[ CAS No. 406235-30-1 ]

Name: 406235-30-1|1-Boc-4-Hydroxy-4-methylpiperidine|97%
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Quality Control of [ 406235-30-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 406235-30-1 ]

CAS No. :	406235-30-1	MDL No. :	MFCD04972471
Formula :	C₁₁H₂₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SWUCHJAQBNXPBO-UHFFFAOYSA-N
M.W :	215.29	Pubchem ID :	22730812
Synonyms :

Calculated chemistry of [ 406235-30-1 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	62.6
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) :	-6.78 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.67
Log Po/w (XLOGP3) :	1.17
Log Po/w (WLOGP) :	1.39
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	1.04
Consensus Log Po/w :	1.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.71
Solubility :	4.16 mg/ml ; 0.0193 mol/l
Class :	Very soluble
Log S (Ali) :	-1.81
Solubility :	3.33 mg/ml ; 0.0155 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.31
Solubility :	10.5 mg/ml ; 0.0488 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.21

Safety of [ 406235-30-1 ]

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

Application In Synthesis of [ 406235-30-1 ]

* 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 [ 406235-30-1 ]
Downstream synthetic route of [ 406235-30-1 ]

[ 406235-30-1 ] Synthesis Path-Upstream 1~9

1
[ 406235-30-1 ]
[ 3970-68-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With trifluoroacetic acid In dichloromethane at 20℃; for 1 h;	4-methyl-piperidin-4-ol (Intermediate 79b)A solution of Intermediate 79a (5.50 g, 25.6 mmol) in TFA (20 mL) and DCM (40 mL) was stirred at RT for 1 h. The reaction mixture was applied to SCX- 2 cartridges (2 70 g) and washed with MeOH. The product was eluted with 2M NH₃ in MeOH; concentration in vacuo gave the title compound (3.19 g, 99percent). NMR (400 MHz, CDC1₃): 1.24 (3H, s), 1.51-1.61 (4H, m), 2.75-2.87 (2H, m), 2.89-3.02 (2H, m).
93.46%	With trifluoroacetic acid In dichloromethane at 20℃; for 1 h;	Synthesis of compound 221.3. To a solution of 221.2 (1.3 g, 6.04 mmol, l .Oeq) in CH₂C1₂ (10 mL) was added trifluoroacetic acid (5mL). The reaction was allowed to stir at room temperature for lh. After completion of reaction, solvent was evaporated under reduced pressure to obtain pure TFA salt of 221.3 (0.650g, 93.46percent). MS(ES): m/z 115.18 [M+H]⁺.

Reference： [1] Patent: WO2013/83604, 2013, A1, . Location in patent: Page/Page column 278
[2] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001155; 001157
[3] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0604; 0605

2
[ 75-16-1 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	at -10 - 20℃; for 2 h; Inert atmosphere	a) tert-Butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (A 141) ferf-Butyl 4-oxopiperidine-1 -carboxylate (1.0 g, 5.0 mmol) was dissolved in anhydrous Et₂0 (10 mL) and cooled to -10°C under nitrogen. A solution of methylmagnesium bromide (3 M in Et₂0, 2.5 mL, 7.5 mmol) was added drop-wise and the mixture stirred for 5 minutes. The cooling bath was removed and the slurry was stirred at room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride (10 mL) and then diluted with water (20 mL) and diethyl ether (20 mL). The aqueous phase was extracted with diethyl ether (2 ^χ 30 mL), the pooled organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (1.05 g, 97percent). H NMR (400 MHz, CDCI₃) δ 3.76-3.64 (m, 2H), 3.29-3.16 (m, 2H), 1.66 (s, 1 H), 1.45 (s, 9H), 1.25 (s, 3H) 4H obscured by solvent.
97%	Stage #1: at -30 - 20℃; Inert atmosphere Stage #2: With water; ammonium chloride In diethyl ether	To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at -25 to -30 °C was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97percent). ¹H NMR (CDCl₃, 300MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
90%	at -25 - 20℃; for 2 h; Inert atmosphere	Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°Cand quenched by the addition of sat. aq. ammonium chloride. Another 20 mL ofether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (4.30g, 18.0 mmol, 90 percent) as a colorless oil. ‘H NMR (400MHz, CDC13) ö 3.84 - 3.65 (m,2H), 3.34 -3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50- 1.45 (m,9H), 1.32- 1.27 (m, 3H).

90%	at -25 - 20℃; for 2 h; Inert atmosphere	Under an N2 atmosphere, a 3N solution in ether ofmethylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to oocand quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04 , filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percentEtOAc/hexane to obtain tert-butyl4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. 1H NMR (400MHz, CDCh) 8 3.84- 3.65 (m,2H), 3.34-3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61- 1.53 (m, 4H), 1.50- 1.45 (m,9H), 1.32- 1.27 (m, 3H).
90%	at -25 - 20℃; for 2 h; Inert atmosphere	Int rmediate 43 tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS0₄, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. 1H NMR (400MHz, CDC1₃) δ 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90%	at -25 - 20℃; for 2 h; Inert atmosphere	tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS0₄, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. 1H NMR (400MHz, CDC1₃) δ 3.84 - 3.65 (i 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90%	at -25 - 20℃; Inert atmosphere	Intermediate 9 (0109) tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N₂ atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 °C and quenched by the addition of sat. NH₄CI. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS0₄, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent yield) as a colorless oil. ¹H NMR (500 MHz, CDC1₃) δ 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90%	at -25 - 20℃; for 2 h; Inert atmosphere	Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (−25° C.) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4 g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0° C. and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO₄, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90percent) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.84-3.65 (m, 2H), 3.34-3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61-1.53 (m, 4H), 1.50-1.45 (m, 9H), 1.32-1.27 (m, 3H).
90%	at -25 - 20℃; for 2 h; Inert atmosphere	Intermediate 1 (0119) tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N₂ atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 °C and quenched by the addition of sat. NH₄CI. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS0₄, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent yield) as a colorless oil. ¹H NMR (500 MHz, CDC1₃) δ 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
62%	at 0 - 20℃; for 1 h;	a. 4-Hydroxy-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (Intermediate 79a) To a solution of l-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0°C was added methylmagnesium bromide (3.0 M in Et₂O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10°C. The reaction mixture was allowed to warm to T over 1 h. The reaction was quenched by addition of sat. aq. NH₄C1 solution, then the mixture was extracted with diethyl ether (2 x). The combined organic layers were washed with brine, dried (MgSO₄), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100percent EtOAc in cyclohexane, to give the title compound (6.76 g, 62percent). NMR (400 MHz, CDC1₃): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
62%	at 0 - 20℃; for 1 h;	To a solution of 1-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0° C. was added methylmagnesium bromide (3.0 M in Et₂O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10° C. The reaction mixture was allowed to warm to RT over 1 h. The reaction was quenched by addition of sat. aq. NH₄Cl solution, then the mixture was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO₄), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100percent EtOAc in cyclohexane, to give the title compound (6.76 g, 62percent). ¹H NMR (400 MHz, CDCl₃): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
60.2%	at -20 - 20℃; for 2 h; Inert atmosphere	Synthesis of compound 221.2. To a solution of tert-butyl 221.1 (2.0g, 10.03 mmol, l .Oeq) in Et₂0 (20 ml) was added 1M MeMgBr in Et₂0 (1.196g, 10.03mmol, l .Oeq.) at - 20 °C under argon atmosphere. The reaction mixture was allowed to stir at room temperature for 2 hrs. After completion of reaction, mixture was poured in to satd. NH₄C1 solution and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 221.2 (1.3g, 60.2 percent). MS(ES): m/z 215.29 [M+H]⁺.
19%	Stage #1: at -78 - 23℃; for 6 h; Stage #2: With ammonium chloride In tetrahydrofuran; diethyl ether	Step-1: Preparation of intermediate-46a; To a stirred solution of intermediate 32b (500 mg, 2.70 mmol) in dry THF (15 mL) was added methyl magnesium bromide (3 M in diethyl ether, 0.90 mL, 2.70 mmol) at -78° C. The reaction mass was stirred at -78° C. for 4 h and then at 23° C. for 2 h. The reaction mass was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. The crude mass was purified by flash column chromatography to afford intermediate 46a (100 mg, 19percent).

Reference： [1] Journal of the American Chemical Society, 2013, vol. 135, # 41, p. 15342 - 15345
[2] Patent: WO2014/128465, 2014, A1, . Location in patent: Page/Page column 156
[3] Patent: WO2009/151598, 2009, A1, . Location in patent: Page/Page column 148-149
[4] Patent: WO2014/164409, 2014, A1, . Location in patent: Page/Page column 32; 33
[5] Patent: WO2014/164428, 2014, A1, . Location in patent: Page/Page column 25
[6] Patent: WO2014/159959, 2014, A1, . Location in patent: Page/Page column 68; 69
[7] Patent: WO2014/159076, 2014, A1, . Location in patent: Page/Page column 41; 42
[8] Patent: WO2015/123182, 2015, A1, . Location in patent: Page/Page column 23; 24
[9] Patent: US2015/232481, 2015, A1, . Location in patent: Paragraph 0093
[10] Patent: WO2015/126758, 2015, A1, . Location in patent: Page/Page column 24
[11] Patent: WO2013/83604, 2013, A1, . Location in patent: Page/Page column 278
[12] Patent: US2013/150343, 2013, A1, . Location in patent: Paragraph 1050; 1051
[13] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001155; 001156
[14] Patent: US2011/92475, 2011, A1, . Location in patent: Page/Page column 19
[15] Patent: WO2008/132502, 2008, A1, . Location in patent: Page/Page column 96

3
[ 676-58-4 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	at -78 - 0℃; for 2 h;	To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in dry THF (25 mL) was added methylmagnesium chloride (2.17 mL, 6.52 mmol) at -78° C. The reaction mixture was slowly warmed to 0° C. with stirring for 2 hours and quenched with saturated aq. NH₄Cl. The mixture was extracted with EtOAc twice, and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to afford tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.08 g, >99percent) as a colorless oil, which was used for the next reaction without further purification. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.27 (3H, s), 1.46 (9H, s), 1.50-1.58 (4H, m), 3.20-3.27 (2H, m), 3.64-3.76 (2H, m).
93%	Stage #1: at -40 - 20℃; for 2.16667 h; Stage #2: With water; ammonium chloride In tetrahydrofuran at 0℃;	Preparation of 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester; A solution of N-boc piperidin-4-one (3 g, 15 mmol) in dry THF (30 mL) was cooled to - 40⁰C, 3M MeMgCI (21 mL, 60.24 mmol) was added slowly over 10 min. The reaction mixture was allowed to rt and maintained for 2h. The reaction mixture was cooled to O⁰C, sat. NH₄CI was added and then was extracted with EtOAc (250 mL). The organic layer was washed with water (250 mL), brine solution, dried over anhydrous sodium sulfate and concentrated to obtain the crude product as yellow liquid (3 g, 93percent). ¹HNMR(CDCI₃): δ 3.56-3.8(m, 2H), 3.12-3.35(m, 2H), 1.5-1.62(m, 4H), 1.45(s, 9H) and 1.26(s, 3H).
66%	at 0℃; for 1 h;	PREPARATION /; SYNTHESIS OF 4-METHYL-4-(2-TRIFLUOROMETHYLPHENOXY)PIPERIDINEA.; To a stirred solution of 4-oxopiperidine-1-carboxylic acid terf-butyl ester (2.000 g, 10.04 mmol) in THF (30 mL) was added methyl magnesiumchloride (3.7 mL, 11.04 mmol) at 0⁰C. The resulting mixture was stirred at 0⁰C for 60 minutes. Ethyl acetate (40 mL) was added to the mixture and the organic solution was washed with water (20 mL), saturated NaCI (20 mL), dried over MgSO₄ and then concentrated in vacuo. The crude product was purified by column chromatography to yield the desired product, 4-hydroxy-4-methylpiperidine-1-carboxylic acid terf-butyl ester, in 66percent yield (1.418 g). ¹H NMR (300 MHz, CDCI₃) δ 3.67-3.60 (m, 2H), 3.23-3.13 (m, 2H), 1.50-1.46 (m, 4H), 1.40 (s, 9H), 1.20 (s, 3H).

Reference： [1] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0602; 0603
[2] Patent: WO2008/84300, 2008, A1, . Location in patent: Page/Page column 105
[3] Patent: WO2006/34338, 2006, A1, . Location in patent: Page/Page column 47
[4] Patent: WO2013/134226, 2013, A1, . Location in patent: Page/Page column 91; 92

4
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With methylmagnesium bromide In diethyl ether at 20℃; for 2 h; Inert atmosphere	tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate: Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporatedto obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. ‘H NMR (400MHz, CDC13) ö 3.84 - 3.652H), 3.34 -3.18 (m, 2H), 2.59 -2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50- 1.45 (m, 9H), 1.32- 1.27 (m, 3H).

Reference： [1] Patent: WO2015/127003, 2015, A1, . Location in patent: Page/Page column 21
[2] Patent: US2002/86887, 2002, A1,

5
[ 75-16-1 ]
[ 109384-19-2 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	at -25 - 20℃; for 2 h; Inert atmosphere	Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 °C and quenched by the addition ofNH4C1. Another 20 mL of ether was added and the mixture was partitioned in aseparatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 percent yield) as a colorless oil. NMR (500 MHz, CDCl3) 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 -2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).

Reference： [1] Patent: WO2014/28384, 2014, A1, . Location in patent: Page/Page column 78
[2] Patent: WO2015/126743, 2015, A1, . Location in patent: Paragraph 26

6
[ 917-54-4 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	at -78 - 20℃; for 1.5 h;	1) 4-Hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester In an argon atmosphere, methyllithium (0.98M diethyl ether solution, 64.5 mL) was added dropwise to a suspension of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (12.0 g) in diethyl ether (120 mL) at -78°C over 15 minutes, and the mixture was stirred for 30 minutes, at 0°C for 15 minutes, and at room temperature for 30 minutes. Water, saturated brine, and chloroform were added for partitioning the reaction mixture, and the organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate - hexane), to thereby give 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester as an oily product (12.2 g, 94percent). ¹H-NMR(400MHz,CDCl₃)δ:1.26(3H,s), 1.46(9H,s), 1.49-1.55(4H,m), 3.20-3.27(2H,m), 3.69-3.72(2H,m). EI-MSm/z:215 (M⁺).

Reference： [1] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 49

7
[ 586375-35-1 ]
[ 24424-99-5 ]
[ 406235-30-1 ]

Reference： [1] Patent: US2009/192156, 2009, A1, . Location in patent: Page/Page column 27-28

8
[ 15721-22-9 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Reference： [1] Patent: US2002/55631, 2002, A1,

9
[ 79099-07-3 ]
[ 406235-30-1 ]

Reference： [1] Patent: US2013/236468, 2013, A1, . Location in patent: Paragraph 0321

[ 406235-30-1 ] Synthesis Path-Downstream 1~37

1
[ 15721-22-9 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	With methylmagnesium bromide; In diethyl ether;	tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate A solution of 3M methyl magnesium bromide in diethyl ether (2.0 mL) in diethyl ether (3 1mL) at 0 C. was treated with a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.00 mmol) in diethyl ether (5 mL), warmed to room temperature, stirred for 18 hours, treated with saturated NHCl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 20%-50% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 216 (M+H)+.

Reference： [1]Patent: US2002/55631,2002,A1

2
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With methylmagnesium bromide; In diethyl ether; at 20℃; for 2h;Inert atmosphere;	tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate: Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporatedto obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (4.30 g, 18.0 mmol, 90 %) as a colorless oil. ?H NMR (400MHz, CDC13) oe 3.84 - 3.652H), 3.34 -3.18 (m, 2H), 2.59 -2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50- 1.45 (m, 9H), 1.32- 1.27 (m, 3H).
	With methylmagnesium bromide; ammonium chloride; In diethyl ether;	tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate A solution of 3M methyl magnesium bromide in diethyl ether (2.0 mL) in diethyl ether (3 mL) at 0 C. was treated with a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.00 mmol) in diethyl ether (5 mL), warmed to room temperature, stirred for 18 hours, treated with saturated NH4Cl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentratet was purified by flash chromatography on silica gel with 20%-50% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 216 (M+H)+.

Reference： [1]Patent: WO2015/127003,2015,A1 .Location in patent: Page/Page column 21
[2]Patent: US2002/86887,2002,A1

3
[ 676-58-4 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	In tetrahydrofuran; at -78 - 0℃; for 2h;	To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in dry THF (25 mL) was added methylmagnesium chloride (2.17 mL, 6.52 mmol) at -78 C. The reaction mixture was slowly warmed to 0 C. with stirring for 2 hours and quenched with saturated aq. NH4Cl. The mixture was extracted with EtOAc twice, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.08 g, >99%) as a colorless oil, which was used for the next reaction without further purification. 1H-NMR (CDCl3, Varian, 400 MHz): delta 1.27 (3H, s), 1.46 (9H, s), 1.50-1.58 (4H, m), 3.20-3.27 (2H, m), 3.64-3.76 (2H, m).
96%	In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere;	The starting material, 4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (25 mL). Under nitrogen protection reagent methyl magnesium chloride was added at 0 C (9mL, 27mmol, 1.1eq). After 2 hours of reaction, the reaction was complete by TLC. The mixture was diluted with hydrochloric acid to adjust pH=4, then water (30mL), ethyl acetate (30mL×3) was extracted, the organic phase was dried, filtered, decompressed. The product was purified by silica gel column chromatography (PE: EA=5:1) (5.2 g, yield: 96%).
93%		Preparation of 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester; A solution of N-boc piperidin-4-one (3 g, 15 mmol) in dry THF (30 mL) was cooled to - 400C, 3M MeMgCI (21 mL, 60.24 mmol) was added slowly over 10 min. The reaction mixture was allowed to rt and maintained for 2h. The reaction mixture was cooled to O0C, sat. NH4CI was added and then was extracted with EtOAc (250 mL). The organic layer was washed with water (250 mL), brine solution, dried over anhydrous sodium sulfate and concentrated to obtain the crude product as yellow liquid (3 g, 93%). 1HNMR(CDCI3): delta 3.56-3.8(m, 2H), 3.12-3.35(m, 2H), 1.5-1.62(m, 4H), 1.45(s, 9H) and 1.26(s, 3H).

66%	In tetrahydrofuran; at 0℃; for 1h;	PREPARATION /; SYNTHESIS OF 4-METHYL-4-(2-TRIFLUOROMETHYLPHENOXY)PIPERIDINEA.; To a stirred solution of 4-oxopiperidine-1-carboxylic acid terf-butyl ester (2.000 g, 10.04 mmol) in THF (30 mL) was added methyl magnesiumchloride (3.7 mL, 11.04 mmol) at 00C. The resulting mixture was stirred at 00C for 60 minutes. Ethyl acetate (40 mL) was added to the mixture and the organic solution was washed with water (20 mL), saturated NaCI (20 mL), dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography to yield the desired product, 4-hydroxy-4-methylpiperidine-1-carboxylic acid terf-butyl ester, in 66% yield (1.418 g). 1H NMR (300 MHz, CDCI3) delta 3.67-3.60 (m, 2H), 3.23-3.13 (m, 2H), 1.50-1.46 (m, 4H), 1.40 (s, 9H), 1.20 (s, 3H).
	In tetrahydrofuran; at -78 - 0℃; for 1h;	To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.00 g, 4.92 mmol) in dry THF (50 mL) at -78C is added 3.0M methyl magnesium chloride in THF (3.00 mL, 9.00 mmol) drop wise over 1 min. The reaction is warmed to 0C over lh. The reaction is cooled to -20C and quenched by addition of cold sat. NH4C1 (100 mL) with vigorous stirring. To the suspension is added EtOAc (200 mL) and the biphase partitioned. The aqueous layer is re-extracted with EtOAc (200 mL) and the combined organics washed with brine (100 mL) and dried (Na2S04). The solvent is removed in vacuo to give R-1 as a gum.

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0602; 0603
[2]Patent: CN109575016,2019,A .Location in patent: Paragraph 0678-0681
[3]Patent: WO2008/84300,2008,A1 .Location in patent: Page/Page column 105
[4]Patent: WO2006/34338,2006,A1 .Location in patent: Page/Page column 47
[5]Patent: WO2013/134226,2013,A1 .Location in patent: Page/Page column 91; 92

4
[ 406235-30-1 ]
[ 444-30-4 ]
[ 881391-40-8 ]

Yield	Reaction Conditions	Operation in experiment
5%	With triphenylphosphine; diethylazodicarboxylate; In toluene; for 18h;Heating / reflux;	B. To a stirred solution of 4-hydroxy-4-methylpiperidine-1-carboxylic acid fe/t-butyl ester (0.500 g, 2.32 mmol) in toluene (10 mL) was added 2- hydroxybenzotrifluoride (0.414 g, 2.56 mmol), triphenylphosphine (0.682 g, 2.555 mmol) and diethyl azocarboxylate (0.5 mL, 2.56 mmol). The resulting mixture was stirred at reflux for 18 hours. Toluene was removed in vacuo and the obtained crude product was purified by column chromatography to yield the desired product, 4-methyl- 4-(2-trifluoromethyl-phenoxy)piperidine-1-carboxylic acid te/t-butyl ester, in 5% yield EPO <DP n="49"/>(0.025 g). 1H NMR (300 MHz, CDCI3) delta 7.57-7.54 (m, 1H), 7.41-7.36 (m, 1H), 7.09 (d, J = 7.9 Hz1 1 H), 7.02-6.97 (m, 1H), 3.81-3.76 (m, 2H), 3.28 (t, J = 11.9 Hz, 2H), 2.15- 2.11 (m, 2H), 1.67-1.58 (m, 2H), 1.44 (s, 9H), 1.39 (s, 3H).

Reference： [1]Patent: WO2006/34338,2006,A1 .Location in patent: Page/Page column 47-48

5
[ 917-54-4 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	In diethyl ether; chloroform; water; at -78 - 20℃; for 1.5h;	1) 4-Hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester In an argon atmosphere, methyllithium (0.98M diethyl ether solution, 64.5 mL) was added dropwise to a suspension of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (12.0 g) in diethyl ether (120 mL) at -78C over 15 minutes, and the mixture was stirred for 30 minutes, at 0C for 15 minutes, and at room temperature for 30 minutes. Water, saturated brine, and chloroform were added for partitioning the reaction mixture, and the organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate - hexane), to thereby give 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester as an oily product (12.2 g, 94%). 1H-NMR(400MHz,CDCl3)delta:1.26(3H,s), 1.46(9H,s), 1.49-1.55(4H,m), 3.20-3.27(2H,m), 3.69-3.72(2H,m). EI-MSm/z:215 (M+).

Reference： [1]Patent: EP1762568,2007,A1 .Location in patent: Page/Page column 49

6
[ 406235-30-1 ]
[ 74-88-4 ]
tert-butyl 4-methoxy-4-methyl-piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Preparation of 4-Methoxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester; 50% NaH (2.3 g, 96.7 mmol) was initially washed with dry THF, cooled to O0C and then a solution of 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (5.2 g, 24.18 mmol) in dry DMF (40 mL) was added. The resulted reaction mixture was allowed to rt, methyl iodide (3.1 mL, 43.3 mmol) was added and maintained for 7 h. The reaction mixture was quenched with water and then extracted with DCM (500 mL). The organic <n="108"/>layer was washed with water (250 ml_), brine solution and concentrated to obtain the crude product (as brown liquid (5 g, 90%). 1HNMR(CDCI3): delta 3.6-3.8(m, 2H), 3.02- 3.22(m, 5H), 1.62-1.8(m, 2H), 1.38-1.52(m, 11 H) and 1.1 (s, 3H). LC-MS APCI (m/z) = 130 (M+H-Boc)+.
74%		2) 4-Methoxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester In an argon atmosphere, a solution of the above <strong>[406235-30-1]4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester</strong> (8.61 g) in N,N-dimethylformamide (86 mL) was added dropwise to a suspension of sodium hydride (55%, 2.09 g) in N,N-dimethylformamide (86 mL) at 0C over 15 minutes, and the mixture was stirred for 1 hour. A solution of methyl iodide (2.99 mL) in N,N-dimethylformamide (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 15 minutes and at room temperature for 6 hours. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate - hexane), to thereby give 4-methoxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester as an oily product (6.79 g, 74%). 1H-NMR(400MHz,CDCl3)delta:1.15(3H,s), 1.37-1.49(2H,m), 1.45(9H,s), 1.69-1.73(2H,m), 3.01-3.22(2H,m), 3.18(3H,s), 3.67-3.70(2H,m). FAB-MS m/z:230(M+H)+.
63%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;	To a solution of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (0.15 g, 0.69 mmol) in DMF (0.5 mL) under argon atmosphere were added sodium hydride (60%, suspension, 0.llg, 4.67 mmol, 4 equiv) and iodomethane (0.198 mL, 1.3 mmol, 2 equiv) at 0 C. Thereaction mixture was stirred at room temperature for 12 h. After completion, the reaction wasquenched with ice cold water and extracted with EtOAc. The combined organic extract wasdried sodium sulfate and concentrated under reduced pressure. Purification using silica gelcolumn chromatography (10% EtOAc Hexanes as eluent) to afford 0.1 g of tert-butyl 4-methoxy-4-methylpiperidine- 1 -carboxylate (Yield = 63%).

57%	With sodium hydroxide; In tetrahydrofuran; for 8h;	The intermediate <strong>[406235-30-1]4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester</strong> (500 mg, 2.32 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and sodium hydrogen (186 mg, 4.64 mmol, 2.0 eq) After 1 h of reaction, iodomethane (659 mg, 4.64 mmol, 2.0 eq) was added, and the reaction was carried out for 8 h. To the reaction flask was added water (10 mL), extracted with ethyl acetate (20mL × 3), the organic phase was dried, filtered, and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE: 1: EA = 20) to give the purified product (306 mg, Yield: 57%).
		(b) tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate (22) Sodium hydride (60% dispersion on mineral oil) (198 mg, 4.95 mmol) was added portionwise to <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (21) (710 mg, 3.30 mmol) in N,N-dimethylformamide (12 mL) at ambient temperature over a period of 30 seconds under an air atmosphere. The resulting suspension was stirred at 25 C. for 20 minutes. Methyl iodide (0.411 mL, 6.60 mmol) was then and the resulting suspension was stirred at 25 C. for 18 hours. The reaction mixture was diluted with water (150 mL) and saturated brine (25 mL), then washed sequentially with dichloromethane (3*100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was used directly in the next stage.
		A suspension of sodium hydride (60% dispersion in mineral oil, 0.44 g, 1 1.66 mmol) in DMF (20 mL) was cooled to 0 C then 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-buty ester (2.09 g, 9.72 mmol) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h then sodium iodide (3.03 mL, 48.6 mmol) was added and stirring continued at room temperature for 16 h then heated at 70 C for 16 h. The reaction mixture was allowed to cool to room temperature and ice-cold brine was added before the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic phase was dried over sodium sulfate, filtered and evaporated and the resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 0-20% ethyl acetate in cyclohexane) to afford a colourless oil (0.94 g). The resultant oil was dissolved in DCM (5 mL) and TFA (5 mL) and stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an SCX-2 cartridge which was washed with acetonitrile and methanol then eluted with 2N ammonia in methanol. The basic methanol fractions were evaporated to afford the title compound (0.50 g, 40%) 1H NMR (CDCl3, 300MHz): 3.19 (s, 3H), 2.96-2.85 (m, 2H), 2.81-2.70 (m, 2H), 1.79-1.66 (m, 2H), 1.51-1.38 (m, 2H), 1.15 (s, 3H) plus 1 exchangeable not observed.

Reference： [1]Patent: WO2008/84300,2008,A1 .Location in patent: Page/Page column 105-106
[2]Patent: EP1762568,2007,A1 .Location in patent: Page/Page column 49
[3]Patent: WO2016/100940,2016,A1 .Location in patent: Page/Page column 252
[4]Patent: CN109575016,2019,A .Location in patent: Paragraph 0678; 0682-0684
[5]Patent: US2009/192156,2009,A1 .Location in patent: Page/Page column 27-28
[6]Patent: WO2009/151598,2009,A1 .Location in patent: Page/Page column 149

7
[ 75-16-1 ]
[ 79099-07-3 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	In diethyl ether; at -10 - 20℃; for 2h;Inert atmosphere;	a) tert-Butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (A 141) ferf-Butyl 4-oxopiperidine-1 -carboxylate (1.0 g, 5.0 mmol) was dissolved in anhydrous Et20 (10 mL) and cooled to -10C under nitrogen. A solution of methylmagnesium bromide (3 M in Et20, 2.5 mL, 7.5 mmol) was added drop-wise and the mixture stirred for 5 minutes. The cooling bath was removed and the slurry was stirred at room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride (10 mL) and then diluted with water (20 mL) and diethyl ether (20 mL). The aqueous phase was extracted with diethyl ether (2 chi 30 mL), the pooled organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (1.05 g, 97%). H NMR (400 MHz, CDCI3) delta 3.76-3.64 (m, 2H), 3.29-3.16 (m, 2H), 1.66 (s, 1 H), 1.45 (s, 9H), 1.25 (s, 3H) 4H obscured by solvent.
97%		To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at -25 to -30 C was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97%). 1H NMR (CDCl3, 300MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0Cand quenched by the addition of sat. aq. ammonium chloride. Another 20 mL ofether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (4.30g, 18.0 mmol, 90 %) as a colorless oil. ?H NMR (400MHz, CDC13) oe 3.84 - 3.65 (m,2H), 3.34 -3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50- 1.45 (m,9H), 1.32- 1.27 (m, 3H).

90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Under an N2 atmosphere, a 3N solution in ether ofmethylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to oocand quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04 , filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50%EtOAc/hexane to obtain tert-butyl4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 %) as a colorless oil. 1H NMR (400MHz, CDCh) 8 3.84- 3.65 (m,2H), 3.34-3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61- 1.53 (m, 4H), 1.50- 1.45 (m,9H), 1.32- 1.27 (m, 3H).
90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Int rmediate 43 tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 %) as a colorless oil. 1H NMR (400MHz, CDC13) delta 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 %) as a colorless oil. 1H NMR (400MHz, CDC13) delta 3.84 - 3.65 (i 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90%	In diethyl ether; at -25 - 20℃;Inert atmosphere;	Intermediate 9 (0109) tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 C and quenched by the addition of sat. NH4CI. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 % yield) as a colorless oil. 1H NMR (500 MHz, CDC13) delta 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25 C.) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4 g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 C. and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 3.84-3.65 (m, 2H), 3.34-3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61-1.53 (m, 4H), 1.50-1.45 (m, 9H), 1.32-1.27 (m, 3H).
90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Intermediate 1 (0119) tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 C and quenched by the addition of sat. NH4CI. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 % yield) as a colorless oil. 1H NMR (500 MHz, CDC13) delta 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
62%	In diethyl ether; at 0 - 20℃; for 1h;	a. 4-Hydroxy-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (Intermediate 79a) To a solution of l-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0C was added methylmagnesium bromide (3.0 M in Et2O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10C. The reaction mixture was allowed to warm to T over 1 h. The reaction was quenched by addition of sat. aq. NH4C1 solution, then the mixture was extracted with diethyl ether (2 x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (6.76 g, 62%). NMR (400 MHz, CDC13): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
62%	In diethyl ether; at 0 - 20℃; for 1h;	To a solution of 1-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0 C. was added methylmagnesium bromide (3.0 M in Et2O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10 C. The reaction mixture was allowed to warm to RT over 1 h. The reaction was quenched by addition of sat. aq. NH4Cl solution, then the mixture was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (6.76 g, 62%). 1H NMR (400 MHz, CDCl3): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
60.2%	In diethyl ether; at -20 - 20℃; for 2h;Inert atmosphere;	Synthesis of compound 221.2. To a solution of tert-butyl 221.1 (2.0g, 10.03 mmol, l .Oeq) in Et20 (20 ml) was added 1M MeMgBr in Et20 (1.196g, 10.03mmol, l .Oeq.) at - 20 C under argon atmosphere. The reaction mixture was allowed to stir at room temperature for 2 hrs. After completion of reaction, mixture was poured in to satd. NH4C1 solution and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 221.2 (1.3g, 60.2 %). MS(ES): m/z 215.29 [M+H]+.
19%		Step-1: Preparation of intermediate-46a; To a stirred solution of intermediate 32b (500 mg, 2.70 mmol) in dry THF (15 mL) was added methyl magnesium bromide (3 M in diethyl ether, 0.90 mL, 2.70 mmol) at -78 C. The reaction mass was stirred at -78 C. for 4 h and then at 23 C. for 2 h. The reaction mass was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. The crude mass was purified by flash column chromatography to afford intermediate 46a (100 mg, 19%).
		Intermediate 43 tert-Butyl 4-hvdroxy-4-methylpiperidine- 1 -carboxylateMethylmagnesium bromide (1.795 g, 15.06 mmol) (3M solution in ether) was cooled at an dry- ice bath, tert-butyl 4-oxopiperidine-l -carboxylate (3.00 g, 15.06 mmol) in THF was added to the reaction mixture drop-wise. The reaction was stirred at -78C for Ih, and quenched with saturated NH4Cl solution at the same temperature. Ethyl acetate was added, and the organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by ISCO (80 g column, 35-65 EtOAc/hexanes) afforded 1.86 g of the title compound. IH NMR (300 MHz, DICHLOROMETHANE-J2) delta ppm 1.15 (s, 3 H) 1.35 (s, 9 H) 1.37 - 1.46 (m, 4 H) 2.92 - 3.24 (m, 2 H) 3.46 - 3.66 (m, 2 H).

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 15342 - 15345
[2]Patent: WO2014/128465,2014,A1 .Location in patent: Page/Page column 156
[3]Patent: WO2009/151598,2009,A1 .Location in patent: Page/Page column 148-149
[4]Patent: WO2014/164409,2014,A1 .Location in patent: Page/Page column 32; 33
[5]Patent: WO2014/164428,2014,A1 .Location in patent: Page/Page column 25
[6]Patent: WO2014/159959,2014,A1 .Location in patent: Page/Page column 68; 69
[7]Patent: WO2014/159076,2014,A1 .Location in patent: Page/Page column 41; 42
[8]Patent: WO2015/123182,2015,A1 .Location in patent: Page/Page column 23; 24
[9]Patent: US2015/232481,2015,A1 .Location in patent: Paragraph 0093
[10]Patent: WO2015/126758,2015,A1 .Location in patent: Page/Page column 24
[11]Patent: WO2013/83604,2013,A1 .Location in patent: Page/Page column 278
[12]Patent: US2013/150343,2013,A1 .Location in patent: Paragraph 1050; 1051
[13]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 001155; 001156
[14]Patent: US2011/92475,2011,A1 .Location in patent: Page/Page column 19
[15]Patent: WO2008/132502,2008,A1 .Location in patent: Page/Page column 96

8
[ 406235-30-1 ]
[ 586375-35-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; methanol; at 0 - 20℃; for 4h;	To solution of tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (5 g, 23.2 mmol) inMeOH (5 mL) was added 4.0 M HC1 in 1,4-Dioxane (17 mL) at 0 C. The reaction mixturewas stirred at room temperature for 4 h. After completion, the volatiles were concentrated under reduced pressure to afford 3 g of 4-methylpiperidin-4-ol hydrochloride (Quantitative).
> 99%	With hydrogenchloride; In 1,4-dioxane; at 0 - 23℃; for 2h;	Step-2: Preparation of intermediate-47a; To a stirred solution of intermediate 46a (100 mg, 0.49 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (5 mL) at 0 C. The reaction mass was stirred for 2 h at 23 C. The organics were evaporated off under reduced pressured. The residue was washed with dry ether and dried under vacuum to afford intermediate 47a (50 mg, >99%) as its HCl salt.
79%	With hydrogenchloride; In 1,4-dioxane; for 3h;	b) 4-Methylpiperidin-4-ol hydrochloride (A 142) fert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate A141 (1.05 g, 4.90 mmol), 1 ,4-dioxane (30 mL) and 4 M HCI in 1 ,4-dioxane (10 mL) were stirred together for 3 hours. The mixture was concentrated in vacuo, the solid residue suspended in diethyl ether (20 mL), the solvent decanted from the solid and the solid washed with diethyl ether (20 mL). The solid was dried under vacuum to give the title compound as a white solid (584 mg, 79%). H NMR (400 MHz, cf DMSO) delta 8.97 (br s, 1 H), 8.85 (br s, 1 H), 4.66 (br s, 1 H), 3.08-2.93 (m, 4H), 1.74- 1.53 (m, 4H), 1.15 (s, 3H). LCMS-A rt: 1.38 min, m/z (positive ion) 116.3 [M+H]+.

	With hydrogenchloride; In diethyl ether; at 20℃; for 4h;	To tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (1.0 g, 4.6 mmol) was added hydrogen chloride, 1.0 M solution in diethyl ether (4.6 ml, 4.6 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated down to give a yellow oil which was used directly in the following step.
	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 25℃; for 18h;	To a solution of 4-hydroxy-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (1.08 g, 4.87 mmol) in DCM (25 mL) is added 4M HCI in 1,4-dioxane (20 mL, 80 mmol) and the reaction stirred at about 25 C for 18 hours. The reaction is concentrated, suspended in Et20 and heptane, and filtered to afford the title compound (R) as a white powder.
	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 25℃; for 18h;	To a solution of <strong>[406235-30-1]4-hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.08 g, 4.87 mmol) in DCM (25 mL) is added 4M HCl in 1,4-dioxane (20 mL, 80 mmol) and the reaction stirred at about 25 C. for 18 hours. The reaction is concentrated, suspended in Et2O and heptane, and filtered to afford the title compound ( R) as a white powder.
	With hydrogenchloride; In 1,4-dioxane; methanol; at 0 - 20℃; for 2h;	Intermediate 444-Methylpiperidin-4-ol hydrochloride tert-Butyl 4-hydroxy-4-methylpiperidine-l -carboxylate (Intermediate 43, 1.82 g, 8.45 mmol) in methanol (10 ml) was cooled to 00C. HCl (7 ml, 4N in dioxane) was added to the reaction. Ice- bath was removed, and the reaction was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure to afford 1.26 g product as HCl salt. 1H NMR (300 MHz, DICHLOROMETHANE-J2) delta ppm 0.66 - 0.93 (m, 2 H) 1.08 - 1.32 (m, 4 H) 1.64 - 1.74 (m, 1 H) 1.87 - 2.08 (m, 2 H) 3.06 - 3.31 (m, 2 H)

Reference： [1]Patent: WO2016/100940,2016,A1 .Location in patent: Page/Page column 161
[2]Patent: US2011/92475,2011,A1 .Location in patent: Page/Page column 19
[3]Patent: WO2014/128465,2014,A1 .Location in patent: Page/Page column 156
[4]Patent: WO2010/57121,2010,A1 .Location in patent: Page/Page column 93
[5]Patent: WO2013/134226,2013,A1 .Location in patent: Page/Page column 91; 92
[6]Patent: US2013/236468,2013,A1 .Location in patent: Paragraph 0322
[7]Patent: WO2008/132502,2008,A1 .Location in patent: Page/Page column 96

9
[ 586375-35-1 ]
[ 24424-99-5 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
		(a) tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (21) Sodium hydride (60% dispersion on mineral oil) (158 mg, 3.96 mmol) was added portionwise to 4-methylpiperidin-4-ol hydrochloride (500 mg, 3.30 mmol) and triethylamine (0.506 mL, 3.63 mmol) in N,N-dimethylformamide (8 mL) at 25 C. over a period of 1 minute under an air atmosphere. The resulting suspension was stirred at 25 C. for 20 minutes. A solution of Di-tert-butyl dicarbonate (1.668 mL, 7.25 mmol) in DMF (2 mL) was then added in one portion and the resulting suspension was stirred at 25 C. for 18 hours. The reaction mixture was diluted with water (125 mL) and saturated brine (25 mL), then washed sequentially with dichloromethane (3*50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude desired product, which was used without further purification; 1H NMR (400.132 MHz, CDCl3) delta 1.46 (9H, s), 1.51-1.56 (7H, m), 3.21-3.28 (2H, m), 3.65-3.73 (2H, m)

Reference： [1]Patent: US2009/192156,2009,A1 .Location in patent: Page/Page column 27-28

10
[ 406235-30-1 ]
[ 14199-15-6 ]
[ 1295646-00-2 ]

Yield	Reaction Conditions	Operation in experiment
45%		Intermediate 1884-(2-Hydroxy-5-methoxycarbonylmethyl-phenyl)-4-methyl-piperidine-l-carboxylic acid tert-butyl esterTo a solution of (4-hydroxy-phenyl)-acetic acid methyl ester (200 mg, 0.93 mmol) and 4- hydroxy-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (772 mg, 4.64 mmol) in nitrobenzene (0.8 mL) was added triflic acid (2.05 mL, 23.22 mmol). The resulting mixture was stirred for 18 h then neutralised with saturated aqueous NaHC03 and extracted with CHC13. The combined organic phases were washed with water, brine, dried (Na2S04) and concentrated in vacuo. The resulting residue was purified on SCX-2 cartridge (eluting with 2M NH3 in MeOH) then dissolved in DCM (30 mL) before the addition of triethylamine (762 mu, 5.47 mmol) and tert-butoxycarbonyl anhydride (1.1 g, 5.02 mmol). The resulting mixture was stirred for 30 min then diluted with DCM and washed with saturated aqueous NaHC03. The organic phase was dried (Na2S04) and cocnetrated in vacuo and the resulting residue purified by chromatography wluting with 30% EtOAc in cyclohexane to afford the title compound as a yellow foam (1.0 g, 45%).LCMS (Method 4): Rt 3.70 min, m/z 364 [M+H+]

Reference： [1]Patent: WO2011/48409,2011,A1 .Location in patent: Page/Page column 81

11
[ 406235-30-1 ]
[ 3970-68-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h;	4-methyl-piperidin-4-ol (Intermediate 79b)A solution of Intermediate 79a (5.50 g, 25.6 mmol) in TFA (20 mL) and DCM (40 mL) was stirred at RT for 1 h. The reaction mixture was applied to SCX- 2 cartridges (2 70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (3.19 g, 99%). NMR (400 MHz, CDC13): 1.24 (3H, s), 1.51-1.61 (4H, m), 2.75-2.87 (2H, m), 2.89-3.02 (2H, m).
93.46%	With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h;	Synthesis of compound 221.3. To a solution of 221.2 (1.3 g, 6.04 mmol, l .Oeq) in CH2C12 (10 mL) was added trifluoroacetic acid (5mL). The reaction was allowed to stir at room temperature for lh. After completion of reaction, solvent was evaporated under reduced pressure to obtain pure TFA salt of 221.3 (0.650g, 93.46%). MS(ES): m/z 115.18 [M+H]+.
	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 12h;	To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.08 g, 5.02 mmol) in DCM was added TFA (1.93 mL, 25.1 mmol) at 0 C. The reaction mixture was stirred at room temperature for 12 hours. After basified with saturated aq. NaHCO3, the separated aqueous layer was concentrated in vacuo (The compound was dissolved in aqueous layer). The residue was diluted with MeOH and then filtered through a SiO2 pad while washing with MeOH. The filtrate was concentrated in vacuo to afford 4-methylpiperidin-4-ol (235 mg, 40%) as a viscous oil, which was used for the next reaction without further purification.

Reference： [1]Patent: WO2013/83604,2013,A1 .Location in patent: Page/Page column 278
[2]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 001155; 001157
[3]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0604; 0605

12
[ 406235-30-1 ]
chloro N-phthalimidoyl oxalate [ No CAS ]
C₂₁H₂₄N₂O₈ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 6012 - 6024
[2]Journal of the American Chemical Society,2013,vol. 135,p. 15342 - 15345
[3]Chemical Communications,2016,vol. 52,p. 7292 - 7294

13
[ 79099-07-3 ]
methylmagnesium chloride [ No CAS ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at -78 - 0℃; for 1h;	To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.92 mmol) in dry THF (50 mL) at -78 C. is added 3.0M methyl magnesium chloride in THF (3.00 mL, 9.00 mmol) dropwise over 1 min The reaction is warmed to 0 C. over 1 h. The reaction is cooled to -20 C. and quenched by addition of cold sat. NH4Cl (100 mL) with vigorous stirring. To the suspension is added EtOAc (200 mL) and the biphase partitioned. The aqueous layer is re-extracted with EtOAc (200 mL) and the combined organics washed with brine (100 mL) and dried (Na2SO4). The solvent is removed in vacuo to give R-1 as a gum.

Reference： [1]Patent: US2013/236468,2013,A1 .Location in patent: Paragraph 0321

14
[ 75-16-1 ]
[ 109384-19-2 ]
[ 406235-30-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 C and quenched by the addition ofNH4C1. Another 20 mL of ether was added and the mixture was partitioned in aseparatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 % yield) as a colorless oil. NMR (500 MHz, CDCl3) 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 -2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
	In diethyl ether; at -25 - 20℃; for 2h;Inert atmosphere;	Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 C and quenched by the addition of sat. NH4Cl. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50% EtOAc hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 % yield) as a colorless oil. 1H NMR (500 MHz, CDC13) delta 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).

Reference： [1]Patent: WO2014/28384,2014,A1 .Location in patent: Page/Page column 78
[2]Patent: WO2015/126743,2015,A1 .Location in patent: Paragraph 26

15
[ 406235-30-1 ]
[ 1567215-29-5 ]

Reference： [1]Patent: WO2014/28384,2014,A1
[2]Patent: WO2014/164409,2014,A1
[3]Patent: WO2014/164467,2014,A1
[4]Patent: WO2014/164428,2014,A1
[5]Patent: WO2014/159959,2014,A1
[6]Patent: WO2014/159076,2014,A1
[7]Patent: WO2015/123182,2015,A1
[8]Patent: WO2015/126743,2015,A1
[9]Patent: WO2015/127003,2015,A1

16
[ 406235-30-1 ]
[ 1567215-32-0 ]

Reference： [1]Patent: WO2014/28384,2014,A1
[2]Patent: WO2015/123182,2015,A1
[3]Patent: WO2015/126743,2015,A1

17
[ 406235-30-1 ]
[ 106-95-6 ]
[ 1551896-48-0 ]

Yield	Reaction Conditions	Operation in experiment
86%		tert-Butyl 4- (allyloxy)-4-methylpiperidine-1-carboxylate: To a mixture of tertbutyl 4-hydroxy-4-methylpiperidine-1-carboxylate (6.10 g, 28.3 mmol) in DMF (20 mL) at 0C was added NaH (2.27 g, 56.7 mmol) and the mixture was then stirred at rtfor 30 mm. Then allyl bromide (12.3 mL, 142 mmol) was slowly added and the mixture was stirred at rt for 3h. The reaction was then cooled to 0C, quenched with sat aq NH4C1, extracted with ether and the organic was then dried over Na2504, filtered and concentrated to obtain a colorless oil, which was then purified by biotage,eluting with EtOAc/hexane gradient to isolate the expected product tert-butyl 4- (allyloxy)-4-methylpiperidine-1-carboxylate (6.2 g, 24 mmol, 86% yield) consistent byNMR. ?H NMR (400MHz, CDC13) oe 5.99-5.87 (m, 1H), 5.31 (dd, J=17.1, 1.8 Hz, 1H), 5.14 (dd, J=10.4, 1.4 Hz, 1H), 3.89 (d, J=5.3 Hz, 2H), 3.72 (d, J13.3 Hz,2H), 3.21 - 3.12 (m, 2H), 1.77 (d, J=12.8 Hz, 2H), 1.46 (s, 9H), 1.43 (d, J13.6 Hz,2H), 1.20 (s, 3H).
61%		To a mixture of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was addedslowly over the course of 5 mm. The reaction mixture was stirred at rt for 3h. It was then cooled to 0 C and quenched with sat. NH4Cl. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (6 1%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 6.02 - 5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H),3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 -1.42 (m, 1 1H), 1.21 (s, 3H).
61%		To a mixture of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (4.30 g, 20.0 mmol) in DMF (50 mL) at 0C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was thenstirred at rt for 2h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 mm. The reaction mixture was stirred at rt for 3h. It was then cooled to 0C and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, elutingwith 0-25% EtOAc/hexane to isolate 3.1 g (6 1%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. ?H NMR (500 MHz, CDC13) oe6.02 - 5.90 (m, 1H), 5.32 (dd, J17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H),3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 -1.42 (m, 11H), 1.21 (s, 3H).

61%		To a mixture of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (4.30 g, 20.0 mmol) in DMF (50 mL) at 0C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0C and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 6.02 - 5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 1.42 (m, 11H), 1.21 (s, 3H).
61%		To a mixture of tertbutyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at ooc was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowlyover the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to ooc and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgS04 , filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) oftert-butyl4-(allyloxy)-4- methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCh) 86.02-5.90 (m, 1H), 5.32 (dd, 1=17.2, 1.7 Hz, 1H), 5.16 (dd, 1=10.4, 1.4 Hz, 1H),3.94-3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, 1=13.1 Hz, 2H), 1.53-1.42 (m, llH), 1.21 (s, 3H).
61%		Intermediate 44 tert-Butyl 4-(allyloxy)-4-methylpiperidine-l-carboxylate: To a mixture of tert- butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0C and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgS04, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-l-carboxylate as a colorless oil. 1H NMR (500 MHz, CDC13) delta 6.02 - 5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 - 1.42 (m, 11H), 1.21 (s, 3H).
61%		tert-Butyl 4-(allyloxy)-4-methylpiperidine-l-carboxylate To a mixture of tert- butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0C and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSC^, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-l-carboxylate as a colorless oil. 1H NMR (500 MHz, CDC13) delta 6.02 - 5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 - 1.42 (m, 11H), 1.21 (s, 3H).
61%		To a mixture of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C. was added NaH (60 wt %) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3 h. It was then cooled to 0 C. and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 6.02-5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94-3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53-1.42 (m, 11H), 1.21 (s, 3H).
61%		Intermediate 10 (0111) tert-Butyl 4-(allyloxy)-4-methylpiperidine-l-carboxylate: To a mixture of tert- butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0 C and quenched with sat. NH4CI. The reaction mixture was extracted with ether. The organic phase was dried over MgSC"4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-l-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCI3) delta 6.02 - 5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 - 1.42 (m, 11H), 1.21 (s, 3H).
61%		To a mixture of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0 C and quenched with sat. NH4Cl. The reaction mixture was extracted with ether. The organic phase was dried over MgSC"4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 6.02 - 5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 - 1.42 (m, 11H), 1.21 (s, 3H).
61%		To a mixture of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C. was added NaH (60 wt %) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3 h. It was then cooled to 0 C. and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 6.02-5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94-3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53-1.42 (m, 11H), 1.21 (s, 3H).
61%		Intermediate 2 (0121) tert-Butyl 4-(allyloxy)-4-methylpiperidine-l-carboxylate: To a mixture of tert- butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0 C and quenched with sat. NH4C1. The reaction mixture was extracted with ether. The organic phase was dried over MgS04, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-l-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCI3) delta 6.02 - 5.90 (m, IH), 5.32 (dd, J=17.2, 1.7 Hz, IH), 5.16 (dd, J=10.4, 1.4 Hz, IH), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 - 1.42 (m, 11H), 1.21 (s, 3H).
61%		tert-Butyl 4- (allyloxy)-4-methylpiperidine-1-carboxylate: To a mixture of tertbutyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0 C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was addedslowly over the course of 5 mm. The reaction mixture was stirred at rt for 3h. It was then cooled to 0 C and quenched with sat. NH4C1. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-1-carboxylate as a colorless oil. ?H NMR (500 MHz, CDC13) oe 6.02-5.90 (m, 1H), 5.32 (dd, J17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H),3.94-3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d,J=13.1 Hz, 2H), 1.53-1.42 (m, 11H), 1.21 (s, 3H).
61%		tert-Butyl 4-(allyloxy)-4-methylpiperidine-l-carboxylate: To a mixture of tert- butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0C was added NaH (60 wt%) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3h. It was then cooled to 0C and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSC^, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4- methylpiperidine-l-carboxylate as a colorless oil. 1H NMR (500 MHz, CDC13) delta 6.02 - 5.90 (m, IH), 5.32 (dd, J=17.2, 1.7 Hz, IH), 5.16 (dd, J=10.4, 1.4 Hz, IH), 3.94 - 3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53 - 1.42 (m, 11H), 1.21 (s, 3H).

Reference： [1]Patent: WO2015/126765,2015,A1 .Location in patent: Page/Page column 32; 33
[2]Patent: WO2014/28384,2014,A1 .Location in patent: Page/Page column 78; 79
[3]Patent: WO2014/164409,2014,A1 .Location in patent: Page/Page column 33
[4]Patent: WO2014/164467,2014,A1 .Location in patent: Page/Page column 76
[5]Patent: WO2014/164428,2014,A1 .Location in patent: Page/Page column 25; 26
[6]Patent: WO2014/159959,2014,A1 .Location in patent: Page/Page column 69; 70
[7]Patent: WO2014/159076,2014,A1 .Location in patent: Page/Page column 42
[8]Patent: US2015/232480,2015,A1 .Location in patent: Paragraph 0102
[9]Patent: WO2015/123182,2015,A1 .Location in patent: Page/Page column 24
[10]Patent: WO2015/126743,2015,A1 .Location in patent: Paragraph 26; 27
[11]Patent: US2015/232481,2015,A1 .Location in patent: Paragraph 0094
[12]Patent: WO2015/126758,2015,A1 .Location in patent: Page/Page column 24-25
[13]Patent: WO2015/126376,2015,A1 .Location in patent: Page/Page column 32; 33
[14]Patent: WO2015/127003,2015,A1 .Location in patent: Page/Page column 21; 22

18
[ 406235-30-1 ]
[ 1567220-39-6 ]

Reference： [1]Patent: WO2014/164409,2014,A1
[2]Patent: WO2014/159959,2014,A1
[3]Patent: WO2015/127003,2015,A1

19
[ 406235-30-1 ]
[ 350-46-9 ]
tert-butyl 4-methyl-4-(4-nitrophenoxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		To a suspension of sodium hydride (60% suspension, 0.36 g, 9.29 mmol, 2 equiv) in 3 mL ofdry THF was added <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (1 g, 4.64 mmol,1 equiv) in dry THF (7 mL) drop wise at 0C. The reaction mixture was stirred for 15 mi 4-fluoro nitro benzene (0.98 g, 6.97 mmol, 1.5 equiv) was added at 0C and the reaction washeated at 70C for 12 h. After completion, the reaction was quenched with ice cold water andextracted with EtOAc. The organic extract was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Purification using silica gel column chromatography (10% EtOAc hexane as eluent) to afford 1.0 g of tert-butyl 4-methyl-4-(4- nitrophenoxy)piperidine- 1 -carboxylate (Yield = 64%).

Reference： [1]Patent: WO2016/100940,2016,A1 .Location in patent: Page/Page column 154; 155

20
[ 406235-30-1 ]
2,2,2-trifluoro-1-(4-methoxy-4-methyl-1λ4-piperidin-1-yl)ethan-1-one trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2016/100940,2016,A1
[2]Patent: WO2008/84300,2008,A1
[3]Patent: CN109575016,2019,A

21
[ 406235-30-1 ]
[ 100-39-0 ]
tert-butyl 4-(benzyloxy)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 12h;Inert atmosphere;	To a solution of <strong>[406235-30-1]ter<strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong></strong> (0.3 g, 1.39 mmol) in THF (5 mL) were added sodium hydride (60% suspension, 0.22 g 9.29 mmol, 4 equiv) under argon atmosphere and benzyl bromide (0.477 g, 2.79 mmol, 2 equiv) at 0 C. The reactionmixture was stirred at room temperature for 12 h. After completion, the reaction was quenched with cold water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel column chromatography (10% EtOAc Hexanes as eluent) to afford 0.12 g of tert-butyl 4- (benzyloxy)-4-methylpiperidine- 1 -carboxylate (Yield = 28%).

Reference： [1]Patent: WO2016/100940,2016,A1 .Location in patent: Page/Page column 254; 255

22
[ 406235-30-1 ]
3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide [ No CAS ]
tert-butyl 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		EXAMPLE 19 Synthesis of 4-((1-benzyl-4-methylpiperidin-4-yl)oxy)-3-chloro-//-(thiazol-2- yl)benzenesulfonamide Step 1. Preparation of te/f-butyl 4-(2-chloro-4-(A/-(2,4-dimethoxybenzyl)-A/-(thiazol-2- yl)sulfamoyl)phenoxy)-4-methylpiperidine-1-carboxylate To a solution of terf-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (0.75 g, 3.49 mmol) in anhydrous A/,A/-dimethylformamide (12 mL) was added a dispersion of 60% sodium hydride in mineral oil (0.14 g, 3.49 mmol) and the reaction mixture was stirred at ambient temperature for 45 minutes. To it was then added 3-chloro-/V-(2,4- dimethoxybenzyl)-4-fluoro-/V-(thiazol-2-yl)benzenesulfonamide (0.77 g, 1.75 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched by careful addition of water (50 ml_), and extracted with ethyl acetate (100 ml_). The organic layer was washed with saturated ammonium chloride (2 chi 50 ml_), brine (50 ml_), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography eluting with a gradient of 0 to 100% of ethyl acetate in hexanes to provide the title compound as a colorless foam (0.98 g, 44% yield): H NMR (300 MHz, CDCI3) 7.82- 7.79 (m, 1 H), 7.66-7.61 (m, 1 H), 7.46-7.41 (m, 1 H), 7.18-7.14 (m, 1 H), 7.11-7.02 (m, 2H), 6.40-6.35 (m, 2H), 5.08 (s, 2H), 3.78-3.72 (m, 6H), 3.31-3.20 (m, 8H), 1.46 (s, 9H), 1.27 (s, 3H); MS (ES+) m/z 638.2 (M + 1), 640.1 (M + 1).

Reference： [1]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 124-125

23
[ 406235-30-1 ]
tert-butyl 4-bromo-4-methylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 18307 - 18312

24
[ 406235-30-1 ]
[ 1795-48-8 ]
tert-butyl 4-((isopropylcarbamoyl)oxy)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		A solution of 2-isocyanatopropane (50.5 mg, 0.593 mmol) in DCM (2 mL) and 12 M HCl(aq) (2.44 mu., 0.0297 mmol) was stirred 5 min at ambient temperature, then added to tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (172.1 mg, 0.7994 mmol). The reaction mixture was stirred overnight at ambient temperature before introducing additional 2- isocyanatopropane (50.5 mg, 0.593 mmol) and 12 M HCl(aq) (2.44 mu,, 0.0297 mmol). The resulting mixture was stirred for 3 h at ambient temperature before another equivalent of 2- isocyanatopropane (50.5 mg, 0.593 mmol) was introduced. After stirring overnight at ambient temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified directly by silica chromatography (using 0-100% Hexanes/ EtOAc as the gradient eluent) to cleanly provide the title compound (180 mg, quantitative yield). MS (apci) m/z = 201.2 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 001407; 001408; 001409

25
[ 406235-30-1 ]
[ 372-48-5 ]
tert-butyl 4-methyl-4-(pyridin-2-yloxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-methyl-4-(pyridin-2-yloxy)piperidine-l- carboxylate. To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (266 mg, 1.24 mmol) in DMF (2.6 mL) was added sodium hydride (60% w/w, 91 mg, 2.27 mmol). The reaction was stirred for 5 min at ambient temperature. Then 2-Fluoropyridine (100 mg, 1.03 mmol) was added and reaction stirred overnight at 70C. The reaction was cooled to ambient temperature and diluted with DCM and washed with saturated NaHC03(aq), water, and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (5-50% EtOAc in hexanes as the gradient eluent) to afford the title compound (assumed quantative yield, 301 mg) in sufficient purity for step 2. MS (apci) m/z = 293.3 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 001987; 001989

26
[ 406235-30-1 ]
[ 33332-31-9 ]
tert-butyl 4-((5-methoxypyrazin-2-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-((5-methoxypyrazin-2-yl)oxy)piperidine-l- carboxylate. To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (278 mg, 1.38 mmol) in DMF (1.7 mL) was added sodium hydride (60% w/w, 61 mg, 1.52 mmol). The reaction was stirred for 5 min at ambient temperature. Then <strong>[33332-31-9]2-chloro-5-methoxypyrazine</strong> (100 mg, 0.692 mmol) was added and reaction stirred overnight at 95C. The reaction was cooled to ambient temperature and diluted with DCM and washed with saturated NaHC03(aq), water, and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (5-40% EtOAc in hexanes as the gradient eluent) to afford the title compound (assumed quantative yield, 214 mg) in sufficient purity for step 2. MS (apci) m/z = 210.1 (M-Boc).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 001992; 001994

27
[ 406235-30-1 ]
[ 17228-69-2 ]
tert-butyl 4-((4-methoxypyridin-2-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-((4-methoxypyridin-2-yl)oxy)piperidine-l- carboxylate. To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (146 mg, 0.725 mmol) in DMF (2.4 mL) was added sodium hydride (60% w/w, 37.7 mg, 0.943 mmol). The reaction was stirred for 10 min at ambient temperature. Then <strong>[17228-69-2]2-chloro-4-methoxypyridine</strong> (104 mg, 0.725 mmol) was added and reaction stirred 92 h at 95C. The reaction was cooled to ambient temperature and diluted with water and extracted with EtOAc. Combined organics were washed with saturated NaHC03(aq), water, and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 224 mg) in sufficient purity for step 2. MS (apci) m/z = 309.1 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002026; 002028

28
[ 1120-95-2 ]
[ 406235-30-1 ]
tert-butyl 4-(pyridazin-3-yloxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-(pyridazin-3-yloxy)piperidine-l-carboxylate. To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (140 mg, 0.696 mmol) in DMF (2.3 mL) was added sodium hydride (60percent w/w, 56 mg, 1.39 mmol). The reaction was stirred for 10 min at ambient temperature. Then <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (159 mg, 1.39 mmol) was added and reaction stirred 3 h at 95°C. The reaction was cooled to ambient temperature and diluted with water and extracted with EtOAc. Combined organics were washed with saturated NaHC03(aq), water, and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 194 mg) in sufficient purity for step 2. MS (apci) m/z = 280.2 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002031; 002033

29
[ 89466-38-6 ]
[ 406235-30-1 ]
tert-butyl 4-((6-methoxy-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-((6-methoxy-5-methylpyridazin-3- yl)oxy)piperidine- 1 -carboxylate. To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-l- carboxylate (761 mg, 3.78 mmol) in DMF (7.9 mL) was added sodium hydride (60% w/w, 164 mg, 4.10 mmol). The reaction was stirred for 5 min at ambient temperature. Then 6-chloro-3- methoxy-4-methylpyridazine (500 mg, 3.15 mmol) was added and reaction stirred overnight at 95C. The reaction was cooled to ambient temperature and diluted with water and extracted with EtOAc. Combined organics were washed with saturated NaHC03(aq), water, and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 1.019 g) in sufficient purity for step 2. MS (apci) m/z = 324.1 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002036; 002038

30
[ 406235-30-1 ]
[ 90196-32-0 ]
tert-butyl 4-((5-ethylpyridin-2-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-((5-ethylpyridin-2-yl)oxy)piperidine-l- carboxylate. To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (1.42 g, 7.06 mmol) in DMF (11.8 mL) was added sodium hydride (60% w/w, 311 mg, 7.77mmol). The reaction was stirred for 15 min at ambient temperature. Then 2-chloro-5-ethylpyridine (1.00 g, 3.15 mmol) was added and reaction stirred 48 h at 90C. The reaction was cooled to ambient temperature and additional tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (1.42 g, 7.06 mmol) and sodium hydride (60% w/w, 311 mg, 7.77 mmol) were added. The reaction was stirred for 60 h at 90C. The reaction was cooled to ambient temperature and additional tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (1.42 g, 7.06 mmol) and sodium hydride (60% w/w, 311 mg, 7.77 mmol) were added. The reaction was stirred for 4 h at 90C The reaction was cooled to ambient temperature and diluted with water and saturated NaHCCb(aq) and extracted with EtOAc. Combined organics were washed with water and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The crude residue was resuspended in DCM and the solution was purified by silica chromatography (5-50% EtOAc in Hexanes as the gradient eluent) to afford the title compound (assumed quantative yield, 2.163g) in sufficient purity for step 2. MS (apci) m/z = 307.2 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002041; 002043

31
[ 1121-79-5 ]
[ 406235-30-1 ]
tert-butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-l- carboxylate. To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (313 mg, 1.56 mmol) in DMF (1.94 mL) was added sodium hydride (60% w/w, 68.4 mg, 1.71mmol). The reaction was stirred for 5 min at ambient temperature. Then 3-chloro-6-methylpyridazine (100 mg, 0.778 mmol) was added and reaction stirred overnight at 95C. The reaction was cooled to ambient temperature and diluted with saturated NaHC03(aq) and extracted with EtOAc. Combined organics were washed with water and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 228 mg) in sufficient purity for step 2. MS (apci) m/z = 294.20 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002064; 002066

32
[ 406235-30-1 ]
6-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]
tert-butyl 4-((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		To a dry scintillation vial purged with N2, <strong>[406235-30-1]1-boc-4-methylpiperidin-4-ol</strong> (567 mg,2.63 mmol) was added, dissolved in 3 mL DMF and the solution was cooled to 0 C. 60%by weight sodium hydride in mineral oil (175 mg, 4.39 mmol) was slowly added to the stirring solution and the reaction was allowed to warm to rt following the addition. The frothy reaction was stirred for 30 minutes before being cooled once again to 0 C. A solution of 6-bromo-4-fluoro- 1 -(tetrahydro-2H-pyran-2-yl)- 1H-indazole (525 mg, 1.755mmol) in 1 mL DMF was slowly added into the scintillation vial containing the organosodium solution. Following the addition, the reaction was warmed to rt and stirred for 2 hours upon which LCMS indicated full conversion of the starting material to the desired product. The reaction was quenched with the slow addition of 2 mL H20 and 2 mL EtOAc, which was allowed to stir for 5 minutes. The biphasic solution was thentransferred to a separatory funnel and an additional 10 mL H20 were added. The mixture was extracted with 3 times 20 mL of EtOAc and the aqueous layer was discarded. The combined organic fractions were then washed with 3x10 mL 1:1 H20:brine to remove residual DMF. The organic was then dried over Na2SO4, filtered, and concentrated to a lightly yellow oil. The oil was then purified by flash column chromatography using a 0-40% EtOAc:hexanes gradient. The product was isolated pure as a clear, colorless, viscous oil (389 mg, 45% yield). (m/z): [M+Hj calcd for C23H32BrN3O4 494.17 found 494.4.

Reference： [1]Patent: WO2019/27960,2019,A1 .Location in patent: Page/Page column 93

33
[ 406235-30-1 ]
[ 954123-46-7 ]
t-butyl 4-((3-bromo-5-(trifluoromethyl)benzyl)oxy)-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		A flask was charged with <strong>[406235-30-1]t-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate</strong> (1.H g,5.16 mmol, 1.10 equiv), DMF (10 mL), and sodium hydride (566 mg, 14.2 mmol, 3.00 equiv, 60% in mineral oil). The mixture was stirred for 30 mm at 0 C prior to addition of 1-bromo-3- (bromomethyl)-5 -(trifluoromethyl)benzene (1.50 g, 4.72 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 265 mg (12% yield) of t-butyl 4-((3 -bromo-5 -(trifluoromethyl)benzyl)oxy)-4-methylpiperidine- 1 -carboxylate as a yellow oil. LCMS (ESI, m/z): 454 [M+H].

Reference： [1]Patent: WO2019/46330,2019,A1 .Location in patent: Paragraph 00381

34
[ 406235-30-1 ]
[ 76-05-1 ]
4-methylpiperidin-4-ol trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 0℃; for 1h;	The starting material 4-hydroxy-piperidine-1-carboxylate (380mg, 1.77mmol, 1.0eq) was dissolved in dichloromethane (5mL), was added trifluoroacetic acid (3mL) at 0 C. The reaction was stirred for 1h, TLC the reaction was complete, concentrated under reduced pressure to give the product (404 mg, yield: 100%).

Reference： [1]Patent: CN109575016,2019,A .Location in patent: Paragraph 0723-0726

35
[ 189321-63-9 ]
[ 406235-30-1 ]

Reference： [1]Journal of the American Chemical Society,2020,vol. 142,p. 1211 - 1216
[2]Journal of Organic Chemistry,2020,vol. 85,p. 5019 - 5026
[3]Nature,2019,vol. 573,p. 398 - 402

36
[ 406235-30-1 ]
[ 36404-30-5 ]
4-(4,5-dichloro-2-methoxyphenyl)-4-methylpiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluorormethanesulfonic acid In 1,2-dichloro-ethane at 20℃; for 24h; Inert atmosphere;	10.a Step a: To a stirred solution of 1,2-dichloro-4-methoxybenzene (0.30 g, 1.70 mmol) and tert- butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.82 g, 8.47 mmol) in DCE (5 mL) was added TfOH (6.36 g, 42.37 mmol) dropwise at room temperatureunder nitrogenatmosphere. The reaction solution was stirred at room temperature for 24 h. The reaction was quenched with water (50 mL) at room temperature. The reaction mixture was extracted with EA (5 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4,5- dichloro-2-methoxyphenyl)-4-methylpiperidine as a brown solid (0.24 g, crude), which was used in the next step directly without further purification: LCMS (ESI) calc’d for C13H17Cl2NO [M + H]+: 274, 276 (3 : 2), found 274, 276 (3 : 2).

Reference： [1]Current Patent Assignee: D.E. SHAW RESEARCH LLC - WO2021/71802, 2021, A1 Location in patent: Paragraph 0279-0280

37
[ 406235-30-1 ]
[ 36404-30-5 ]
4,5-dichloro-2-(4-methylpiperidin-4-yl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trifluorormethanesulfonic acid / 1,2-dichloro-ethane / 24 h / 20 °C / Inert atmosphere 2: boron tribromide / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: D.E. SHAW RESEARCH LLC - WO2021/71802, 2021, A1

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H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 406235-30-1 ]

Quality Control of [ 406235-30-1 ]

Related Doc. of [ 406235-30-1 ]

Product Details of [ 406235-30-1 ]

Calculated chemistry of [ 406235-30-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 406235-30-1 ]

Application In Synthesis of [ 406235-30-1 ]

[ 406235-30-1 ] Synthesis Path-Upstream 1~9

[ 406235-30-1 ] Synthesis Path-Downstream 1~37

Related Functional Groups of [ 406235-30-1 ]

Alcohols

Amides

Related Parent Nucleus of [ 406235-30-1 ]

Aliphatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 406235-30-1 ]

Related Parent Nucleus of
[ 406235-30-1 ]