* 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.
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: for 0.166667 h;
[00443] Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88percent yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: for 0.166667 h;
[006271 Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHCO3 (2 x 50 mL), dried (MgSO4), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88percent yield). ‘H NMR (CDCI3) ö 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: for 0.166667 h;
Intermediate 162 1 -(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)-2-methylpropan-2-ol [00558] Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88percent yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: for 0.166667 h;
To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2 aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88percent yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: for 0.166667 h;
1007561 Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1 M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -.78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mE, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mE). The organic phases were combined and washed with saturated aqueous NaHCO3 (2 x 50 mL), dried (MgSO4), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88percent yield). ‘H NMR (CDC13) 6 4.18 (q, 311), 2.49 (s, 2H), 1.29 (m,
88%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78℃; for 0.166667 h;
To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HCl (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88percent yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
Reference：
[1] Patent: WO2014/78322, 2014, A1, . Location in patent: Paragraph 00443
[2] Patent: WO2014/78325, 2014, A1, . Location in patent: Paragraph 00627
[3] Patent: WO2014/78408, 2014, A1, . Location in patent: Paragraph 00558
[4] Patent: WO2014/78328, 2014, A1, . Location in patent: Paragraph 00555
[5] Patent: WO2014/78331, 2014, A1, . Location in patent: Paragraph 00756
[6] Patent: WO2014/78454, 2014, A1, . Location in patent: Paragraph 00696
[7] Tetrahedron, 2007, vol. 63, # 51, p. 12547 - 12561
[8] Synthesis, 1979, p. 463 - 465
[9] Journal of Organic Chemistry, 1960, vol. 25, p. 1693 - 1699
2
[ 105-36-2 ]
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[2] Russian Journal of Organic Chemistry, 1994, vol. 30, # 7.2, p. 1129 - 1130[3] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 7, p. 1070 - 1071
[4] Journal of the Chemical Society, 1925, vol. 127, p. 620
[5] Justus Liebigs Annalen der Chemie, 1963, vol. 667, p. 35 - 47
[6] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1990, # 2, p. 267 - 271
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[1] Journal of the Chemical Society, 1949, p. 1827,1829
[2] Zhurnal Obshchei Khimii, 1948, vol. 18, p. 1646[3] Chem.Abstr., 1949, p. 2570
[4] Recueil des Travaux Chimiques des Pays-Bas, 1961, vol. 80, p. 1285 - 1304
6
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[1] Bulletin de la Societe Chimique de France, 1958, p. 1122,1123
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[1] Journal of Organic Chemistry, 1969, vol. 34, p. 1181 - 1187
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[1] Israel Journal of Chemistry, 1970, vol. 8, p. 731 - 736
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[1] Zhurnal Obshchei Khimii, 1948, vol. 18, p. 1646[2] Chem.Abstr., 1949, p. 2570
12
[ 18267-36-2 ]
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[1] Journal of Organic Chemistry, 2016, vol. 81, # 1, p. 57 - 65
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 44, p. 10511 - 10515
[3] Patent: CN106631968, 2017, A, . Location in patent: Paragraph 0077-0081
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[ 31912-02-4 ]
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[1] Journal of Organic Chemistry, 2016, vol. 81, # 1, p. 57 - 65
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[1] Journal of Organic Chemistry, 2016, vol. 81, # 1, p. 57 - 65
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h;
Stage #2: propan-2-one In tetrahydrofuran at -78℃; for 0.5h;
67.4 Step 4) ethyl 3-hydroxy-3-methylbutanoate
To a solution of LiHMDS (1 mol/L in THF, 20 mL, 20 mmol) was added EtOAc (2 mL, 20.5 mmol) dropwise at -78 °C. After addition, the reaction mixture was stirred for 1 h and acetone (1.8 mL, 24 mmol) was added dropwise. After addition, the reaction mixture was continued to stir for 0.5 h, quenched with a HC1 aqueous solution (2 M, 15 mL, 30 mmol) and extracted with EtOAc (30 mL c 2). The combined organic phases were washed with a saturate NaHCO, aqueous solution (15 mL), dried over Na2S04 and concentrated in vacuo to give the title compound as yellow oil (2.99 g, 100%).1H NMR (400 MHz, CDCl3): d (ppm) 4.18 - 4.04 (m, 2H), 3.66 (s, 1H), 2.43 (s, 2H), 1.27 - 1.14 (m, 9H).
100%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 1h;
Stage #2: propan-2-one In tetrahydrofuran for 0.5h;
67.4 Step 4) Ethyl 3-hydroxy-3-methylbutanoate
At -78 ° C,To LiHMDS (1 mol/L in THF, 20 mL, 20 mmol)EtOAc (2 mL, 20.5 mmol) was added dropwise.After the addition,The reaction mixture was moved to room temperature and stirred for 1 hour.Then acetone (1.8 mL, 24 mmol) was added dropwise.After the addition,The reaction mixture was moved and stirred for 0.5 hours.The reaction was quenched with EtOAc EtOAc (EtOAc m. The combined organic phase was washed with aqueous NaHCO3 (15mL) saturated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (2.99g, 100%).
89%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: propan-2-one In tetrahydrofuran for 0.166667h;
166.1 Step 1: Ethyl 3-hydroxy-3-methyl-butanoate
Ethyl acetate (5.0512 g, 5.6 mL, 57.332 mmol) was added dropwise to a solution of (bis(trimethylsilyl)amino)lithium (in THF) (39 mL of 1.5 M, 58.500 mmol) in THF (56 mL) at - 78 °C. The reaction mixture was stirred at this temperature for 30 min. Acetone (3.9550 g, 5 mL, 68.097 mmol) was added and the reaction mixture was left stirring 10 min. HCl (2 M, 35 ml) was added to the reaction mixture which was then left to warm up to room temperature. The reaction mixture was extracted with ethyl acetate (2x100 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 3-hydroxy-3-methyl-butanoate (7.84 g, 89%) as a clear yellow oil 1H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.1 Hz, 2H), 3.59 (s, 1H), 2.48 (s, 2H), 1.31 - 1.26 (m, 9H). ESI-MS m/z calc.146.0943, found 169.2 (M+23)+; Retention time: 1.3 minutes; LC method X.
88%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: propan-2-one In tetrahydrofuran for 0.166667h;
A [00443] Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate
[00443] Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: propan-2-one In tetrahydrofuran for 0.166667h;
A [006271 Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate:
[006271 Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHCO3 (2 x 50 mL), dried (MgSO4), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). ‘H NMR (CDCI3) ö 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: propan-2-one In tetrahydrofuran for 0.166667h;
A Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate
Intermediate 162 1 -(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)-2-methylpropan-2-ol [00558] Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: propan-2-one In tetrahydrofuran for 0.166667h;
A Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate
To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2 aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
88%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: propan-2-one In tetrahydrofuran for 0.166667h;
Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate
1007561 Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate: To a solution of lithium bis(trimethylsilyl)amide (1 M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -.78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HC1 (2M aqueous, 70 mE, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mE). The organic phases were combined and washed with saturated aqueous NaHCO3 (2 x 50 mL), dried (MgSO4), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). ‘H NMR (CDC13) 6 4.18 (q, 311), 2.49 (s, 2H), 1.29 (m,
88%
Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: propan-2-one In tetrahydrofuran at -78℃; for 0.166667h;
A Step A: Preparation of ethyl 3-hydroxy-3-methylbutanoate:
To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78 °C was added ethyl acetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HCl (2M aqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with saturated aqueous NaHC03 (2 x 50 mL), dried (MgS04), filtered and concentrated to afford the product as a yellow oil (12.8 g, 88% yield). 1H NMR (CDC13) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
77%
Stage #1: ethyl acetate With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 1h;
Stage #2: propan-2-one In tetrahydrofuran at -60℃; for 0.166667h; Further stages.;
(i) LiNEt2, biphenyl, THF, Et2O, (ii) /BRN= 635680/; Multistep reaction;
(i) LiNH2, liq. NH3, (ii) /BRN= 635680/; Multistep reaction;
1-ethoxy-3-methyl-1,3bis(trimethylsilyloxy)but-1-ene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: ethyl 3-hydroxy-3-methylbutanoate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h;
Stage #2: chloro-trimethyl-silane In tetrahydrofuran at -78 - 20℃; for 14h; Further stages.;
3-(1-hydroxy-1-methylethyl)-4-trimethylsilylethynyl-2-azetidinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With diisopropylamine
13 Synthesis of compound (7) STR33
EXAMPLE 13 Synthesis of compound (7) STR33 The reaction procedure of Example 1 is followed using trimethylsilylpropynal (1.26 g), 1,1,1,3,3,3-hexamethyldisilazane (0.61 g) and commercial butyllithium (1.60M)-hexane (6.2 ml) as well as ethyl 3-hydroxy-3-methylbutanoate (1.46 g), diisopropylamine (2.40 g) and commercial butyllithium-hexane (14 ml). The reaction mixture containing the desired product is concentrated under reduced pressure and the residue is subjected to silica gel column chromatography (eluent: 30% ethyl acetate-70% hexane) to give 0.278 g of 3-(1-hydroxy-1-methylethyl)-4-trimethylsilylethynyl-2-azetidinone (1:2 cis-trans mixture). M.p.: 137°-140° C. IR (Nujol): 3500, 3260, 2960, 1735, 1710 cm-1. NMR (CDCl3, ppm) of the cis compound 0.10 (9H, s), 1.33 (6H, s), 2.86 (1H, s) 3.33 (1H, dd, J=6.3 and 2.0 Hz), 4.30 (1H, d, J=6.3 Hz), 6.47 (1H, m). NMR (CDCl3, ppm) of the trans compound 0.10 (9H, s), 1.13 (3H, s), 1.40 (3H, s), 2.06 (1H, s), 3.16 (1H, d, J=3.3 Hz), 4.13 (1H, d, J=3.3 Hz), 6.30 (1H, m).
Stage #1: ethyl 3-hydroxy-3-methylbutanoate; 1-benzyl-3-(chloromethyl)-5-methoxy-1H-indazole With sodium hydride In N,N-dimethyl-formamide at 40℃;
Stage #2: With water; sodium hydroxide In ethanol for 6h; Reflux;
Stage #3: With hydrogenchloride; water
2.d
2d) 2-[(1 -benzyl-5-methoxy-1 H-indazol-3-yl)methoxy]-2-methylpropanoic acid; To a solution containing 1-benzyl-3-(chloromethyl)-5-methoxy-1 H-indazole (2.95 g; 0.01 mol) and ethyl 3-hydroxy-3-methylbutanoate (1.98 g; 0.015 mol) in DMF (30 ml) stirred at room temperature was slowly added 60% NaH (0.36 g; 0.015 mol). The mixture was then heated at 400C for 24 hours. The reaction was stopped by cooling the suspension to room temperature and adding water (200 ml). The solvent was evaporated off under reduced pressure and the residue was treated at reflux with NaOH (0.84 g; 0.021 mol) in water (6 ml) and 95° ethanol (6 ml) for 6 hours. The mixture was then cooled to room temperature and diluted with water (50 ml). The alkaline phase was washed with diethyl ether (2x20 ml) and then acidified with concentrated HCI and extracted with diethyl ether (3x30 ml).The combined organic phases were concentrated under reduced pressure and the crude residue obtained was purified by crystallization from 10/1 hexane/ethyl acetate mixture to give 0.8 g of 2-[(1-benzyl-5-methoxy-1 H- indazol-3-yl)methoxy]-2-methylpropanoic acid with a melting point of 128- 1300C.1H-NMR (DMSO-d6, δ ppm): 1.44 (s, 6 H), 3.77 (s, 3 H), 4.69 (s, 2 H), 5.55 (s, 2 H), 7.02 (dd, J = 9.15; 2.38 Hz, 1 H), 7.17-7.33 (m, 5 H), 7.41 (d, J = 2.38 Hz, 1 H), 7.55 (d, J = 9.15 Hz, 1 H), 12.79 (s, 1 H).
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl 3-hydroxy-3-methylbutanoate In tetrahydrofuran at -78 - 0℃; for 2.5h;
B [00444] Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile
[00444] Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile: To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with H20 (100 mL) and extracted with Et20 (50 mL). The phases were separated and the basic aqueous phase was neutralized with HC1 (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgS04), filtered, and concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). 1H NMR (CDC13) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
63%
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl 3-hydroxy-3-methylbutanoate In tetrahydrofuran at -78 - 0℃; for 2.5h;
B [00559] Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile:
[00559] Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile: To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with H20 (100 mL) and extracted with Et20 (50 mL). The phases were separated and the basic aqueous phase was neutralized with HC1 (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgS04), filtered, and concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). 1H NMR (CDC13) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
63%
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl 3-hydroxy-3-methylbutanoate In tetrahydrofuran at -76 - 0℃; for 2.5h;
B Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile
To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with H20 (100 mL) and extracted with Et20 (50 mL). The phases were separated and the basic aqueous phase was neutralized with HC1 (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgS04), filtered, and concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). lH NMR (CDC13) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
63%
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl 3-hydroxy-3-methylbutanoate In tetrahydrofuran at -78 - 0℃; for 2.5h;
Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile
1007571 Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile: To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with 1120 (100 mL) and extracted with Et20 (50 mL). The phases were separated and the basic aqueous phase was neutralized with HC1 (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgSO4), filtered,concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). ‘H NMR (CDC13) 6 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
63%
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl 3-hydroxy-3-methylbutanoate In tetrahydrofuran at -78 - 0℃; for 2.5h; Inert atmosphere;
B Step B: Preparation of 5-hvdroxy-5-methyl-3-oxohexanenitrile:
To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3- hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with H20 (100 mL) and extracted with Et20 (50 mL). The phases were separated and the basic aqueous phase was neutralized with HCl (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgS04), filtered, and concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). 1H NMR (CDC13) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: ethyl 3-hydroxy-3-methylbutanoate In tetrahydrofuran at -78 - 0℃; for 2.5h;
B [006281 Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile:
[006281 Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile: To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) under N2 at -78 °C was added lithium bis(trimethylsilyl)amide (1M in THF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl 3- hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then stirred at 0 °C for 1.5 hours, then diluted with H20 (100 mL) and extracted with Et20 (50 mE). The phases were separated and the basic aqueous phase was neutralized with HC1 (6M aqueous, 4.5 mL), then extracted with Et20 (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgSO4), filtered, and concentrated to afford the product as a pale yellow oil (1.24 g, 63% yield). ‘H NMR (CDC13)o 3.54 (m, 111), 2.89 (s, 2H), 1.50 (d, 311), 1.32 (s, 3H), 1.31 (s, 3H).
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine; In 5,5-dimethyl-1,3-cyclohexadiene; at 120℃; for 15h;Inert atmosphere;
trifluoroacetic acid palladium (0.025mmol, 8 mg), three-ring hexyl phosphine (0.05mmol, 14 mg), cesium carbonate (0.75mmol, 244 mg) and 1a (0.5mmol, 101 mg) is put into the 25 ml reaction tube, sufficient vacuum, nitrogen (three times). Under the protection of nitrogen injected through the syringe 2b (1.5mmol, 219 mg), xylene 3 ml. In the 120 C pot oil bath stirring 15h, after cooling to room temperature the temperature of the reaction system by adding 20 ml water, add 25 ml ethyl acetate extraction, grass-roots takes has saturated salt water for washing, for Na2 SO4 Drying, then adding a small amount of silica gel turns on lathe the main column chromatography.
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 15h; Schlenk technique; Sealed tube; Inert atmosphere;
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 15h; Schlenk technique; Inert atmosphere; chemoselective reaction;
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 110℃; for 15h; Inert atmosphere;
9.1
trifluoroacetic acid palladium (0.025mmol, 8 mg), three-ring hexyl phosphine (0.05mmol, 14 mg, cesium carbonate (0.75mmol, 244 mg) and 1b (0.5mmol, 108 mg) is put into the 25 ml reaction tube, sufficient vacuum, nitrogen (three times). Under the protection of nitrogen injected through the syringe 2b (1.5mmol, 219 mg), xylene 3 ml. In 110 °C pot oil bath stirring 15h, after cooling to room temperature the temperature of the reaction system by adding 20 ml water, add 25 ml ethyl acetate extraction, grass-roots takes has saturated salt water for washing, for Na2 SO4 Drying, then adding a small amount of silica gel turns on lathe the main column chromatography.
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 15h; Schlenk technique; Sealed tube; Inert atmosphere;
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 15h; Schlenk technique; Sealed tube; Inert atmosphere;
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine; In 5,5-dimethyl-1,3-cyclohexadiene; at 120℃; for 15h;Inert atmosphere;
trifluoroacetic acid palladium (0.025mmol, 8 mg), three-ring hexyl phosphine (0.05mmol, 14 mg), cesium carbonate (0.75mmol, 244 mg) and 1f (0.5mmol, 86 mg) is put into the 25 ml reaction tube, sufficient vacuum, nitrogen (three times). Under the protection of nitrogen injected through the syringe 2b (1.5mmol, 219 mg), xylene 3 ml. In the 120 C pot oil bath stirring 15h, after cooling to room temperature the temperature of the reaction system by adding 20 ml water, add 25 ml ethyl acetate extraction, grass-roots takes has saturated salt water for washing, for Na2 SO4 Drying, then adding a small amount of silica gel turns on lathe the main column chromatography.
(1,2-diamino-5-bromopyridin-1-ium) 2,4,6-trimethylbenzenesulfonate[ No CAS ]
1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium hydroxide In methanol at 70℃;
67.5 Step 5) 1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol
To a solution of l,2-diamino-5-bromopyridin-l-ium 2,4,6- trimethylbenzenesulfonate (2.01 g, 5.2 mmol) in methnoal (20 mL) were added ethyl 3-hydroxy- 3-methylbutanoate (1.50 g, 10.3 mmol) and NaOH (212.3 mg, 5.3 mmol). The reaction mixture was stirred at 70 °C overnight and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 1/1) to give the title compound as a white solid (719.0 mg, 51%).MS (ESI, pos. ion) m/z: 270.2 [M+H]+;1H NMR (400 MHz, CDCl3): d (ppm) 8.67 (s, 1H), 7.57 (s, 2H), 4.10 (s, 1H), 3.06 (s, 2H), 1.27 (s, 6H).
6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 4 steps
1: sodium hydroxide / methanol / 70 °C
2: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
3: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
Multi-step reaction with 4 steps
1: sodium hydroxide / methanol / 70 °C
2: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
3: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
To a solution of ethyl 3 -hydroxy-3 -methylbutanoate (1.56 g, 10.7 mmol) in water (20 mL) was added hydroxyl sodium (851.0 mg, 21.3 mmol). The reaction mixture was stirred at rt overnight and neutralized by concentrated hydrochloric acid to pH = 5, then extracted with EtOAc (50 mL c 3). The combined organic phases were dried over Na2S04 and concentrated in vacuo to give the title compound as yellow oil (1.17 g, 93percent).
93%
With sodium hydroxide; In water; at 20℃;
toEthyl 3-hydroxy-3-methylbutanoate (1.56 g, 10.7 mmol)In water (20mL) solutionSodium hydroxide (851.0 mg, 21.3 mmol).The reaction mixture was stirred at room temperature overnight.It was then adjusted to pH = 5 with hydrochloric acid and extracted with EtOAc (50 mL×3).The combined organic phases were dried over anhydrous sodium sulfate.Filter and concentrate under reduced pressure.The title compound is yellowOil (1.17 g, 93percent).
6-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 6 steps
1: sodium hydroxide; water / 20 °C
2: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / tetrahydrofuran / 20 °C
3: acetic acid / 0.67 h / 180 °C / Microwave irradiation
4: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
5: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
6: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; potassium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
Multi-step reaction with 6 steps
1: sodium hydroxide / water / 20 °C
2: triethylamine; HATU / tetrahydrofuran / 20 °C
3: acetic acid / 0.67 h / 180 °C / Microwave irradiation
4: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
5: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
6: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; potassium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
6-(4-((5-chloro-2-((3-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 6 steps
1: sodium hydroxide; water / 20 °C
2: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / tetrahydrofuran / 20 °C
3: acetic acid / 0.67 h / 180 °C / Microwave irradiation
4: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
5: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
6: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; potassium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
Multi-step reaction with 6 steps
1: sodium hydroxide / water / 20 °C
2: triethylamine; HATU / tetrahydrofuran / 20 °C
3: acetic acid / 0.67 h / 180 °C / Microwave irradiation
4: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
5: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
6: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; potassium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1: sodium hydroxide / methanol / 70 °C
2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
Multi-step reaction with 2 steps
1: sodium hydroxide / methanol / 70 °C
2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1: sodium hydroxide / methanol / 70 °C
2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; potassium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
Multi-step reaction with 2 steps
1: sodium hydroxide / methanol / 70 °C
2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; potassium carbonate; palladium diacetate / 1,4-dioxane / 100 °C / Inert atmosphere
6-(4-((5-chloro-2-((2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 4 steps
1: sodium hydroxide / methanol / 70 °C
2: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
3: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere
Multi-step reaction with 4 steps
1: sodium hydroxide / methanol / 70 °C
2: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,4-dioxane / 100 °C / Inert atmosphere
3: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C
4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere
1,2,4-triaminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate[ No CAS ]
1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With sodium hydroxide In methanol at 70℃;
77.2 Step 2) 1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol
To a solution of l,2,4-triaminopyridin-l-ium 2,4,6-trimethylbenzenesulfonate(2.00 g, 6.2 mmol) in methnoal (20 mL) were added ethyl 3 -hydroxy-3 -methylbutanoate (3.60 g, 24.7 mmol) and NaOH (493.6 mg, 12.3 mmol). The reaction mixture was stirred at 70 °C overnight, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/DCM (v/v) = 1/10) to give the title compound as a yellow solid (183.2 mg, 14%).MS (ESI, pos. ion) m/z: 207.1 [M+H]+;1H NMR (400 MHz, DMSO-76): d (ppm) 8.35 (d, J= 7.3 Hz, 1H), 6.45 (dd, J= 7.3, 2.3 Hz, 1H), 6.41 (d, J= 1.9 Hz, 1H), 6.08 (s, 2H), 4.69 (s, 1H), 2.74 (s, 2H), 1.15 (s, 6H).
1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium hydroxide In methanol at 70℃;
67.5 Step 5) 1-(6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol
To 1,2-diamino-5-bromopyridine-1-indole 2,4,6-trimethylbenzenesulfonate (2.01 g, 5.2 mmol)Add in methanol (20mL) solutionEthyl 3-hydroxy-3-methylbutanoate (1.50 g, 10.3 mmol) andNaOH (212.3 mg, 5.3 mmol).The reaction mixture was stirred at 70 ° C overnight.It was then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc /EtOAcThe title compound was obtained as a white solid (719.0mg, 51%).
1,2,4-triaminopyridin-1-ium 2,4,6-trimethylbenzenesulfonate[ No CAS ]
1-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With sodium hydroxide In methanol at 70℃;
77.2 Step 2) 1-(7-Amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methylpropan-2-ol
To 1,2,4-aminopyridine-1--indole 2,4,6-trimethylbenzenesulfonate (2.00 g, 6.2 mmol)(20 mL) of methanol (20 mL)Ethyl 3-hydroxy-3-methylbutanoate (3.60 g, 24.7 mmol) was added to the solution.And NaOH (493.6 mg, 12.3 mmol).The reaction mixture was stirred at 70 ° C overnight.It was then concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (MeOH / DCThe title compound was obtained as a yellow solid (183.2mg, 14%).
benzyl (4-ethoxy-2-methyl-4-oxobutan-2-yl) oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With pyridine In diethyl ether at 23℃; for 1h;
3.2. General Procedure B. Synthesis of oxalic acids via alkyl benzyl oxalates.
General procedure: B1. Benzyl alcohol (1.0 equiv) in dry Et2O (0.3 M) was added dropwise over 1 h to an ice-cooled solution of oxalyl chloride (2.0 equiv) in dry Et2O (0.6 M). The resulting solution was stirred for 1 h after addition. The reaction mixture was then concentrated to give a slightly yellow oil that was dried in vacuo to remove traces of oxalyl chloride. In a separate round-bottom flask, the substrate alcohol (1.0 equiv) and pyridine (1.2 equiv) were dissolved in dry Et2O (0.1 M). A solution of the benzyl chlorooxoacetate in a minimal amount of Et2O was added dropwise at 23°C, causing the formation of a white precipitate. The resulting mixture was stirred for 1 h. Upon completion, the reaction mixture was transferred to a separatory funnel and washed successively with water and brine. The organic phase was dried over MgSO4, filtered and concentrated to afford the desired alkyl benzyl oxalate, which was purified by flash column chromatography over silica gel.
166.2 Step 2: Ethyl 3-fluoro-3-methyl-butanoate
Deoxo-Fluor (solution in toluene) (26 g, 50 %w/w, 58.759 mmol) was added to a solution of ethyl 3-hydroxy-3-methyl-butanoate (7.5 g, 48.740 mmol) in DCM (125 mL) at -78 °C. The reaction was then left to warm-up to room temperature and stirred for 4 h. The reaction mixture was quenched with aqueous sodium bicarbonate (200 mL). The aqueous phase was extracted with DCM (2x100 mL) and the combined organic phases were washed with saturated aqueous ammonium chloride (100 mL), dried with magnesium sulfate, filtered and concentrated under reduced pressure to provide crude ethyl 3-fluoro-3-methyl-butanoate (4.8 g, 53%) as a clear oil 1H NMR (400 MHz, CDCl3) δ 4.16 (q, J = 7.2 Hz, 2H), 2.66 (d, J = 16.1 Hz, 2H), 1.49 (d, J = 21.8 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H). Which was used directly in the next step without further purification.
With [bis(2-methoxyethyl)amino]-sulfur trifluoride In dichloromethane at -78 - 20℃; for 4h;
1 Step 1: ethyl 3-fluoro-3-methylbutanoate
To a dichloromethane (15 mL) solution of ethyl 3-hydroxy-3-methylbutanoate (750 mg, 5.1 mmol) at -78 was added bis (2-methoxyethyl) aminosulfur trifluoride (1.25 g, 5.6 mmol) . The reaction mixture was then allowed to warm up to room temperature and stirred for 4 hours. It was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) , and the aqueous layer was extracted with dichloromethane (10 mL) . The combined organic extracts were washed with saturated aqueous ammonium chloride (10 mL) , dried (magnesium sulfate) , filtered and concentrated in vacuo to afford the title compound, which was used in the subsequent reaction without further purification.1H-NMR (CDCl3, 400 MHz) δ 4.16 (q, J = 7.1 Hz, 2H) , 2.66 (d, J = 15.9 Hz, 2H) , 1.49 (d, J = 21.8 Hz, 6H) , 1.28 (t, J = 7.1 Hz, 3H) .
ethyl 3-((4-fluorophenyl)thio)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With copper(II) bis(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 60℃; for 12h; Schlenk technique;
General procedure for the reaction of tertiary alkyl alcohols with thiols
General procedure: To a flame-dried Schlenk tube was charged with a tertiary alcohol (0.30 mmol, 100 mol %), Cu(OTf)2 (1.1 mg, 0.003 mmol, 1 mol %). The tube was capped with a rubber septum. Mercaptan (0.30 mmol, 100 mol %) was added followed by addition of DCE (1 mL) via syringes. The reaction mixture was allowed to stir in an oil bath for 12 h under an air atmosphere at 70oC. Then, the reaction mixture was directly loaded onto a silica column without work-up. The residue was rinsed with PE or the eluent for column chromatography, with which the product was isolated.
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