* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 39, p. 11981 - 11985[2] Angew. Chem., 2017, vol. 129, p. 12143 - 12147,5
2
[ 4518-10-9 ]
[ 691-64-5 ]
[ 118684-31-4 ]
[ 176980-36-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 39, p. 11981 - 11985[2] Angew. Chem., 2017, vol. 129, p. 12143 - 12147,5
3
[ 118684-31-4 ]
[ 176980-36-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
With manganese(IV) oxide In dichloromethane at 20℃; for 16 h;
To a solution of 3-(tert-butoxycarbonylamino)-benzyl alcohol (2.0 g, 9.0 mmol) in CH2CI2 (50 mL) was added activated MnO2 (7.8 g, 90 mmol). The resulting suspension was stirred for 16 h at r. . The reaction mixture was filtered through a pad of Celite and a filtrated was concentrated under reduced pressure yielding 1.7 g (85percent) of the desired product. - 1H NMR (400 MHz, CDCh): 9.97 (s, 1 H), 7.92 (t, J = 1.8 Hz, 1 H), 7.63 (dd, J = 8.0, 1.1 Hz, 1 LI), 7.55 (ddd, J= 7.6, 1.4, 1.1 Hz, 1 H), 7.44 (t, J= 7.6 Hz, 1 H), 1.53 (s, 9 H).
22%
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14B: tert—butyl (3—formylphenyl)carbamate Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 percent) of compound 14B in the form of a white solid.
22%
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1 :30) to yield 3 g (22 percent) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 percent) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 percent) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 percent) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Comp nd 14B: tert-but l 3-form l hen l carbamate Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1 :30) to yield 3 g (22 percent) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14B: tert-butyl (3-formylphenyl)carbamate Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and MnO2 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22percent) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide In 1,2-dichloro-ethane at 20℃; for 72 h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica colunm with a mixture of EtOAc and PE (1:30) to yield 3 g (22 percent) of compound 14B in the form of a whitesolid.
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 26, p. 8814 - 8822
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 49, p. 15746 - 15750[3] Angew. Chem., 2017, vol. 129, p. 15952 - 15957,6
[4] Patent: WO2018/114965, 2018, A1, . Location in patent: Page/Page column 27
[5] Chemistry of Materials, 2011, vol. 23, # 21, p. 4844 - 4856
[6] Organic and Biomolecular Chemistry, 2018, vol. 16, # 17, p. 3114 - 3120
[7] Patent: WO2015/162291, 2015, A1, . Location in patent: Page/Page column 136
[8] Patent: WO2016/173682, 2016, A1, . Location in patent: Page/Page column 66
[9] Patent: WO2014/174060, 2014, A1, . Location in patent: Page/Page column 63
[10] Patent: WO2014/174064, 2014, A1, . Location in patent: Page/Page column 52
[11] Patent: WO2014/174062, 2014, A1, . Location in patent: Page/Page column 59
[12] Patent: WO2015/162293, 2015, A1, . Location in patent: Page/Page column 160
[13] Patent: US2017/112943, 2017, A1, . Location in patent: Paragraph 0390; 0391
[14] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3614 - 3622
[15] Patent: WO2017/72196, 2017, A1, . Location in patent: Page/Page column 137
4
[ 79-37-8 ]
[ 118684-31-4 ]
[ 176980-36-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethanolamine In dichloromethane; water; dimethyl sulfoxide
Step 3 Synthesis of 3-N-(1,1-dimethylethoxy-carbonyl)aminobenzaldehyde (12) To a solution of 5.63 mL (64.50 mmol) of oxalyl chloride in CH2Cl2 (60 mL) was slowly added a solution of 6.92 mL (96.74 mmol) of DMSO in CH2Cl2 (60 mL) at -78° C. After 10 minutes, a solution of 7.2 g (32.3 mmol) of compound 11 in CH2Cl2 (60 mL) was added slowly and the reaction mixture was stirred for 30 minutes. 34 mL of TEA was added slowly. The reaction mixture was warmed to room temperature. CH2Cl2 and water were added and organic layer was separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The resulting solid was washed with n-hexane to give 6.55 g (29.60 mmol) of compound 12 as a white solid in 92percent yield. 1H NMR (CDCl3):. 9.99 (t, J=3.4 Hz, 1H), 7.92 (t, 1H), 7.64 (d, 1H), 7.62 (d, 1H), 7.45 (t, 1H), 6.70 (s, 1H), 1.55 (s, 9H)
Reference：
[1] Patent: US2003/220337, 2003, A1,
5
[ 111331-82-9 ]
[ 176980-36-2 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 73, p. 10228 - 10231
6
[ 24424-99-5 ]
[ 1709-44-0 ]
[ 176980-36-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2007, # 28, p. 4646 - 4650
With triethanolamine; In dichloromethane; water; dimethyl sulfoxide;
Step 3 Synthesis of 3-N-(1,1-dimethylethoxy-carbonyl)aminobenzaldehyde (12) To a solution of 5.63 mL (64.50 mmol) of oxalyl chloride in CH2Cl2 (60 mL) was slowly added a solution of 6.92 mL (96.74 mmol) of DMSO in CH2Cl2 (60 mL) at -78 C. After 10 minutes, a solution of 7.2 g (32.3 mmol) of compound 11 in CH2Cl2 (60 mL) was added slowly and the reaction mixture was stirred for 30 minutes. 34 mL of TEA was added slowly. The reaction mixture was warmed to room temperature. CH2Cl2 and water were added and organic layer was separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated. The resulting solid was washed with n-hexane to give 6.55 g (29.60 mmol) of compound 12 as a white solid in 92% yield. 1H NMR (CDCl3):. 9.99 (t, J=3.4 Hz, 1H), 7.92 (t, 1H), 7.64 (d, 1H), 7.62 (d, 1H), 7.45 (t, 1H), 6.70 (s, 1H), 1.55 (s, 9H)
Step 4 Synthesis of N-isopropyl-alpha-[3-N-(1,1-dimethylethoxycarbonyl)amino ] phenyl nitrone(13) 6.55 g (29.6 mmol) of compound 12, 6.65 ml (74.03 mmol) of 2-nitropropane (4), and 6.78 g (103.65 mmol) of zinc were placed in a round-bottomed flask along with 95% ethanol (100 mL) and cooled to 0 C. 11.9 mL (207.9 mmol) of acetic acid was added slowly with stirring. The solution was allowed to come to room temperature, stirred for 12 hours. CH2Cl2 was added to the reaction mixture and it was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by short flash column chromatography (silica, CH2Cl2:EtOAc=1:2) to give 7.0 g (21.3 mmol) of compound 13 (mp: 189~191 C.) in 72% yield. 1H NMR (CDCl3): 8.37 (s, 1H), 7.8 (d, J=7.7 Hz, 1H), 7.5 (d, J=7.7 Hz, 1H), 7.42 (s, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.60 (s, 1H), 4.19 (septet, J=6.5 Hz, 1H), 1.53 (s, 9H), 1.48 (d, J=6.5 Hz, 6H).
Example 17; Synthesis of the present compound (IIa') [Compound No. (3a-37)]; To a solution of 2.93 g of 3-[N-(t-butoxycarbonyl)amino]benzaldehyde in 20 ml of dimethylformamide was added 0.58 g of sodium hydride (60 % oily) under ice-cooling. After stirring at room temperature for 1 hour, a solution of 0.93 ml of 2-bromoethanol in 5 ml of dimethylformamide was added dropwise under ice-cooling. After stirring at room temperature for 14 hours, the mixture was heated to stir at 115C for 6 hours. Ethyl acetate was added, and this was washed successively with water and an aqueous saturated sedum chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.75 g of oily 3-(2-oxo-oxazolidin-3-yl)benzaldehyde.
To a solution of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30 mg, 0.097 mM) in ethanol (4.0 mL), there were added 3-tert-butoxy-carbonylamino-benzaldehyde (32 mg, 0.15 mM) and acetic acid (5.0 muL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and then washed with ethanol. The resulting solid was suspended in dichloromethane (1.0 mL), then a 4N hydrochloric acid/1,4-dioxane solution (3.0 mL) was added to the suspension and the mixture was stirred at room temperature for 3 hours. After basifying the mixture by the addition of an excess amount of a saturated aqueous solution of sodium bicarbonate, it was extracted with ethyl acetate, the resulting organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to thus give the title compound (15 mg, overall yield of these two steps: 38%). 1H-NMR (300 MHz, DMSO): delta 3.73 (4H, m), 3.88 (4H, m), 6.26 (1H, s), 6.56 (1H, s), 6.65 (1H, J=7.2 Hz, d), 6.93 (1H, J=7.2 Hz, d), 6.99 (1H, s), 7.09-7.14 (2H, m), 7.38-7.46 (3H, m), 7.94-7.96 (3H, m), 11.15 (1H, s) MS (ESI) m/z (M+H)+ 414
With manganese(IV) oxide; In dichloromethane; at 20℃; for 16h;
To a solution of 3-(tert-butoxycarbonylamino)-benzyl alcohol (2.0 g, 9.0 mmol) in CH2CI2 (50 mL) was added activated MnO2 (7.8 g, 90 mmol). The resulting suspension was stirred for 16 h at r. . The reaction mixture was filtered through a pad of Celite and a filtrated was concentrated under reduced pressure yielding 1.7 g (85%) of the desired product. - 1H NMR (400 MHz, CDCh): 9.97 (s, 1 H), 7.92 (t, J = 1.8 Hz, 1 H), 7.63 (dd, J = 8.0, 1.1 Hz, 1 LI), 7.55 (ddd, J= 7.6, 1.4, 1.1 Hz, 1 H), 7.44 (t, J= 7.6 Hz, 1 H), 1.53 (s, 9 H).
22%
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14B: tert-butyl (3-formylphenyl)carbamate Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 %) of compound 14B in the form of a white solid.
22%
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1 :30) to yield 3 g (22 %) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 %) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 %) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was leftunder agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22 %) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Comp nd 14B: tert-but l 3-form l hen l carbamate Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1 :30) to yield 3 g (22 %) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14B: tert-butyl (3-formylphenyl)carbamate Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and MnO2 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica column with a mixture of EtOAc and PE (1:30) to yield 3 g (22%) of compound 14B in the form of a white solid.
3 g
With manganese(IV) oxide; In 1,2-dichloro-ethane; at 20℃; for 72h;
Compound 14A (13.8 g, 61.81 mmol, 1.00 equiv) was dissolved in DCE (400 mL) and Mn02 (54 g, 621.14 mmol, 10.05 equiv) was then added. The mixture was left under agitation at ambient temperature for 3 days after which the solids were removed by filtering. The filtrate was evaporated to dryness and the residue was purified on a silica colunm with a mixture of EtOAc and PE (1:30) to yield 3 g (22 %) of compound 14B in the form of a whitesolid.
1-(3-tert-butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(1 .001 a): 1 -(3-tert-Butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid ethyl ester A mixture of <strong>[176980-36-2](3-formyl-phenyl)-carbamic acid tert-butyl ester</strong> (Schadendorf T et al., Tetrahedron Letters (2007), 48(51 ), 9044-9047), (1 g, 4.52 mmol), ethyl isonipecotate (800 mg, 5.09 mmol) and TEA (0.7 mL, 5 mmol) in MeOH (50 mL) is treated with acetic acid (1 .03 mL, 18 mmol) and stirred at RT for 2 h. Sodium cyanoborohydride (398 mg, 6.33 mmol) is added at once and the reaction mixture is stirred for 18 h at RT. Water (5 mL) is added to the mixture and the solvents are evaporated. The residue is partitioned between diethyl ether (50 mL) and aqueous 0.1 N HCI (50 mL). The aqueous phase is separated, washed twice with diethyl ether (25 mL) and basified with 1 N NaOH solution (10 mL). The aqueous phase is extracted three times with DCM (3 X 50 mL). The combined organic phases are dried over MgS04 and evaporated. The title compound is obtained as a thick oil; LC-MS A: tR = 0.71 min; [M+H]+ = 363.48.
(1.001a): 1-(3-tert-Butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid ethyl ester A mixture of <strong>[176980-36-2](3-formyl-phenyl)-carbamic acid tert-butyl ester</strong> (Schadendorf T et al., Tetrahedron Letters (2007), 48(51), 9044-9047), (1 g, 4.52 mmol), ethyl isonipecotate (800 mg, 5.09 mmol) and TEA (0.7 mL, 5 mmol) in MeOH (50 mL) is treated with acetic acid (1.03 mL, 18 mmol) and stirred at RT for 2 h. Sodium cyanoborohydride (398 mg, 6.33 mmol) is added at once and the reaction mixture is stirred for 18 h at RT. Water (5 mL) is added to the mixture and the solvents are evaporated. The residue is partitioned between diethyl ether (50 mL) and aqueous 0.1N HCl (50 mL). The aqueous phase is separated, washed twice with diethyl ether (25 mL) and basified with 1N NaOH solution (10 mL). The aqueous phase is extracted three times with DCM (3*50 mL). The combined organic phases are dried over MgSO4 and evaporated. The title compound is obtained as a thick oil; LC-MS A: tR=0.71 min; [M+H]+=363.48
tert-butyl (3-(((trans-4-methoxycyclohexyl)amino)methyl)phenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of tert-butyl (3- formylphenyl)carbamate (0.137 g, 0.619 mmol) and trans-4-methoxycyclohexanamine (0.08 g, 0.6 19 mmol) in methylene chloride (5 mL) was added Mg504 (0.224 g, 1.858 mmol). The mixture was stirred at room temperature overnight, and then NaBH4 (0.023 g, 0.6 19 mmol) was added and stirred additional 16 h. It was quenched with methanol and diluted with 20 mL methylene chloride, and washed with water 10 mL. The aqueous layer was extracted with three 15 mL portions of methylene chloride. The combined organic extracts were washed with 10 mL of brine, dried with Na2504 and concentrated. The residue was used for the next step without further purification.
benzyl (S)-2-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF inthe presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) andNaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silicacolumn with a mixture of EtOAc and PE (1:50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF inthe presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) andNaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silicacolumn with a mixture of EtOAc and PE (1:50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF inthe presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) andNaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silicacolumn with a mixture of EtOAc and PE (1:50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14C: benzyl (S)-2-((3-((tert-butoxycarbonyl)amino)benzyl) (methyl)amino)-3-methylbutanoate Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF in the presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) and NaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica column with a mixture of EtOAc and PE (1 :50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF in the presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) and NaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica column with a mixture of EtOAc and PE (1 :50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14C: benzyl (S)-2-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-3-methylbutanoate Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF in the presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) and NaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica column with a mixture of EtOAc and PE (1:50) to yield 1.9 g (99%) of compound 14C in the form of a white solid.
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF in thepresence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) and NaBH(OAc)3(1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left under agitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica column with a mixture of EtOAc and PE(1:50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
tert-butyl (3-((3S,6S,9S,10R)-9-((S)-sec-butyl)-3,6-diisopropyl-10-(2-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-2-oxoethyl)-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)phenyl)carbamate[ No CAS ]
benzyl (2S)-3-methyl-2-(methylamino)butanoate hydrochloride[ No CAS ]
[ 176980-36-2 ]
benzyl (S)-2-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Compound 14C: benzyl (S)-2-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-3-methylbutanoate Compound 14B (1 g, 4.52 mmol, 1.00 equiv) was dissolved in 20 mL of THF in the presence of compound 1ZC (1.16 g, 4.50 mmol, 1.00 equiv), DIEA (3 mL) and NaBH(OAc)3 (1.92 g, 9.06 mmol, 2.01 equiv). The reaction mixture was left underagitation overnight at ambient temperature and then neutralised with 100 mL of water and extracted 3 times with 50 mL of AcOEt. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica column with a mixture of EtOAc and PE (1:50) to yield 1.9 g (99 %) of compound 14C in the form of a white solid.
6-(2-morpholinoethoxy)benzo[d]thiazol-2-amine[ No CAS ]
[ 176980-36-2 ]
C25H30N4O4S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With titanium(IV)isopropoxide; In tetrahydrofuran;Inert atmosphere; Reflux;
The compound prepared in step 1 6- (2-morpholinoethoxy) benzo [d] thiazol-2-amine (1.0 equiv.) And tert-butyl 3-formyl phenyl carbamate (1.2 equiv.)To the THF in which the mixture is dissolved,Ti (iPrO) 4 (2.0 equiv.) Was added under a stream of nitrogen. The reaction mixture was refluxed and stirred until an imine intermediate was formed.After lowering the temperature to room temperature, NaCNBH3 (2.0 equiv.) Was added,And the mixture was stirred at 50 C for 5 hours.The THF was removed under reduced pressure and the residue was diluted with water. The solid was filtered off and the filtrate was extracted with EtOAc.The organic layer was collected, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane: EtOAc: MeOH = 1: 1: 0.3) to yield the title compound.
ethyl 3-(3-((tert-butoxycarbonyl)amino)phenyl)-2,2-difluoro-3-hydroxypropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
To a mixture of ethyl 2-bromo-2,2-difluoroacetate (181.4 g, 893.6 mmol, 114.8 mL, 1.0 eq.), Zn (210.3 g, 3.22 mol, 3.6 eq.) and THF (1200 mL) was added DIBAL-H (1 M, 35.7 mL, 0.04 eq.) at 10-15 C. Then the mixture was stirred at 30 C for 1 hr. A solution of ethyl 2-bromo-2,2-difluoroacetate (18.1 g, 89.3 mmol, 11.4 mL, 1.0 eq.), tert-butyl (3- formylphenyl)carbamate (WO2017072196) (208.0 g, 893.6 mmol, 1.0 eq.) and THF (300 mL) was added drop-wise to the mixture at 30 C. After the addition, the mixture was stirred at 30-50 C for 6 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic phases were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate to give the title compound (545.0 g, 1.58 mol, 88%) as a yellow oil.
Chemistry
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Material Science
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110K+ Compounds
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