[ CAS No. 129888-60-4 ] {[proInfo.proName]}

Name: 129888-60-4|tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate|95%
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SKU: A110474
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2D 3D

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Quality Control of [ 129888-60-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 129888-60-4 ]

SDS Specification

Alternatived Products of [ 129888-60-4 ]

Product Details of [ 129888-60-4 ]

CAS No. :	129888-60-4	MDL No. :	MFCD07787193
Formula :	C₁₁H₂₁NO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WLAZHMYDLUILKR-UHFFFAOYSA-N
M.W :	279.35	Pubchem ID :	568122
Synonyms :

Calculated chemistry of [ 129888-60-4 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	71.45
TPSA :	81.29 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.74
Log Po/w (XLOGP3) :	1.09
Log Po/w (WLOGP) :	2.06
Log Po/w (MLOGP) :	0.93
Log Po/w (SILICOS-IT) :	0.0
Consensus Log Po/w :	1.37

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.93
Solubility :	3.29 mg/ml ; 0.0118 mol/l
Class :	Very soluble
Log S (Ali) :	-2.39
Solubility :	1.14 mg/ml ; 0.00408 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.32
Solubility :	13.2 mg/ml ; 0.0474 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.44

Safety of [ 129888-60-4 ]

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

Application In Synthesis of [ 129888-60-4 ]

* 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 [ 129888-60-4 ]
Downstream synthetic route of [ 129888-60-4 ]

[ 129888-60-4 ] Synthesis Path-Upstream 1~5

1
[ 85275-45-2 ]
[ 124-63-0 ]
[ 129888-60-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 0 - 20℃; for 3 h;	Step 1. methanesulfonyl chloride (3.130 g, 2.115 mL, 27.32 mmol) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol) and Et₃N (5.027 g, 6.924 mL, 49.68 mmol) in DCM (50 mL) cooled to 0° C. on an ice-bath. The reaction was allowed to warm to ambient temperature over 3 hours. The reaction mixture was washed with water and 1M HCl, dried (MgSO₄), filtered and concentrated in vacuo to give tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate as a yellow oil (7.9 g, Quantitative yield-some residual solvent). ¹H NMR (400.0 MHz, CDCL₃) δ 1.49 (s, 9H), 1.60-1.57 (m, 1H), 2.04-1.79 (m, 3H), 3.08 (s, 3H), 3.38-3.32 (m, 1H), 3.50-3.43 (m, 1H), 3.70-3.60 (m, 2H) and 4.74 (br s, 1H) ppm; Step 2.
100%	With triethylamine In dichloromethane at 0 - 20℃; for 2 h;	To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) in DCM (16 mL) was added TEA (0.895 mL, 6.46 mmol) followed by MsCl (0.465 mL, 5.96 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with water, 2 N aq. HCl, saturated aq. NaHCO₃, and brine successively, dried over Na₂SO₄, filtered and concentrated in vacuo to afford tert-butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate (1.39 g, 100percent) as a colorless oil, which was used for the next reaction without further purification. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.47 (9H, s), 1.55 (1H, br. s), 1.78-2.01 (3H, m), 3.06 (3H, s), 3.28-3.38 (1H, m), 3.42-3.48 (1H, m), 3.54-3.68 (2H, m), 4.72 (1H, br. s).
95.1%	at 0 - 20℃;	The solution of N-Boc-3-hydroxypiperidine (2.1 g, 10 mmol, 1.0 eq) and DIPEA (2.1 mL, 15 mmol, 1.5 eq) in 20 mL DCM was stirred. To the solution was slowly added dropwise methanesulfonyl chloride (1.0 mL, 13 mmol, 1.3 eq) after cooling to 0° C., and mixture was allowed to raise to room temperature. Then the reaction mixture was washed successively with a 1 M HCl solution, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and water. The obtained DCM layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the product as a yellow solid (2.65 g, 95.1percent yield). MS m/z (ESI): 280.1 [M+H].

95%	With triethylamine In dichloromethane at 0 - 20℃; for 1 h;	Triethylamine (15 g, 150 mmol, 3.0 eq.) and methanesulfonyl chloride (6.3 g, 55 mmol, 1.1 eq.) were sequentially added dropwise to a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (10.0 g, 50 mmol, 1.0 eq.) in dichloromethane (100 mL) at 0° C. The reaction was stirred at 20° C. for 1 hour, quenched with saturated NaHCO₃ (100 mL), and then extracted with methylene chloride (200 mL*3). The organic phase was dried over anhydrous sodium sulfate, and concentrated to give the title compound (13 g, yield: 95percent).
93%	With triethylamine In dichloromethane at 0 - 20℃; for 3 h;	tert-Butyl 3-hydroxypiperidine-1-carboxylate (1.01 g, 4.97 mmol) , methylsufonyl chloride (0.77 mL, 9.94 mmol) and triethylamine (1.4 mL, 9.94 mmol) were mixed in DCM (15 mL) at 0 . The mixture was warmed to rt and stirred for 3 h. The reaction mixture was diluted with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a yellow liquid product (1.3 g, 93) .[1856]MS (ESI, pos. ion) m/z: 224.0 [M-t-Bu+2]⁺.
85%	With dmap In dichloromethane at 0℃; for 2 h;	Hydroxypiperidine 20a (20.10 g, 0.1 mol) and DMAP (61.08 g, 0.5 mol) were co-evaporated with anhydrous dichloromethane (DCM) and suspended in 1 L DCM. The mixture was cooled to 0 °C and mesyl chloride (38 ml, 0.5 mol) was added dropwise under cooling and vigorous stirring. After 2 h TLC (10percent EtOH/CHCl₃, ninhydrin detection) showed the complete consumption of the starting material. Water (20 ml) was added to the mixture and stirring continued for an additional 10 min. The mixture was extracted with saturated NaHCO₃ (3.x.), and the combined organic phases were dried over anhydrous Na₂SO₄. Sodium sulfate was filtered off and the filtrate was evaporated. The product was purified by flash chromatography on a silica gel using a linear of gradient ethyl acetate in toluene. The product was obtained as a white amorphous solid in a 85percent yield (23.90 g, 85.5 mmol).ν_max (KBr) 1693 (vs), 1463 (s), 1428 (s), 1245 (s), 1391 (m), 1365 (s), 1351 (vs), 1179 (vs), 976 (s), 938 (s), 929 (s), 904 (s), 543 (s), 524 (s); δ_H (DMSO, 499.8 MHz, 50 °C) 4.70 (1H, m, H-3), 3.60-3.64 (2H, m, H-2), 3.42 (1H, ddd, J_gem 13.4 Hz, J_6b-5 7.2 and 3.9 Hz, H-6b), 3.34 (1H, ddd, J_gem 13.4 Hz, J_6a-5 7.6 and 3.8 Hz, H-6a), 3.03 (3H, s, CH₃SO₂), 1.97 (1H, m, H-4b), 1.89 (1H, m, H-4a), 1.82 (1H, m, H-5b), 1.54 (1H, m, H-5a), 1.46 (9H, s, (C(CH₃)₃)); δ_C (CDCl₃, 125.7 MHz, 50 °C) 154.7 (COO), 80.1 (C(CH₃)₃), 75.3 (C-3), 47.9 (C-2), 43.5 (C-6), 38.8 (SO₂CH₃), 30.5 (C-4), 28.3 (C(CH₃)₃), 21.7 (C-5); HRMS (FAB) C₁₁H₂₂NO₅S (M+H)⁺ calcd 280.1212, found 280.1223.
85%	With triethylamine In dichloromethane at 18℃; for 1 h;	To a mixture of compound 20-4-1A (200 g, 0.995 mol) and TEA (120.23 g, 1.19 mol) in DCM (700 mL), methylsufonyl chloride (125.24 g, 1.09 mol) was added in portions, and the reaction mixture was stirred at 18° C. for 1 h, followed by washed with water (1500 mL). The aqueous phase was extracted with DCM (500 mL×3), and then the organic phases were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to give compound 20-4-1 (211 g, Yield 85percent) as white solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.72 (s, 1H), 3.55-3.70 (m, 2H), 3.40-3.50 (m, 1H), 3.27-3.38 (m, 1H), 3.09-3.16 (m, 1H), 3.05 (s, 3H), 1.76-2.02 (m, 3H), 1.47 (s, 9H).
77%	With triethylamine In tetrahydrofuran for 0.166667 h; Cooling	Stage (i): tert-Butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate 1-Boc-3-hydroxypiperidine (0.5 g, 2.49 mmol) was dissolved in tetrahydrofuran (5 ml), triethylamine (0.75 g, 7.46 mmol) was added and the mixture was cooled. Methanesulfonic acid chloride (0.23 ml, 3 mmol) was added, the mixture was stirred in an ice bath for 10 min, saturated sodium bicarbonate solution (10 ml) was then added, as well as ethyl acetate (10 ml). Phase separation, the aqueous phase was extracted with ethyl acetate (2*20 ml) and the combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. Yield: 0.54 g (77percent)

Reference： [1] Patent: US2013/115310, 2013, A1, . Location in patent: Paragraph 0248; 0249
[2] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0485; 0486
[3] Carbohydrate Research, 1990, vol. 204, # 1, p. 11 - 25
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4334 - 4343
[5] Patent: US2017/305920, 2017, A1, . Location in patent: Paragraph 0151; 0152
[6] Patent: US2016/200730, 2016, A1, . Location in patent: Paragraph 0132; 0133
[7] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00739
[8] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500
[9] Patent: US2017/313683, 2017, A1, . Location in patent: Paragraph 0537-0538
[10] Patent: US2010/152158, 2010, A1, . Location in patent: Page/Page column 60
[11] Patent: WO2016/202253, 2016, A1, . Location in patent: Page/Page column 111
[12] Patent: US2005/165005, 2005, A1, . Location in patent: Page/Page column 61
[13] Patent: EP1908750, 2008, A1, . Location in patent: Page/Page column 6
[14] Patent: WO2011/134831, 2011, A1, . Location in patent: Page/Page column 44
[15] Patent: WO2012/58127, 2012, A2, . Location in patent: Page/Page column 83
[16] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 2986 - 2992
[17] Chemistry - A European Journal, 2018, vol. 24, # 33, p. 8343 - 8349

2
[ 85275-45-2 ]
[ 7143-01-3 ]
[ 129888-60-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine In tetrahydrofuran at 20℃; for 16 h;	Example 138Reagents and conditions: (a) NaH, DMF, 100 C, 16 h. (b) TFA, DCM, rt 1 h. (c) C₈H₇O₂NCI_2, HBTU, DIEA, THF, 50 C 16 h.[0567] Synthesis of tert-butyl 3-((methylsulfonyl)oxy)piperidine-l-carboxylate: To the solution of tert-butyl 3-hydroxypiperidine-l-carboxylate (2.01 g, 10 mmol, 1.0 eq) in THF (30 mL) was added DMAP (122 mg, 1.0 mmol, 0.1 eq), TEA (2.8 mL, 20 mmol, 2.0 eq) and methanesulfonic anhydride (1.91 g, 11 mmol, 1.1 eq). The mixture was stirred at rt for 16 h, filtered off and concentrated in vacuo to afford a residue which purified by column chromatography (silica gel, PE/EtOAc= 3: 1) to give the title product (2.5 g, yield: 90percent) as a colorless oil. 1H NMR (400 MHz, CDC1₃) δ: 4.72 (s, 1H), 3.74-3.61 (m, 3H), 3.45-3.42 (m, 1 H), 3.34-3.32 (m, 1H), 2.05-1.08 (m, 4H), 1.45-1.40 (m, 11H). ESI-MS (M+H⁺-56): 224.0.

Reference： [1] Patent: WO2012/58645, 2012, A1, . Location in patent: Page/Page column 210
[2] Patent: US5932606, 1999, A,

3
[ 85275-45-2 ]
[ 124-63-0 ]
[ 121-44-8 ]
[ 129888-60-4 ]

Reference： [1] Patent: US5571832, 1996, A,
[2] Patent: US5346908, 1994, A,

4
[ 6859-99-0 ]
[ 129888-60-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4334 - 4343
[2] Carbohydrate Research, 1990, vol. 204, # 1, p. 11 - 25
[3] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500
[4] Patent: WO2012/58127, 2012, A2,
[5] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 2986 - 2992

5
[ 24424-99-5 ]
[ 129888-60-4 ]

[ 129888-60-4 ] Synthesis Path-Downstream 1~8

1
[ 85275-45-2 ]
[ 7143-01-3 ]
[ 129888-60-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine In tetrahydrofuran at 20℃; for 16h;	138 Example 138Reagents and conditions: (a) NaH, DMF, 100 C, 16 h. (b) TFA, DCM, rt 1 h. (c) C8H7O2NCI2, HBTU, DIEA, THF, 50 C 16 h.[0567] Synthesis of tert-butyl 3-((methylsulfonyl)oxy)piperidine-l-carboxylate: To the solution of tert-butyl 3-hydroxypiperidine-l-carboxylate (2.01 g, 10 mmol, 1.0 eq) in THF (30 mL) was added DMAP (122 mg, 1.0 mmol, 0.1 eq), TEA (2.8 mL, 20 mmol, 2.0 eq) and methanesulfonic anhydride (1.91 g, 11 mmol, 1.1 eq). The mixture was stirred at rt for 16 h, filtered off and concentrated in vacuo to afford a residue which purified by column chromatography (silica gel, PE/EtOAc= 3: 1) to give the title product (2.5 g, yield: 90%) as a colorless oil. 1H NMR (400 MHz, CDC13) δ: 4.72 (s, 1H), 3.74-3.61 (m, 3H), 3.45-3.42 (m, 1 H), 3.34-3.32 (m, 1H), 2.05-1.08 (m, 4H), 1.45-1.40 (m, 11H). ESI-MS (M+H+-56): 224.0.
63%	With triethylamine In dichloromethane at 20 - 30℃;	58.1 Step 1: Synthesis of tert-butyl 3-(methanesulfonyloxy)piperidine-1-carboxylate A solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (950 mg, 4.72 mmol, 1.00 equiv), TEA (955 mg, 9.44 mmol, 2.00 equiv), methanesulfonyl methanesulfonate (1.64 g, 9.41 mmol, 2.00 equiv) in DCM (10 mL) was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3*30 mL of sodium bicarbonate/H2O. The resulting mixture was concentrated under vacuum. This resulted in 826 mg (63%) of the title compound as a solid. LCMS (ESI, m/z): 280.10 [M+H]+.
	With triethylamine In dichloromethane	B Step B Step B 3-Methanesulfonyloxy-N-t-butoxycarbonylpiperidine Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0° C. After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 and dried (Na2 SO4). Concentration gave the title compound. 1 H NMR (CDCl3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC.; SUNESIS PHARMACEUTICALS INC - WO2012/58645, 2012, A1 Location in patent: Page/Page column 210
[2]Current Patent Assignee: RIBON THERAPEUTICS INC; RIBON THERAPEUTICS INC - US2019/330194, 2019, A1 Location in patent: Paragraph 0937
[3]Current Patent Assignee: MERCK & CO INC - US5932606, 1999, A

2
[ 850197-67-0 ]
[ 129888-60-4 ]
[ 940890-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene; In acetonitrile; at 120.0℃; for 0.25h;Microwave irradiation;	22A: 3-(1-chloroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester The 1-chloro-6-methoxyisoquinoline was prepared as described in WO 00/24718 (Akzo Nobel N.V.). Alternatively it can be prepared from 3-methoxybenzaldehyde using the same procedure as in Example 15A (for the synthesis of 1-chloro-6-methoxy-7-methyl-isoquinoline). The 1-chloro-6-methoxyisoquinoline is demethylated according to the procedure described in WO 00/24718 to afford <strong>[850197-67-0]1-chloro-6-hydroxyisoquinoline</strong>. A suspension of <strong>[850197-67-0]1-chloro-6-hydroxyisoquinoline</strong> (0.18 g, 1 mmol), 3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (336 mg, 1.2 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (500 mg, 2.2mmol/g loading) in acetonitrile (4 ml) were heated at 120 C. over a period of 900 seconds using the microwave. The excess supported reagent was removed by filtration, washing with methanol, and the filtrate evaporated to dryness under reduced pressure. Since the reaction had not gone to completion, the above procedure was repeated. Purification of the crude material was achieved by chromatography on silica (eluent: 0-25% ethyl acetate in heptane) to afford 3-(1-chloroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (106 mg), El-MS: m/z=363.7 [M+H]+.
	With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine bound on polystyrene; In acetonitrile; at 120.0℃; for 0.25h;Microwave irradiation;	22A: 3-(1-chloroisoquinolin-6-yloxy)piperidine-1-carboxylic acid fe/f-butyl esterThe 1-chloro-6-methoxyisoquinoline was prepared as described in WO 00/24718(Akzo Nobel N. V.). Alternatively it can be prepared from 3-methoxybenzaldehyde using the same procedure as in Example 15A (for the synthesis of 1-chloro-6-methoxy-7- methyl-isoquinoline). The 1-chloro-6-methoxyisoquinoline is demethylated according to the procedure described in WO 00/24718 to afford i-chloro-6-hydroxyisoquinoline.A suspension of <strong>[850197-67-0]1-chloro-6-hydroxyisoquinoline</strong> (0.18g, 1 mmol), 3-methanesulfonyloxy- piperidine-1-carboxylic acid te/t-butyl ester (336mg, 1.2mmol) and 2-te/t-butylimino-2- diethylamino-1 ,3-dimethyl-perhydro-1 ,3,2-diazaphosphorine on polystyrene (500 mg, ~2.2mmol/g loading) in acetonitrile (4 ml) were heated at 120 C over a period of 900 seconds using the microwave. The excess supported reagent was removed by filtration, washing with methanol, and the filtrate evaporated to dryness under reduced pressure. Since the reaction had not gone to completion, the above procedure was repeated. Purification of the crude material was achieved by chromatography on silica (eluent: 0- 25% ethyl acetate in heptane) to afford 3-(1-chloroisoquinolin-6-yloxy)piperidine-1- carboxylic acid terf-butyl ester (106 mg), EI-MS: m/z = 363.7 [M+H]+.

Reference： [1]Patent: US2007/135479,2007,A1 .Location in patent: Page/Page column 12
[2]Patent: WO2007/65916,2007,A1 .Location in patent: Page/Page column 27-28

3
[ 129888-60-4 ]
[ 65-71-4 ]
[ 1271239-56-5 ]
[ 131667-57-7 ]
[ 85838-94-4 ]

Yield	Reaction Conditions	Operation in experiment
16%; 28%; 23%	With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 3h;	General procedure: Nucleobase (1.5 mmol) and base (1.5 mmol) were heated at 100 C in dry DMF/DMSO (15 ml). Mesyl derivative (1 mmol) dissolved in dry DMF/DMSO (10 ml) was then added dropwise and the mixture was heated at 120 C for 3 h. The solvent was evaporated and product purified on a silica gel using flash chromatography.

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

4
[ 2075-45-8 ]
[ 129888-60-4 ]
[ 1092564-21-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 4-bromo-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 1-(tert-Butoxycarbonyl)-3-(methanesulfonyloxy)piperidine In N,N-dimethyl-formamide at 0 - 120℃; for 1h; Microwave irradiation;	4-Bromo-1H-pyrazole (Intermediate 61) (526 mg, 3.58 mmol) was dissolved in DMF (10 mL), sodium hydride suspension in mineral oil (60 %, 260 mg, 6.45 mmol) was added at 0 °C and the resulting mixture was stirred for 30 min. tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.00 g, 3.58 mmol) as a solution in DMF (5 mL) was added dropwise at 0 °C and the mixture was stirred at 120 °C for 1 h using microwave heating. The reaction mixture was partitioned between H20 (50 mL) and EtOAc (20 mL) and the aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2S04) and the solvent was removed in-vacuo. The residue was purified by column chromatography (Normal-Phase 60-120 mesh silica gel, 0 to 3 % MeOH in DCM) to give tert-butyl 3-(4-bromo-1 /-/-pyrazol-1-yl)piperidine-1-carboxylate (1.10 g, 93 %) as a gum.LCMS (System 1 , Method B): m/z 274/276 (M-56+H)+(ESI +ve), at 1.82 min, 230 nm.
	Stage #1: 4-bromo-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Stage #2: 1-(tert-Butoxycarbonyl)-3-(methanesulfonyloxy)piperidine In N,N-dimethyl-formamide at 100℃;	7 4-Bromopyrazole (2.94 gs 20 mmol) dissolved in DMF (20 mL) was cooled to 0°C, sodium hydride (900 mg, 22.5 mmol) was added portion- wise over lh. After warmed to room temperature and stirred for lh, tert-butyl 3-(methylsulfonyloxy)-piperidine-l-carboxylate (5.03 g, 20 mmol) was added, and the reaction mixture was heated at 100 °C overnight. The reaction mixture was quenched with saturated NH4C1, and extracted with EtOAc. The organic layer was washed with ¾0, brine, dried and concentrated. Crude mixture was column purified with mixture of EtOAc and hexane to give tert-butyl 3-(4-bromo-lH-pyrazol-l-yi)piperidine-l- carboxylate (1.97 g) as white solid.

Reference： [1]Current Patent Assignee: SOSEI GROUP CORPORATION - WO2020/79457, 2020, A1 Location in patent: Paragraph 46; 47
[2]Current Patent Assignee: MERCK & CO INC - WO2012/58127, 2012, A2 Location in patent: Page/Page column 83

5
[ 129888-60-4 ]
[ 2380-63-4 ]
[ 1374250-98-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	A10 54g (4mmo1), A31 · 67g (6 mmol, 1.5 eq.) And potassium carbonate 1 · lg (8 mmol, 2 eq.) Was added to 1 OmL DMF solution, 100 C overnight, After extraction with ethyl acetate, dry, Biotage silica gel column chromatography (dichloromethane / methanol = 1%), Pale yellow solid Alpha40.92g, The yield was 72%.
50%		Synthesis of tert-butyl 3-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-1-carboxylate: To a solution of lH-pyrazolo[3,4-J]pyrimidin-4-amine (675 mg, 5 mmol) in DMF (12 mL) was added NaH (60%wt in mineral oil, 240 mg, 6.0 mmol, 1.2 eq) and the mixture was stirred at rt for 0.5 h. The tert-butyl 3-((methylsulfonyl)oxy)piperidine-l-carboxylate (1.67 g, 6 mmol, 1.2 eq) was added and the mixture was heated to 100 C for 16 h. The solution was cooled to rt and the reaction was quenched with brine (50 mL) and extracted with EtOAc (80 mL x 4). The organic layers were dried over Na2S04i concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, pure EtOAc) to give the title product (700 n yield: 50%) as a light yellow solid. lH NMR (400 MHz, DMSO-d6) delta: 9.24 (br s, IH), 8.72 (br IH), 8.41 (s, IH), 8.33 (s, IH), 4.67-4.62 (m, IH), 4.05-3.58 (m, 3H), 3.40-3.33 (m, IH), 2.9 2.95 (m 1 H), 2.16-2.04 (m, IH), 1.61-1.24 (m, 11H). ESI-MS (M+H+): 319.0.

Reference： [1]Patent: CN103113375,2017,B .Location in patent: Paragraph 0039-0040
[2]Patent: WO2012/58645,2012,A1 .Location in patent: Page/Page column 210

6
[ 877060-47-4 ]
[ 129888-60-4 ]
tert-butyl 3-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		To a solution of <strong>[877060-47-4]3-iodo-1H-pyrrolo[3,2-c]pyridine</strong> (150 mg, 0.62mmol) in DMF (3 mL) was added NaH (26 mg, 0.65 mmol, 60% in mineral oil) at RT. The suspension stirred at RT for 15 min followed by the addition of tert-butyl 3- ((methylsulfonyl)oxy)piperidine-1-carboxylate (273 mg, 0.98 mmol) at RT. The reaction mixture was then heated at 80 oC for 5 hours. After cooling to RT, a saturated aq. solution of NH4Cl (5 mL) was added followed by EtOAc (10 mL). The aq. layer was separated and extracted with EtOAc (2 x 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and evaporated. Purification of the crude product using ISCO flash column chromatography (100% Hexane to 100% EtOAc) gave tert-butyl 3-(3-iodo- 1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate (53 mg, 20%). LCMS Method C: tR = 5.194; [M + H]+ = 428.40.

Reference： [1]Patent: WO2018/53267,2018,A1 .Location in patent: Page/Page column 168; 169

7
[ 129888-60-4 ]
[ 156454-43-2 ]
tert-butyl 3-(5-bromo-7-methyl-2H-indazol-2-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 8276 - 8295

8
[ 129888-60-4 ]
[ 1017798-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 16 h / 20 - 65 °C 2: sodium tetrahydridoborate / methanol / 16 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: TRANSLATIONAL GENOMICS RESEARCH INSTITUTE - WO2022/61155, 2022, A1

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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

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[ 129888-60-4 ] Synthesis Path-Upstream 1~5

[ 129888-60-4 ] Synthesis Path-Downstream 1~8

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Amides

Sulfonates

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Aliphatic Heterocycles

Piperidines

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[ 129888-60-4 ]

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[ 129888-60-4 ]