* 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 aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0℃; for 0.5 h; Stage #2: With potassium hydrogensulfate; water In tetrahydrofuran; diethyl ether for 0.166667 h;
Boc-Gly-N-methoxy-N-methylaride (19) (4.37 g, 20 mmole) in 150 ml of anhydrous THF was stirred in a ice-water bath under argon for 30 min. A solution of LAH in diethyl ether (1 M) (30 ml, 30 mmole) was added to the above well stirred solution by cannula under argon. The resulting solution was stirred for 30 min. A solution of potassium hydrogensulfate (4.77 g, 35 mmole) in 60 ml of water was gradually added to the reaction solution and stirred for 10 min. Organic solvents in the reaction mixture were evaporated under reduced pressure. An additional 60 ml of water was added to the aqueous residue, which was then extracted with DCM (100 ml.x.4). The combined DCM extracts were washed with 1 M hydrochloric acid solution (100 ml.x.4), saturated sodium bicarbonate solution (100 ml.x.2), and saturated sodium chloride solution (100 ml), dried with 4 g of magnesium sulfate overnight, and filtered. Evaporation of the solvent under reduced pressure left a yellowish oil 20 (2.83 g) which was used without further purification. Yield: 89percent. TLC Rf=0.44 (hexane-EtOAc=1:1). 1H-NMR (90 MHz, CDCl3) δ ppm: 9.60 (s, 1 H), 5.26 (s, br, 1 H), 4.04 (d, 2 H, J=5.1 Hz), and 1.46 (s, 9 H).
50%
With lithium aluminium tetrahydride In tetrahydrofuran at -78℃; for 0.166667 h; Inert atmosphere
Boc-Gly-N(Me)-OMe (1, 5.00 mmol) was dissolved in THF (10mL) and injected through a septum to a suspension of LiAlH4 (6.25 mmol) inTHF (10 mL) at 78 °C under argon atmosphere. TLC control after 10 min usingCH2Cl2/EtOAc (8.5+1.5) indicated the completion of the reaction. Subsequently,the reaction mixture was quenched with 10percent KHSO4 (1 20 mL) and extractedwith diethyl ether (30 mL). The organic layer was washed with 10percent KHSO4 (1 20 mL) and sat. NaHCO3 (2 x 20 mL), dried over Na2SO4 and evaporatedyielding 2 as a colorless resin (50percent). 1H NMR (500 MHz, DMSO-d6) d 1.38 (s,9H), 3.72 (d, 3J = 5.7 Hz, 2H), 7.16 (br t, 1H), 9.44 (s, 1H). 13C NMR (125 MHz,DMSO-d6) d 28.26, 50.48, 78.46, 156.09, 200.74.
9.6 g
With lithium aluminium tetrahydride In tetrahydrofuran for 1 h; Cooling with ice
To an ice cooled suspension of 653 LiAlH4 (2.13g, 56mmol) in dry THF (20ml) was added F1 (12.2g, 56mmol) in small batches to avoid drastic reaction. After the addition, the mixture was stirred for a further 1h. Then the reaction was quenched cautiously by addition of saturated Na2CO3 solution dropwise until no gas bubbles were generated, followed by addition of water dropwise with vigorous stirring. The solid so formed was filtered off under reduced pressure and washed with THF. The filtrate was concentrated to afford F2 (9.6g) as a jelly which could be used in next step without further purification.
9.6 g
With lithium aluminium tetrahydride In tetrahydrofuran for 1 h;
To an ice cooled suspension of LiA1H4 (2.13 g, 56 mmol) in dry THF (20 ml) was added Fl (12.2 g, 56 mmol) in small batches to avoid drastic reaction. After the addition, the mixture was stirred for a further 1 h. Then the reaction was quenched cautiously by addition of saturated Na2CO3 solution dropwise until no gas bubbles were generated, followed by addition of water dropwise with vigorous stirring. The solid so formed was filtered off under reduced pressure and washed with THF. The filtrate was concentrated to afford F2 (9.6 g) as a jelly which could be used in next step without thrther purification.
Reference：
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[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 65 - 77
[4] Tetrahedron, 2001, vol. 57, # 23, p. 4903 - 4923
[5] European Journal of Medicinal Chemistry, 1991, vol. 26, # 9, p. 921 - 928
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[7] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2008 - 2012
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[15] Journal of Medicinal Chemistry, 2007, vol. 50, # 23, p. 5790 - 5806
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[18] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0553
[19] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0916
[20] Patent: WO2017/21730, 2017, A1, . Location in patent: Page/Page column 54; 55
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2
[ 26690-80-2 ]
[ 89711-08-0 ]
Yield
Reaction Conditions
Operation in experiment
69%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃; Inert atmosphere
A round-bottom flask was charged with 48 (0.80 g, 10.0 mmol)and IBX36 (2.80 g, 10.0 mmol) under argon atmosphere. DMSO(25 mL) was added to the mixture and then stirring was continued overnight at rt. The reaction mixture was quenched with water(200 mL) and filtered under reduced pressure. The filtrate was extracted with ethyl acetate. The organic layer was dried (Na2SO4)and concentrated under reduced pressure. Purification of the crude residue by SiO2 column chromatography (CHCl3:EtOAc = 7:3) gave49 (69percent; lit. 55percent37) as an oil; 1H NMR (500 MHz, CDCl3): d 9.65 (2H,br s, HCO), 5.16 (1H, br, NH), 4.06 (2H, s, CH2), 1.45 (9H, s, C(CH3)3).
66%
With sulfur trioxide pyridine complex In dimethyl sulfoxide at 20℃; Ice cooling
Reference Example 1 tert-Butyl (2-oxoethyl) carbamateTo a mixed solution of tert-butyl (2- hydroxyethyl) carbamate (10.0 g) in dimethyl sulfoxide (50 mL) and triethylamine (12.3 g) was added sulfur trioxide pyridine complex (15.0 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent :hexane-ethyl acetate=17 : 3-->13 : 7) to give the title compound as a pale-yellow oil (yield 6.50 g, 66percent). 1H-NMR (CDCl3) δ:l.46 ( 9H, s) , 4.08 (2H, d, J=4.5Hz) , 5.19 (lH,brs) , 9.66(lH,s) .
14%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 1 h;
Oxalyl chloride (1.3 mL, 15 mmol) was added to a reaction chamber containing methylene chloride (120 mL) at -78° C. and a solution of dimethyl sulfoxide (2.45 mL, 30 mmol) dissolved in methylene chloride (20 mL) was added. The resulting solution was stirred for 10 minutes at -78° C. A solution of N-Boc-ethanolamine (2 g, 12.4 mmol) dissolved in methylene chloride (20 mL) was slowly added and then triethylamine (8.64 ml, 62 mmol) was added. The resulting solution was stirred for 30 minutes at -78° C. and additional 30 minutes at room temperature, washed with water (100 mL) and saline (100 mL). The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and applied to column chromatography (n-hex:EA=3:11:1) to yield Compound I (270 mg (14percent)).1H NMR (600 MHz, DMSO-d6) δ=7.83 (s, 1H), 7.49 (s, 1H), 6.88 (d, J=5.4 Hz, 1H), 6.36 (br, 2H), 4.81 (br, 1H), 3.13 (m, 4H), 1.39 (s, 9H)
14%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 1.16667 h;
Oxalyl chloride (1.3 mL, 15 mmol) was added to a reaction chamber containing methylene chloride (120 mL) at -78°C and a solution of dimethyl sulfoxide (2.45 mL, 30 mmol) dissolved in methylene chloride (20 mL) was added. The resulting solution was stirred for 10 minutes at -78°C. A solution of N-Boc-ethanolamine (2g, 12.4 mmol) dissolved in methylene chloride (20 mL) was slowly added and then triethylamine (8.64 ml, 62 mmol) was added. The resulting solution was stirred for 30 minutes at -78°C and additional 30 minutes at room temperature, washed with water (100 mL) and saline (100 mL). The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and applied to column chromatography (n-hex : EA = 3 :1∼1:1) to yield Compound I (270 mg (14percent)). 1H NMR (600MHz, DMSO-d6) δ= 7.83(s, 1H), 7.49(s, 1H), 6.88(d, J = 5.4Hz, 1H), 6.36(br, 2H), 4.81(br, 1H), 3.13(m, 4H), 1.39(s, 9H)
80%
With triethylamine In dichloromethane; dimethyl sulfoxide
Step B: 2-(t-Butoxycarbonylamino)acetaldehyde To a solution of 700 mg (4.34 mmol) of 2-(t-butoxycarbonylamino)ethanol in 35 mL of dry methylene chloride was added 4.0 mL of dimethylsulfoxide and 4.8 mL (35 mmol) of triethylamine, followed by 2.8 g (17 mmol) of pyridine sulfur trioxide complex in three portions over 5 minutes. The reaction was stirred at room temperature for 3 hours then diluted with 500 mL of ether. The mixture was transferred to a separatory funnel and washed with 1N HCl (2*50 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under vacuum to afford 550 mg (80percent) of product which was used without further purification. 1 H NMR (200 MHz,CDCl3): 1.40 (s,9H), 4.05 (d,7 Hz,2H), 5.17 (s,1H), 9.62 (s,1H).
80%
With triethylamine In dichloromethane; dimethyl sulfoxide
Step C: N-(t-Butoxycarbonyl)glycinal To a solution of 700 mg (4.34 mmol) of 2-(t-butoxycarbonylamino)ethanol in 35 mL of dry methylene chloride was added 4.8 mL (35 mmol) of triethylamine and 4.0 mL of dry dimethylsulfoxide. To the resulting solution was added in portions 2.8 g (17 mmol) of pyridine-sulfur trioxide complex. The resulting brown solution was s stirred at room temperature for 3 hours. The mixture was diluted with 500 mL of ether and transferred to a separatory funnel. The mixture was washed with 1N aqueous hydrochloric acid (2*50 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was removed, dried over magnesium sulfate, filtered and the solvent removed under vacuum to afford 550 mg (80percent) of the product as an oil. 1 H NMR (200 MHz, CDCl3): δ1.42 (s, 9H), 4.04 (d, 4 Hz, 2H), 5.18 (s, 1H), 9.62 (s, 1H).
2 g
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 16 h;
Step 2: Preparation of tert-butyl (2-oxoeth l)carbamate To a solution of tert-butyl (2-hydroxyethyl)carbamate (4 g, 24.81 mmol) in DCM (200 mL) was added Dess-Martin reagent (12.62 g, 29.77 mmol) at 0 °C. The reaction was stirred at ambient temperature for 16 h. Saturated aqueous Na2C03 (80 mL) and Na2S203 (80 mL) were added to the reaction and stirred for lh. The resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (3 x 200 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10percent) and hexanes (90 percent) to provide tert-butyl (2- oxoethyl)carbamate (2 g, 12.56 mmol) as a colorless oil. LCMS [M+H]+ = 160.1.
Reference：
[1] Synthesis, 2011, # 14, p. 2321 - 2333
[2] Chemical Communications, 2007, # 21, p. 2136 - 2138
[3] Journal of the American Chemical Society, 2015, vol. 137, # 32, p. 10036 - 10039
[4] Helvetica Chimica Acta, 1997, vol. 80, # 4, p. 1244 - 1259
[5] Organic and Biomolecular Chemistry, 2003, vol. 1, # 20, p. 3527 - 3534
[6] Phytochemistry (Elsevier), 1990, vol. 29, # 3, p. 701 - 703
[7] European Journal of Organic Chemistry, 2014, vol. 2014, # 24, p. 5331 - 5345
[8] Tetrahedron Letters, 1999, vol. 40, # 26, p. 4905 - 4908
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 3, p. 1094 - 1112
[10] Patent: WO2010/24451, 2010, A1, . Location in patent: Page/Page column 50; 51
[11] Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278
[12] Journal of Organic Chemistry, 2002, vol. 67, # 12, p. 4017 - 4029
[13] Chemical and pharmaceutical bulletin, 2002, vol. 50, # 2, p. 239 - 252
[14] Patent: US2012/264727, 2012, A1, . Location in patent: Page/Page column 33; 34
[15] Patent: EP2706062, 2014, A2, . Location in patent: Paragraph 0069
[16] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2487 - 2493
[17] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2891 - 2893
[18] Heterocycles, 2003, vol. 60, # 4, p. 791 - 798
[19] Synthesis, 2003, # 18, p. 2805 - 2810
[20] Synlett, 2003, # 10, p. 1539 - 1541
[21] Journal of Organic Chemistry, 2005, vol. 70, # 6, p. 1963 - 1977
[22] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1486 - 1490
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[24] Patent: US5206235, 1993, A,
[25] Patent: US5438136, 1995, A,
[26] Patent: WO2005/41888, 2005, A2, . Location in patent: Page/Page column 86
[27] Patent: US7544794, 2009, B1, . Location in patent: Page/Page column 14-15
[28] Patent: WO2004/55008, 2004, A1, . Location in patent: Page 49
[29] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 288
[30] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 11, p. 3140 - 3144
[31] Patent: WO2015/88565, 2015, A1, . Location in patent: Paragraph 00225
[32] RSC Advances, 2016, vol. 6, # 31, p. 25713 - 25723
[33] Patent: JP2016/190813, 2016, A, . Location in patent: Paragraph 0066-0068
[34] Patent: CN108129404, 2018, A, . Location in patent: Paragraph 0106; 0107
[35] Patent: WO2005/41888, 2005, A2, . Location in patent: Page/Page column 86
3
[ 137618-48-5 ]
[ 89711-08-0 ]
Yield
Reaction Conditions
Operation in experiment
56%
With sodium periodate In water at 20℃; for 2 h;
Step 2 tert-Butyl 2-oxoethylcarbamate: Sodium periodate (41.52 g; 194 mmol; 1.00 equiv) was added in several batches to tert-butyl 2,3-dihydroxypropylcarbamate (37 g; 194 mmol; 1.00 equiv) dissolved in water (300 mL). The resulting solution was stirred at ambient temperature for about 2 hours. The solids were were removed by filtration. Standard extractive workup with dichloromethane, gave the title product as a white solid (17 g; 56percent yield). 1H NMR (300 MHz, CDCl3) δ 9.65 (s, 1H), 5.26 (s, 1H), 4.07 (d, J=4.5 Hz, 2H), 1.46 (s, 9H).
Reference：
[1] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 2, p. 445 - 451
[2] Journal of the American Chemical Society, 2015, vol. 137, # 39, p. 12442 - 12445
[3] Journal of the American Chemical Society, 2005, vol. 127, # 10, p. 3339 - 3345
[4] Patent: US2010/9950, 2010, A1, . Location in patent: Page/Page column 24
[5] Patent: US6750348, 2004, B1, . Location in patent: Page column 66
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4969 - 4974
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4509 - 4512
[8] Patent: WO2018/175927, 2018, A2, . Location in patent: Paragraph 00303
4
[ 31954-27-5 ]
[ 89711-08-0 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 7, p. 2197 - 2205
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2812 - 2815
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 7, p. 1937 - 1939
[4] Heterocycles, 1998, vol. 48, # 7, p. 1331 - 1335
[5] Heterocycles, 2003, vol. 60, # 4, p. 791 - 798
[6] Angewandte Chemie - International Edition, 2006, vol. 45, # 35, p. 5870 - 5874
[7] Organic Letters, 2002, vol. 4, # 17, p. 2913 - 2916
[8] Heterocycles, 2003, vol. 60, # 4, p. 791 - 798
[9] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2487 - 2493
[10] Journal of Organic Chemistry, 2008, vol. 73, # 13, p. 5180 - 5182
[11] Chemistry - A European Journal, 2009, vol. 15, # 14, p. 3457 - 3473
[12] Patent: WO2004/83173, 2004, A2, . Location in patent: Page 31
[13] Patent: EP1721905, 2006, A1, . Location in patent: Page/Page column 24
[14] Synlett, 2011, # 2, p. 211 - 214
[15] Journal of Organic Chemistry, 2012, vol. 77, # 8, p. 4005 - 4016
[16] Biochemistry, 2013, vol. 52, # 36, p. 6182 - 6196
5
[ 78888-18-3 ]
[ 89711-08-0 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3457 - 3465
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 6, p. 711 - 712
[3] Journal of Medicinal Chemistry, 1986, vol. 29, # 1, p. 104 - 111
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1067 - 1075
[5] Journal of the American Chemical Society, 2010, vol. 132, # 6, p. 1748 - 1749
[6] Patent: US2002/19527, 2002, A1,
[7] Organic Letters, 2015, vol. 17, # 7, p. 1774 - 1777
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 41, p. 11075 - 11078
With hydrogenchloride; sodium hydroxide In water; ethyl acetate
(a) Preparation of (bocamino) acetaldehyde 3-Amino-1,2-propanediol(80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4° C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0° C. and the pH was adjusted to 2.5 by the addition of 4M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8*500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86percent) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6*400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuoo Yield 102 g (93percent) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84° C. and 0.3 mmHg in two portions. The yield 79 g (77percent) of a colorless oil.
93%
With hydrogenchloride; sodium hydroxide In water; ethyl acetate
(a) Preparation of (bocamino)acetaldehyde 3-Amino-1,2-propanediol(80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4° C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0° C. and the pH was adjusted to 2.5 by the addition of 4 M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8*500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86percent) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6*400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93percent) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84° C. and 0.3 mmHg in two portions. The yield 79 g (77percent) of a colorless oil.
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 10, p. 1501 - 1510
[2] European Journal of Medicinal Chemistry, 1991, vol. 26, # 9, p. 921 - 928
[3] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2487 - 2493
[4] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 1254 - 1264
[5] Patent: EP2725024, 2014, A1,
[6] Patent: US2014/171431, 2014, A1,
[7] RSC Advances, 2016, vol. 6, # 31, p. 25713 - 25723
[8] Patent: WO2017/21730, 2017, A1,
[9] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2008 - 2012
12
[ 7790-21-8 ]
[ 616-30-8 ]
[ 24424-99-5 ]
[ 137618-48-5 ]
[ 89711-08-0 ]
Yield
Reaction Conditions
Operation in experiment
93%
With hydrogenchloride; sodium hydroxide In water; ethyl acetate
(a) Preparation of (bocamino)acetaldehyde 3-Amino-1,2-propanediol (80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4° C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0° C. and the pH was adjusted to 2.5 by the addition of 4 M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8*500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86percent) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6*400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93percent) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84° C. and 0.3 mmHg in two portions. The yield 79 g (77percent) of a colorless oil.
Reference：
[1] Patent: US6713602, 2004, B1,
13
[ 118517-02-5 ]
[ 89711-08-0 ]
Reference：
[1] Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278
14
[ 4202-14-6 ]
[ 89711-08-0 ]
[ 92136-39-5 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 1254 - 1264
With diisobutylaluminium hydride In toluene at -78℃; for 2h;
67%
With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1h;
With diisobutylaluminium hydride In toluene at -78℃;
With diisobutylaluminium hydride In toluene at -78℃; for 2h;
With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 2h;
With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 1.5h;
Multi-step reaction with 2 steps
1.1: lithium aluminum hydride / tetrahydrofuran / 0.33 h
1.2: aq. potassium hydroxide / tetrahydrofuran / 1 h / 20 °C
2.1: oxalyl chloride; DMSO / CH2Cl2 / 0.5 h / -45 °C
2.2: diisopropylethylamine / CH2Cl2 / -45 - 0 °C
Multi-step reaction with 2 steps
1: 70 percent / anhydrous lithium chloride, sodium borohydride / tetrahydrofuran; ethanol / Ambient temperature
2: triethylamine, DMSO, sulfur trioxide pyridine complex / benzene / 0.33 h / 20 - 25 °C
With diisobutylaluminium hydride In hexane; toluene at -78℃;
With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; Inert atmosphere;
With diisobutylaluminium hydride In dichloromethane at -78℃; for 1h;
1 EXAMPLE 1 N- 2-F4-(4, 5-DIHYDRO-LH-IMIDAZOL-2-YL) PHENYLLETHYL T-2-R (2R)-3-OXO-1-(1, 2. 3. 4-TETRAHYDROQUINOLIN-8- YLSULFONYL) PIPERAZIN-2-YLL ACETAMIDE
To a solution of methyl [ (TERT-BUTOXYCARBONYL) AMINO] ACETATE, la (8. 59 g, 45.45 mmol) in CH2C12 (150 ML) AT-78°C, was added diisobutylaluminum hydride (100 mL, 1M solution in CH2C12). The reaction mixture stirred at-78°C for approximately one hour before it was quenched with 1N HCl (104 mL). The reaction mixture was then warmed to 0°C, neutralized with saturated NAHCO3, and further warmed to room temperature. After overnight stirring, the reaction mixture was filtered through celite, and partitioned bewtween CH2C12 and water. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude product was distilled under high vacuum, collecting between 95°C and 102°C, to give tert-butyl 2-OXOETHYLCARBAMATE.
Stage #1: N-(tert-butoxycarbonyl)glycine methyl ester With diisobutylaluminium hydride In toluene at -70℃; for 1h;
Stage #2: With methanol In toluene at -70℃;
21.1 Synthesis of Compound 71
(1) A 1.02M solution of diisobutylalminium hydride in toluene (27 ml) was added dropwise to a solution of methyl tert-butoxycarbonylaminoacetate (2.00 g) in toluene (40 ml) at -70°C, and the mixture was stirred for 1 hour. The reaction solution, to which methanol (10 ml) was added at -70°C, was quenched and then left to room temperature. After the reaction solution was diluted with ethyl acetate, this solution was washed with a 1N aqueous hydrochloric acid solution. The organic layer was washed with a brine filtered through celite, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40 → 30:70) to yield tert-butyl(2-oxoethyl)carbamate (895 mg) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm: 1.46 (9H, s), 4.05-4.11 (2H, m), 5.18 (1H, s), 9.66 (1H, s)
With diisobutylaluminium hydride In toluene at -78℃;
Stage #1: N-(tert-butoxycarbonyl)glycine methyl ester With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 3h; Inert atmosphere;
Stage #2: With acetic acid In hexane; dichloromethane; benzene at -78 - 20℃; Inert atmosphere;
With diisobutylaluminium hydride In dichloromethane at -78℃; for 1h; Molecular sieve;
With Dess-Martin periodane In dichloromethane at 0℃; for 0.5h; Inert atmosphere;
92%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate for 3h; Reflux; Schlenk technique; Inert atmosphere;
87%
With sodium hypochlorite; potassium hydrogencarbonate; potassium bromide In dichloromethane at 20℃; for 0.5h;
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 23℃; for 3h; Inert atmosphere;
80%
With sulfur trioxide pyridine complex; triethylamine In dichloromethane; dimethyl sulfoxide for 3h; Ambient temperature;
78%
With pyridine-SO3 complex; TEA In dichloromethane; dimethyl sulfoxide
77%
With Dess-Martin periodane In dichloromethane; water at 20℃; for 2.5h;
4.3.1. tert-Butyl (R)-(1-oxopropan-2-yl)carbamate (3a)
General procedure: To a solution of tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate(2a) (10.00 g, 57.1 mmol) in DCM (300 mL) was added solid Dess-Martin periodinane (33.89 g, 79.9 mmol) in one portion. Water(1.4 mL) was added dropwise within 0.5 h to the vigourously stirredsuspension, and the stirring was continued for 2 h at room temperature,whereupon EtOAc (1000 mL) was added. The suspension was filteredthrough a pad of Celite, and the filter-cake was washed with EtOAc(500 mL). Combined filtrates were washed sequentially with aqueoussaturated NaHCO3, aqueous 10% Na2S2O3 (1:1), brine, and dried(Na2SO4). Volatiles were evaporated and the residue was dried in vacuoto give aldehyde 3a as a white solid (9.30 g, 94%). 1H NMR (400 MHz,CDCl3) δ: 9.56 (s, 1H), 5.09 (m, 1H), 4.23 (qui, J=7.3 Hz, 1H), 1.45 (s,9H), 1.33 (d, J=7.3 Hz, 3H). 1H NMR spectrum was in agreement withthat reported in the literature.40
75%
With pyridinium chlorochromate In dichloromethane for 3.5h; Ambient temperature;
74%
With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 3h;
70%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃;
69%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃; Inert atmosphere;
4.2.7. Oxidation of 48 by 2-iodoxybenzoic acid (IBX); synthesis of tertbutyl(2-oxoethyl)carbamate
A round-bottom flask was charged with 48 (0.80 g, 10.0 mmol)and IBX36 (2.80 g, 10.0 mmol) under argon atmosphere. DMSO(25 mL) was added to the mixture and then stirring was continued overnight at rt. The reaction mixture was quenched with water(200 mL) and filtered under reduced pressure. The filtrate was extracted with ethyl acetate. The organic layer was dried (Na2SO4)and concentrated under reduced pressure. Purification of the crude residue by SiO2 column chromatography (CHCl3:EtOAc = 7:3) gave49 (69%; lit. 55%37) as an oil; 1H NMR (500 MHz, CDCl3): d 9.65 (2H,br s, HCO), 5.16 (1H, br, NH), 4.06 (2H, s, CH2), 1.45 (9H, s, C(CH3)3).
66%
With sulfur trioxide pyridine complex In dimethyl sulfoxide at 20℃; Ice cooling;
1
Reference Example 1 tert-Butyl (2-oxoethyl) carbamateTo a mixed solution of tert-butyl (2- hydroxyethyl) carbamate (10.0 g) in dimethyl sulfoxide (50 mL) and triethylamine (12.3 g) was added sulfur trioxide pyridine complex (15.0 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent :hexane-ethyl acetate=17 : 3→13 : 7) to give the title compound as a pale-yellow oil (yield 6.50 g, 66%). 1H-NMR (CDCl3) δ:l.46 ( 9H, s) , 4.08 (2H, d, J=4.5Hz) , 5.19 (lH,brs) , 9.66(lH,s) .
62%
With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at -10℃;
55%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃;
55%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate at 80℃; for 4h;
tert-Butyl (2-oxoethyl)carbamate (S2)
Compound S1 (350 mg, 2.17 mmol) and 2-iodoxybenzoic acid (2.40 g, 8.69 mmol) were dissolved in EtOAc (10 cm3). The resulting suspension was heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature and the suspension was filtered. The filtrate was then concentrated in vacuo to afford a crude residue which was purified by flash chromatography on silica gel (0% to 40% EtOAc in Hexane) to yield aldehyde S2 as a colourless oil (252 mg, 55%). The isolated compound exhibited identical spectroscopic data to those in the literature. δH (400 MHz, CDCl3): 1.43 (9H, s), 4.05-4.06 (2H, d, J 4.6), 5.16 (1H, br s), 9.63 (1H, s) LRMS (m/z -APCI): Found: 160.1 [M+H]+ C7H14NO3; Requires: 160.1
55%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate at 80℃; for 4h;
tert-Butyl (2-oxoethyl)carbamate (S2)
Compound S1 (350 mg, 2.17 mmol) and 2-iodoxybenzoic acid (2.40 g, 8.69 mmol) were dissolved in EtOAc (10 cm3). The resulting suspension was heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature and the suspension was filtered. The filtrate was then concentrated in vacuo to afford a crude residue which was purified by flash chromatography on silica gel (0% to 40% EtOAc in Hexane) to yield aldehyde S2 as a colourless oil (252 mg, 55%). The isolated compound exhibited identical spectroscopic data to those in the literature. δH (400 MHz, CDCl3): 1.43 (9H, s), 4.05-4.06 (2H, d, J 4.6), 5.16 (1H, br s), 9.63 (1H, s) LRMS (m/z -APCI): Found: 160.1 [M+H]+ C7H14NO3; Requires: 160.1
42%
With sulfur trioxide pyridine complex; triethylamine In dichloromethane; dimethyl sulfoxide at 35℃; for 0.166667h;
14%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 1h;
1.1-1
Oxalyl chloride (1.3 mL, 15 mmol) was added to a reaction chamber containing methylene chloride (120 mL) at -78° C. and a solution of dimethyl sulfoxide (2.45 mL, 30 mmol) dissolved in methylene chloride (20 mL) was added. The resulting solution was stirred for 10 minutes at -78° C. A solution of N-Boc-ethanolamine (2 g, 12.4 mmol) dissolved in methylene chloride (20 mL) was slowly added and then triethylamine (8.64 ml, 62 mmol) was added. The resulting solution was stirred for 30 minutes at -78° C. and additional 30 minutes at room temperature, washed with water (100 mL) and saline (100 mL). The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and applied to column chromatography (n-hex:EA=3:11:1) to yield Compound I (270 mg (14%)).1H NMR (600 MHz, DMSO-d6) δ=7.83 (s, 1H), 7.49 (s, 1H), 6.88 (d, J=5.4 Hz, 1H), 6.36 (br, 2H), 4.81 (br, 1H), 3.13 (m, 4H), 1.39 (s, 9H)
14%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 1.16667h;
1-1
Oxalyl chloride (1.3 mL, 15 mmol) was added to a reaction chamber containing methylene chloride (120 mL) at -78°C and a solution of dimethyl sulfoxide (2.45 mL, 30 mmol) dissolved in methylene chloride (20 mL) was added. The resulting solution was stirred for 10 minutes at -78°C. A solution of N-Boc-ethanolamine (2g, 12.4 mmol) dissolved in methylene chloride (20 mL) was slowly added and then triethylamine (8.64 ml, 62 mmol) was added. The resulting solution was stirred for 30 minutes at -78°C and additional 30 minutes at room temperature, washed with water (100 mL) and saline (100 mL). The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and applied to column chromatography (n-hex : EA = 3 :1∼1:1) to yield Compound I (270 mg (14%)). 1H NMR (600MHz, DMSO-d6) δ= 7.83(s, 1H), 7.49(s, 1H), 6.88(d, J = 5.4Hz, 1H), 6.36(br, 2H), 4.81(br, 1H), 3.13(m, 4H), 1.39(s, 9H)
With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In benzene at 20 - 25℃; for 0.333333h;
With 4-acetylamino-2,2,6,6-tetramethylpiperidine-N-oxyl; sodium hypochlorite; sodium bromide In ethyl acetate; toluene at -10℃;
Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -45℃; for 0.5h;
Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at -45 - 0℃;
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In 1,2-dimethoxyethane at 80℃; for 1h;
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In 1,2-dimethoxyethane at 80℃; for 1h;
With Dess-Martin periodane In dichloromethane for 2h;
With Dess-Martin periodane In dichloromethane
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane
550 mg (80%)
With triethylamine In dichloromethane; dimethyl sulfoxide
85.B Step B:
Step B: 2-(t-Butoxycarbonylamino)acetaldehyde To a solution of 700 mg (4.34 mmol) of 2-(t-butoxycarbonylamino)ethanol in 35 mL of dry methylene chloride was added 4.0 mL of dimethylsulfoxide and 4.8 mL (35 mmol) of triethylamine, followed by 2.8 g (17 mmol) of pyridine sulfur trioxide complex in three portions over 5 minutes. The reaction was stirred at room temperature for 3 hours then diluted with 500 mL of ether. The mixture was transferred to a separatory funnel and washed with 1N HCl (2*50 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under vacuum to afford 550 mg (80%) of product which was used without further purification. 1 H NMR (200 MHz,CDCl3): 1.40 (s,9H), 4.05 (d,7 Hz,2H), 5.17 (s,1H), 9.62 (s,1H).
550 mg (80%)
With triethylamine In dichloromethane; dimethyl sulfoxide
5.C Step C:
Step C: N-(t-Butoxycarbonyl)glycinal To a solution of 700 mg (4.34 mmol) of 2-(t-butoxycarbonylamino)ethanol in 35 mL of dry methylene chloride was added 4.8 mL (35 mmol) of triethylamine and 4.0 mL of dry dimethylsulfoxide. To the resulting solution was added in portions 2.8 g (17 mmol) of pyridine-sulfur trioxide complex. The resulting brown solution was s stirred at room temperature for 3 hours. The mixture was diluted with 500 mL of ether and transferred to a separatory funnel. The mixture was washed with 1N aqueous hydrochloric acid (2*50 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was removed, dried over magnesium sulfate, filtered and the solvent removed under vacuum to afford 550 mg (80%) of the product as an oil. 1 H NMR (200 MHz, CDCl3): δ1.42 (s, 9H), 4.04 (d, 4 Hz, 2H), 5.18 (s, 1H), 9.62 (s, 1H).
With Dess-Martin periodane In dichloromethane at 20℃; for 2h;
Oxime. tert-Butyl N-(2-hydroxyethyl)carbamate (900 mg; 5.5 mmol) is dissolved in anhydrous dichloromethane (40 mL) at room temperature. Dess-Martin periodinane (2.12 g; 5.0 mmol) is added. The solution is stirred at room temperature for 2 h during which it turned into a milky suspension. Aqueous NaHCO3/Na2S2O3 (sat., 40 mL) is added and the mixture stirred for an additional 30 minutes. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2×50 mL). The combined organic phase is dried with brine (30 mL) and Na2SO4 and concentrated in vacuo, to give a yellow slime. The crude aldehyde is taken up in acetonitrile (30 mL) and THF (20 mL). O-Allylhydroxylamine hydrochloride hydrate (720 mg; ca. 6.5 mmol) and potassium carbonate (900 mg; 6.5 mmol; powdered) are added and the suspension is stirred at room temperature for 30 minutes. The solids are removed by filtration, and the filtrate is concentrated in vacuo. Aqueous work-up (dichloromethane) and flash liquid chromatography (silica; eluent EtOAc/hexanes, 1:4 to 1:2) gives the oxime (expected 670 mg; 63%) as a colorless oil which solidifies at -20° C. 1H-NMR (CDCl3; 300 MHz): δ (ppm)=1.45 (s, 9H); 3.89 (t, J=5.0 Hz, 1.2H); 4.01 (t, J=4.9 Hz, 0.8H); 4.53 (dt, J=5.7, 1.4 Hz, 1.2H); 4.58 (dt, J=5.7, 1.4 Hz, 0.8H); 4.94 (br s, 1H); 5.19-5.33 (m, 2H); 5.90-6.04 (m, 1H); 6.74 (t, J=4.3 Hz, 0.4H); 7.44 (t, J=4.8 Hz, 0.6H). 13C-NMR (CDCl3; 75 MHz): δ (ppm)=28.6, 36.8, 40.0, 75.0, 75.3, 80.1, 117.8, 118.2, 134.1, 134.3, 146.8, 149.9, 155.8. HRMS-EI: [MH+] calcd for C10H19O3N2, 215.1396; found, 215.1486.
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.25h;
Stage #2: 2-(N-tert-butoxycarbonylamino)ethanol In dichloromethane at -78℃; for 0.75h;
Stage #3: With triethylamine In dichloromethane at -78 - 20℃;
1.a Example 1; 3-BENZYL-7-CHLORO-2- [2-METHYL-1- (7-OXO- [1, 4] DIAZEPAN-1-YL)-PROPYL]-3H- quinazolin-4-one; a) Preparation of (2-oxo-ethyl)-carbamic acid TERT-BUTYL ester:
To a stirred solution of OXALYL CHLORIDE (1.92 mL, 22 MMOL) in CH2CI2 (40 mL) was added dropwise DMSO (3.12 mL, 44 MMOL) AT-78° C. After 15 min. , a solution of (2-hydroxy-ethyl)-carbamic acid TERT-BUTYL ESTER (3.22 g, 20 MMOL) in CH2CI2 (20mL) was added. After another 45 min., Et3N (13.9 mL, 100 MMOL) was added. The reaction mixture was then warmed to room temperature, diluted with CH2CI2 (100 mL), washed with water, 10% HCI, brine, dried and concentrated. Purification by flash chromatography on silica gel (10-15% EtOAc in hexane) gave the title compound (600 mg) as a clear oil : 1 H NMR (400 MHz, CDCl3) No.9. 58 (S, 1 H), 5.16 (br s, 1 H), 4.02 (s, 2 H), 1.46 (s, 9 H).
With 2-iodoxybenzoic acid In ethyl acetate at 20℃; for 2h; Reflux;
1
Compound 367l-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(2-aminoethyl)amino)propyl)-3-(4-(tert-butyl)phenyl)ureaStep 1. Preparation of tert-butyl N-(2-oxoethyl)carbamateHUnder nitrogen atmosphere, a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (300 mg, 1.86 mmol) and IBX (1.56 g, 5.58 mmol) in EA (15 mL) was refluxed for 2 h. The reaction mixture was cooled to rt and filtered. The filter cake was washed with EA (5 mL x 2) and the filtrate was concentrated to afford tert-butyl N-(2-oxoethyl)carbamate (290 mg, crude) as colorless oil which was used for next reaction directly.
With Dess-Martin periodane at 0 - 20℃; for 1h;
2 g
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 16h;
2 Step 2: Preparation of tert-butyl (2-oxoeth l)carbamate
Step 2: Preparation of tert-butyl (2-oxoeth l)carbamate To a solution of tert-butyl (2-hydroxyethyl)carbamate (4 g, 24.81 mmol) in DCM (200 mL) was added Dess-Martin reagent (12.62 g, 29.77 mmol) at 0 °C. The reaction was stirred at ambient temperature for 16 h. Saturated aqueous Na2C03 (80 mL) and Na2S203 (80 mL) were added to the reaction and stirred for lh. The resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (3 x 200 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and hexanes (90 %) to provide tert-butyl (2- oxoethyl)carbamate (2 g, 12.56 mmol) as a colorless oil. LCMS [M+H]+ = 160.1.
With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide
With sodium hydrogencarbonate; Dess-Martin periodane; sodium thiosulfate In dichloromethane at 20℃; for 0.5h;
1.1
Dess Martin Periodinane (DMP; 9.08 g, 21.4 mmol) was added to a stirred solution of 2-(tert-butoxycarbonylamino)-1-ethanol (Compound 6) (2.88 g, 17.8 mmol) in CH2Cl2 (100 mL) And the mixture was stirred. A saturated aqueous solution of NaHCO3-Na2S2O3 (100 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solution was extracted with CHCl3, dried over MgSO 4, and evaporated under reduced pressure to give crude Aldehyde. A solution of crude Aldehyde, Cbz-L-Lys-OMe (5.25 g, 17.8 mmol) and MS 4 Å (1 g) in CH2Cl2 (100 mL) was stirred at 0 ° C for 1 hour. (4.80 g, 22.7 mmol) was added to the stirred solution, and then the mixture was stirred at room temperature overnight. The solution was extracted with CHCl 3 and dried over MgSO 4. The solvent was removed to give a residue which was purified by column chromatography on silica gel (10% MeOH in CHCl 3) to give Cbz-L-Lys [AEt (Boc)] - OMe Compound 8) (2.63 g, 34%).
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium hydrogencarbonate; sodium bromide In Isopropyl acetate; water at -5 - 0℃;
9 Synthesis of N-Boc-aminoacetaldehyde
43 g of N-Boc-ethanolamine was dissolved in 700 mL of isopropyl acetate and cooled to -5 to 0 °C.Stir,Add 51 g of sodium bromide to the solution.31g sodium bicarbonate,0.4g of TEMPO (tetramethylpiperidine oxynitride),31 g of sodium bicarbonate and 250 mL of water.Slowly add 320 mL of sodium hypochlorite solution.The temperature of the reaction system was kept below 0 °C.TLC monitoring,After the reaction has been completed,The reaction was quenched by the addition of sodium thiosulfate.Liquid separation.Collect organic phase,It was dried over anhydrous sodium sulfate for 4 h.filter,The filtrate was concentrated under reduced pressure.A colorless liquid of 30 g was obtained.The crude product obtained in this example was directly fed to the next reaction without purification.
Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.75h;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃;
2.f
To a stirred solution of oxalyl chloride (1.92 mL, 22 mMol) in CH2Cl2 (40 mL) was added dropwise DMSO (3.12 mL, 44 mMol) at-78 °C. After 15 min. , a solution of (2- hydroxy-ethyl) -carbamic acid tert-butyl ester (3.22 g, 20 mMol) in CHZC12 (20mL) was added. After another 45 min., Et3N (13.9 mL, 100 mMol) was added. The reaction mixture was then warmed to room temperature, diluted with CH2C12 (100 mL), washed with water, 10% HCl, brine, dried and concentrated. Purification by flash chromatography on silica gel (10-15% EtOAc in hexane) gave the title compound (600 mg) as a clear oil :'H NMR (400 MHz, CDC13) 69. 58 (S, 1 H), 5.16 (brs, 1 H), 4.02 (s, 2 H), 1. 46 (s, 9 H).
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 2h;
42 Example 42: 2-(aminomethyl)-1-(1,8-difluoroindeno[1,2-a]inden-4b(9H)-yl)-5-hydroxy-3-methyl-2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine-4,6-dione (A106) and 2- (aminomethyl)-1-(1,8-difluoro-9a,10-dihydroindeno[1,2-a]inden-4b(9H)-yl)-5-hydroxy-3- methyl-2, 3-dihydro-1 H-pyrido[2, 1 -f][1 ,2,4]triazine-4,6-dione (A107)
To a stirred solution of tert-butyl (2-hydroxyethyl) carbamate (5 g, 31.05 mmol) in dichloromethane (50 ml_) was added dess- martinperiodinane (15.8 g, 37.26 mmol) at 0 °C and stirred at RT for 2 h. The reaction was mixture diluted with dichloromethane (150 ml_) and quenched with 20% hypo solution (5 X 100 ml_), dried over sodium sulfate and concentrated under reduced pressure to afford crude tert-butyl (2-oxoethyl) carbamate 2. This residue was used for next step without further purification.
Boc-Gly-N-methoxy-N-methylaride (19) (4.37 g, 20 mmole) in 150 ml of anhydrous THF was stirred in a ice-water bath under argon for 30 min. A solution of LAH in diethyl ether (1 M) (30 ml, 30 mmole) was added to the above well stirred solution by cannula under argon. The resulting solution was stirred for 30 min. A solution of potassium hydrogensulfate (4.77 g, 35 mmole) in 60 ml of water was gradually added to the reaction solution and stirred for 10 min. Organic solvents in the reaction mixture were evaporated under reduced pressure. An additional 60 ml of water was added to the aqueous residue, which was then extracted with DCM (100 ml×4). The combined DCM extracts were washed with 1 M hydrochloric acid solution (100 ml×4), saturated sodium bicarbonate solution (100 ml×2), and saturated sodium chloride solution (100 ml), dried with 4 g of magnesium sulfate overnight, and filtered. Evaporation of the solvent under reduced pressure left a yellowish oil 20 (2.83 g) which was used without further purification. Yield: 89%. TLC Rf=0.44 (hexane-EtOAc=1:1). 1H-NMR (90 MHz, CDCl3) delta ppm: 9.60 (s, 1 H), 5.26 (s, br, 1 H), 4.04 (d, 2 H, J=5.1 Hz), and 1.46 (s, 9 H).
50%
With lithium aluminium tetrahydride; In tetrahydrofuran; at -78℃; for 0.166667h;Inert atmosphere;
Boc-Gly-N(Me)-OMe (1, 5.00 mmol) was dissolved in THF (10mL) and injected through a septum to a suspension of LiAlH4 (6.25 mmol) inTHF (10 mL) at 78 C under argon atmosphere. TLC control after 10 min usingCH2Cl2/EtOAc (8.5+1.5) indicated the completion of the reaction. Subsequently,the reaction mixture was quenched with 10% KHSO4 (1 20 mL) and extractedwith diethyl ether (30 mL). The organic layer was washed with 10% KHSO4 (1 20 mL) and sat. NaHCO3 (2 x 20 mL), dried over Na2SO4 and evaporatedyielding 2 as a colorless resin (50%). 1H NMR (500 MHz, DMSO-d6) d 1.38 (s,9H), 3.72 (d, 3J = 5.7 Hz, 2H), 7.16 (br t, 1H), 9.44 (s, 1H). 13C NMR (125 MHz,DMSO-d6) d 28.26, 50.48, 78.46, 156.09, 200.74.
9.6 g
With lithium aluminium tetrahydride; In tetrahydrofuran; for 1h;Cooling with ice;
To an ice cooled suspension of 653 LiAlH4 (2.13g, 56mmol) in dry THF (20ml) was added F1 (12.2g, 56mmol) in small batches to avoid drastic reaction. After the addition, the mixture was stirred for a further 1h. Then the reaction was quenched cautiously by addition of saturated Na2CO3 solution dropwise until no gas bubbles were generated, followed by addition of water dropwise with vigorous stirring. The solid so formed was filtered off under reduced pressure and washed with THF. The filtrate was concentrated to afford F2 (9.6g) as a jelly which could be used in next step without further purification.
9.6 g
With lithium aluminium tetrahydride; In tetrahydrofuran; for 1h;
To an ice cooled suspension of LiA1H4 (2.13 g, 56 mmol) in dry THF (20 ml) was added Fl (12.2 g, 56 mmol) in small batches to avoid drastic reaction. After the addition, the mixture was stirred for a further 1 h. Then the reaction was quenched cautiously by addition of saturated Na2CO3 solution dropwise until no gas bubbles were generated, followed by addition of water dropwise with vigorous stirring. The solid so formed was filtered off under reduced pressure and washed with THF. The filtrate was concentrated to afford F2 (9.6 g) as a jelly which could be used in next step without thrther purification.
With lithium aluminium tetrahydride; In tetrahydrofuran; at -30℃; for 0.333333h;
tert-Butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (4.50 g, 20.6 mmol), was dissolved in THF (50.0 mL) and Intermediate 87, lithium aluminium hydride (1 .0 M in THF, 20.6 mL, 20.6 mmol) was added at - 30 C dropwise. The mixture was stirred for 20 mm at - 30 C, then excess sodium sulfate decahydrate was added portionwise. The mixture was stirred for 30 mm, then filtered through a Celite pad and the filtrate was concentrated in vacuo to give crude tert30 butyl (2-oxoethyl)carbamate (390 mg, 85 %) as a gum which was used without furtherpurification.1H NMR: (400 MHz, DMSO-d6) O: 1.39- 1.40 (m, 12 H), 2.46-2.47 (m, 3 H), 2.89-2.95 (m, 1 H), 3.05-3.12 (m, 1 H), 4.11 -4.19 (m, 1 H).
Step 2 tert-Butyl 2-oxoethylcarbamate: Sodium periodate (41.52 g; 194 mmol; 1.00 equiv) was added in several batches to <strong>[137618-48-5]tert-butyl 2,3-dihydroxypropylcarbamate</strong> (37 g; 194 mmol; 1.00 equiv) dissolved in water (300 mL). The resulting solution was stirred at ambient temperature for about 2 hours. The solids were were removed by filtration. Standard extractive workup with dichloromethane, gave the title product as a white solid (17 g; 56% yield). 1H NMR (300 MHz, CDCl3) delta 9.65 (s, 1H), 5.26 (s, 1H), 4.07 (d, J=4.5 Hz, 2H), 1.46 (s, 9H).
With sodium periodate; In water; for 2h;
To a solution of N-Boc-3-aminopropane-1,2-diol (191 mg, 1.0 mmol) in water (10 mL) was added sodium periodate (255 mg, 1.2 mmol). The mixture was then stirred rapidly for 2 hours. Work-up via dichloromethane extraction gave the crude aldehyde, which was used directly in the next step without further purification.
With sodium periodate; In water; for 1h;Darkness;
11 (10 g, 52 mmol) was suspended in H2O (0.6M, 87.2mL) and the flask was covered in foil (to protect NaIO4 from light). NaIO4 (13.4 g, 62.8 mmol) was then added and the reaction was stirred for 1 h. A white precipitate had formed after 1 h, and TLC analysis showed full consuption of the starting material. The precipitate was filtered off, and the aqueous layer was extracted with CHCl3 (8x50 mL). The organic layer was dried with MgSO4, filtered, and evaporated to yield 12 as a yellow oil, which was used immediately without further purification (7.7g, 93% yield). 1H NMR (500 MHz, CDCl3) delta 9.68 (s, 1H), 5.23 (s, 1H), 4.10 (d, J = 5.2 Hz, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, CDCl3) delta 197.21, 155.67, 80.19, 51.39, 28.28.
With sodium periodate; In dichloromethane;Cooling with ice;
This general procedure can also be used to prepare the N-(boc)- aminoacetaldehyde suitable for use without further purification. Generally however, for the N-[boc-(3-Amino)]-1 ,2-propanediol, only DCM is used in the reaction (not a mix of ethyl acetate and DCM) in roughly the same total concentration of organic to aqueous (ice) except that the reaction is not allowed to warm to RT and is always kept cold by precooling the extraction mixtures. The N-(boc)-aminoacetaldehyde can be used in a reductive amination to make the N-boc protected backbone ester, whereas the N-(Fmoc)- aminoacetaldehyde can be used in the reductive amination to prepare the N-Fmoc protected backbone ester.
In methanol; for 0.5h;Product distribution / selectivity;
4 mmol C-Thiophen-3-yl-methylamine and 1 mmol (2-Oxo-ethyl)-carbamic acid tert-butyl ester were added in 5 ml MeOH (dry). After 30 min the 1 mmol 2-Chloro-4-fluoro-1-[isocyano-(toluene-4-sulfonyl)-methyl]-benzene was added. The reaction was heated to 40 C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.; C-<strong>[27757-86-4]thiophen-3-yl-methylamine</strong> (4 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (1 mmol) were added to methanol (5 ml, dry). After 30 min 2,4-dichloro-1-[isocyano-(toluene-4-sulfonyl)-methyl]-benzene (1 mmol) was added. The reaction was heated to 40 C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
With sodium tris(acetoxy)borohydride In dichloromethane at 20℃;
1.b; 8.a b) Preparation of {2- [1- (3-BENZYL-7-CHLORO-4-OXO-3, 4-dihydro- QUINAZOLIN-2-YL)-2-METHYL-PROPYLAMINO]-ETHYL}-CARBAMIC acid tert-butyl ester:
Sodium TRIACETOXYBOROHYDRIDE (172 mg, 0.81 MMOL) was added to a solution containing 2- (1-AMINO-2-METHYL-PROPYL)-3-BENZYL-7-CHLORO-3H-QUINAZOLIN-4- one (185 mg, 0.54 MMOL) (prepared using the general procedure described in WO 0130768) and tert-butyl N-(2-oxoethyl) carbamate (103 mg, 0.65 MMOL) in CH2CI2 (5.4 mL). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with CH2CI2 (10 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (5-10% EtOAc in hexane) gave the title compound (105 mg) as a white solid : MS (ES) m/e 485 (M + H) +. Example 8 3-BENZYL-7-CHLORO-2- [1- (6, 6-DIMETHYL-7-OXO- [1, 4] DIAZEPAN-1-YL)-2-METHYL- PROPYL]-3H-QUINAZOLIN-4-ONE a) Preparation of {2- [1- (3-BENZYL-7-CHLORO-4-OXO-3, 4-dihydro- QUINAZOLIN-2-YL)-2-METHYL-PROPYLAMINO]-ETHYL}-CARBAM IC acid TERT-BUTYL ESTER : Following the procedure of Example 1B, 2- (1-AMINO-2-METHYL-PROPYL)-3- BENZYL-7-CHLORO-3H-QUINAZOLIN-4-ONE, (2-OXO-ETHYL)-CARBAMIC acid tert-butyl ester and sodium ACETOXYBOROHYDRIDE gave the title compound as a white solid : MS (ES) m/e 485.2 (M + H) +.
(1) Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (1.22 g) obtained in Reference Example 2(1) is suspended in dichloromethane (10 ml), and thereto is added triethylamine (1.76 ml) and the mixture is stirred for several minutes. After a solution of t-butyl (2-oxoethyl)carbamate (1.00 g) in dichloromethane (5 ml) and sodium triacetoxy borohydride (1.46 g) are added successively under ice-cooling, the reaction solution is warmed to the room temperature and stirred for 15 hours. Saturated aqueous sodium hydrogen carbonate solution is poured to the reaction solution, and the mixture is extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. A portion (1.71 g) of the resulting residue (2.33 g) is purified by silica gel column chromatography (eluent: chloroform/methanol = 10/1) to give methyl trans-4-({2-[(t-butoxycarbonyl)amino]ethyl}amino)-cyclohexanecarboxylate (793 mg). APCI-MS M/Z:301[M+H]+.
3-Amino-1,2-propanediol(80.0 g; 0.88 mol)[ No CAS ]
[ 24424-99-5 ]
[ 137618-48-5 ]
[ 89711-08-0 ]
Yield
Reaction Conditions
Operation in experiment
102 g (93%)
With hydrogenchloride; sodium hydroxide; In water; ethyl acetate;
(a) Preparation of (bocamino) acetaldehyde 3-Amino-1,2-propanediol(80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4 C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0 C. and the pH was adjusted to 2.5 by the addition of 4M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8*500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86%) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6*400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuoo Yield 102 g (93%) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84 C. and 0.3 mmHg in two portions. The yield 79 g (77%) of a colorless oil.
102 g (93%)
With hydrogenchloride; sodium hydroxide; In water; ethyl acetate;
(a) Preparation of (bocamino)acetaldehyde 3-Amino-1,2-propanediol(80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4 C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0 C. and the pH was adjusted to 2.5 by the addition of 4 M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8*500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86%) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6*400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93%) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84 C. and 0.3 mmHg in two portions. The yield 79 g (77%) of a colorless oil.
With acetic acid In dichloromethane at 20℃; for 24h;
41
0,226 g (0.85 mmoli) of 4-(2,3,4-trymethoxybenzyl)piperazine was added to N-BOC- 2-aminoacetaldehyde (0,135 g; 0,85 mmoli), acetic acid (0,486 ml; 8,50 mmoli) and MP-CN-BH3 (1 ,104 g; 2,550 mmoli) in 36 ml of anhydrous CH2CI2.The reaction was left at T = room temperature for 24 hours under slow magnetic stirring. The reaction mixture was then evaporated under reduced pressure. The raw product obtained is purified by silica gel chromatography using chloroform/methanol=97/3 as eluent. 0.179 g of product with a yield of 51 % will be obtained. Silica gel TLC with eluent CHCIs/MeOH 2/8 Rf = 0.7. ESI-MS m/z 410 [M+H]+, 432 [M+Na]+ .
With hydrogenchloride; sodium hydroxide; In water; ethyl acetate;
(a) Preparation of (bocamino)acetaldehyde 3-Amino-1,2-propanediol (80.0 g; 0.88 mol) was dissolved in water (1500 ml) and the solution was cooled to 4 C., whereafter Boc anhydride (230 g; 1.05 mol) was added at once. The solution was gently heated to room temperature with a water bath. The pH was kept at 10.5 by the dropwise addition of sodium hydroxide. Over the course of the reaction a total of 70.2 g NaOH, dissolved in 480 ml water, was added. After stirring overnight, ethyl acetate (1000 ml) was added and the mixture was cooled to 0 C. and the pH was adjusted to 2.5 by the addition of 4 M hydrochloric acid. The ethyl acetate layer was removed and the acidic aqueous solution was extracted with more ethyl acetate (8*500 ml). The combined ethyl acetate solution was reduced to a volume of 1500 ml using a rotary evaporator. The resulting solution was washed with half saturated potassium hydrogen sulphate (1500 ml) and then with saturated sodium chloride. It then was dried over magnesium sulphate and evaporated to dryness, in vacuo. Yield. 145.3 g (86%) 3-Bocamino-1,2-propanediol (144.7 g; 0.757 mol) was suspended in water (750 ml) and potassium periodate (191.5 g; 0.833 mol) was added. The mixture was stirred under nitrogen for 2.5 h and the precipitated potassium iodate was removed by filtration and washed once with water (100 ml). The aqueous phase was extracted with chloroform (6*400 ml). The chloroform extracts were dried and evaporated to dryness, in vacuo. Yield 102 g (93%) of an oil. The (bocamino)acetaldehyde was purified by kugelrohr distillation at 84 C. and 0.3 mmHg in two portions. The yield 79 g (77%) of a colorless oil.
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 65h; Molecular sieve;
119.i
(i) 3-Amino-2-methylpyridine (0.61 g, 5.65 mmol) was dissolved in dichloromethane (25 ml). 4A molecular sieves (0.2 g), 1 ,1-dimethylethyl(2-oxoethyl)carbamate (1.0 g, 6.28 mmol), acetic acid (0.54 ml, 9.42 mmol) and sodium triacetoxyborohydride (2.0 g, 9.42 mmol) were added and the reaction was stirred at room temperature for approximately 65 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (15 ml) and stirred for 5 minutes. The organic layer was separated using a hydrophobic frit and concentrated in vacuo to give 1 ,1-dimethylethyl {2-[(2-methyl- 3-pyridinyl)amino]ethyl}carbamate (1.56 g) as an orange gum, which was used without purification.
[01289] Step 1 : Synthesis of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-chloro- 2-methylbenzoate[01290] To a stirred solution of <strong>[294190-18-4]methyl 3-amino-5-chloro-2-methylbenzoate</strong> ( 1 g, 4.6 mmol) and tert-butyl (2-oxoethyl)carbamate ( 1 .4 g, 8.8 mmol) in methanol ( 10 mL), acetic acid (0.027 g, 4.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.352 g, 4.68 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired product (0.62 g, 38 %).
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane for 20h;
Step 1 : benzyl 5-aminopentylcarbamate, HC1 (1401 mg, 5.14 mmol), tert-butyl 2- oxoethylcarbamate (545 mg, 3.42 mmol), AcOH (0.196 mL, 3.42 mmol) were dissolved in DCM (Volume: 2 mL) and stirred for 16 h followed by the addition of Sodium triacetoxyborohydride (1016 mg, 4.79 mmol). The reaction was stirred for 4 h. The solvent was removed under vacuum and the crude product was purified silica gel chromatography using a gradient of 5 - 10% MeOH/DCM with 2% Et3N. The product fractions were collected and concentrated under vacuum to give 470 mg (36%) of intermediate 1 as an oil. Intermediate 1MS (M+H)+ Calcd. 380.3MS (M+H)+ Observ. 380.2Retention Time 0.81 minLC ConditionSolvent A 100% Water: 0.05% TFASolvent B 100% ACN: 0.05% TFAStart % B 2Final % B 98Gradient Time 2.2 minFlow Rate 0.8 mL/minWavelength 220Solvent Pair ACN: Water: TFAColumn Acquity UPLC BEH CI 8 1.7 μιη
A solution of the aldehyde A1IJl g, 18.85 mmol) in MeOH (20 ml) was treated with ethylamine (10.37 ml, 20.73 mmol) and stirred at RT for 5 min. The mixture was treated with sodium borohydride (0.856 g, 22.62 mmol). After stirring for 5 min, the mixture was quenched with water and concentrated. The residue was diluted with water, saturated with NaCl, and extracted twice with THF. The organic phase was dried over Na2SO4, filtered and concentrated to yield A-2 as a colorless cloudy oil.
Sodium hydride (60 % dispersion in mineral oil) (233.2 mg, 5.83 mmol) in tetrahydrofuran (0.17 M, 34.3 mL) was cooled to 0 C with stirring, followed by the dropwise addition of diethyl(methylsulfonylmethyl)phosphonate (Oakwood) (1342.2 mg, 5.83 mmol) in 5 mL THF. The reaction was stirred at 0 Cfor 20 min, then 12 (928 mg, 5.83 mmol) in 5 mL THF was added. The reaction was allowed to warm to 23 C and was stirred for 1 h. TLC showed conversion to the product. THF was removed under reduced pressure, and the residue was then diluted with ethyl acetate (30 mL) and water (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x30 mL). The organic layer was then dried over MgSO4, filtered, and evaporated.The residue was purified by flash column chromatography with an ethyl acetate/hexanes gradient 25 % EtOAc ? 50% EtOAc to yield 15 (530.4 mg, 56 % yield). 1HNMR (400 MHz, CDCl3) delta 6.38 (dd, J = 11.7, 5.8 Hz, 1H), 6.28 (dt, J= 11.4, 1.7 Hz, 1H), 5.01 (s, 1H), 4.23 (td, J = 6.3, 1.7 Hz, 2H), 3.00 (s,3H), 1.41 (s, 9H).
A mixture of 4-amino-l-N-Cbz-piperidine (0.683 g, 2.91 mmol) and N-Boc-2- aminoacetaldehyde (0.463 g, 2.91 mmol) in methanol (12 mL) was stirred under argon at room temperature for 17 h. Sodium borohydride (0.220 g, 5.82 mmol) was added and the reaction stirred for additional 7 h. The reaction was quenched with water and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (0-100% EtOAc/hexane then 5-10% CH3OH:DCM) provided 0.250 g (23%) of product. ESI-MS m/z 378 (MH)+
[4-(2-tert-butoxycarbonylaminoethyl)-2-oxopiperazin-1-yl]acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium 10% on activated carbon; hydrogen; In methanol; for 22.0h;Inert atmosphere;
Palladium (0.161 g, 10% on carbon) was added to a mixture of 2-Oxo-1-piperazineacetic acid (0.497 g, 3.14 mmol) and (2-Oxo-ethyl)-carbamic acid tert-butyl ester (0.503 g, 3.16 mmol) in methanol (6.2 mL) under argon. The flask was evacuated and the reaction placed under a hydrogen atmosphere for 22 h. The reaction was filtered through a Celite -plugged filter frit, washed with methanol and DCM, and concentrated in vacuo to afford crude product which was carried to the next step without purification. ESI-MS m/z 324 (M+Na)+.
Stage #1: N-(t-butoxycarbonyl)glycinal; isopropylamine In tetrahydrofuran for 1h; Reflux; Inert atmosphere;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran at 20℃;
(S)-2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)-3-methylbutanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With borane pyridine; acetic acid; In methanol;
100 mg (0.76 mmol) of commercially available <strong>[2480-23-1]N-methyl-L-valine</strong> and 182 mg (1.14 mmol) of commercially available tert-butyl 2-oxoethyl carbamate were combined in 20 ml of methanol and admixed with 340 mg (3.66 mmol) of borane-pyridine complex and 65 μl of acetic acid. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was purified by flash chromatography on silica gel with dichloromethane/methanol/17% aqueous ammonia solution (1540.5) as the eluent. After concentration of the corresponding fractions and lyophilization from 1:1 dioxane/ water, 190 mg in 39% purity (35% of theory) of the intermediate were obtained, which were converted further without further purification. [2411] 50 mg (0.07 mmol) of this intermediate were dissolved in 10 ml of DMF and admixed with 52 mg (0.07 mmol) of N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 220), 32 mg (0.09 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 37 μl (0.2 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT overnight and then concentrated. The residue was taken up in ethyl acetate and extracted by shaking first with 5% aqueous citric acid solution and then with water. The organic phase was concentrated and the residue was purified by means of preparative HPLC. The corresponding fractions were combined and the solvent was removed under reduced pressure. After lyophilization from dioxane, 53 mg (76% of theory) of the protected intermediate were obtained. [2412] HPLC (Method 12): Rt=2.0 min; [2413] LC-MS (Method 1): Rt=1.02 min; MS (ESIpos): m/z=984 (M+H)+. [2414] 53 mg (0.05 mmol) of this intermediate were taken up in 10 ml of dichloromethane, 2 ml of trifluoroacetic acid were added, and the reaction mixture was stirred at RT for 30 min Subsequently, the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were combined, the solvent was removed under reduced pressure and the residue was lyophilized from dioxane/water. In this way, 21 mg (40% of theory) of the title compound were obtained in 65% purity. [2415] HPLC (Method 12): Rt=1.7 min; [2416] LC-MS (Method 1): Rt=0.87 min; MS (ESIpos): m/z=884 (M+H)+.
With borane-pyridine complex; acetic acid; In methanol; at 20℃;
[4793] 100 mg (0.76 mmol) of commercially available<strong>[2480-23-1]N-methyl-L-valine</strong> and 182 mg (1.14 mmol) of commerciallyavailable tert-butyl 2-oxoethyl carbamate were combined in20 ml of methanol and admixed with 340 mg (3.66 mmol) ofborane-pyridine complex and 65 fll of acetic acid. The reactionmixture was stirred at RT overnight. This was followedby concentration under reduced pressure, and the residue wasSep.3,2015purified by flash chromatography on silica gel with dichloromethane/methanol/17% aqueous ammonia solution (15/4/0.5) as the eluent. After concentration of the correspondingfractions and lyophilization from 1: 1 dioxane/water, 190 mgin 39% purity (35% of theory) of the intermediate wereobtained, which were converted further without further purification.
tet-butyl 2-(4-bromo-2-chlorophenylamino)ethylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
[00388] 4-Bromo-2-chloroaniline (500 mg, 2.44 mmol), tert-bu y 2-oxoethylcarbamate (388 mg, 2.44 mmol) was dissolved in dry tetrahydrofuran (5 mL). To this mixture was added titanium(IV) isopropoxide (1039 mg, 3.66 mmol). After stirring at room temperature for 3 h, sodium cyanoborohydride (307 mg, 4.81 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 ml x 3). The organic layers were combined, dried over anhydrous Na2S04, and concentrated to give the crude product, which was purified by silica gel chromatography (10%) EtO Ac/petroleum ether) to give 2-(4-bromo-2- chlorophenylamino)ethylcarbamate (41) as a white solid. Yield (84 mg, 10%). LCMS: m/z 349.7 [M+H]+; tR = 1.92 min.
methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-4-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-4-fluorobenzoate (I-44)Methyl 3-amino-4-fluorobenzoate (8.4 mmol) and tert-butyl (2-oxoethyl)carbamate (12.6 mmol) were dissolved in MeOH (100 ml_) and AcOH (10 ml_). After stirring for 1 hr at room temperature the reaction mixture was treated with NaCNBH3(16.6 mmol) and stirred for 2 hrs. After removal of solvent (aspirator) the mixture was dissolved in EtOAc and washed with NaHC03(sat., 1x). The aqueous phase was washed with EtOAc (1x) and the combined organic layers were dried (MgSO^. The product (I-44) was taken on crude for the next step. 1H NMR (400 MHz, CDCl3): delta 7.40-7.38 (m, 2H), 7.02 (dd, J = 8.8 Hz, 11 .1 , 1 H), 4.88 (s, 1 H), 3.91 (s, 3H), 3.40-3.38 (m, 4H), 1.47 (s, 9H). MS (m/z): 313.1 (M+H)+.
tert-butyl (2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
620 mg
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 24.0h;
Step 3: Preparation of tert-butyl (2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)amino)ethyl)carb To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.00 g, 4.22 mmol) in DCM (50 mL) was added tert-butyl (2-oxoethyl)carbamate (1.34 g, 8.44 mmol), sodium triacetoborohydride (3.58 g, 16.88 mmol) and AcOH (0.4 mL). The reaction was stirred at ambient temperature for 24 h. Saturated aqueous NaHC03 (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the organic phase was extracted with DCM (3 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc (10%) and hexanes (90 %) to EtOAc (15%) and hexanes (85 %) to provide tert-butyl (2-((3- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)carbamate (620 mg, 1.63 mmol) as a colorless oil.
tert-butyl 2-(4-(oxazol-5-yl)phenylamino)ethyl carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
Step 1: tert-Butyl 2- (4- (oxazol-5-yl)phenylamino)ethylcarbamateTo a solution of <strong>[1008-95-3]4-(oxazol-5-yl)aniline</strong> (0.5 g, 3.12 mmol, Eq: 1.00) in dichloromethane (31.5 ml) at 0 C were added tert-butyl 2-oxoethylcarbamate (628 mg, 3.75 mmol, Eq: 1.2) and AcOH (187 mg, 179 jil, 3.12 mmol, Eq: 1.00). The solution was stuffed at 0 C for 0.5 h. Then sodium triacetoxyborohydride (992 mg, 4.68 mmol) was added, and the solution was stirred at 23 C for 6h. The mixture was diluted with water (20 ml), the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were washed with brine, dried over Mg504 and evaporated. The crude product (1.25 g) was purified by flash chromatography to give the title compound (0.92 g, 97 %). MS: 304.2 (M+H).
97%
To a solution of <strong>[1008-95-3]4-(oxazol-5-yl)aniline</strong> (0.5 g, 3.12 mmol, Eq: 1.00) in dichloromethane (31.5 ml) at 0 C. were added tert-butyl 2-oxoethylcarbamate (628 mg, 3.75 mmol, Eq: 1.2) and AcOH (187 mg, 179 mul, 3.12 mmol, Eq: 1.00). The solution was stirred at 0 C. for 0.5 h. Then sodium triacetoxyborohydride (992 mg, 4.68 mmol) was added, and the solution was stirred at 23 C. for 6 h. The mixture was diluted with water (20 ml), the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were washed with brine, dried over MgSO4 and evaporated. The crude product (1.25 g) was purified by flash chromatography to give the title compound (0.92 g, 97%). MS: 304.2 (M+H)+.
tert-butyl ((6-bromo-4-oxochroman-2-yl)methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With pyrrolidine In methanol at 70℃; for 2h;
180.I Synthesis of tert-Butyl ((6-bromo-4-oxochroman-2-yl)methyl)carbamate
A mixture of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (3.31 g, 15.39 mmol), tert-butyl N-(2-oxoethyl)carbamate (4.89 g, 30.72 mmol), and pyrrolidine (2.56 mL, 30.7 mmol) in methanol (31 mL) was stirred for two hours at 70 oC. The mixture was concentrated and the resulting residue was purified via MPLC eluting withe ethyl acetate/petroleum ether (1:2) to afford tert-butyl ((6-bromo-4-oxochroman-2-yl)methyl)carbamate (4.76 g, 87%) as a brown solid.
tert-butyl {2-[(4-((3-bromophenyl)amino)quinazolin-6-yl)amino]ethyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
tert-Butyl {2-[(4-((3-bromophenyl)amino)quinazolin-6-yl)amino]ethyl}carbamate (B).[0108] To a solution of A (500 mg, 1.6 mmol) and HOAc (90.8 ml, 1.6 mmol) in anhydrous MeOH (16 ml) containinga 3-4 A molecular sieve was added N-boc-2-aminoacetaldehyde (303 mg, 1.9 mmol) and the resulting mixture wasstirred under Ar at room temperature for 1 h. Sodium cyanoborohydride (120 mg, 1.9 mmol) was added and the resultingsuspension was stirred at room temperature overnight. The solvent was removed under reduced pressure and theresidue was dissolved in EtOAc (200 ml), washed with 1 M HCl (150 ml), sat. NaHCO3 (150 ml), and brine (150 ml).The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and dried in vacuo to give abright yellow solid. Yield: 615 mg (85%). 1H NMR (500.1 MHz, DMSO-d6): delta 1.40 (s, 9H), 3.26 (s, 4H), 6.22 (s, 1H), 6.97(s, 1H), 7.23 (s, 1H), 7.27-7.29 (m, 2H), 7.36 (dd, J= 8.0 Hz, J= 8.0 Hz, 1H), 7.57 (d, J= 9.0 Hz, 1H), 7.91 (d, J = 8.0 Hz,1H), 8.17 (s, 1H), 8.41 (s, 1H), 9.36 (s, 1H) ppm.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 17℃;Inert atmosphere;
Step 1. Conjugation of t-boc-glycine to Irinotecan.HCl Salt (>95% Yield) (0321) Irinotecan.HCl.trihydrate (1 mole or 677 g) and DMF (10 L) were charged into a distiller at 60 C. Upon dissolution of the irinotecan.HCl.trihydrate in DMF, full vacuum was slowly applied in order to remove water from the irinotecan.HCl.trihydrate by azeotropic distillation at 60 C. Upon solids formation from the residual DMF, heptane (up to 60 L) was charged into the distiller to remove residual DMF at 40-50 C. Upon removal of heptane by visual inspection, the azeotropic distillation was stopped and the solid (irinotecan.HCl) was allowed to cool to 17±2 C. For the coupling reaction, t-boc-glycine (1.2 mole), 4-DMAP (0.1 mole) dissolved in DCM (1 L), and DCM (19 L) were charged into the distiller. Once the mixture was visually well dispersed, melted DCC (1.5 mole) was added and reaction was allowed to proceed. The reaction was carried out under an argon or nitrogen blanket, with sufficient mixing and pot temperature at 17±2 C. (0322) After a 2-4 hour reaction time, a sample was withdrawn to measure residual irinotecan (IRT) peak area percent by chromatography. Residual irinotecan was determined to be present in an amount of no more than 5%. DCU formed during the coupling reaction was removed by filtration, and washed with DCM. The resulting filtrates containing crude t-boc-glycine-irinotecan.HCl salt were combined and concentrated below 45 C. under vacuum to remove DCM. When approximately 75% of its initial volume was removed by distillation. IPA was then added to the concentrate to reach the initial volume, and the mixture further distilled until the condensate volume reached about 25% of its initial volume. The resulting clear solution was cooled to room temperature, followed by its addition to heptane with mixing. The mixture was mixed for an additional 0.5 to 1 hour, during which time a precipitate formed. The precipitate was drained and filtered to obtain a wet cake, and then washed with heptane (up to 6 L). The wet cake was vacuum-dried to yield t-boc-glycine-irinotecan powder for use in Step 2. Yield >95%.
With sodium cyanoborohydride; In chloroform; at 20℃;
General procedure: Compounds 2-19 were synthesized by reductive alkylation ofcommercially available anilines with N-Boc-2-aminoacetaldehydeand benzoylation with 2,4-dichlorobenzoyl chloride with subsequentremoval of Boc-protecting group with 4 N HCl in dioxane.Compound precipitated from hexane/ dioxane reaction mixtureas HCl salt.
With sodium cyanoborohydride; In chloroform; at 20℃;
General procedure: Compounds 2?19 were synthesized by reductive alkylation ofcommercially available anilines with N-Boc-2-aminoacetaldehydeand benzoylation with 2,4-dichlorobenzoyl chloride with subsequentremoval of Boc-protecting group with 4 N HCl in dioxane.Compound precipitated from hexane/ dioxane reaction mixtureas HCl salt.
With sodium cyanoborohydride In chloroform at 20℃;
5.1.1. General synthesis of compounds 2-19
General procedure: Compounds 2-19 were synthesized by reductive alkylation ofcommercially available anilines with N-Boc-2-aminoacetaldehydeand benzoylation with 2,4-dichlorobenzoyl chloride with subsequentremoval of Boc-protecting group with 4 N HCl in dioxane.Compound precipitated from hexane/ dioxane reaction mixtureas HCl salt.
With sodium cyanoborohydride In chloroform at 20℃;
5.1.1. General synthesis of compounds 2-19
General procedure: Compounds 2-19 were synthesized by reductive alkylation ofcommercially available anilines with N-Boc-2-aminoacetaldehydeand benzoylation with 2,4-dichlorobenzoyl chloride with subsequentremoval of Boc-protecting group with 4 N HCl in dioxane.Compound precipitated from hexane/ dioxane reaction mixtureas HCl salt.
Compound 1 (20 g, 154.8 mmol) was dissolved in dichloromethane (300 mL) N-tert-butoxycarbonyl-2-aminoacetaldehyde (29.57 g, 185.7 mmol) was added,Stirred for 15 minutes, acetic acid (0.93 g, 15.48 mmol) was added, stirred at room temperature for half an hour, After cooling to 0 C, sodium triacetoxyborohydride (98.0 g, 464.6 mmol) was added,Slowly rose to room temperature for 12 hours.The reaction mixture was concentrated, dissolved in dichloromethane (200 mL), stirred with water (200 mL), and the aqueous phase was washed with dichloromethane (200 mL x 2). The resulting aqueous phase was adjusted to pH = 8-9 with sodium carbonate and extracted with dichloromethane (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give brown oil 16 (40 g, 87% , Yield 82.5%).
KOtBu (6.00mmol) was added at 0 C to a solution of diethyl (phenylsulfonyl)methyl)phosphonate (3, R = SO2Ph, 5.00 mmol, prepared as described in dry THF (10mL),6 cooled to 0 C and stirred for 30 min. Boc-Gly-H (2, 5.00 mmol) wasdissolved in dry THF (5 mL) and added dropwise leading to an orange color ofthe solution. After stirring at rt for 2 h the solvent was evaporated underreduced pressure. The residue was dissolved in EtOAc (50 mL), washed withsat. NaHCO3 (2 50 mL), H2O (50 mL) and brine (50 mL) and dried over Na2-SO4. The crude product was purified by column chromatography usingpetroleum ether/EtOAc (2+1) to obtain a colorless resin (27%); 1H NMR (500MHz, DMSO-d6) d 1.38 (s, 9H), 3.97 (d, 3J = 7.8 Hz, 2H), 4.79-4.83 (m, 1H), 6.43-6.48 (m, 1H), 7.63 (t, 3J = 7.7 Hz, 2H), 7.72 (t, 3J = 7.5 Hz, 1H), 7.79-7.84 (m, 2H),9.29 (br s, 1H); 13C NMR (125 MHz, DMSO-d6) d 28.33, 56.88, 79.54, 128.00,129.29, 129.73, 132.82, 133.71, 138.99, 156.33; LC-ESI/MS LC-MS (ESI) (90%H2O to 100% MeOH in 10 min, then 100% MeOH for 10 min, DAD 200.0-400.0nm): tr = 9.31 min, 95% purity, m/z = 298.3 ([M+H+]).
General procedure: Sodium hydride (1.5 eq) in tetrahydrofuranwas cooled to 0C,and diethyl((phenylsulfonyl)methyl)phosphonate in tetrahydrofuran was added dropwise. The reaction was stirred at0C for 20 min, then compounds B3a-fin tetrahydrofuranwere added. The reaction was quenched with saturated sodium bicarbonate afterstirring for 5 min. The mixture was diluted with ethyl acetate and water. Thelayers were separated followed by the extraction of the aqueous phase withethyl acetate. The organic layer was dried over MgSO4, filtered andevaporated. The mixture was purified by flash column chromatography to obtaincompound B4a-f (40-70 % yield).
tert-butyl (1-bromopropan-2-yl)carbamate[ No CAS ]
[ 89711-08-0 ]
[ 89830-98-8 ]
tert-butyl N-[2-[[2-(4-cyclopropylimidazol-1-yl)-1-methylethyl]amino]ethyl]carbamate[ No CAS ]
tert-butyl N-[2-[[2-(5-cyclopropylimidazol-1-yl)-1-methylethyl]amino]ethyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Potassium hydroxide (73.9 mg, 1.3 177 mmol%) and tert-butyl N-[(2R)-2-bromopropyl]carbamate (230.1mg, 0.96634 mmol) are added to a solution of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (100 mg, 0.087849 mmol) in DMSO (2 mL) at 0 C. The mixture is stirred at room temperature for 65 hours. The reaction is quenched with water and extracted with EtOAc (3x). The organic extracts are washed with saturated NaC1 (3x), dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified bysilica gel flash chromatography with 4% MeOH in DCM to give the title compounds as a mixture of 2 regioisomers (112 mg, 22.82%) and as a yellow oil. ES/MS (m/z): 266 (M+ 1). TFA (2 mL, 26.45 mmol) is added to racemic tert-butyl N-[2-(4-cyclopropylimidazol- i-yl)-i -methyl-ethyl] carbamate and to racemic tert-butyl N- [2-(5 -cyclopropylimidazol-1-yl)-1-methyl-ethyl]carbamate (112 mg, 0.2005 mmol) in DCM(10 mL) at room temperature. The mixture is stirred at room temperature for 1 hour andis concentrated to give the crude title compounds as a mixture of regioisomers (69.8 mg,100%) as a yellow oil. ES/MS (m/z): 166 (M+1). Sodium triacetoxyborohydride (56.9 mg, 0.260 mmol) is added to a solution of racemi c-i -(4-cyclopropylimidazol -1 -yl)propan-2-amine and racemic- 1 -(5- cyclopropylimidazol- 1 -yl)propan-2-amine (69.7 mg, 0.200 mmol) and tert-butyl N-(2- oxoethyl)carbamate (33.6 mg, 0.200 mmol) in DCM (5 mL) and acetic acid (15.6 mg, 0.260 mmol) at room temperature. The mixture is stirred at room temperature for 18 hours. The reaction is quenched by the addition of saturated NaHCO3. The mixture is extracted with DCM (3x), the organic extracts are dried over Na2SO4, filtered, and concentrated to give the crude title compound as a mixture of regioisomers (130 mg, 100%) as a yellow oil. ES/MS (m/z): 309 (M+1).
tert-butyl (1-bromopropan-2-yl)carbamate[ No CAS ]
[ 89711-08-0 ]
[ 89830-98-8 ]
1-[2-(4-cyclopropylimidazol-1-yl)-1-methylethyl]imidazolidin-2-one[ No CAS ]
1-[2-(5-cyclopropylimidazol-1-yl)-1-methylethyl]imidazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Potassium hydroxide (73.9 mg, 1.3 177 mmol%) and tert-butyl N-[(2R)-2-bromopropyl]carbamate (230.1mg, 0.96634 mmol) are added to a solution of <strong>[89830-98-8]4-cyclopropyl-1H-imidazole</strong> (100 mg, 0.087849 mmol) in DMSO (2 mL) at 0 C. The mixture is stirred at room temperature for 65 hours. The reaction is quenched with water and extracted with EtOAc (3x). The organic extracts are washed with saturated NaC1 (3x), dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified bysilica gel flash chromatography with 4% MeOH in DCM to give the title compounds as a mixture of 2 regioisomers (112 mg, 22.82%) and as a yellow oil. ES/MS (m/z): 266 (M+ 1). TFA (2 mL, 26.45 mmol) is added to racemic tert-butyl N-[2-(4-cyclopropylimidazol- i-yl)-i -methyl-ethyl] carbamate and to racemic tert-butyl N- [2-(5 -cyclopropylimidazol-1-yl)-1-methyl-ethyl]carbamate (112 mg, 0.2005 mmol) in DCM(10 mL) at room temperature. The mixture is stirred at room temperature for 1 hour andis concentrated to give the crude title compounds as a mixture of regioisomers (69.8 mg,100%) as a yellow oil. ES/MS (m/z): 166 (M+1). Sodium triacetoxyborohydride (56.9 mg, 0.260 mmol) is added to a solution of racemi c-i -(4-cyclopropylimidazol -1 -yl)propan-2-amine and racemic- 1 -(5- cyclopropylimidazol- 1 -yl)propan-2-amine (69.7 mg, 0.200 mmol) and tert-butyl N-(2- oxoethyl)carbamate (33.6 mg, 0.200 mmol) in DCM (5 mL) and acetic acid (15.6 mg, 0.260 mmol) at room temperature. The mixture is stirred at room temperature for 18 hours. The reaction is quenched by the addition of saturated NaHCO3. The mixture is extracted with DCM (3x), the organic extracts are dried over Na2SO4, filtered, and concentrated to give the crude title compound as a mixture of regioisomers (130 mg, 100%) as a yellow oil. ES/MS (m/z): 309 (M+1).
tert-butyl N-[2-[(1-phenylcyclopropyl)amino]ethyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.75%
With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h; Inert atmosphere;
1 tert-butyl N-[2-[(1-phenylcyclopropyl)amino]ethyl]carbamate
To a stirred mixture of 1-phenylcyclopropan-1-amine (200 mg, 1.50 mmol, 1 equiv.) and NaBH(OAc)3(636.5 mg, 3.00 mmol, 2 equiv.) in DCM(30 mL) was added tert-butyl N-(2- oxoethyl)carbamate(262.9 mg, 1.65 mmol, 1.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether/EtOAc =3:1) to afford tert-butyl N-[2-[(1- phenylcyclopropyl)amino]ethyl]carbamate(360 mg, 86.75%) as a yellow solid
1-tert-butyl 2-methyl (2S,4R)-4-[2-(tert-butoxycarbonylamino)ethylamino]pyrrolidine-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
Acetic acid (42 pL, 0.73 mmcl) was added to a solution of 1 -(tert-butyl) 2-methyl (2S,4R)-4-aminopyrrolidine- 1 ,2-dicarboxylate (7.48 g, 30.6 mmcl) and tert-butyl (2-oxoethyl)carbamate (4.64 g, 29.2 mmcl) in MeOH (194 mL) and the reaction stirred at roomtemperature for 3 h. The solution was cooled to 0 00 and sodium triacetoxyborohydride (9.27 g,43.7 mmol) was added portion-wise. The reaction stirred overnight while slowly warming toroom temperature. The reaction mixture was concentrated under reduced pressure and theresulting residue was diluted with DCM washed sequentially with saturated sodiumbicarbonate, water and saturated sodium chloride. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM/EtOAc/MeOH) to afford 1 -tert-butyl 2-methyl (2S,4R)-4-[2-(tert- butoxycarbonylamino)ethylamino]pyrrolidine- 1 ,2-dicarboxylate (Intermediate 72, 4.77 g, 42%yield) as a colorless oil. 1H NMR (500MHz, DMSO-d6) 51.25- 1.48 (20H, m), 1.84-2.07 (3H,m), 2.88-2.98 (2H, m), 3.02-3.17 (1H, m), 3.17-3.27 (1H, m), 3.40-3.51 (1H, m), 3.64(3H,s), 4.14-4.24 (1 H, m), 6.63-6.74 (1 H, m); m/z: (ESj [M+H] = 388.
1-tert-butyl 3-methyl 4-(2-(tert-butoxycarbonylamino)ethyl)piperazine-1,3-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
A solution of /ert-butyl (2-oxoethyl)carbamate (4.89 g, 30.7 mmol) in 1,2- dichloroethane (50 mL) was added to a solution of l-(tert-butyl) 3-methyl piperazine- 1,3- dicarboxylate (5 g, 20.5 mmol) in l,2-dichloroethane (25 mL). The solution stirred at 25 C under nitrogen atmosphere for 30 min. Sodium triacetoxyborohydride (8.69 g, 41.0 mmol) was added, and the resulting mixture stirred at 25 C for 15 h. The reaction was quenched by the addition of water (50 mL) at 25 C. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and the solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1 : 1 ethyl acetate/petroleum ether) to afford l-ter/-butyl 3- methyl 4-(2-(/er/-butoxycarbonylamino)ethyl)piperazine-l,3-dicarboxylate as yellow oil (5.1 g, 64%). LCMS (ES, m/z): 388 [M+H]+.
tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With sodium cyanoborohydride; acetic acid In methanol at 50℃; for 12h;
Tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl)carbamate(18)
To a solution of lenalidomide (311mg, 1.2 mmol) and tert-butyl (2-oxoethyl) carbamate (190 mg, 1.2 mmol) in MeOH (10 mL) was added NaBH3CN (114 mg, 1.8 mmol), and 1 drop AcOH. The mixture was stirred at 50 oC for 12 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried, and evaporated. The residue was purified by flash column chromatography to afford 18 as a white solid (215 mg, 45% yield).
tert-butyl (2-(2-(2,6-dichlorophenyl)hydrazinyl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
to the solution of N-tert-butoxycarbonyl-2-aminoacetaldehyde (15.5 g, 97.4 mmol) in DCM (300 mL) were added <strong>[14763-24-7](2,6-dichlorophenyl)hydrazine</strong> (15.7 g, 88.7 mmol) and sodium triacetoxyborohydride (37 g, 174.5 mmol) in sequence. The reaction liquor was stirred at room temperature overnight, and then sodium cyanoborohydride (11 g, 175 mmol) was further added. After addition, the reaction liquor was stirred for 3 hours at room temperature. An aqueous solution of sodium bicarbonate (300 mL) was added to the reaction system, the organic layer was separated, and the aqueous layer was extracted with DCM (150 mL*2). The organic layers were collected, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether (PE): ethyl acetate (EA)=6:1 as the eluent) to give the targeted compound (12.5 g, 44% yield, yellow solid). LC-MS (ESI): m/z (M+H)+ 320.72.
benzyl (3S,5S,6R)-3-((R)-2-((tert-butoxycarbonyl)amino)-1-hydroxyethyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate[ No CAS ]
benzyl (5S,6R)-3-(2-((tert-butoxycarbonyl)amino)-1-hydroxyethyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With sodium hexamethyldisilazane; zinc dibromide; In tetrahydrofuran; at -78 - 20℃; for 2h;Inert atmosphere;
General procedure: A solution of diphenyloxazinone (S,R)-4 (11.00g, 28.4mmol) in anhydrous DCM (300mL) was cooled to -5C (dry ice/acetone bath) under argon atmosphere and Bu2BOTf (1M solution in DCM, 56.8mL, 56.8mmol) over 15min was added, followed by Et3N (8.62g, 85.2mmol). The yellowish solution was stirred for 15min at -5C, then it was cooled to -78C and a solution of aldehyde 3a (8.85g, 51.1mmol) in anhydrous DCM (40mL) was added over 30min. After stirring at -78C for 1h the reaction was quenched by addition of phosphate buffer (pH 7) (100mL) at-78C. After warming to room temperature layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and volatiles were evaporated to afford crude 6a as 85:15 mixture of diastereomers. The crude oily 6a was mixed with EtOAc (100mL) and hexane (300mL), the obtained white suspension was stirred overnight and filtered. The precipitate (16g) was suspendedin EtOAc (100mL), stirred for 1h, filtered, and dried in vacuo to give desired compound (3S,5S,6R)-6a (9.04g, 56%) as a white solid (99% de). [alpha]21D [alpha]D21 +25.9 (c 1.16, MeOH). 1H NMR (400MHz, DMSO-d6) delta: (2:1 rotamer mixture) 7.43 - 7.06 (m, 10H), 7.03-6.95 (m, 2H), 6.70 - 6.53 (m, 4H), 6.51-6.48 (m, 1H), 6.00-5.91 (m, 1H), 5.29 (d, J=3.0Hz, 0.67H), 5.23 (d, J=3.0Hz, 0.33H), 5.14 - 5.05 (m, 1.66H), 5.02 (d, J=13.1Hz, 0.67H), 4.88 (d, J=13.1Hz, 0.67H), 4.06 - 3.97 (m, 1H), 3.85-3.68 (m, 1H), 1.39 (s, 9H), 1.28 (d, J=6.6Hz, 2H), 1.10 (d, J=6.6, 1H). 13C NMR (DMSO-d6) delta: 167.1, 167.0, 155.3, 153.8, 153.2, 136.7, 136.2, 136.1, 136.0, 134.9, 134.8, 128.3, 128.2, 128.1, 128.0, 127.7, 127.5, 127.4, 127.3, 127.2, 126.5, 126.1, 126.1, 78.3, 78.1, 77.5, 76.3, 75.4, 67.2, 66.4, 60.2, 60.0, 59.6, 48.9, 28.3, 18.0. HRMS (ESI) m/z: Calculated for C32H36N2NaO7 [M+Na]+ 583.2415, found 583.2416.
tert-butyl (2-((2-bromo-3-fluorophenyl)amino)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.3 g
With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 24h;
Synthesis of tert-butyl (2-((2-bromo-3-fluorophenyl)amino)ethyl)carbamate (N-l)
At RT sodium triacetoxyborohydride (12.68 g, 59.8 mmol) was added to a stirred solution of 2- bromo-3-fluoroaniline (3.79 g, 20 mmol) and tert-butyl (2-oxoethyl)carbamate (3.65 g, 23 mmol) in DCM (30 mL) and stirring at RT was continued for 1 day. DCM was added followed by a sat solution of NaHC03. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 30% EtOAc) to afford the title compound (2.30 g). UPLC-MS 1 : m/z 333.1 [M+H]+ . tR = 1.19 min. 1H NMR (400 MHz, DMSO-d6) d 7.23 - 7.10 (m, 1 H), 7.00 (t, J = 5.7 Hz, 1 H), 6.60 - 6.42 (m, 2H), 5.56 (d, J = 5.6 Hz, 1 H), 3.15 (dt, J = 16.8, 6.0 Hz, 4H), 1.37 (s, 9H).
Stage #1: N-(t-butoxycarbonyl)glycinal; 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione With acetic acid In methanol at 20℃; for 1h;
Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 2h;
1.4 Step 4: Preparation oftert-butyi (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)amino)ethyl)carbamate (E)
D (250.00 mg, 0.964 mmol, 1.00 equiv), fe/ -butyl N-(2-oxoethyl)carbamate (153.50 mg, 0.964 mmol, 1.00 equiv) and AcOH (0.10 ml_, 1.745 mmol, 1.81 equiv) were suspended in MeOH (10.00 ml_). The reaction mixture was stirred at room temperature for 1 h after which time NaBh CN (60.60 mg, 0.964 mmol, 1.00 equiv) was added. The mixture was stirred for another 2 h, then diluted with sat. NaHCCb (20 ml_). The aqueous layer was extracted with DCM (3 x 40 ml_) and the combined organic layers were dried over Na2SC>4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (1 :1) to afford E (100 mg, 25.77%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+ = 403.
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