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Structure of 124-68-5 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Tetrahedron Letters, 2004, vol. 45, # 8, p. 1585 - 1588
[2] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 109, p. 62 - 69
[3] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 109, p. 62 - 69
3
[ 124-68-5 ]
[ 105-58-8 ]
[ 26654-39-7 ]
Reference：
[1] Tetrahedron, 1991, vol. 47, # 16-17, p. 2801 - 2820
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 1840,1842
[3] Patent: US5641770, 1997, A,
[4] Patent: US2399118, 1942, ,
4
[ 124-68-5 ]
[ 57-13-6 ]
[ 26654-39-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 170 - 220℃; for 2 h;
[00121] Preparation of 4,4-dimethyloxazolidin-2-one (DMO) [00122] A mixture of 2-amino-2-methyl-l-propanol (10.0 g, 112 mmole) and urea (13.5 g, 224 mmole) was heated for 1 h at 170-180 °C, for 1 h at 210-220 °C, cold to rt and dissolved in water (50 mL). The solution was extracted with DCM (5 x 50 mL). The combined extracts were dried over Na2S04, filtered and concentrated in vacuo to afford 10.3 g (80percent) of 4,4-dimethyloxazolidin-2-one. lH NMR (CDC13): δ 6.13 (br s, 1H, NH), 4.07 (s, 2H, CH2), 1.32 (s, 6H, 2 CH3) ppm. 13C NMR (CDC13) δ 159.4, 77.1, 55.4, 27.7 ppm.
Reference：
[1] Asian Journal of Chemistry, 2011, vol. 23, # 2, p. 929 - 930
[2] Patent: WO2015/68159, 2015, A2, . Location in patent: Paragraph 00121-00122
5
[ 541-41-3 ]
[ 124-68-5 ]
[ 26654-39-7 ]
Reference：
[1] Chemistry - A European Journal, 2001, vol. 7, # 19, p. 4117 - 4125
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 481 - 486
10
[ 108-24-7 ]
[ 124-68-5 ]
[ 26654-39-7 ]
Reference：
[1] Molecules, 2016, vol. 21, # 12,
11
[ 201230-82-2 ]
[ 75-31-0 ]
[ 124-68-5 ]
Yield
Reaction Conditions
Operation in experiment
93%
With tricresyl phosphate; hydrogen; palladium diacetate In diphenylether at 140℃; Autoclave
(50 mmol) of palladium acetate and 88 g (250 mmol) of trimethyl phosphite were successively added to a 1000 mL autoclave, and the synthesis gas was fed to a high-pressure autoclave The reactor was pressurized to 3 MPa and the synthesis gas was a mixed gas of H2 and CO in a molar ratio of 1: 1. The stirring was started and the temperature was raised to 140 ° C. When the temperature rose to 140 ° C, the synthesis gas was used to replenish the pressure to 8 MPa and the reaction was started. During the reaction, the synthesis gas pressure was intermittently added so that the reaction pressure was maintained at 7 to 8 MPa. The yield of 2-amino-2-methyl-1-propanol was 93percent after tracing to isopropylamine no longer reacted by gas chromatography. The reaction mixture was removed, distilled under reduced pressure at 2.5 kPa, and the fraction between 68-72 ° C was collected to give 2-ammoniaMethyl-1-propanol as pure product, 21 g, and the isolated yield was 93percent.
Reference：
[1] Patent: CN105418440, 2016, A, . Location in patent: Paragraph 0060; 0061; 0062
With sodium hypochlorite; sodium hydroxide In water at 0 - 70℃; for 0.333333 h;
109 g of sodium hypochlorite and 106 g of sodium hydroxide were weighed and dissolved in 600 g of water. The above solution was dissolved in a temperature of about 0 ° C,The crude product of 2,2-dimethyl-3-hydroxypropionamide was added dropwise with stirring, and the temperature was raised to 70 ° C for 20 min. After the reaction is overThe water was distilled off, and the mixture was purified by filtration to obtain 103 g of 2-amino-2-methyl-1-propanol and 99.2 wtpercent purity.The target product yield was about 86.3percent.The total yield of 2-amino-2-methyl-1-propanol was about 57.4percent.
Reference：
[1] Patent: CN107129435, 2017, A, . Location in patent: Paragraph 0034; 0038; 0039; 0044; 0045; 0050; 0051
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10632 - 10641
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 31, p. 8878 - 8883[3] Angew. Chem., 2016, vol. 128, # 31, p. 9024 - 9029,6
[4] Advanced Synthesis and Catalysis, 2011, vol. 353, # 11-12, p. 2093 - 2110
30
[ 124-68-5 ]
[ 67-64-1 ]
[ 90032-83-0 ]
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 52, p. 15840 - 15844[2] Angew. Chem., 2015, vol. 127, # 52, p. 16066 - 16070,5
31
[ 24424-99-5 ]
[ 124-68-5 ]
[ 102520-97-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In dichloromethane at 20℃; for 2.83333 h;
(3a) (2-Hydroxy-1,1-dimethylethyl)carbamic acid t-butyl ester 230.4 ml of di-t-butyl dicarbonate (1.00 mol) was added to a solution of 98.05 g of 2-amino-2-methyl-1-propanol (1.10 mol) and 154 ml of triethylamine (1.10 mol) in methylene chloride (500 ml) at room temperature over 20 minutes, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and diluted with a 10percent citric acid aqueous solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 189.25 g of the crude title compound (yield: quant.). Colorless solid. 1H NMR spectrum (CDCl3, 400 MHz), δ: 4.64 (br s, 1H), 4.01 (br s, 1H), 3.59 (d, 2H, J = 6.3 Hz), 1.43 (s, 9H), 1.25 (s, 6H).
99%
With iron(III) trifluoromethanesulfonate In neat (no solvent) at 20℃; for 0.0666667 h; Green chemistry
General procedure: Fe(OTf)3 (1 molpercent) was added to a magnetically stirred mixture of anamine (1 mmol) and Boc2O (1 mmol) at room temperature. The mixturewas stirred until completion of the reaction (TLC), then diluted withEtOAc and washed with water. The organic layer was dried overanhydrous MgSO4, then the solvent was distillated off under vacuum toyield the highly pure N‑Boc derivatives
98%
at 0 - 20℃; for 2 h;
Di-tert-butyl dicarbonate (21.82 g, 100.00 mmol) was added in portions to a solution of 2- amino-2-methylpropan-i-ol (8.91 g, 100.0 mmol) in DCM (270 ml) at 0 °C. The reaction was stirred at room temperature for 2 hours, then was washed with 2N HC1 (100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give tert-butyl (1-hydroxy- 2-methylpropan-2-yl)carbamate (18.56 g, 98 percent) as a white solid. ‘H NMR (400 MHz,CDC13, 27 °C) 1.25 (6H, s), 1.43 (9H, s), 3.58 (2H, d), 4.67 (1H, s).
97%
With triethylamine In dichloromethane at 22 - 25℃; for 4 h;
2-Amino-2-methyl-l-propanol (5 g, 56.1 mmol), (Boc)20 (13.46 g, 61.7 mmol) and triethyl amine (6.24 g, 61.7 mmol) were dissolved in 50 mL of dichloromethane. The reaction mixture was stirred for 4 h at 22 to 25 °C. Above mixture was washed with water (25 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to get tert-buty] (1- hydroxy-2-methylpropan-2-yl)carbamate (10.3 g, 97percent yield).
90%
With 1,3-disulfonic acid imidazolium hydrogen sulfate In neat (no solvent) at 20℃; for 0.0333333 h; Green chemistry
General procedure: Amine (1 mmol) was added to the mixture of (Boc)2O (1 mmol) and DSIMHS (6.5 mg, ~ 0.02 mmol) with constant stirring at room temperature under solvent-free conditions. After completion of the reaction (monitored by TLC), ethyl acetate (3 × 5 mL) was added to the reaction mixture and the catalyst was decanted and washed with ethyl acetate (2 × 5 mL) and dried. The product was purified by column chromatography, using ethyl acetate–petroleum ether (2:8) eluent.
75.36%
With triethylamine In dichloromethane at 0 - 20℃; for 1 h;
To a solution of compound 1 (10.00 g, 112.18 mmol, 1.00 Eq) in DCM (200 mL) was added Et3N (23.00 g, 227.30 mmol, 2.03 Eq). The mixture was cooled to 0° C. and Boc2O (38.40 g, 175.95 mmol, 1.57 Eq) was added, the mixture was stirred at 20° C. for 1 hr. The mixture was diluted with EA and washed with water. The organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=15/1) to afford compound 2 (16.00 g, 84.54 mmol, 75.36percent yield) as white solid.
75.36%
With triethylamine In dichloromethane at 0 - 20℃; for 0.5 h;
To a solution of compound 1 (10.00 g, 112.18 mmol, 1.00 Eq) in DCM (200 mL) was added Et3N (23.00 g, 227.30 mmol, 2.03 Eq). The mixture was cooled to 0° C. and Boc2O (38.40 g, 175.95 mmol, 1.57 Eq) was added, the mixture was stirred at 20° C. for 1 hr. The mixture was diluted with EA and washed with water. The organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=15/1) to afford compound 2 (16.00 g, 84.54 mmol, 75.36percent yield) as white solid.
68%
at 20℃;
Example 4 (tert-Butoxy)-N-(1-hydroxy-2-methylpropyl)carboxamide (4) Following the general procedure for the N-Boc-protection of ω-amino-2,2-dimethylalcohols of Description 2, 1.783 g (20.0 mmol) of 2-amino-2-methyl-1-propanol was reacted with 3.274 g (15.0 mmol) of di-tert-butyl-dicarbonate in a mixture of 20 mL of a saturated aqueous solution of sodium bicarbonate (NaHCO3) and 40 mL of acetonitrile to provide 1.937 g (68percent yield) of the title compound (4) as a colorless solid of sufficient purity to be used in subsequent steps without further isolation and purification. 1H NMR (400 MHz, CDCl3): δ=1.26 (s, 6H), 1.44 (s, 9H), 3.59 (d, J=6.0 Hz, 2H), 4.00-4.20 (br. m, 1H), 4.64-4.72 (br. m, 1H) ppm. MS (ESI) m/z 212.92 (M+Na)+.
53%
at 25℃; for 1 h;
2-Amino-2-methyl-propan-1-ol (53 g, 0.59 mol) and di-tert-butyl dicarbonate (65.0 g, 0.297 mol) were combined in H2O (500 mL) and stirred at 25 °C for 1 h. The reaction mixture was extracted with CHCl3 (2 x 250 mL). The organics were dried and concentrated to a white amorphous solid which was recrystallized from hot hexanes to afford desired material (30 g, 53percent) as a white solid: 13C NMR (CD3OD, 100 MHz) δ 157.76, 80.135, 70.095, 54.992, 29.247, 24.695.
750 g
With sodium hydrogencarbonate; sodium carbonate In tetrahydrofuran; water at 0 - 20℃; for 18 h;
Intermediate 12: tert-butyl (l-hydroxy-2-meth lpropan-2-yl)carbamate - Preparation 2 To a solution of 2-amino-2-methylpropan-l-ol (500 g, 5.61 mol, Alfa) in THF (3.0 L) and water (1.0 L) was added Na2C03 (10.11 g, 95 mmol) and sodium bicarbonate (10.37 g, 123 mmol) and stirring continued at 0 QC. di-ferf-Butyl dicarbonate (1.56 L, 6.7 mol) was added. The reaction mixture was stirred at RT for 18 h. The THF layer was separated and the aqueous layer extracted with ethyl acetate (1.5 L). The combined organic layers were washed with brine solution (2 x 2 L), were dried over anhydrous Na2S04 and then concentrated under reduced pressure to afford crude title compound. The crude material was dissolved in petroleum ether (750 mL) and cooled to -50 °C. The resulting solid was filtered and washed with petroleum ether to give the title compound (750 g) as a white solid. (0250) *H NMR (400 MHz, DMSO-d6) δ: 6.08 (1H, s), 4.67 (1H, t), 3.29 (2H, s), 1.37 (9H, s), 1.13 (6H, s).
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 20, p. 6368 - 6380
[2] Patent: EP2036896, 2009, A1, . Location in patent: Page/Page column 149
[3] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1188 - 1197
[4] Journal of Chemical Research, 2013, vol. 37, # 12, p. 757 - 760
[5] Patent: US6140326, 2000, A,
[6] Organic and Biomolecular Chemistry, 2009, vol. 7, # 4, p. 655 - 659
[7] Patent: WO2016/162325, 2016, A1, . Location in patent: Page/Page column 139
[8] Patent: WO2015/79459, 2015, A1, . Location in patent: Paragraph 00290
[9] Journal of the American Chemical Society, 1991, vol. 113, # 23, p. 8879 - 8886
[10] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1110 - 1114
[11] Journal of Molecular Liquids, 2013, vol. 177, p. 386 - 393
[12] Journal of the Iranian Chemical Society, 2012, vol. 9, # 4, p. 495 - 502
[13] Journal of the Iranian Chemical Society, 2013, vol. 10, # 2, p. 181 - 188
[14] RSC Advances, 2015, vol. 5, # 26, p. 19790 - 19798
[15] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5164 - 5169
[16] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 11, p. 2061 - 2069
[17] Patent: US2015/197493, 2015, A1, . Location in patent: Paragraph 0766; 0767; 0768
[18] Patent: US2015/225355, 2015, A1, . Location in patent: Paragraph 0763
[19] Patent: US2009/82464, 2009, A1, . Location in patent: Page/Page column 39
[20] Patent: US2003/232832, 2003, A1,
[21] Patent: WO2003/99286, 2003, A1, . Location in patent: Page 96
[22] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 24, p. 3051 - 3056
[23] Synlett, 1997, vol. 1997, # 8, p. 893 - 894
[24] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 743 - 746
[25] Patent: WO2006/81392, 2006, A1, . Location in patent: Page/Page column 50
[26] Patent: US6013658, 2000, A,
[27] Patent: US4622418, 1986, A,
[28] Patent: US4843072, 1989, A,
[29] Patent: US6350767, 2002, B1, . Location in patent: Page column 36
[30] Patent: WO2004/108661, 2004, A1, . Location in patent: Page/Page column 49
[31] Patent: WO2005/28454, 2005, A1, . Location in patent: Page/Page column 51
[32] Patent: WO2010/103312, 2010, A1, . Location in patent: Page/Page column 10
[33] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2877 - 2879
[34] Patent: WO2014/48065, 2014, A1, . Location in patent: Page/Page column 94
[35] Patent: WO2014/114694, 2014, A1, . Location in patent: Page/Page column 28
[36] Patent: WO2015/92819, 2015, A2, . Location in patent: Paragraph 0202; 0203
[37] Synthesis (Germany), 2016, vol. 48, # 6, p. 906 - 916
[38] Patent: WO2016/12916, 2016, A1, . Location in patent: Page/Page column 29; 30
With triethylamine; In dichloromethane; at 20℃; for 2.83333h;
(3a) (2-Hydroxy-1,1-dimethylethyl)carbamic acid t-butyl ester 230.4 ml of di-t-butyl dicarbonate (1.00 mol) was added to a solution of 98.05 g of 2-amino-2-methyl-1-propanol (1.10 mol) and 154 ml of triethylamine (1.10 mol) in methylene chloride (500 ml) at room temperature over 20 minutes, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and diluted with a 10% citric acid aqueous solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 189.25 g of the crude title compound (yield: quant.). Colorless solid. 1H NMR spectrum (CDCl3, 400 MHz), delta: 4.64 (br s, 1H), 4.01 (br s, 1H), 3.59 (d, 2H, J = 6.3 Hz), 1.43 (s, 9H), 1.25 (s, 6H).
99%
With iron(III) trifluoromethanesulfonate; In neat (no solvent); at 20℃; for 0.0666667h;Green chemistry;
General procedure: Fe(OTf)3 (1 mol%) was added to a magnetically stirred mixture of anamine (1 mmol) and Boc2O (1 mmol) at room temperature. The mixturewas stirred until completion of the reaction (TLC), then diluted withEtOAc and washed with water. The organic layer was dried overanhydrous MgSO4, then the solvent was distillated off under vacuum toyield the highly pure N-Boc derivatives
99%
With potassium carbonate; In tetrahydrofuran; water; at 20℃;
Potassium carbonate (31.5 g, 225 mmol) was added to water (150 mL), and dissolved upon stirring, to give areaction mixture. 2-amino-2-methyl-1-propanol (Compound a-3, 13.35 g, 150 mmol) was dissolved in tetrahydrofuran(50 mL), and the resulting solution was added to the above reaction mixture. Then, a solution of di-tert-butyl dicarbonate(32.7 g, 150 mmol) in tetrahydrofuran was added dropwise and stirred at room temperature overnight. Ethyl acetate (50mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate twice. The organicphases were combined, washed with a saturated NaCl solution, dried, and concentrated to afford Compound b-3 (28 g,yield 99%).
98%
In dichloromethane;
STR93 a) Synthesis of N-(tert-butoxycarbonyl)-2-amino-2-methyl-1-propanol To solution of 2-amino-2-methyl-1-propanol (87 mmol, 8.3 ml) in 200 ml of CH2 Cl2 is added di-tert-butyl dicarbonate (96 mmol, 21.52 g) in 50 ml of CH2 Cl2. After 14 hours under argon, the solvent is evaporated under vacuum and 16.08 g (98% yield of pure compound is obtained. 1 H NMR (200 MHz, CDCl3): delta 4.70 (1 H, bs), 4.09 (1 H, bs), 3.57 (1H, d, J=6.0), 1.42 (9 H, s), 1.24 (6 H, s).
98%
In dichloromethane; at 0 - 20℃; for 2h;
Di-tert-butyl dicarbonate (21.82 g, 100.00 mmol) was added in portions to a solution of 2- amino-2-methylpropan-i-ol (8.91 g, 100.0 mmol) in DCM (270 ml) at 0 C. The reaction was stirred at room temperature for 2 hours, then was washed with 2N HC1 (100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give tert-butyl (1-hydroxy- 2-methylpropan-2-yl)carbamate (18.56 g, 98 %) as a white solid. ?H NMR (400 MHz,CDC13, 27 C) 1.25 (6H, s), 1.43 (9H, s), 3.58 (2H, d), 4.67 (1H, s).
97%
With triethylamine; In dichloromethane; at 22 - 25℃; for 4h;
2-Amino-2-methyl-l-propanol (5 g, 56.1 mmol), (Boc)20 (13.46 g, 61.7 mmol) and triethyl amine (6.24 g, 61.7 mmol) were dissolved in 50 mL of dichloromethane. The reaction mixture was stirred for 4 h at 22 to 25 C. Above mixture was washed with water (25 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to get tert-buty] (1- hydroxy-2-methylpropan-2-yl)carbamate (10.3 g, 97% yield).
90%
With 1,3-disulfonic acid imidazolium hydrogen sulfate; In neat (no solvent); at 20℃; for 0.0333333h;Green chemistry;
General procedure: Amine (1 mmol) was added to the mixture of (Boc)2O (1 mmol) and DSIMHS (6.5 mg, ~ 0.02 mmol) with constant stirring at room temperature under solvent-free conditions. After completion of the reaction (monitored by TLC), ethyl acetate (3 × 5 mL) was added to the reaction mixture and the catalyst was decanted and washed with ethyl acetate (2 × 5 mL) and dried. The product was purified by column chromatography, using ethyl acetate-petroleum ether (2:8) eluent.
85.77%
With sodium hydrogencarbonate; sodium carbonate; In 1,4-dioxane; water; at 0℃; for 6h;
2-amino-2-methyl-1-propanol (4.5g,50.56mmol), sodium bicarbonate (8.4g, 100mmol) and sodium carbonate (10.6g, 100mmol) were mixed in a 250mLreaction flask,, a mixture of dioxane and water (160mL, 3:1) was added, the reaction solution was cooled below 0Cunder an ice bath, a solution of di-tert-butyl dicarbonate (13.1g, 59.82mmol) in dioxane (5mL) was added dropwise under stirring. After completion of the addition, the reaction solution was stirred for 6 hours. After completion of the reaction,dioxane was evaporated under reduced pressure, the residue was extracted with ethyl acetate. The organic phase waswashed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silicagel column chromatography to give 8.2g product with a yield of 85.77%.
75.36%
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;
To a solution of compound 1 (10.00 g, 112.18 mmol, 1.00 Eq) in DCM (200 mL) was added Et3N (23.00 g, 227.30 mmol, 2.03 Eq). The mixture was cooled to 0 C. and Boc2O (38.40 g, 175.95 mmol, 1.57 Eq) was added, the mixture was stirred at 20 C. for 1 hr. The mixture was diluted with EA and washed with water. The organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=15/1) to afford compound 2 (16.00 g, 84.54 mmol, 75.36% yield) as white solid.
75.36%
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;
To a solution of compound 1 (10.00 g, 112.18 mmol, 1.00 Eq) in DCM (200 mL) was added Et3N (23.00 g, 227.30 mmol, 2.03 Eq). The mixture was cooled to 0 C. and Boc2O (38.40 g, 175.95 mmol, 1.57 Eq) was added, the mixture was stirred at 20 C. for 1 hr. The mixture was diluted with EA and washed with water. The organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=15/1) to afford compound 2 (16.00 g, 84.54 mmol, 75.36% yield) as white solid.
68%
In water; acetonitrile; at 20℃;
Example 4 (tert-Butoxy)-N-(1-hydroxy-2-methylpropyl)carboxamide (4) Following the general procedure for the N-Boc-protection of omega-amino-2,2-dimethylalcohols of Description 2, 1.783 g (20.0 mmol) of 2-amino-2-methyl-1-propanol was reacted with 3.274 g (15.0 mmol) of di-tert-butyl-dicarbonate in a mixture of 20 mL of a saturated aqueous solution of sodium bicarbonate (NaHCO3) and 40 mL of acetonitrile to provide 1.937 g (68% yield) of the title compound (4) as a colorless solid of sufficient purity to be used in subsequent steps without further isolation and purification. 1H NMR (400 MHz, CDCl3): delta=1.26 (s, 6H), 1.44 (s, 9H), 3.59 (d, J=6.0 Hz, 2H), 4.00-4.20 (br. m, 1H), 4.64-4.72 (br. m, 1H) ppm. MS (ESI) m/z 212.92 (M+Na)+.
53%
In water;
A (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester 2-Amino-2-methyl-propan-1-ol (53 g, 0.59 mol) and di-tert-butyl dicarbonate (65.0 g, 0.297 mol) were combined in H2O (500 mL) and stirred at 25 C. for 1 h. The reaction mixture was extracted with CHCl3 (2*250 mL) The organics were dried and concentrated to a white amorphous solid which was recrystallized from hot hexanes to afford desired material (30 g, 53%) as a white solid: 13C NMR (CD3OD, 100 MHz) delta 157.76, 80.135, 70.095, 54.992, 29.247, 24.695.
53%
In water; at 25℃; for 1h;
2-Amino-2-methyl-propan-1-ol (53 g, 0.59 mol) and di-tert-butyl dicarbonate (65.0 g, 0.297 mol) were combined in H2O (500 mL) and stirred at 25 C for 1 h. The reaction mixture was extracted with CHCl3 (2 x 250 mL). The organics were dried and concentrated to a white amorphous solid which was recrystallized from hot hexanes to afford desired material (30 g, 53%) as a white solid: 13C NMR (CD3OD, 100 MHz) delta 157.76, 80.135, 70.095, 54.992, 29.247, 24.695.
In dichloromethane; at 0 - 20℃;
2-Amino-2-methyl-l-propanol (Aldrich, 5.0 g, 56 mmol, 1.0 equiv.) was taken in DCM(100 ml), BOC anhydride (14.6 g, 67 mmol, 1.2 equiv.) was added portion wise at 0 C and the mixture was stirred over night at rt. The solution was allowed to warm up slowly overnight without the ice bath being removed. Solvent was removed by rotoevaporation. EtOAc (50 ml) was added followed by water (50 ml). The organic layer was separated and washed one more time with water and brine, and then dried (Na2SO4) and concentrated to give 12 g of the crude product.
With sodium hydroxide; In tetrahydrofuran; water;
4-Amino-4-methyl-pent-2-enoic acid [(1R)-1-{(1R)-1(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl)ethyl]amide STR47 Prepared according to method E. N-2-Hydroxy-1,1-dimethylethyl carbamic acid tert-butyl ester STR48 2-Amino-2-methylpropan-1-ol (10.0 g, 112 mmol) was dissolved in tetrahydrofuran (100 ml). A 1N solution of sodium hydroxide in water (112 ml, 112 mmol) was added. A solution of di-tert-butyl dicarbonate (29.3 g, 134 mmol) in tetrahydrofuran (100 ml) was added over a period of 15 min. The solution was stirred at 20 C. for 16 h. Water (100 ml) was added. The phases were separated. The aqueous phase was extracted with ethyl acetate (3*150 ml) and the combined organic phases were dried (magnesium sulfate). The solvent was removed in vacuo and the crude product was chromatographed on silica gel (180 g) with ethyl acetate/heptane 1:1 as eluent to give 19.6 g of N-2-hydroxy-1,1-dimethylethyl carbamic acid tert-butyl ester. mp 53 C. 1 H-NMR (CDCl3): delta 1.22 (s, 6H); 1.45 (s, 9H); 3.58 (d, 2H); 4.05 (br, 1H); 4.65 (br, 1H).
In sodium hydrogencarbonate; tert-butyl alcohol;
Method C 2-Methyl-2-aminopropanol is dissolved in saturated aqueous NaHCO3 at room temperature. Di-tert-butyldicarbonate is added in tert-butanol. The contents are stirred overnight and then extracted with ethyl acetate. The organic layer is dried over MgSO4 and filtered. The filtrate is evaporated to give N-Boc-2-amino-2-methylpropanol.
In water;
1-a. A mixture of 2-amino-2-methyl-1-propanol (53 g), di-t-butyl dicarbonate (65 g) and water (500 ml) was stirred at room temperature for 1 hour. The reaction mixture was extracted with chloroform, and the chloroform layer was dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was recrystallized from hexane to give 2-(t-butoxycarbonylamino)-2-methyl-1-propanol (44.4 g). NMR (CDCl3)delta: 1.25 (6H, singlet), 1.43 (9H, singlet), 3.20-5.50 (2H, multiplet), 3.56 (2H, singlet).
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 16h;
N-2-Hydroxy-1,1-dimethylethyl carbamic acid tert-butyl ester 2-Amino-2-methylpropan-1-ol (10.0 g, 112 mmol) was dissolved in tetrahydrofuran (100 ml).. A 1N solution of sodium hydroxide in water (112 ml, 112 mmol) was added.. A solution of di-tert-butyl dicarbonate (29.3 g, 134 mmol) in tetrahydrofuran (100 ml) was added over a period of 15 min.. The solution was stirred at 20 C. for 16 h.. water (100 ml) was added.. The phases were separated.. The aqueous phase was extracted with ethyl acetate (3*150 ml) and the combined organic phases were dried (magnesium sulfate).. The solvent was removed in vacuo and the crude product was chromatographed on silica gel (180 g) with ethyl acetate/heptane 1:1 as eluent to give 19.6 g of N-2-hydroxy-1,1-dimethylethyl carbamic acid tert-butyl ester. mp 53 C. 1H-NMR (CDCl3): delta1.22 (s, 6 H); 1.45 (s, 9 H); 3.58 (d, 2 H),; 4.05 (br, 1 H); 4.65 (br, 1 H).
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 2h;
Reference P; Synthesis of 2-amino-2-methyl-1-oxazolo[4,5-b]pyridin-2-yl-propan-1-ol; Step 1; 2-Amino-2-methyl-l-propanol (17.8 g, 200 mmol) was dissolved in a mixture of waterand dioxane (100 mL) and cooled to 0 C. NaOH (8g, 200mmol) and di-t-butyl-dicarbonate(52.4 g, 240 mmol) were added and the reaction was allowed to warm to room temperature withstirring for 2 h. After removing the dioxane, the residue was extracted with EtOAc, washed withbrine, dried with anhydrous MgSC>4, filtered and concentrated to yield 35g of 2-5oc-amino-2-methyl-1 -propanol.
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 2h;
Reference N Synthesis of 2-AMINO-2-METHYL-1-OXAZOLO [4,5-b] PYRIDIN-2-YL-PROPAN-1-OL Step 1 2-AMINO-2-METHYL-1-PROPANOL (17.8 g, 200 mmol) was dissolved in a mixture of water and dioxane (100 mL) and cooled to 0 C. NAOH (8 g, 200 mmol) and di-tert-butyldicarbonate (52.4 g, 240 mmol) were added and the reaction was allowed to warm to room temperature with stirring for 2 h. After removing the dioxane, the residue was extracted with EtOAc, washed with brine, dried with anhydrous MGS04, filtered and concentrated to yield 35g of 2-Boc-amino-2- METHYL-1-PROPANOL.
With sodium hydrogencarbonate; sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃;
N-methyl-2-amino-2-methyl-propan-1 -ol (4)2-Amino-2-methylpropanol (3) (10 g, 0.11 mol), Na2CO3 (0.41 g), NaHCO3 (0.41 g) and 3:1 dioxane/water (41 ml) were stirred together at 00C. Boc anhydride (29.4 g, 0.13 mol) was added slowly and the reaction was stirred at room temperature for 6 h. The salts formed were filtered and washed with DCM. The filtrate was diluted with water (50ml) and extracted with DCM (3 x 50 ml), dried (Na2SO4) and evaporated to dryness, giving a white solid. This was dissolved in THF (100 ml) and added dropwise to a mixture of lithium aluminium hydride (12.7 g, 0.33 mol) in THF (200 ml). The mixture was heated to reflux overnight then cooled to room temperature. Water (15 ml) was added slowly with ice-cooling followed by 4 M NaOH (15 ml), and then more water (45 ml). The white solids were filtered, washed with THF, and the filtrate was evaporated to dryness, giving a pink solid (8.9 g, 77%). 1H NMR (400 MHz, CDCI3): 0.97 (6H, s), 2.24 (3H, s), 3.26 (2H, s); 13C NMR (100 MHz, CDCI3): 23.27, 28.41 , 53.62, 68.26.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1.5h;
Step 1 : Et3N (140 mL) and 2-methyl-2-aminopropan-l-ol (100 mL) were dissolved in dry THF (1.5 L) and the mixture was cooled to 0C. (Boc)20 (230 g) was added and the cooling bath was removed. After stirring for 90 minutes at room temperature, the solvent was removed by vacuum distillation. Water was added to the residue, and the mixture was extracted with EtOAc. The organic layer was recrystallized from EtO Ac/petroleum ether to afford tert-butyl (1- hydroxy-2-methylpropan-2-yl)carbamate as a white solid.
With sodium hydrogencarbonate; sodium carbonate; In 1,4-dioxane; water; at 0 - 25℃; for 6h;
D16(c) tert-butyl (l-hydroxy-2-methylpropan-2-yl)carbamate Di-tert-butyl dicarbonate (118 g, 539 mmol) was added slowly to a solution of 2-amino-2- methylpropan-lol (40 g, 449 mmol), sodium bicarbonate (0.82 g, 9.76 mmol) and sodium carbonate (0.82 g, 7.74 mmol) in l,4-dioxane(120 mL)/water (40 mL) at 0 C with stirring. Then, the reaction mixture was stirred at 25 C for 6 h, concentrated, and then EtOAc (1000 mL) was added. The organic phase was washed with water and saturated brine, dried over sodium sulphate, and concentrated in vacuo to afford the title compound (94 g, 111%>) as a white solid.
With triethylamine; In dichloromethane;
2-amino-2-methylpropan-l-ol is reacted with boc-anhydride, using triethylamine as base and DCM solvent to yield the tert-butyl (l-hydroxy-2-methylpropan-2-yl)carbamate (Compound 7a).
In ethanol; at 40℃; for 2h;
General procedure: A microwave tube was charged with 2i (1 mmol), NaOH (120 mg, 3 mmol), and EtOH (10 mL). The tube was sealed, placed in a microwaveoven and heated (T = 135 C; t = 10 min). After release, Boc2O(655 mg, 3 mmol) was added at r.t. and the reaction mixture wasstirred for 2 h at 40 C. H2O (10 mL) and Et2O (20 mL) were added andthe layers were separated. The aqueous phase was extracted withEt2O (2 × 20 mL) and the combined organic layers were dried overMgSO4, filtered, and the solvent was removed in vacuo. The crude residuewas purified on silica gel chromatography (cyclohexane-EtOAc,95:5 to 40:60) to afford the desired N-Boc-protected amino alcohol 4.
750 g
With sodium hydrogencarbonate; sodium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 18h;
Intermediate 12: tert-butyl (l-hydroxy-2-meth lpropan-2-yl)carbamate - Preparation 2 To a solution of 2-amino-2-methylpropan-l-ol (500 g, 5.61 mol, Alfa) in THF (3.0 L) and water (1.0 L) was added Na2C03 (10.11 g, 95 mmol) and sodium bicarbonate (10.37 g, 123 mmol) and stirring continued at 0 QC. di-ferf-Butyl dicarbonate (1.56 L, 6.7 mol) was added. The reaction mixture was stirred at RT for 18 h. The THF layer was separated and the aqueous layer extracted with ethyl acetate (1.5 L). The combined organic layers were washed with brine solution (2 x 2 L), were dried over anhydrous Na2S04 and then concentrated under reduced pressure to afford crude title compound. The crude material was dissolved in petroleum ether (750 mL) and cooled to -50 C. The resulting solid was filtered and washed with petroleum ether to give the title compound (750 g) as a white solid. (0250) *H NMR (400 MHz, DMSO-d6) delta: 6.08 (1H, s), 4.67 (1H, t), 3.29 (2H, s), 1.37 (9H, s), 1.13 (6H, s).
With potassium carbonate; In ethylene glycol; glycerol; at 110℃; for 12h;Inert atmosphere;
General procedure: K2CO3 (0.12g, 0.1 equiv.) and glycerol(10ml) were charged to a schlenk flask and placed under an argon atmosphere. To this was addednitrile 6B (1.0g, 1.0 equiv), 2-amino-2-methyl propan-1-ol (1.63g, 1.7 equiv.) and dry ethyleneglycol (12ml). The resulting clear colourless solution was heated to 110 C for 72 hr to form apurple solution. This was cooled and quenched into sat. aq. NH4Cl (100ml) and extracted withdiethyl ether (3 x 100ml). Combined organic was dried (Mg2SO4) and stripped to give a purple oil,this was purified by filtration through a short alumina plug (washing with Et2O) to give a clearyellow oil (1.52g, 93%)
With potassium carbonate; In ethylene glycol; glycerol; at 110℃; for 72h;Inert atmosphere;
K2CO3 (0.12g, 0.1 equiv.) and glycerol(10ml) were charged to a schlenk flask and placed under an argon atmosphere. To this was addednitrile 6B (1.0g, 1.0 equiv), 2-amino-2-methyl propan-1-ol (1.63g, 1.7 equiv.) and dry ethyleneglycol (12ml). The resulting clear colourless solution was heated to 110 C for 72 hr to form apurple solution. This was cooled and quenched into sat. aq. NH4Cl (100ml) and extracted withdiethyl ether (3 x 100ml). Combined organic was dried (Mg2SO4) and stripped to give a purple oil,this was purified by filtration through a short alumina plug (washing with Et2O) to give a clearyellow oil (1.52g, 93%)
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 2h;
Reference O Synthesis of [2-AMINO-2-METHYL-1-OXAZOLO] [4,5-b] [PYRIDIN-2-YL-PROPAN-1-OL] Step 1 [2-AMINO-2-METHYL-1-PROPANOL] (17. [8] g, 200 mmol) was dissolved in a mixture of water and dioxane (100 mL) and cooled to [0 C. NAOH] (8g, [200MMOL)] and di-t-butyl- dicarbonate (52.4 g, 240 mmol) were added and the reaction was allowed to warm to room temperature with stirring for 2 h. After removing the dioxane, the residue was extracted with EtOAc, washed with brine, dried with anhydrous [MGS04,] filtered and concentrated to yield 35g of [2-BOC-AMINO-2-METHYL-1-PROPANOL.] Step 2 A solution of oxalyl chloride (15.24 g, 120 mmol) in 200 mL of MeCl2 was stirred and cooled to-60 C followed by the drop wise addition [OF DIMETHYLSULFOXIDE] (19.7 g, 252 mmol) in 60mL of MeCl2. After 10 min, a solution of [2-BOC-AMINO-2-METHYL-1-PROPANOL] (18.9 g, 100 mmol) in MeCl2 (60 mL) was added drop wise [AT-70 C.] The reaction mixture was allowed to warm [TO-40 C] for 10 min followed by cooling to-70 C before the addition of a solution of triethylamine (28.28 g, 280 mmol) in [MECL2] (60 mL). The reaction mixture was allowed to warm to room temperature over a two-hour period and 40 mL of saturated sodium dihydrogen phosphate was added. The organic layer was washed with brine and dried over [MGS04.] The solvent was removed to yield 17.3 g of 2-Boc-amino-2- methylpropionaldehyde. Step 3 A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 mL) and p-toluenesulfonic acid (61 mg) was heated at [140 C] for 8 h. Excess [TRIETHYLORTHOFORMATE] was removed under vacuum. The product was crystallized from ethyl acetate to yield 9g of 1-oxazolo [4,5-b] pyridine. Step 4 To a stirred solution [OF THE 1-OXAZOLO] [4,5-b] pyridine (2.4 g, [20MMOL)] in THF (100 mL) was added n-BuLi (1.6 M solution in 12.5 mL of hexane) drop wise under N2 [AT-78 C.] After 1 h, MgBr. [ET20] (5.16 g, 20 mmol) was added and the reaction mixture was allowed to warm to-45 [C] for 1 h before being treated with 2-Boc-amino-2-methylpropionaldehyde (2.24 g, 12 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated [NH4C1,] and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgS04 and concentrated. The residue was purified by silica gel column chromatography to yield 2-Boc-amino-2-methyl-1-oxazolo [4,5-b] [PYRIDIN-2-YL-1-PROPANOL] [(1. 18G).] Step 5 [2-BOC-AMINO-2-METHYL-1-OXAZOLO] [4,5-b] pyridin-2-yl-1-propanol (156 mg, 0.508 mmol) and [MECL2] (5 mL) were mixed and TFA (0.5 [ML)] was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed under vacuum to produce 2- amino-2-methyl-1-oxazolo [4,5-b] [PYRIDIN-2-YL-PROPAN-1-OL.] TFA salt (165 mg).
4-(2-hydroxy-1,1-dimethyl-ethylamino)-2-trifluoromethyl-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 140℃; for 0.305556h;Microwave irradiation;
Example 18 4-(2-Hydroxy-1,1-dimethyl-ethylamino)-2-trifluoromethyl-benzonirile 2-Amino-2-methyl-propan-1-ol (25 mg, 0.275 mmol) was dissolved in 0.7 mLDMSO and DIPEA (36 mg, 0.275 mmol) was added. 4-fluoro-2-hifluoromethyl-benzonitrile (40 mg, 0.212 mmol) was then added and the reaction was heated to 140 C for 1100 seconds in a microwave oven (Parameters : high absorbance, fixed holding time, pre-stiiring 25 seconds). The reaction was then diluted with 10 mL EtOAc, washed with an aqueous solution of NH4C1, dried with anhydrous MgSO4, filtered and then the organic phase was evaporated in vacuo. The crude product was purified on silica column with 3: 1 n- heptane: EtOAc as the mobile phase. Upon dissolving the crude product in the mobile phase, an insoluble precipitate was collected. On analysis this showed to be mainly pure product All insoluble precipitate was dissolved in acetone, celite TM was added, whereafter the acetone was evaporated. The celite was then applied to a silica column with 2 : 1 n-heptane: EtOAc as the mobile phase to give 34 mg (62%) of 4- (2-hydroxy-1, 1- dimethyl-ethylamino)-2-trifluoromethyl-benzonitrile as beige crystals.
2-methyl-2-(6-methyl-5-nitro-pyridin-2-ylamino)-propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
In pentan-1-ol;Heating / reflux;
(d) 6-Chloro-3-nitro-2-picoline (6.055 g, 35.1 mmol) and 2-amino-2-methyl-propan-1-ol (6.2 g, 73.7 mmol) were suspended in 1-pentanol (30 ml) and the mixture refluxed under inert atmosphere overnight The thin layer chromatography (dichloromethane 4/EtOAc 1) revealed some remaining starting material, so the reaction was refluxed for another 3.5 hrs. The reaction mixture was cooled and water was added under stirring. A sticky, yellow precipitate was filtered off, washed well with water and dried. The crude product (6.04 g) was re-crystallised from either pentane-acetone or dichloromethane. Collecting the crops furnished 5.71 (72 percent) of 2-methyl-2- (6-methyl-5-nitro-pyridin-2-ylamnio- propan-l-ol as yellow crystals.
2-(2,3-dimethyl-4-nitro-phenylamino)-2-methyl-propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 160℃; for 120h;
Example 16 2- (2, 3-D6hyl-4-nitro-phenylamino} 2-methyl-propan-1-ol Fuming nitric acid (1.4 g, 20.3 mmol) was cooled to 0C and acetic anhydride (2.89 g, 28.4 mmol) was added. This solution was added to a cold (0C) solution of 3-fluoro-1, 2- dimethylbenzene (1.0 g, 8.1 mmol) in acetic anhydride (4 ml) over 10 min. The reaction mixture was stirred for 25 min, poured slowly over ice and the water solution extracted with EtOAc (x 3). The collected organic phase was washed with diluted saturated aqueous solution of NaHCO3 followed by brine before evaporation to dryness. The residue was flash purified on a silica gel column using hexane as a mobile phase to give 2, 3-dimethyl-4-fluoro-1-nitro-benzene 0.74 g (54%) as a yellow oil which crystallised upon standing. The fluoride (0.576 g, 3. 4 mmol) was mixed with 2-amino-2-methylpropanol (0.61 g, 6.8 mmol) in a tube, and the tube was sealed before immersing it into an oil bath and heating at 160C for 5 days. TLC (Hexane) showed remaining starting material. The reaction mixture was cooled and diluted with EtOAc before purification by flash silica gel chromatography (dry application; 6: 4 hexane and EtOAc) to give 0.34 g (59% recovery) of the starting material 2, 3-dimethyl-4-fluoro-1-nitro-benzene and 0.20 g (61% based on recovered starting material) of the 2- (2, 3-dimethyl-4-nitro-phenylamino)-2-methyl- propan-1-ol.
2-methyl-2-(4-nitro-3-trifluoromethyl-phenylamino)-propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 180℃; for 0.25h;Microwave irradiation;
Example 1 2-Methyl-2- 3-trifluoIomethyl-phenylamino)-propan-l-ol 4-Fluoro-l-nitro-2-trifluoromethyl-benzene (1.226 g, 5.86 mmol) was dissolved in 7 mL DMSO and 2-amino-2-methyl-propan-1-ol (784 mg, 8.795 mmol) was added, followed by diisopropyl ethylamin (DIPEA) (985 mg, 7.622 mmol). The reaction was heated to 180 C for 900 seconds in a microwave oven (Parameters: high absorbance, fixed holding time, pre-stirring 25 seconds). The mixture was diluted with 20 mL of EtOAc and then washed three times with an aqueous solution of ammonium chloride (NH4Cl). The organic phase was collected, dried with MgS04 (anhydrous) and filtered. The dry organic phase was evaporated in vacuo. The crude product was a bright yellow powder. The crude product was purified on a silica column with 5: 1 n-heptane: EtOAc as mobile phase. This gave 1.1 g (68 %) of 2-methyl-2- (4-nitro-3-trifluoromethyl-phenylamino)- propan-l-ol as a yellow solid.
4-chloro-3-nitro-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium hydroxide; In water; at 20℃; for 16h;
To a stirred solution of 2-amino-2-methyl-1-propanol (3.48 g, 39 mmol) in 1N NaOH (25 ml) was added at room temperature 4-chloro-3-nitrobenzenesulfonyl chloride (5.0 g, 19.5 mmol). The reaction mixture was stirred at room temperature for 16h, poured into brine (50 ml) and extracted with ethyl acetate (3 x 70 ml). The combined organic layers were washed with brine (50 ml), dried (MgS04) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ ethyl acetate 1:4) and subsequent crystallization from ethyl acetate/ heptane to yield 4-chloro-3-nitro-(2- hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (0.93 g, 15%) as an off-white solid. MS (ISP) 307.0 [(M-H)-]; mp 119C.
In acetonitrile; at 20℃; for 96 - 144h;Product distribution / selectivity;
EXAMPLE 12; [R-(R*, R*)]-2-(4-Fluorophenyl)-p,6-dihydroxy-5-(1 -methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, 2-amino-2-methylpropan-1-ol (<strong>[134523-00-5]atorvastatin</strong> 2-amino- 2-methylpropan-1-ol);. Method A;The 2-amino-2-methylpropan-1-ol salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (0.8 g in 25 mL of ACN). A solution of 2-amino-2-methylpropan-1-ol was prepared by dissolving 6.1 mg of 2-amino-2-methylpropan-1- ol (1 equivalents) in 0.5 mL of acetonitrile. The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (1.21 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile was added as necessary. After 6 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with acetonitrile and air dried at ambient conditions to afford atoravastatin 2-amino-2-methylpropan-1-ol. Method B - The 2-amino-2-methylpropan-1-ol salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of 2-amino-2-methylpropan-1-ol was prepared by dissolving 173.08 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Seed crystals of the 2-amino-2-methylpropan-1-ol salt were added. Over time, additional acetonitrile was added to aid in stirring (100 mL), and the solid was allowed to stir. After 4 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry for two days to afford <strong>[134523-00-5]atorvastatin</strong> 2-amino-2-methylpropan-1-ol.
2-acetamido-4-methylthiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With triethylamine; In 1,4-dioxane; at 0 - 20℃; for 17h;
a) To a stirred solution of 2-amino-2-methyl-1-propanol (1.14 g, 13 mmol) in dioxane (20 ml) was added at 0 C. (ice water bath) commercially available <strong>[69812-29-9]2-acetamido-4-methylthiazole-5-sulfonyl chloride</strong> (2.95 g, 12 mmol) and triethylamine (1.78 ml, 13 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (2*10 ml). The combined organic layers were washed with sat. NaHCO3 solution (2*70 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/MeOH 9:1) and subsequent crystallization (ethyl acetate/MeOH/heptane) to yield 2-acetamido-4-methylthiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (1.15 g, 32%) as a light brown solid. MS (ISP) 306.1 [(M-H)-]; mp 194 C.
PREPARATION 8 To a solution of <strong>[72587-15-6]2-chloro-3-nitro-5-(trifluoromethyl)pyridine</strong> (1 g) in N,N-dimethylformamide (10 mL) was added 2-amino-2-methyl-1-propanol (1.18 g) at 0 C. The mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2-(1,1-dimethyl-2-hydroxyethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.23 g) as a yellow oil. NMR(DMSO-d6, delta): 1.46(6H, s), 3.53(2H, d, J=5.5 Hz), 5.33(1H, t, J=5.5 Hz), 8.63(1H, d, J=2.0 Hz), 8.81(1H, d, J=2.0 Hz), 8.82(1H, s). MS m/z: 278(M+-1).
With sodium hydroxide; thionyl chloride; In diethyl ether; ethanol; dichloromethane; benzene;
iii) To a suspension of <strong>[28917-43-3]3,5-dibenzyloxybenzoic acid</strong> (14.7 g, 44 mmol) in dry benzene (35 ml) was added, dropwise, thionyl chloride (9.65 ml, 132 mmol). The mixture was then heated under reflux, to give a clear, dark solution. After 1.5 hours the reaction mixture was allowed to cool, and then evaporated in vacuo to give an amber oil, which crystallized on standing. The crude acid chloride was then dissolved in dry CH2 Cl2 (25 ml) and the solution added dropwise to a solution of 2-amino-2-methyl-1-propanol (7.84 g, 88 mmol) in CH2 Cl2 (25 ml) at 5 C. (ice-bath). The mixture was then stirred at ambient temperature for 2 hours before filtering over celite. The filtrates were washed with water, dried over magnesium sulphate, filtered and evaporated in vacuo to give a dark oil. To the stirred, crude amide was then added, dropwise, thionyl chloride (9.65 ml, 132 mmol). When addition was complete, the liquid was poured into stirred, dry diethyl ether (150 ml). The ether was then decanted off, the oil dissolved in ethanol (150 ml) and the solution poured into stirred, ice-cold 5M sodium hydroxide (40 ml). The basic solution was then extracted with diethyl ether (3*), and the combined ethereal extracts dried over magnesium sulphate, filtered and evaporated to give a dark oil. The crude oil was purified by flash chromatography on silica (eluant hexane:diethyl ether=1:1) to give 4,4-dimethyl-2-(3,5-dibenzyloxyphenyl)-oxazoline as a yellow solid.
5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
In tetrahydrofuran; at 0 - 23℃; for 14h;
To a solution of <strong>[65001-21-0]5-bromo-pyridine-3-sulfonyl chloride</strong> (Example B.2 step 2) (1.28 g, 5 mmol) in THF (20 mL, dioxane, or other suitable solvent) at 0 C. was added an excess of the amine, 2-amino-2-methyl-1-propanol (5 mL, 55 mmol), and the mixture was stirred at 23 C. for 14 h. Alternatively, Et3N can be added in excess with only one equivalent of the amine. The reaction is worked up by neutralization with an acid (5% citric acid, 1N HCl, or dilute AcOH), and extracted with a suitable organic solvent (ether, EtOAc, or CH2Cl2), washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, filtered and concentrated to give a dark brown oil, which was purified by column chromatography with heptane/EtOAc (or CH2Cl2/MeOH/Et3N) gave the title compound as a light brown solid (640 mg, 41%). Typically, no chromatography is necessary and the sulfonamide purified by recrystallization. MS (ISP)=309.2 [(M+H)+], 311.1 [(M+2+H)+]. mp 112 C.
2-(3-bromo-4-methoxyphenyl)4,4-dimethyl-4,5-dihydrooxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With sodium hydroxide; thionyl chloride; In dichloromethane; water; ethyl acetate; N,N-dimethyl-formamide; toluene;
PREPARATIVE EXAMPLE 32 3-Bromo-4-methoxybenzoic acid (8.75 g, 37.9 mmol), toluene (80 ml), ethyl acetate (20 m1l), methylene chloride (20 ml) and DMF (1 drop) were mixed, and to this solution was added thionyl chloride (6.5 ml, 90 mmol). The mixture was stirred at 70 C. for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and toluene was added. The mixture was further concentrated under reduced pressure. Methylene chloride (160 ml) was added to the obtained residue, and this solution was cooled to 0 C. 2-Amino-2-methyl-1-propanol (7.64 nil, 80 mmol) was added dropwise, and the mixture was stirred at room temperature for 14 hours. The precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 ml), and this solution was washed with 1N hydrochloric acid (50 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue and methylene chloride (150 ml) were mixed, and thionyl chloride (10.9 ml, 150 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. To this reaction mixture were successively added water (13 ml) and a 50% aqueous sodium hydroxide solution (40 ml) under ice-cooling. The aqueous layer was extracted 3 times with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (100 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1-1/2) to give 2-(3-bromo-4-methoxyphenyl)4,4-dimethyl-4,5-dihydrooxazole (7.10 g, 66%) as a colorless oil. 1 H-NMR (CDCl3)delta: 8.15(1H, s), 7.85(1H, d, J=8.5 Hz), 6.90(1H, d, J=8.5 Hz), 4.09(2H, s), 3.93(3H, s), 1.37(6H, s). FABMS (m/z): 285[M+ H+ ] (200), 286(90), 284(100).
· 3-(2-Amino-2-methylpropoxy)-5-chloro-1,2-benzoisoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; water; ethyl acetate;
(1) To a suspension of 0.43 g of 60% (w/w) sodium hydride in 15 ml of tetrahydrofuran is added a solution of 0.80 g of 2-amino-2-methyl-1-propanol in 20 ml of tetrahydrofuran at 20-25 C., and they are refluxed for two hours. To the reaction mixture is added a solution of 2.36 g of <strong>[16263-53-9]3,5-dichloro-1,2-benzoisoxazole</strong> in 20 ml of tetrahydrofuran under reflux, and they are refluxed for a further one hour. After cooling, the solvent is removed by distillation under reduced pressure, and ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then purified by a column chromatography [eluant:chloroform:methanol=20:1], to obtain 1.59 g of oily 3-(2-amino-2-methylpropoxy)-5-chloro-1,2-benzoisoxazole.
(1) Synthesis of N-(1,1-dimethyl-2-hydroxyethyl)-6-chloropicolinic acid amide STR39 To THF (20 ml) was added 3.0 g (34 mmol) of 2-amino-2-methylpropanol, and a THF (20 ml) solution of 3.0 g (17 mmol) of <strong>[80099-98-5]6-chloropicolinic acid chloride</strong> was added dropwise thereto at 5 C. over 15 minutes. After stirring the mixture at room temperature for 2.5 hours, ethyl acetate (100 ml) was added thereto. The resulting mixture was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to obtain 4.1 g of the desired compound. An oily substance.
2,5-dichloro-4-(1,1-dimethyl-2-hydroxyethylamino)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2,5-Dichloro-4-(1,1-dimethyl-2-hydroxyethylamino)quinazoline, m.p. 147-150 C., from <strong>[134517-55-8]2,4,5-<strong>[134517-55-8]trichloroquinazoline</strong></strong> and 2-amino-2-methyl-1-propanol.
2-(tert-Butoxycarbonylamino)-2-methyl-1-propanol A mixture of 2-amino-2-methyl-1-propanol (8.9 g, 0.1 mol), di-tert-butyldicarbonate (22.0 g, 0.1 mol), and N32CO3 (21.0 g, 0.2 mol) in water/THF (150/150 mL) was refluxed for 1 hour. After removal of THF, the residue was partitioned between ether (200 mL) and water (150 mL). The separated organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to give 17.97 g (95%) of 2-(tert-butoxycarbonylamino)-2-methyl-1-propanol as waxy, white solid: 1H NMR (CDCl3) delta 1.23 (s, 6H), 1.41 (s, 9H), 3.56 (s, 2H).
[178] A stirred solution of commercially available ethyl 3-oxo-3-(2,3,4,5- tetrafluorophenyl)propanoate (6) (15 g, 56.8 mmol), acetic anhydride (13.4 mL, 142 mmol) and triethyl orthoformate (14.1 mL, 18 mmol) was heated at 120 C for 1.5 h. <n="51"/>The mixture was concentrated in vacuo and dried under high vacuum for 5 hours. 10.1 g (31.5 mmol) of the crude product were dissolved in EtOH/DCM (30 mL) and cooled to 0 C. 2-Amino-2-methylpropan-l-ol (3.36 mL, 34.7 mmol) was added very slowly to this solution. After 30 minutes, the solvent was removed by evaporation and the product was freeze-dried to yield 7, as a yellow solid (1 1.9 g crude) that was used in the next step without further purification.
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (866 mg, 5.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (50 mL) and cooled to 0 C. in an ice bath. The flask was charged with N-methyl morpholine (720 muL, 7.5 mmol) and isobutlychloroformate (752 muL, 5.75 mmol) via syringe addition. The reaction was allowed to stir at 0 C. for 10 min until the solution became cloudy. At which point 2-methyl-2-aminopropanol (550 uL, 5.75 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched after 2 h with 1M HCl solution (30 mL) and transferred to a separatory funnel with DCM (50 mL). The layers were partitioned and the organic phase was washed with H2O (2×30 mL) and brine (1×40 mL). After drying over Na2SO4 and filtration, the mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography eluting with a 1:1 mixture of EtOAc and hexanes to afford N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide as a colorless oil in 91% yield (1.112 g, 4.55 mmol) according to the following reaction
88%
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; Schlenk technique;
A solution of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (346 mg, 2.0 mmol), N,N'-dicyclohexylcarbodiimide (870 mg, 4.2 mmol), N-hydroxybenzotriazole (300 mg, 2.2 mmol), and 2-amino-2-methylpropan-1-ol (178 mg, 2.2 mmol) in dry THF was stirred at 0 C for 1 h and then at room temperature for overnight. The reaction was monitored by TLC for a complete conversion. The resulting mixture was filtered through celite, concentrated under reduced pressure, adn purified by silica gel column chromatography to give N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide in 88% yield as a white solid. The amide was dissolved in dry dichloromethane (50 mL) together with 4-dimethylaminopyridine (12 mg, 0.1 mmol) and triethylamine (0.60 mL). The mxiture was coolded in an ice-water bath and methanesulfonyl chloride (230 muL, 3.0 mmol) was added. The mixtrue was stirred at 0 C for 0.5 h, and another portion of triethylamine (2.40 mL) was added. The resulting mixture was warmed to 40 C. The reaction was monitored with TLC for a complete conversio. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (pre-neutralized with Et3N) to give 4,4-dimethyl-2-(quinolin-2-yl)-oxazoline (8) in 72% ytield as a white solid, m.p. 75 - 77 C.
2-Amino-2-methyl-1 -propanol (14.5 g, 163.5 mmol, 3 eq) was added to a stirred mixture of <strong>[14161-11-6]3,4,5-<strong>[14161-11-6]trichloropyridazine</strong></strong> (10 g, 54.5 mmol, 1 eq) in acetonitrile (250 mL) . The reaction was stirred at room temperature overnight then at 100C for 3 days. The solvents were removed under reduced pressure. The residue was purified by biotage flash column chromatography (cyclohexane/EtOAc 50 to 100% EtOAc) to afford two fractions. The more polar fraction of the two in the silica flash column contained the desired product 2-(5,6-dichloro-pyridazin-4- ylamino)-2-methyl-propan-1-ol (3.23 g, 25% yield).HPLC-MS (method 4): Rt =3.12 min, [M+HJ* 236.1.1H NMR (300 MHz, DMSO-d6) delta 9.02 (s, 1 H), 5.88 (s, 1 H), 5.47 (t, J = 5.5 Hz, 1 H), 3.45 (d, J = 5.5 Hz, 2H), 1.37 (s, 6H).
To a solution of 2-amino-2-methylpropan-l-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small portions at 0 C under nitrogen. The mixture was stirred at 0 C for 30 minutes and then stirred at room temperature for another 30 minutes. The solution was cooled down to 0 C again, and to this solution was added dropwise a solution of <strong>[77326-36-4]2-amino-6-fluorobenzonitrile</strong> (20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture was then refluxed overnight under nitrogen. The reaction mixture was cooled down to room temperature and carefully quenched with aqueous NH4CI solution and extracted with ethyl acetate (3X). The combined organic layers were washed with brine, dried over MgSC>4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel eluting with 10% MeOH in DCM to give the title compound as yellow solid (23.4 g 71%). 'H NMR (400 MHz, DMSO-i¾ delta 1.08 (s, 6H), 3.15 (s, 2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J= 8.0 Hz, 1H), 6.31 (d, J= 8.4 Hz, 1H), 7.15 (t, J= 8.4 Hz, 1H). MS 236 (MH+).
71%
Example 24d 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small portions at 0 C. under nitrogen. The mixture was stirred at 0 C. for 30 minutes and then stirred at room temperature for another 30 minutes. The solution was cooled down to 0 C. again, and to this solution was added dropwise a solution of <strong>[77326-36-4]2-amino-6-fluorobenzonitrile</strong> (20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture was then refluxed overnight under nitrogen. The reaction mixture was cooled down to room temperature and carefully quenched with aqueous NH4Cl solution and extracted with ethyl acetate (3*). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel eluting with 10% MeOH in DCM to give the title compound as yellow solid (23.4 g 71%). 1H NMR (400 MHz, DMSO-d6) delta 1.08 (s, 6H), 3.15 (s, 2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH+).
65%
General procedure: To a solution of amino alcohol (0.91 eq.) inanhydrous THF (5 ml) was added NaH as a 60% dispersion in oil (1.0 eq.). Themixture was stirred at 0 C for 30 min, at r.t. for another 30 min beforecooling down to 0 C again. 2-Amino-6-fluorobenzonitrile (1.0 eq.) was addedand the reaction was refluxed for 2 hours before cooling down to r.t. H2O(0.7 ml) was added and the solvents were evaporated in vacuo. The residue was purified by flash column chromatography.
With NaH; In tetrahydrofuran; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; mineral oil;
Example 24d 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small portions at 0 C. under nitrogen. The mixture was stirred at 0 C. for 30 minutes and then stirred at room temperature for another 30 minutes. The solution was cooled down to 0 C. again, and to this solution was added dropwise a solution of <strong>[77326-36-4]2-amino-6-fluorobenzonitrile</strong> (20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture was then refluxed overnight under nitrogen. The reaction mixture was cooled down to room temperature and carefully quenched with aqueous NH4Cl solution and extracted with ethyl acetate (3*). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel eluting with 10% MeOH in DCM to give the title compound as yellow solid (23.4 g 71%). 1H NMR (400 MHz, DMSO-d6) delta 1.08 (s, 6H), 3.15 (s, 2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH+).
With NaH; In tetrahydrofuran; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; mineral oil;
Example 24d 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small portions at 0 C. under nitrogen. The mixture was stirred at 0 C. for 30 minutes and then stirred at room temperature for another 30 minutes. The solution was cooled down to 0 C. again, and to this solution was added dropwise a solution of <strong>[77326-36-4]2-amino-6-fluorobenzonitrile</strong> (20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture was then refluxed overnight under nitrogen. The reaction mixture was cooled down to room temperature and carefully quenched with aqueous NH4Cl solution and extracted with ethyl acetate (3*). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel eluting with 10% MeOH in DCM to give the title compound as yellow solid (23.4 g 71%). 1H NMR (400 MHz, DMSO-d6) delta 1.08 (s, 6H), 3.15 (s, 2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH+).
2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-6-methylphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With zinc(II) chloride; In chlorobenzene; at 131.0℃; for 72.0h;Inert atmosphere;
ZnCl2 (0.23g, 0.1 equiv.) wascharged to a schlenk flask and heated under vacuum until molten (heatgun) before being allowed tocool under an argon atmosphere. 2-amino-2-methylpropan-1-ol (Alfa Aesar, 1.48g, 1.7 equiv.) andnitrile 1B (1.30g, 1.0 equiv.) were dissolved in chlorobenzene (50ml) and charged in one go. Theresulting dark red solution was heated to 131 C for 72 hours, before being cooled and stripped. Theresulting dark oil was quenched into 2M HCl (100ml) and extracted with DCM (4 x 100ml).Combined organic was washed with water (100ml) which was re-extracted with DCM (2 x 50ml).Combined organic was dried (Mg2SO4) and stripped to give a dark red oil (1.89g), this was purifiedby flash chromatography (product adhered to silica, eluting with 1:9 EtOAc in hexane, Rf = 0.69) toyield the title compound as a pale orange oil (1.21g, 60%)
Synthesis of 3,5,5-TrimethyI-2-(pyridin-3-yl)morpholin-2-ol (5).; A sample of l-(pyridin-3-yl)propan-l-one (80, 685 mg, 5.00 mmol) was dissolved in CC14 (20 mL). Bromine (0.26 mL, 5 mmol) was added to the reaction flask, and the reaction mixture was gently refluxed for 1 h. The solvent was decanted. The deep red solid at the bottom of flask was washed with ether, dried, suspended in C¾CN (40 mL), and treated with 2-amino-2-methyl-l- propanol (0.89 g, 0.01 mol). The reaction mixture was stirred for 8 h. The precipitate was removed by filtration and the filtrate was extracted with EtOAc. The organic layer was washed with aqueous NaHC03, dried (Na2S0 ) and concentrated to a deep red oil residue. The oily residue was purified by column chromatography on silica gel and CH2Cl2-MeOH (20:1 to 5: 1) with 1% NH4OH) to give 56 mg free base that was converted to 5«tartrate as a yellow solid: mp 1 15-116 C; 1H NMR (CDC13) delta 8.85-8.83 (m, 1H), 8.54 (dd, 1H, J = 4.7, 1.7 Hz), 7.91 (tt, 1H, J = 8.0, 2.0 Hz), 7.31-7.25 (m, 1H), 3.85-3.82 (m, 1H), 3.42 (d, 1H, J = 11.2 Hz), 3.21 (q, 1H, J = 6.5 Hz), 1.40 (s, 3H), 1.10 (s, 3H), 0.81 (d, 3H, J = 6.5 Hz); 13C NMR (CDC13) delta 149.4, 148.1, 137.2, 134.1, 122.8, 95.4, 69.4, 53.55, 49.8, 27.4, 22.8, 16.4; LCMS (ESI) m/z 223.3 [(M - tartrate)+, M = Ci6H24N208]; Anal. (Ci6H24N208O.75H20) calcd: C 48.90, H 6.66, N 7.26; found: C 49.92, H 6.51, N 6.87.
Intermediate Example Int09.024-bromo-N-(1 -hydroxy-2-methylpropan-2-yl)-3-methoxybenzamideTo a stirred solution of <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (1 .7 g) indichloromethane (22 mL) and DMF (1 .0 mL) was added oxalyl chloride (1 .19 g) at 0C. The mixture was stirred at room temperature for 0.5 h. The solvent was removed in vacuum. The residue was dissolved in dichloromethane (30 mL) and 2-amino-2-methylpropan-1 -ol (1 .93 g) were added. The mixture was stirred at room temperature for 3 h. A half -saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1 .90 g of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1 .27 (s, 6H), 3.48 (d, 2H), 3.87 (s, 3H), 4.85 (t, 1 H), 7.30 (dd, 1 H), 7.40 (d, 1 H), 7.57 - 7.62 (m, 2H).
Step 1. Preparation of 2,4,6-trifluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide A flask, fitted with a calcium chloride drying tube, was charged with <strong>[28314-80-9]2,4,6-trifluorobenzoic acid</strong> (25 g, 142 mmol) and taken up in dry dichloromethane (220 mL). The material was cooled to 0 C. (ice bath) and to this was added oxalyl chloride (13.2 ml; 156 mmol) via syringe. Dry dimethylformamide (104 mg; 1.42 mmol) was next added and moderate bubbling was observed. After 15 minutes the cooling bath was removed and the mixture was stirred vigorously for 5 hours. The volatiles were concentrated in vacuo. (rotary evaporator) and the residue was taken up in dry dichloromethane (150 ml) and cooled to 0 C. (ice bath). To this solution was added 2-amino-2-methyl-1-propanol (27.2 ml, 284 mmol) via slow drop-wise addition. After complete addition the cooling bath was removed and the mixture was warmed to ambient over night. The reaction, as described above was repeated on the same scale, and the combined reaction products were worked up as follows: The non-homogeneous mixture was suction filtered, rinsing with dichloromethane (approximately 300 ml). This first filtrate was set aside and the solid was rinsed a second time with dichloromethane (500 ml) using slow gravity filtration. The dichloromethane from the second filtration was concentrated in vacuo, which provided very pure product as a white crystalline solid (22.9 g). The dichloromethane solution from the first filtration was concentrated in vacuo to provide an impure brown colored residue. This material was taken up in dichloromethane (200 ml) and water (250 ml) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phase back extracted with dichloromethane (2*120 ml). The dichloromethane phases were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified via trituration from hot dichloromethane/hexanes to provide additional desired product as a yellow solid (43.8 g). (M+H)+=246 m/e.
Intermediate Example Int09.024-bromo-N-(1 -hydroxy-2-methylpropan-2-yl)-3-methoxybenzamideTo a stirred solution of <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (1.7 g) in DCM (22 mL) and DMF (1.0 mL) was added oxalyl chloride (1.19 g) at 0C. The mixture was stirred at r.t. for 0.5 h. The solvent was removed in vacuum. The residue was dissolved in DCM (30 mL) and 2-amino-2-methylpropan-1 -ol (1 .93 g) were added. The mixture was stirred at r.t. for 3 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.90 g of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.27 (s, 6H), 3.48 (d, 2H), 3.87 (s, 3H), 4.85 (t, 1 H), 7.30 (dd, 1 H), 7.40 (d, 1 H), 7.57 - 7.62 (m, 2H).
Example 29A tert-Butyl {2-[(1-hydroxy-2-methylpropan-2-yl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl}-carbamate (racemate) 360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 10 ml of DMF, and the mixture was stirred at RT for 20 min. The resulting solution was added dropwise to a solution of 168 mg (1.88 mmol) of 2-amino-2-methyl-1-propanol in 2 ml of DMF. The reaction mixture was stirred at RT for 20 min. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 364 mg (74% of theory) of the title compound. LC-MS [Method 3]: Rt=1.21 min; MS [ESIpos]: m/z=391 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.13 (s, 3H), 1.14 (s, 3H), 1.38 (s, 9H), 3.26-3.32 (m, 1H), 3.41 (dd, 1H), 4.79 (t, 1H), 5.29 (d, 1H), 7.35 (d, 1H), 7.57 (t, 1H), 7.63 (d, 1H), 7.67-7.79 (m, 3H).
tert-butyl 3-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
197 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 4.0h;Inert atmosphere;
2-tert-Butoxycarbonylamino-4,5,6,7-tetrahydro-benzo[]thiophene-3-carboxylic acid (200 mg, prepared according Y. Huang et al, Chem. Biol. Drug Des. 2010, 76, 116-129) was dissolved in DMF (5 mL) at RT under argon. Then HATU (264 mg), DIPEA (88.7 mg) and 2- amino-2-methylpropan-l-ol (63.1 mg) were added and the reaction solution was stirred at RT for 4 h until TLC (n-heptane/EtOAc: 1/1) indicated completion of the reaction. The reaction mixture was diluted with H20 and extracted with EtOAc. The combined organic layers were washed with 2M aqueous KHCO3 solution, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/n-heptane, gradient from 0 to 25%) to give the desired compound as a colorless solid (197 mg). MS (ESI): m/z = 369.1 [M+H] +.
General procedure: We have adopted a synthetic route by analogy to other bis(oxazoline) ligands [19,20]. A 100-mL two-necked round bottom flask fixed with a reflux condenser was charged substituted dicyanobenzene (500 mg, 3.50 mmol), zinc triflate (5 mol%, 0.18 mmol, 0.060 g), and dry chlorobenzene (20.0 mL) under free oxygen and free-water conditions. The mixture was stirred for 5 min and then a solution of achiral 2-aminoalcohol (8.80 mmol) in dry chlorobenzene (5.0 mL) was added slowly. The reaction mixture was heated and refluxed at 135 C for 24 h. The solvent was removed under reduced pressure to give an oily residue which was dissolved in 25 mL of dichloromethane. The solution was extracted twice with 15 mL of water and the aqueous phase was washed with 15.0 mL of dichloromethane. The combined organic layers were dried with sodium sulfate and the solvent was removed under vacuum to give the crude oil. Further purification of the ligands was done by silica gel column chromatography (ether/dichloromethane 1/4).
2-Amino-2-methyl-propan-1 -ol (11 mL, 118.8 mmol) is dissolved in dioxane (20 mL)and sodium hydride (60percent suspension in mineral oil, 5.0 g, 124.7 mmol) is added portionwise at 0°C and after 15 minutes <strong>[2369-18-8]2-fluoro-3-methyl-pyridine</strong> (3 mL, 29.7 mmol) is added.The resulting mixture is heated at 100°C for lh. The reaction is diluted with DCM and washed with water. The organic layer is separated, dried and evaporated under reduced pressure to furnish the title compound (5.1 g, 95percent) that is used assuch.HPLC-MS (Method 8): R = 1 .78 mmMS (APCI): mlz = 181 (M+H)+
95%
j0395]Example 2 t 2-Amino-2-methyl-propan- 1 -ol (11 mE, 118.8 mmol) is dissolved in dioxane (20 mE) and sodium hydride (60percent suspension in mineral oil, 5.0 g, 124.7 mmol) is added portionwise at 00 C. and afier 15 minutes 2-fluoro-3-methyl- pyridine (3 mE, 29.7 mmol) is added. The resulting mixture is heated at 1000 C. for 1 h. The reaction is diluted with DCM and washed with water. The organic layer is separated, dried and evaporated under reduced pressure to thmish the title compound (5.1 g, 95percent) that is used as such.10397] HPEC-MS (Method 8): R=1 .78 mm10398] MS (APCI): mlz=181 (M+H7
95%
2-Amino-2-methyl-propan-1 -ol (1 1 mL, 1 18.8 mmol) is dissolved in dioxane (20 mL) and sodium hydride (60percent suspension in mineral oil, 5.0 g, 124.7 mmol) is added portionwise at 0°C and after 15 minutes <strong>[2369-18-8]2-fluoro-3-methyl-pyridine</strong> (3 mL, 29.7 mmol) is added.The resulting mixture is heated at 100°C for 1 h. The reaction is diluted with DCM and washed with water. The organic layer is separated, dried and evaporated under reduced pressure to furnish the title compound (5.1 g, 95percent) that is used as such. HPLC-MS (Method 8): Rt = 1 .78 min MS (APCI+): m/z = 181 (M+H)+
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;
HATU (12 g, 31 .682 mmol), DIPEA (6 mL, 34.322 mmol) and 2-amino-2-methyl-1- propanol (2.5 g, 27.722 mmol) are added to meso-(1 R,55,6r)-3-(tert-butoxycarbonyl)- 3-azabicyclo[3.1 .0]hexane-6-carboxylic acid (6 g, 26.402 mmol) in dry DMF (40 mL)and stirring is continued overnight. Volatiles are evaporated under reduced pressure to furnish a residue that is taken up in EtOAc, washed with 10% citric acid, sat.NaHCO3 and dried using a phase separator cartridge. The resulting solution is evaporated under reduced pressure to furnish a residue that is purified by flash chromatography (eluent 50-90% EtOAc/cyclohexane) to furnish the title compound(6.2 g, 79%).1H NMR (500 MHz, DMSO-d6) : 6 1.15(s, 6H), 1.38 (5, 9H), 1.43 (t, J = 3.3 Hz, 1 H),1 .77 (m, 2H), 3.27-3.31 (m, 2H), 3.35 (d, J = 5.3 Hz, 2H), 3.45-3.48 (m, 2H), 4.82 (t, J = 5.8 Hz, 1 H), 7.54 (5, 1 H)
79%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;
Example 4a j0427] HATU (12 g, 31.682 mmol), DIPEA (6 mE, 34.322 mmol) and 2-amino-2-methyl-1-propanol (2.5 g, 27.722 mmol) are added to meso-(1 R,55,6r)-3-(tert-butoxycarbo- nyl)-3-azabicyclo[3.1 .0]hexane-6-carboxylic acid (6 g, 26.402 mmol) in dry DMF (40 mE) and stirring is continued overnight. Volatiles are evaporated under reduced pressure to thrnish a residue that is taken up in EtOAc, washed with 10% citric acid, sat. NaHCO3 and dried using a phase separator cartridge. The resulting solution is evaporated under reduced pressure to furnish a residue that is purified by flash chromatography (eluent 50-90% EtOAc/cyclohexane) to thrnish the title compound (6.2 g, 79%).10428] ?H NMR (500 MHz, DMSO-d5): oe 1.15 (s, 6H),1.38 (s, 9H), 1.43 (t, J=3.3 Hz, 1H), 1.77 (m, 2H), 3.27-3.31(m, 2H), 3.35 (d, J=5.3 Hz, 2H), 3.45-3.48 (m, 2H), 4.82 (t,J=5.8 Hz, 1H), 7.54 (s, 1H)
2,2'-(4-methylbenzene-1,2-diyl)bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With zinc(II) triflate; In chlorobenzene; at 135℃; for 24h;Inert atmosphere;
General procedure: A 50 mL round bottom flask equipped with a reflux condenser was charged with the appropriate amount of the substituted phthalonitrile (4.0 mM), zinc triflate (5.0 M%, 0.20 mM), and chlorobenzene (30 mL) under argon. The mixture was stirred to dissolve the phthalonitrile and then 2-aminoalcohol (8.0 mM), dissolved in dry chlorobenzene, was slowly added. The temperature was raised to 135 C and the reaction mixture was refluxed for 24 h. The product of the reaction, which was obtained as an oily residue, was dissolved in 30 mL of dichloromethane and then extracted twice with distilled water (20 mL). The aqueous layer was separated and washed with dichloromethane. The separated organic layers were dried using anhydrous sodium sulfate. The dichloromethane was removed under vacuum on a rotary evaporator to give the crude product, which was then purified using silica gel column chromatography with dichloromethane/ether (4/1) as eluent [14, 16, 17].
87%
With zinc trifluoromethanesulfonate; In chlorobenzene; for 24h;Reflux;
A solution of phthalonitrile derivative and zinc triflate in drychlorobenzene was stirred at room temperature for15 min, and then a solution of aminoalcohol in dry chlorobenzene was slowly added. The temperature was raised to 135C, and the reaction mixture was refluxed for 24 h.
5-bromo-N-(1-hydroxy-2-methylpropan-2-yl)picolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
In dichloromethane; at 0 - 20℃; for 48h;
Th ionyl chloride (10 mL, 150 mmol) was added to solid 5-bromopicolinic acid (1 .2 g, 6 mmol) at ambient temperature under N2. The resulting mixture was refluxed for 2 h and the volatiles were removed in vacuo. The crude acid chloride was dissolved in dry DCM (20 mL) and the solution was slowly added at 0 C to a solution of 2-amino-2-methylpropan-1-01 (1.6 g, 18 mmol) in DCM (5 mL). After stirring 48 h at ambient temperature, solvents were removed in vacuo and the crude product was purified by flash chromatography on silica gel (PEIEA= 100/1 to 5/1) to the title compound (1.5 g, 93 %) as a white solid. LCMS: [M+H] = 273.1.
In dichloromethane; at 0 - 20℃; for 48h;
5-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)picolinamide (B46.1) (0495) Thionyl chloride (10 mL, 150 mmol) was added to solid 5-bromopicolinic acid (1.2 g, 6 mmol) at ambient temperature under N2. The resulting mixture was refluxed for 2 h and the volatiles were removed in vacuo. The crude acid chloride was dissolved in dry DCM (20 mL) and the solution was slowly added at 0 C. to a solution of 2-amino-2-methylpropan-1-ol (1.6 g, 18 mmol) in DCM (5 mL). After stirring 48 h at ambient temperature, solvents were removed in vacuo and the crude product was purified by flash chromatography on silica gel (PE/EA=100/1 to 5/1) to the title compound (1.5 g, 93%) as a white solid. LC-MS: [M+H]+=273.1.
To the reaction vessel, 3.18 g (10.24 mmol) of ODPA,1.83 g (20.47 mmol) of 2-amino-2-methyl-1-propanol and 10 ml of EDM were added and refluxed for 3 hours. After completion of the reaction, water generated by EDM and reaction was removed. Subsequently, 20 ml of methyl ethyl ketone, 0.01 g (0.01 mmol) of dibutyltin dilaurate and 0.01 g (0.10 mmol) of 4-methoxyphenol were mixed in the reaction vessel. To this was added dropwise 3.48 g (24.66 mmol) of 2-isocyanatoethyl acrylate. After completion of the dropwise addition, the mixture was stirred at 45 C for 2 hours. After the reaction, in order to react excess 2-isocyanatoethyl acrylate, 2 ml of methanol was poured into the reaction solution and the mixture was stirred on an ice bath for 30 minutes. After stirring, the solvent was removed to obtain 7.68 g of acrylic imide 8.
2-methyl-2-[(1E)-(1,3,5-trimethyl-1H-pyrazol-4-yl)methylidene]amino}propan-1-ol[ No CAS ]
4,4-dimethyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-oxazolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In benzene; at 150℃; for 2h;Microwave irradiation; Molecular sieve; Inert atmosphere;
General procedure: Into a vessel of the microwave reactor, equipped with a stirring bar, was charged 0.22 g (1 mmol) of pyrazolecarbaldehyde 1a, 0.094 g (1.06 mmol, 5% excess) of 2-amino-2-methylpropan-1-ol 2, 2 mL of anhydrous C6H6, and the reactor was filled with argon. The reaction mixture in the presence of molecular sieves 4 A was heated for 2 h at microwave irradiation at 150C, and then the solvent was removed at a reduced pressure. The crude reaction product was washed with hexane (2 × 2 mL), cooled to 0C, dried in a vacuum over P2O5. Yield 0.289 g (99%) of a mixture of azomethine 3a and oxazolidine 4a, 60 : 40, light-yellow crystals.
2-((6-chloro-5-methoxypyrimidin-4-yl)amino)-2-methylpropan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.5 g
With potassium carbonate; In 1,4-dioxane; at 125℃; for 8h;
To a stirred solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.0 g, 27.9 mmol) in 1 ,4-dioxane(50 mL) were added potassium carbonate (4.6 g, 33.5 mmol) followed by 2-amino-2-methylpropanol (2.71 mL, 28.4 mmol) at RT. The resultant mixture was stirred at 125 C for 8 h. The mixture was cooled to RT and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3.5 g of the desiredcompound. ?H NMR (400 MHz, DMSO-d6) oe 1.37 (s, 6H), 3.50 (d, J 5.6 Hz, 2H), 3.74 (s,3H), 5.10 (t, J= 6.0 Hz, 1H), 6.30 (s, 1H), 8.06 (s, 1H).
N-(1-hydroxy-2-methylpropan-2-yl)-2,2-dimethylbut-3-enamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 16h;Inert atmosphere;
2-Amino-2-methylpropan-1-ol (13) (1.0?g, 11.2?mol), WSCI HCl (2.15?g, 11.2?mmol) and HOBt H2O (1.51?g, 11.2?mmol) were added to a chloroform (37?mL) solution of <strong>[10276-09-2]2,2-dimethyl-3-butenoic acid</strong> (12) (1.11?g, 7.48?mmol) in a nitrogen atmosphere, and the mixture was stirred for 16?h at room temperature. Water was added to the reaction liquid, and the mixture was extracted with chloroform. Then, the organic layer was washed with 2-M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution and then dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane:ethyl acetate ratio?=?9:1 to 1:1) to obtain the title compound as a colorless powder (0.70?g, 51%). 1H NMR (300?MHz, CDCl3) delta ppm 1.24 (s, 6H), 1.28 (s, 6H), 3.55 (s, 2H), 5.19-5.30 (m, 2H), 5.74 (br s, 1H), 5.99 (dd, J?=?17.49, 10.65?Hz, 1H).
In toluene; at 105 - 115℃;Inert atmosphere; Industrial scale;
Add <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> 10.0 Kg (33.87) to 100 L of toluene under nitrogen. Mol)And 7.95 Kg (89.19 mol) of 2-amino-2-methyl-1-propanol, heated to 105-115 C for 6-7 hours and the resulting water was separated until the metered amount was reached or no longer increased.Cooling to 10 C ~ 20 C, respectively, adding a mass concentration of 2% aqueous acetic acid solution (the mass concentration refers to the mass of acetic acid as a percentage of the total mass of acetic acid aqueous solution),The mass concentration is 5% sodium carbonate aqueous solution (the mass concentration refers to the mass of sodium carbonate as a percentage of the total mass of the sodium carbonate aqueous solution),The mass concentration is 7% aqueous solution of sodium hydrogencarbonate (the mass concentration refers to the mass of sodium hydrogencarbonate as a percentage of the total mass of the aqueous solution of sodium hydrogencarbonate),The mass concentration is 10% saline (the mass concentration refers to the mass of sodium chloride as a percentage of the total mass of the brine), and the mixture is stirred, allowed to stand, and the aqueous layer is separated.The organic layer was concentrated in vacuo (temperature: 45 C to 65 C, pressure -0.08 MPa to -0.1 MPa) to remove most of the solvent, and n-heptane 70 L was added, and the mixture was cooled to 10 to 20 C and stirred for 2 to 3 hours.Centrifugation, rinsing three times with n-heptane, drying in vacuum (vacuum degree -0.01 MPa ~ -0.1 MPa, temperature 45 ~ 55 C) for 14 to 18 hours,11.4 kg of moxifloxacin hydrochloride intermediate II was obtained in a yield of 96.6%. The HPLC purity was 96.38%.
2-((5-iodopyrimidin-2-yl)amino)-2-methylpropan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
215 mg
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 70℃; for 16h;
a) 2-((5-iodopyrimidin-2-yl)amino)-2-methylpropan-1-ol DIPEA (1.49 mL) was added to a solution of 2-amino-2-methylpropan-1-ol (0.80 mL) and <strong>[32779-38-7]2-chloro-5-iodopyrimidine</strong> (1.0 g) in DMSO (10 mL) at room temperature. The mixture was stirred at 70 C. for 16 hr. The reaction mixture was diluted with water at room temperature, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (215 mg). 1H NMR (300 MHz, DMSO-d6) delta 1.27 (6H, s), 3.46 (2H, d, J=5.9 Hz), 4.84 (1H, t, J=5.9 Hz), 6.63 (1H, s), 8.40 (2H, s).
2-(5-bromo-3-fluoro-2-nitroanilino)-2-methylpropan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;
To a yellow solution of <strong>[147808-42-2]5-bromo-1,3-difluoro-2-nitrobenzene</strong> (1a) (8.0 g, 33.6 mmol) in DMF (30 mL) were added K2CO3 (9.3 g, 67.2 mmol) and 2-amino-2-methylpropan-1-ol (3.0 g, 33.6 mmol). The mixture was stirred at 80 C. for 1 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was cooled to room temperature, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 80 g SiO2, 15% EtOAc/petroleum ether) to provide 2-(5-bromo-3-fluoro-2-nitroanilino)-2-methylpropan-1-ol (26a) (7.0 g, 68% yield) as a yellow solid. m/z (ESI+) for (C10H12BrFN2O3), 307.0 (M+H)+.
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