477293-60-0|(2S,4S)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate| Ambeed

CAS No. :	477293-60-0
Formula :	C₁₀H₁₉NO₃
M.W :	201.26
SMILES Code :	O=C(N1[C@@H](C)C[C@H](O)C1)OC(C)(C)C
MDL No. :	MFCD20278358
InChI Key :	BXZADLGAYWRZCR-YUMQZZPRSA-N
Pubchem ID :	56846373

Safety of [ 477293-60-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H317
Precautionary Statements:	P280

Application In Synthesis of [ 477293-60-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 477293-60-0 ]

[ 477293-60-0 ] Synthesis Path-Downstream 1~46

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References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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[ 477293-60-0 ]
C₃₂H₄₃NO₃S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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[ 477293-60-0 ]
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References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2733 - 2736.

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Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 20.5h;Inert atmosphere;	Mesyl chloride (0.125 mL, 1.61 mmol) was added to a stirred solution of (2LU)-4- hydroxy-2-methyl-pyrrolidine-l -carboxylic acid tert- butyl ester (CAS: 477293-60-0; 250 mg, 1.24) in DCM (5 mL) at 0 C under nitrogen atmosphere. Then, DIPEA (0.368 mL, 2.11 mmol) was added at 5 C over 5 min. The mixture was stirred at 5 C for 30 min, then was stirred at rt for 20 h. The mixture was diluted with an NaHC03 aq. sat. sol and extracted with DCM. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo to yield intermediate (350 mg, 100%) as a brown sticky solid.
87%	With triethylamine; In dichloromethane; at 0 - 18℃; for 2.0h;	To a solution of tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-l-carboxylate (200 mg, 0.994 mmol) and TEA (201 mg, 1.99 mmol) in DCM (10 mL) was added methanesulfonyl chloride (228 mg, 1.99 mmol) at 0C. After addition, the mixture was stirred at 18C for 2 h. The reaction was quenched with aq. NaHCCL (8 mL) and extracted with DCM (10 mL x 3). The combined organics were dried (I^SCL) and evaporatedScheme to dryness to give the title compound as a yellow oil (243 mg, 87%) which was used without further purification. LCMS: ([M-Boc+H] = 163.0).
67%	With triethylamine; In dichloromethane; at 0℃; for 1.5h;Inert atmosphere;	The reaction was performed in anhydrous conditions under Argon atmosphere. To a solution of <strong>[477293-60-0]tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate</strong> (2 g, 9.94 mmol) in DCM (32 mL) cooled at 0 C were added Et3N (2.67 mL, 19.2 mmol) and methanesulfonyl chloride (1.11 mL, 14.4 mmol) and the reaction mixture was stirred at 0 C for 1.5 h. Water (55 mL) was added and the aqueous layer was extracted with DCM (2 x 75 mL). The combined organic layers were washed with HC1 (IN, aq., 50 mL), NaHCCb (sat., aq., 50 mL), dried (NaiSCL), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, mobile phase: cyclohexane/EtOAc, gradient from 80/20 to 40/60) to afford tert-butyl (2S,4S)-2-methyl-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 131 (1.97 g, 67%) as a colorless oil.

With triethylamine; In dichloromethane; at 0℃; for 16.0h;

Intermediate 81,1 -dimethylethyl (2S,4S)-2-methyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate1 ,1-dimethylethyl (2S,4S)-4-hydroxy-2-methyl-1-pyrrolidinecarboxylate (1.0326 g,5.13 mmol) in DCM (~2 mL) was placed under argon and cooled to 0 0C. To the reaction mixture was added triethylamine (1.2973 g, 12.8 mmol) and methanesulfonyl chloride (1.1753 g, 10.3 mmol). The resultant mixture was stirred for 16 hours and diluted in ether (-100 mL) and water (-60 mL). The aqueous layer was extracted with ethyl acetate (x2). The organic layers were combined, washed with 1 N HCI and NaHCO3 solution, dried on MgSO4 and the solvent evaporated under vacuum to afford the title compound as a yellow liquid (0.6395 g). LC-MS: m/z, 280 (M+H).

References: [1]Patent: WO2021/94312,2021,A1 .Location in patent: Page/Page column 74.
[2]Patent: WO2020/163193,2020,A1 .Location in patent: Paragraph 00321.
[3]Patent: WO2020/225230,2020,A1 .Location in patent: Page/Page column 41.
[4]Patent: WO2009/26197,2009,A1 .Location in patent: Page/Page column 31.
[5]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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Yield	Reaction Conditions	Operation in experiment
99.5%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; for 10.0h;Cooling with ice;	Step 2 [0412] Compound iv-8 (2.52g, 7.99mmol) was dissolved in THF (13mL). To the solution was added 1mol/L tetra butylammonium fluoride in THF (15.97mL, 15.97mmol) under ice-cooling, and the mixture was stirred for 10 hours under ice-cooling. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give Compound IV-4 (1.6g, Yield 99.5%). [0413] 1H-NMR (CDCl3) δ: 4.42-4.39 (1H, m), 4.02-3.99 (1H, m), 3.49-3.46 (2H, m), 2.11-2.08 (1H, m), 1.76-1.73 (1H, br m), 1.57-1.53 (1H, m), 1.47 (9H, s), 1.24 (3H, t, J = 5.26 Hz).
	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 3.0h;	Intermediate 7 1,1 -dimethylethyl-(2S,4S)-4-hydroxy-2-methyl-1 -pyrrolidinecarboxylateTo 1 ,1-dimethylethyl (2S,4S)-4-[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1- pyrrolidinecarboxylate (0.19201 g, 6.08 mmol) in THF (~1 ml.) was added TBAF (12 ml_,12.17 mmol) under argon. The resultant mixture was stirred at room temperature for 3 hours and purified by flash chromatography (silica gel) with gradient ethyl acetate:hexanes(1 :2) to (2:1 ) to afford the title compound (1.0326 g). LC-MS: m/z, 202 (M+H).

References: [1]Patent: EP2752410,2014,A1 .Location in patent: Paragraph 0412-0413.
[2]Patent: WO2009/26197,2009,A1 .Location in patent: Page/Page column 31.
[3]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.
[2]Patent: EP2752410,2014,A1 .

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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[ 708274-46-8 ]

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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[ 1123309-12-5 ]

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147.

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[ 477293-60-0 ]
(2S,4R)-tert-butyl 4-(3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: US2017/217970,2017,A1 .

22
[ 603-35-0 ]
[ 151266-23-8 ]
[ 477293-60-0 ]
(2S,4R)-tert-butyl 4-(3-iodo-4-((triphenylphosphoranylidene)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.387 g	With di-isopropyl azodicarboxylate; In tetrahydrofuran; at 20℃;Cooling with ice;	(Step 1) Synthesis of (2S,4R)-tert-butyl 4-(3-iodo-4-((triphenylphosphoranylidene)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpyrrolidine-1-carboxylate tert-Butyl (2S,4S)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (0.30 g), triphenylphosphine, and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine were dissolved in THF (7 mL). To the solution, diisopropyl azodicarboxylate (0.443 mL) was added under ice cooling. The solution was stirred at room temperature for 2 hours, and then, THF (10 mL) was further added thereto. After overnight stirring, triphenylphosphine (0.117 g) and diisopropyl azodicarboxylate (0.089 mL) were further added thereto, and the mixture was further stirred for 1 hour. After concentration of the solution, the residue was suspended in ethyl acetate, and the resulting insoluble matter was removed. Then, the filtrate was concentrated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to obtain the title compound (0.387 g) as a colorless amorphous.
0.387 g	With di-isopropyl azodicarboxylate; In tetrahydrofuran; at 20℃; for 3.0h;Cooling with ice;	tert-Butyl (2S,4S)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (0.30 g), triphenylphosphine, and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine were dissolved in THF (7 mL). To the solution, diisopropyl azodicarboxylate (0.443 mL) was added under ice cooling. The solution was stirred at room temperature for 2 hours, and then, THF (10 mL) was further added thereto. After overnight stirring, triphenylphosphine (0.117 g) and diisopropyl azodicarboxylate (0.089 mL) were further added thereto, and the mixture was further stirred for 1 hour. After concentration of the solution, the residue was suspended in ethyl acetate, and the resulting insoluble matter was removed. Then, the filtrate was concentrated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to obtain the title compound (0.387 g) as a colorless amorphous.

References: [1]Patent: US2017/217970,2017,A1 .Location in patent: Paragraph 0559.
[2]Patent: EP3590516,2020,A1 .Location in patent: Paragraph 0505.

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C₁₅H₂₁IN₆O₂ [ No CAS ]

References: [1]Patent: EP3590516,2020,A1 .

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[ 55758-32-2 ]
[ 477293-60-0 ]
tert-butyl (2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 60℃; for 2.0h;	To a solution of 6-fluoropyridin-3-ol (185 mg, 1.64 mmol) and ieri-butyl (2S,4S)-4-hydroxy-2- methylpyrrolidine- 1 -carboxylate (300 mg, 1.49 mmol) in THF (15.0 mL) were added DIAD (603 mg, 2.98 mmol) and triphenylphosphine (782 mg, 2.98 mmol). The mixture was stirred at 60C for 2 hrs. The solvent was removed and the residue was purified by column chromatograph on silica gel eluted (Petroleum ether/EtOAc = 3/1) to provide the title compound (92.0 mg, 21% yield). 1HNMR: (400 MHz, CDCl3) d 7.78-7.79 (m, 1H), 7.27-7.31 (m, 1H), 6.87 (dd, 7=8.8, 3.2 Hz, 1H), 4.82-4.84 (m, 1H), 4.03-4.09 (m, 1H), 3.75-3.76 (m, 1H), 3.62-3.64 (m, 1H), 2.33-2.36 (m, 1H), 1.93-1.96 (m, 1H), 1.47 (s, 9H), 1.32 (d, 7=6.4 Hz, 3H).

References: [1]Patent: WO2020/61150,2020,A1 .Location in patent: Paragraph 00113.

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tert-butyl (2S,4R)-2-methyl-4-(pyrazolo[1,5-a]pyridin-6-yloxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃; for 12.0h;	A mixture of pyrazolo[l,5-a]pyridin-6-ol (240 mg, 1.79 mmol), tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-l-carboxylate (300 mg, 1.49 mmol), DIAD (603 mg, 2.98 mmol, 585.27 uL) and triphenylphosphine (782 mg, 2.98 mmol) in THF (5 mL) was stirred at 55C for 12 hours. The mixture was evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (petroleum ether/EtOAc; 10: 1) to give the title compound as a yellow oil (220 mg, 46%). H NMR (400MHz, CDCI3) d: 8.03 (s, 1H), 7.86 (d, 7=2.4 Hz, 1H), 7.45 (d, 7=9.6 Hz, 1H), 6.90 (d, 7=9.6 Hz, 1H), 6.47 (s, 1H), 4.76- 4.79 (m, 1H), 3.95-4.10 (m, 1H), 3.62-3.81 (m, 2H), 2.31-2.37 (m, 1H), 1.97-2.05 (m, 1H), 1.47 (s, 9H), 1.34-1.35 (m, 3H).

References: [1]Patent: WO2020/163193,2020,A1 .Location in patent: Paragraph 00306.

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[ 15944-34-0 ]
[ 477293-60-0 ]
tert-butyl (2S,4R)-4-((7-chloro-1,8-naphthyridin-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
180 mg	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 10.0h;	DIAD (241.1 mg, 1.19 mmol) was added to a mixture of 7-chloro-l,8- naphthyridin-2-ol (107.7 mg, 0.596 mmol), tert-butyl (2S,4S)-4-hydroxy-2- methylpyrrolidine-l-carboxylate (120 mg, 0.596 mmol) and PPI13(312.8 mg, 1.19 mmol) in THF (5 mL) and the mixture was stirred at 20C for 10 hours. The mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc; 3: 1) to give the title compound as a white solid (180 mg). LCMS (ESI): [M+H] = 364.1

References: [1]Patent: WO2020/163193,2020,A1 .Location in patent: Paragraph 00336.

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2-methyloxazolo[4,5-b]pyridin-6-ol [ No CAS ]
[ 477293-60-0 ]
tert-butyl (2S,4R)-2-methyl-4-((2-methyloxazolo[4,5-b]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 40℃;	To a solution of triphenylphosphine (350 mg, 1.33 mmol) in THF (6.0 mL) was dropwise added DIAD (1.33 mmol, 262 uL). Light yellow ppt formedafter 5min. The reaction mixture was stirred at rt for 30min. A solution of tert-butyl ( 2S,4S )- 4-hydro xy-2-methyl-pyrrolidine- l-carboxy late (223 mg, 1.11 mmol) in THF (2.0 mL) and added dropwise to the reaction, followed by a mixture of 2-methyloxazolo[4,5-b]pyridin-6-ol (200 mg, 1.33 mmol) in THF (2.0 mL). The reaction was then stirred at 40C overnight. The reaction mixture was concentrated down and the crude was purified by chromatography on silica gel (0-60%EtOAc-EtOH 3: 1 with 2% NH40H in heptane) to give the title compound (252 mg, 68% yield). LCMS (ESI): [M+H] 334;8.17 (d, / = 2.51 Hz, 1H), 7.73 (d, / = 2.51 Hz, 1H), 5.05-5.13 (m, 1H), 3.99-4.08 (m, 1H), 3.78 (dd, / = 5.02, 12.55 Hz, 1H), 3.57-3.66 (m, 1H), 2.67 (s, 3H), 2.44 (br s, 1H), 1.94-2.02 (m, 1H), 1.48 (s, 9H), 1.35 (d, / = 6.27 Hz, 3H).

References: [1]Patent: WO2020/163193,2020,A1 .Location in patent: Paragraph 00343.

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[ 477293-60-0 ]
tert-butyl (2S,4R)-2-methyl-4-((1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]