromomethyl)acrylate (1.63 g, 1 equiv) was added dropwise to the solution over 5 minutes. The mixture was aged for 72 hours. A saturated solution of ammonium chloride was added to the reaction mixture and the mixture was diluted with ethyl acetate. The organic phase was separated and washed twice with water then brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified using column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 920 mg of iert-butyl 4-[2- (memoxycarbonyl)pror 2-en-1-yl]oxy}-4-^ as a colorless oil: [ Naf m/z 362.

Reference： [1]Patent: WO2012/9217,2012,A1 .Location in patent: Page/Page column 73-74

30
[ 203662-51-5 ]
[ 374794-88-4 ]

Yield	Reaction Conditions	Operation in experiment
629 mg	With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	A mixture of BH3 in THF (21 mL, 21 ,0 mmol) was added slowly to a mixture of tert- butyl 4-allyl-4-hydroxypiperidine-l-carboxylate (500 mg, 2,07 mmol) and THF (5 mL) at 0C under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0C and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic extracts were dried over Na2S04 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-huty 4-hydroxy-4-(3- hydroxypropyl) piperidine-l-carboxylate 13B (629 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) delta: 3.65 (t, J = 5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63 - 1.71 (m, 2H), 1.53 - 1.62 (m, 4H), 1.41 - 1.48 (m, 9H).
629 mg		A mixture of BH3 in THF (21 mL, 21.0 mmol) was added slowly to a mixture of <strong>[203662-51-5]tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate</strong> (500 mg, 2.07 mmol) and THF (5 L) at 0 C. under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0 C. and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3*20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl) piperidine-1-carboxylate 13B (629 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) delta: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H).
629 mg	With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	A mixture of BH3 in THF (21 mL, 21 ,0 mmol) was added slowly to a mixture of tert- butyl 4-allyl-4-hydroxypiperidine-l-carboxylate (500 mg, 2,07 mmol) and THF (5 mL) at 0C under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0C and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic extracts were dried over Na2S04 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-huty 4-hydroxy-4-(3- hydroxypropyl) piperidine-l-carboxylate 13B (629 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) delta: 3.65 (t, J = 5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63 - 1.71 (m, 2H), 1.53 - 1.62 (m, 4H), 1.41 - 1.48 (m, 9H).

Reference： [1]Patent: WO2014/139144,2014,A1 .Location in patent: Page/Page column 167; 168
[2]Patent: US2014/288081,2014,A1 .Location in patent: Paragraph 0682; 0683
[3]Patent: WO2014/139325,2014,A1 .Location in patent: Page/Page column 181; 182

31
[ 203662-51-5 ]
(E)-tert-butyl 4-acetoxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/139144,2014,A1
[2]Patent: US2014/288081,2014,A1

32
[ 203662-51-5 ]
(E)-tert-butyl 4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/139144,2014,A1
[2]Patent: US2014/288081,2014,A1

33
[ 203662-51-5 ]
(E)-4-(4,4,4-trifluorobut-1-enyl)piperidin-4-ol [ No CAS ]

Reference： [1]Patent: WO2014/139144,2014,A1
[2]Patent: US2014/288081,2014,A1

34
[ 203662-51-5 ]
(E)-N-(4-(4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide [ No CAS ]

Reference： [1]Patent: WO2014/139144,2014,A1
[2]Patent: US2014/288081,2014,A1

35
[ 203662-51-5 ]
[ 81290-20-2 ]
tert-butyl 4-((2,2-difluorocyclopropyl)methyl)-4-hydroxypiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In tetrahydrofuran; at 80℃;Sealed tube;	To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-l-carboxylate 11B (280 mg, 1.16 mmol), Nal (112 mg, 0.74 mmol), trimethyl(trifSuoromethyl)silane (0.6 mL) and THF (10 mL). The tube was sealed, and then the mixture was stirred at 80C overnight. The resulting mixture was diluted with DC , filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which wras used for next step without further purification, LC-MS: m/z 292.3 (M+H)+
	With sodium iodide; In tetrahydrofuran; at 80℃;Sealed tube;	To a sealed tube was added <strong>[203662-51-5]tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate</strong> 11B (280 mg, 1.16 mmol), NaI (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL), The tube was sealed, and then the mixture was stirred at 80 C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
	With sodium iodide; In tetrahydrofuran; at 80℃;Sealed tube;	To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-l-carboxylate 11B (280 mg, 1.16 mmol), Nal (112 mg, 0.74 mmol), trimethyl(trifSuoromethyl)silane (0.6 mL) and THF (10 mL). The tube was sealed, and then the mixture was stirred at 80C overnight. The resulting mixture was diluted with DC , filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which wras used for next step without further purification, LC-MS: m/z 292.3 (M+H)+

Reference： [1]Patent: WO2014/139144,2014,A1 .Location in patent: Page/Page column 165; 166
[2]Patent: US2014/288081,2014,A1 .Location in patent: Paragraph 0670; 0671
[3]Patent: WO2014/139325,2014,A1 .Location in patent: Page/Page column 178; 179

36
[ 203662-51-5 ]
4-((2,2-difluorocyclopropyl)methyl)piperidin-4-ol [ No CAS ]

Reference： [1]Patent: WO2014/139144,2014,A1

37
[ 203662-51-5 ]
[ 884586-68-9 ]

Reference： [1]Patent: WO2014/139144,2014,A1
[2]Patent: US2014/288081,2014,A1

38
[ 203662-51-5 ]
[ 108-24-7 ]
tert-butyl 4-acetoxy-4-allylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.4 g	With dmap; triethylamine; In dichloromethane; at 20℃;	A solution of tert-butyl 4-allyl-4-hydroxypiperidine-l-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20 C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H) +
3.4 g	With dmap; triethylamine; In dichloromethane; at 20℃;	A solution of <strong>[203662-51-5]tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate</strong> (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20 C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H)+
3.4 g	With dmap; triethylamine; In dichloromethane; at 20℃;	A solution of tert-butyl 4-allyl-4-hydroxypiperidine-l-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20 C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H) +

Reference： [1]Patent: WO2014/139144,2014,A1 .Location in patent: Page/Page column 212; 213
[2]Patent: US2014/288081,2014,A1 .Location in patent: Paragraph 0897; 0898
[3]Patent: WO2014/139325,2014,A1 .Location in patent: Page/Page column 225; 226

39
[ 203662-51-5 ]
C₁₆H₃₁NO₄Si [ No CAS ]