* 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.
Pd/C(10percent, 2 g) was added to a solution of (S)-tert-butyl1-azidopropan-2-ylcarbamate (75.0 g, 0.375 mol) in MeOH (1 L). The suspensionwas stirred under a hydrogen atmosphere at r.t. for 4 h. The reaction was filteredand the solids washed with MeOH (100 mL). The combined filtrate was concentratedin vacuo to give (S)-tert-butyl1-aminopropan-2-ylcarbamate (65.1 g, quantitative yield), which was used innext step without further purification. 1H NMR (300 Hz, CDCl3)δ ppm 4.64 (br s, 1H), 3.64 (m, 1H), 2.75 (dd, J = 13.2, 5.1 Hz, 1H), 2.63 (dd, J = 13.2, 6.6 Hz, 1H), 1.45 (s, 9H), 1.31 (br s, 2H), 1.12 (d, J = 6.6Hz, 3H).
73%
With hydrogen In ethyl acetate for 15 h;
A stirred solution of 11.4 g (57 mmol) of 1c in 165 ml of ethyl acetate was mixed with 1.8 g of Pd/C (10percent) and exposed for 15 hours to a hydrogen atmosphere of 4 bar. The catalyst was separated by filtration (so-called G4 frit). The filtrate was concentrated by evaporation in a rotary evaporator and purified by column chromatography (SiO2-dichloromethane-->dichloromethane:methanol 1:1). The desired product was produced with a yield of 73percent (7.25 g; 42 mmol).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5743 - 5747
[2] Journal of Chemical Research, Miniprint, 1992, # 12, p. 3117 - 3132
[3] Patent: US2004/208828, 2004, A1, . Location in patent: Page 13
[4] Organic Letters, 2011, vol. 13, # 13, p. 3486 - 3489
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 17, p. 2780 - 2786
[6] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3157 - 3163
2
[ 78981-25-6 ]
[ 146552-71-8 ]
Yield
Reaction Conditions
Operation in experiment
33%
With borane-THF In tetrahydrofuran at 20 - 70℃; for 18 h; Inert atmosphere
To a stirred solution of Boc-Ala-NH2 (4.600 g, 24.4 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (100 mL) under nitrogen was added 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran (85.536 mL, 85.5 mmol, 3.5 equiv.). The mixture was stirred for 16 h at room temperature and then heated at 70° C. for 2 h. After cooling, the reaction was quenched with methanol until no bubbles generated. The mixture was heated at 70° C. for 2 h and then concentrated in vacuo. The residue was purified by silica gel column (0-100percent ethyl acetate/hexanes and then 0-30percent methanol/methylene chloride) to afford the desired product as a semi-solid (1.4 g, 33percent). 1H NMR (300 MHz, CDCl3): δ 4.60 (br s, 1H), 3.65 (m, 1H), 2.76 (dd, 1H, J=12.9, 4.8 Hz), 2.64 (dd, 1H, J=12.9, 6.6 Hz), 1.45 (s, 9H), 1.13 (d, 3H, J=6.9 Hz).
Reference：
[1] Patent: US2015/284362, 2015, A1, . Location in patent: Paragraph 0408
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4878 - 4881
[3] Journal of Combinatorial Chemistry, 2010, vol. 12, # 2, p. 248 - 254
[4] Patent: WO2016/206101, 2016, A1, . Location in patent: Page/Page column 356
3
[ 15967-72-3 ]
[ 121103-15-9 ]
[ 146552-71-8 ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
A) (S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with Q dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2- amino-l-methyl-ethyl)-carbamic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, / 5 = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
36%
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water
A) ((S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2-amino-l-methyl-ethyl)-carbarnic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
A) (S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with Q dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2- amino-l-methyl-ethyl)-carbamic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, / 5 = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
36%
Stage #1: With triethylamine In ethanolHeating / reflux Stage #2: With hydrogenchloride In water
A) ((S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the the sub-title compound (211 mg, 36 percent yield) and the by-product ((S)-2-amino-l-methyl-ethyl)-carbarnic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) δ(ppm) 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
Pd/C(10%, 2 g) was added to a solution of (S)-tert-butyl1-azidopropan-2-ylcarbamate (75.0 g, 0.375 mol) in MeOH (1 L). The suspensionwas stirred under a hydrogen atmosphere at r.t. for 4 h. The reaction was filteredand the solids washed with MeOH (100 mL). The combined filtrate was concentratedin vacuo to give (S)-tert-butyl1-aminopropan-2-ylcarbamate (65.1 g, quantitative yield), which was used innext step without further purification. 1H NMR (300 Hz, CDCl3)delta ppm 4.64 (br s, 1H), 3.64 (m, 1H), 2.75 (dd, J = 13.2, 5.1 Hz, 1H), 2.63 (dd, J = 13.2, 6.6 Hz, 1H), 1.45 (s, 9H), 1.31 (br s, 2H), 1.12 (d, J = 6.6Hz, 3H).
73%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 3000.3 Torr; for 15h;
A stirred solution of 11.4 g (57 mmol) of 1c in 165 ml of ethyl acetate was mixed with 1.8 g of Pd/C (10%) and exposed for 15 hours to a hydrogen atmosphere of 4 bar. The catalyst was separated by filtration (so-called G4 frit). The filtrate was concentrated by evaporation in a rotary evaporator and purified by column chromatography (SiO2-dichloromethane?dichloromethane:methanol 1:1). The desired product was produced with a yield of 73% (7.25 g; 42 mmol).
{2-[<i>N</i>'-(2-<i>tert</i>-butoxycarbonylamino-propyl)-<i>N</i>''-octadecyl-guanidino]-1-methyl-ethyl}-carbamic acid <i>tert</i>-butyl ester; hydrochloride[ No CAS ]
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; water; at 0 - 60℃; for 36h;
A stirred solution of 7.2 g (41 mmol) of 1d, 245 ml of water and 245 ml of dichloromethane was mixed with commercially available 12.9 g (42 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-nitro-phenyl)-propionic acid (Bachem) and 6.4 g (42 mmol) of 1-hydroxybenzotriazole-H2O (HOBT). The solution was cooled to 0 C. and mixed with 8.8 g (46 mmol) of 1-(dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). The reaction solution was stirred for seven hours at 0 C., for 12 hours at room temperature, and for 24 hours at 60 C. The solution was cooled to room temperature. The aqueous phase was separated and extracted several times with dichloromethane. The combined organic phases were washed with 5% sodium bicarbonate solution and aqueous, saturated sodium chloride solution. It was dried with sodium sulfate and concentrated by evaporation in a rotary evaporator. The residue was mixed with hexane, torn apart, suctioned off and rewashed with cold hexane. The solid was dried in a vacuum at 30 C. The desired product 1e was produced with a yield of 77% (14.9 g; 32 mmol).
With triethylamine; In dichloromethane; at 20℃; for 2h;
Into a 100 mL round bottom flask, benzyl carbonochloridate (2.94 g, 17.22 mmol) was added dropwise to a stirred mixture of triethylamine (1.16 g, 11.48 mmol),tert-butyl (1- aminopropan-2-yl)carbamate (1.00 g, 5.74 mmol) in DCM (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with brine (2 x 25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether(1/10) to givethe title compound as a solid.LCMS (ESI) calc?d for C,6H24N204 [M + H]:309,found:309. ?H NMR (300 MHz, CDC13): 7.29-7.2 1 (m, 5H), 5.03 (s, 2H), 4.63-4.55 (m, 1H),3.69-3.51(m,1H),3.25-3.18(m,1H),1.35(s, 8H), 1.06(d, J =6.9 Hz 3 H).
A) (S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with Q dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the sub-title compound (211 mg, 36 % yield) and the by-product ((S)-2- amino-l-methyl-ethyl)-carbamic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) delta(ppm) 1.09 (d, 3H, / 5 = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
36%
A) ((S)-2-Amino-propyl)-carbamic acid tert-butyl ester: To a solution of trietylamine (0.95 mL, 6.8 mmol) in 15 mL ethanol was added (s)-(-)- diaminopropane (252 mg, 74.1 mmol). The reaction mixture was stirred under reflux over night. Solvent was evaporated. Water was added and the pH was adjusted to pH 3 by addition of 2 M hydrochloric acid followed by extraction with dichloromethane. The aqueous phase was made alkaline by addition of 2 M sodium hydroxide and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and dried in vacuo over night to give the the sub-title compound (211 mg, 36 % yield) and the by-product ((S)-2-amino-l-methyl-ethyl)-carbarnic acid tert-butyl ester in a 3 : 1 mixture according to NMR.1H NMR (400 MHz; chloroform-d as solvent and internal reference) delta(ppm) 1.09 (d, 3H, J = 6.5 Hz), 1.45 (s, 9H), 2.91 (m, IH), 3.04 (m, IH), 3.16 (m, IH)
With sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 4h;
A solution of 4-(4-bromo-2-(4-trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (4.1 g, 7.7 mmol) in dry NMP (10 mL) was treated with (S)-tert-butyl-1-aminopropan-2-ylcarbamate (1.9 g, 11.0 mmol; Example 23, Step 2), followed by Na2CO3 (0.82, 7.7 mmol). The resulting mixture was heated to 80 C. for 4 h whereupon the reaction was deemed complete by LCMS, and allowed to cool to rt. Water was added and the resulting suspension was compacted by centrifugation. The filtrate was decanted, the remaining solids were washed with water, and dried under vacuum to provide 4.6 g (6.9 mmol, 90%) as (S)-tert-butyl-1-(4-(4-bromo-2-(4-trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, which was carried forward without further purification.
90%
With sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 4h;
A solution of 4-(4-bromo-2-(4-trifiuoromethyl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-5-yl)-2-chloropyrimidine (4.1 g, 7.7 mmol) in dry NMP (10 mL) was treated with (S)-tert- butyl-l-aminopropan-2-ylcarbamate (1.9 g, 11.0 mmol; Example 23, Step 2), followed by Na2CO3 (0.82 , 7.7 mmol). The resulting mixture was heated to 80 0C for 4 h whereupon the reaction was deemed complete by LCMS, and allowed to cool to rt. Water was added and the resulting suspension was compacted by centrifugation. The filtrate was decanted, the the remaining solids were washed with water, and dried under vacuum to provide 4.6 g (6.9 mmol, 90%) as (S)-tert-butyl- l-(4-(4-bromo-2-(4-trifluoromethyl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5- yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, which was carried forward without further purification.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 21h;
A mixture of 4-(4-bromo-2-te/t-butyl-lH-imidazol-5-yl)-2- chloropyrimidine (2.Og, 4.5 mmol; Example 6, Step 4), (^-er-butyl-l-aminopropan^-ylcarbamate (1.0 g, 5.8 mmol; Example 23, Step 2), and diisopropylethyl amine (2.4 mL, 13.5 mmol) in dry acetonitrile was heated at 85 0C for 16 h. An additional charge of (5)-ert-butyl-l-aminopropan-2- ylcarbamate (145 mg, 0.8 mmol) was added and the reaction was maintained at 85 0C for 5 h. After allowing to cool to rt, the reaction was diluted with EtOAc (40 mL), washed with water (2 X 15 mL), dried l-(4-(4-bromo-2-er-butyl- lH-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate which was carried forward without further purification: LCMS (m/z): 585.0 (MH+), tR = 1.07 min.
(S)-tert-butyl (1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbamate[ No CAS ]
[ 146552-71-8 ]
Yield
Reaction Conditions
Operation in experiment
With hydrazine hydrate; In methanol; at 50℃; for 1h;
Hydrazine monohydrate (20 mL, 643 mmol) was added to a suspension of(S)-tert-butyl l-(l,3-dioxxisoindolin-2-yl)propan-2-ylcarbamate (12.5 g, 41.1 mmol) in dry MeOH (150 mL), and the resulting mixture was heated to 50 C for 1 h. After cooling to room temperature, the reaction mixture was filtered through a sintered funnel, and the filtrate concentrated. The resulting residue was suspended in Et20 (300 mL) and filtered, washing the filter cake thoroughly with Et20. The combined filtrates were filtered and concentrated to furnish 6.3 g of (5)-tert-butyl-l-aminopropan-2-ylcarbamate: 1H NMR(CDC13, 400 MHz) 5 4.44-4.71 (br s, 1 H), 3.53-3.74 (br m, 1 H), 2.75 (dd, J= 4.9, 12.9 Hz, 1 H), 2.64 (dd, J = 6.6, 12.9 Hz, 1 H), 1.45 (s, 9 H), 1.21 (d, J= 6.6 Hz, 3 H), 1.15-1.34 (br s, 2 H), 1.12 (d, J = 6.7 Hz, 3 H).
6.3 g
With hydrazine hydrate; In methanol; at 50℃; for 1h;
Hydrazine monohydrate (20 ml, 642.7 mmol) was added to a suspension of (S)-tert-butyl 1-(1,3-dioxxisoindolin-2-yl)propan-2-ylcarbamate (12.50 g, 41.1 mmol) in dry MeOH (150 ml), and the resulting mixture was heated to 50 C. for 1 h. After cooling to rt, the reaction mixture was filtered through a sintered funnel, and the filtrate concentrated. The resulting residue was suspended in Et2O (300 mL) and filtered, washing the filter cake thoroughly with Et2O. The combine filtrates were filtered and concentrated to furnish 6.3 g of (S)-tert-Butyl-1-aminopropan-2-ylcarbamate: 1H NMR (CDCl3, 400 MHz) delta 4.44-4.71 (br s, 1H), 3.53-3.74 (br m, 1H), 2.75 (dd, J=4.9, 12.9 Hz, 1H), 2.64 (dd, J=6.6, 12.9 Hz, 1H), 1.45 (s, 9H), 1.21 (d, J=6.6 Hz, 3H), 1.15-1.34 (br s, 2H), 1.12 (d, J=6.7 Hz, 3H).
With hydrazine; In methanol; at 70℃;Inert atmosphere;
General procedure: To an ice-cooled solution of Boc-protected alcohol in anhydrous THF (15 mL) under N2 were added Phtalimide (1.20 eq) and PPh3 (1.20 eq). The reaction mixture was stirred for 10 min and DIAD (1.20 eq) was added dropwise. The reaction mixture was stirred at room temperature over night. The THF was removed under vacuum and the mixture was dissolved in methanol and heated to 70 C. under N2. Hydrazine (3.00 eq) was added slowly and the mixture was allowed to stir at 70 C. over night. The insoluble product was filtered off and washed with methanol. The filtrate and washings were combined and the solvent was removed under vacuum. The mixture was dissolved in NaHCO3 and CH2Cl2. The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The resulting oil was dissolved in concentrated HCl (pH 2-3) and the aqueous layer was washed with Et2O and EtOAc, the aqueous layer was then basified with K2CO3 until pH 8. The compound was extracted from the aqueous layer with CH2Cl2 (three times) and the organic phases were combined, dried over Na2SO4 and concentrated under reduce pressure.
With hydrazine hydrate; In methanol; at 50℃; for 1h;
Hydrazine monohydrate (20ml, 642.7mmol) was added to a suspension of (5)-tert-butyl l-(l,3-dioxxisoindolin-2-yl)propan- 2-ylcarbamate (12.5Og, 41.1mmol) in dry MeOH (150ml), and the resulting mixture was heated to 50 0C for 1 h. After cooling to rt, the reaction mixture was filtered through a sintered funnel, and the filtrate concentrated. The resulting residue was suspended in Et2O (300 mL) and filtered, washing the filter cake thoroughly with Et2O. The combine filtrates were filtered and concentrated to furnish6.3 g of (5)-tert-Butyl-l -aminopropan-2-ylcarbamate: 1H NMR(CDCl3, 400 MHz) delta 4.44-4.71 (br s, 1 H), 3.53-3.74 (br m, 1 H), 2.75 (dd, J= 4.9, 12.9 Hz, 1 H), 2.64 (dd, J= 6.6, 12.9 Hz, 1 H), 1.45 (s, 9 H), 1.21 (d, J= 6.6 Hz, 3 H), 1.15-1.34 (br s, 2 H), 1.12 (d, J= 6.7 Hz, 3 H).
With borane-THF; In tetrahydrofuran; at 20 - 70℃; for 18h;Inert atmosphere;
To a stirred solution of Boc-Ala-NH2 (4.600 g, 24.4 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (100 mL) under nitrogen was added 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran (85.536 mL, 85.5 mmol, 3.5 equiv.). The mixture was stirred for 16 h at room temperature and then heated at 70 C. for 2 h. After cooling, the reaction was quenched with methanol until no bubbles generated. The mixture was heated at 70 C. for 2 h and then concentrated in vacuo. The residue was purified by silica gel column (0-100% ethyl acetate/hexanes and then 0-30% methanol/methylene chloride) to afford the desired product as a semi-solid (1.4 g, 33%). 1H NMR (300 MHz, CDCl3): delta 4.60 (br s, 1H), 3.65 (m, 1H), 2.76 (dd, 1H, J=12.9, 4.8 Hz), 2.64 (dd, 1H, J=12.9, 6.6 Hz), 1.45 (s, 9H), 1.13 (d, 3H, J=6.9 Hz).
In tetrahydrofuran; at 20 - 70℃; for 4h;
Intoa 250 round bottom flask, borane (6 ml, 60.0 mmol) was added dropwise to a stirred mixture of (S)-tert-butyl (1-amino-i -oxopropan-2-yl)carbamate (6.5 Og, 34.5 mmol) in THF (100 ml)at room temperature. After the reaction mixture was stirred at 70C for 4 hr, it was cooled down to room temperature, quenched with water/ice (100 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3x 4OmL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum/ether(i/i0) to give the title compound as an oil. LCMS (ESI) calc?d for C8H,8N202 [M + H]:i75,found:i75. ?H NMR (300 MHz, DMSO-d6): 4.97 (s, 1H), 3.46 (d, J =6.6 Hz, 2H), 2.25 (s, 3H), 1.39 (s, 9H), 1.28 (s, 6H). LCMS (ESI) calc?d for C8H,6N203 [M + H]:i89,found:i89. ?H NMR (300 MHz, DMSO-d6):7.22 (brs, 1H), 6.93 (brs, 1H), 6.58 (d,J =1.2Hz, 1H,, 3.88-3.81 (m, 1H), 2.48 (d,J=3.3Hz, 2H), 1.37 (s, 9H), 1.16 (d,J=5.7Hz, 3H).
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 0.0833333h;
Compound ISF (435 mg, 1.267 mmol) was dissolved in NMP (5 ml), treated with (S)- tert-butyl 1 -aminopropan-2-ylcarbamale (265 mg, 1.521 mmol) and DIEA (0.443 ml, 2,53 mmol) at 90 *? for 5 minutes. Reaction mixture was then cooled down to room temperature, partitioned between EtOAc/H3O (30 ml/60 ml), EtOAc layer was sequentially washed with H2O (2 x 60 ml), brine (30 ml), dried over NaaSO^ concentrated to yield 15(3 as a light brown waxy residue(569.5 mg, 1 -256 mmol). LCMS (w/2): 455.2 (MH+), Rf: 0.94 min.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; for 0.5h;
Compound ISE (1.4489 g) was dissolved in NMP (10 ml), treated with (S>;tert-butyl 1-amitauu>;prorhoan-2~ykarbamate (0.926 g, 5.31 mmol) and DlEA (1.16 ml, 6.64 mmol) at 50 C for 30 minutes. The reaction mixture was cooled down to room temperature, partitioned between EtOAcZH2O (30 ml/60 ml), the EtOAc layer was sequentially washed with H2O (60 ml), brme(2Q ml), dried over Na^SO^ and concentrated to yield ISF as a light color solid (1.8285 g, 4.18 mmol). LCMS On/*): 439.1 (MH+), R1: 0.89 min.
With hydrazine hydrate; In ethanol; at 20℃; for 2h;
General procedure: Hydrazine·monohydrate (0.076 ml) was added to an ethanol (6 ml) solution containing (S)-tert-butyl(2-((1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate (250 mg), followed by stirring at room temperature for 2 hours. The solvent was distilled away under reduced pressure, and diisopropylether was added, followed by stirring. Insoluble matter was removed. 4M hydrogen chloride/1,4-dioxane (1 ml) was added to the obtained solution, the solid precipitate was collected by filtration, and a white solid of (S)-tert-butyl(1-aminobutan-2-yl)carbamate (160 mg) was thus obtained. MS (ESI m/z): 190 (M+H)
N-(3-(2-tert-butyl-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2- chlorophenyl)propane-l -sulfonamide (XXVI, 30 mg, 0.062 mmol), DIE A (0.017 mL, 0.096 mmol), Na2C03 (13 mg, 0.12 mmol), and (S)-tert-butyl l-aminopropan-2-ylcarbamate (X, 11 mg, 0.062 mmol) were mixed in NMP (1 mL). The reaction mixture was heated at 90 C for 3 days, cooled to room temperature and diluted with water. The water was adjusted to pH 5 with IN HC1 and extracted with EtOAc. The EtOAc layer was washed with brine, dried over magnesium sulfate, filtered and concentrated afford a crude (5)-tert-butyl l-(4-(2-tert- butyl-4-(2-chloro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate (LCMS (m/z): 623.3 (MH+), = 1.05 min) as a yellow oil which was carried forward without further purification.
With 1-methyl-pyrrolidin-2-one; at 20 - 120℃; for 0.5h;
A solution of N-(3-(2-tert-butyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)-2-chloro-5-fluorophenyl)methanesulfonamide (36 mg, 0.069 mmol) and (S)-tert-butyl1- aminopropan-2-ylcarbamate (X, 121 mg, 0.69 mmol) in NMP (1 mL) was stirred for 15 min at rt then heated to 120 C for 15 min. The reaction mixture was allowed to cool to rt, diluted with a saturated aqueous NH4C1 solution and extracted with EtOAc twice. The organics were combined, washed with brine, dried (Na2S04), filtered and concentrated to afford (S)-ierf-butyl l-(4-(2-tert-butyl-4-(2-chloro-5-fiuoro-3-(methylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (40 mg, 0.065 mmol, 94 %) as a yellow oil: LCMS (m/z): 613.3 (MH+), tR = 0.99 min.
With 1-methyl-pyrrolidin-2-one; at 120℃; for 0.166667h;microwave reactor;
A solution of N-(2-chloro-3-(2-cyclopropyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)-5-fluorophenyl)methane-sulfonamide (32 mg, 0.064 mmol) and (S)-tert- butyl l-aminopropan-2-ylcarbamate (X, 111 mg, 0.64 mmol) in NMP (1 ml) was irradiated to 120 C for 10 min in a microwave reactor. LCMS indicated complete conversion and the reaction was diluted with a saturated aqueous solution of NH4C1 and twice extracted with EtOAc. The combined organics were washed with brine, dried (Na2S04), and concentrated to give (S)-tert- vXy- 1 -(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2- cyclopropylthiazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (43 mg, 0.065 mmol) as a yellow oil which was carried to the next step without further purification: LCMS (m/z): 597.4 (MH ), ¾ = 0.88 min.
A solution of N-(5-chloro-3-(2-cyclopropyl-5-(2-(methylsulfinyl)pyrimidin-4-yl)oxazol-4-yl)-2-fluorophenyl)methanesulfonamide (50 mg, 0.106 mmol) and (S)-tert- butyl l-aminopropan-2-ylcarbamate (X, 41 mg, 0.234 mmol) in NMP (1 mL) was heated at 100 C for 2 h. The reaction was allowed to cool to rt, diluted with EtOAc (3 mL) and washed with 0.1 N aqueous sodium phosphate buffer (pH 7, 3 X 3 mL), brine (3 mL), dried (Na2S04), concentrated to provide (S)-tert-bvXy l-(4-(4-(5-chloro-2-fluoro-3- (methylsulfonamido)phenyl)-2-cyclopropyloxazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate (63 mg) as a yellow foam which was carried forward without further purification: LCMS (m/z): 581.4 (MH+), tR = 0.84 min.
A solution of N-(5-chloro-3-(2-cyclopropyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)methanesulfonamide (50 mg, 0.103 mmol) and (S)-tert- butyl l-aminopropan-2-ylcarbamate (X, 39 mg, 0.22 mmol) in NMP (1 mL) was heated at 100 C for 2 h. The reaction mixture was cooled to rt, diluted with EtOAc (3 ml) and washed with 0.1 N sodium phosphate buffer (pH 7, 3 X 3 mL). The EtOAc extracts were combined, washed with brine (3 ml), dried (Na2S04), concentrated to provide {S)-tert- vXy l-(4-(4-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropylthiazol-5- yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (65 mg) as a yellow foam which was carried forward without further purification: LCMS (m/z): 597.4 (MH+), tR = 0.91 min.
[0369] Step 5: To the above solution, was added (S)-tert-butyl l-aminopropan-2- ylcarbamate (0.2 mmol) and DIEA (0.5 mmol). The reaction solution was stirred at 70 C for 15 h and then diluted with ethyl acetate and water. The organic layers were washed with citric acid aq. and brine. After concentrated and dried, treatment with TFA/DCM (1/3) gave desired product (S)-2-(2-aminopropylamino)-6-oxo-4-(quinolin-6-ylamino)-l ,6- dihydropyrimidine-5-carboxamide. MS found for C17H19N702 as (M+H)+ 354.3, lambda=266.8, 292.9.
With N-ethyl-N,N-diisopropylamine; In 1-Methylpyrrolidine; at 60℃; for 16h;
[0382] Step 7: To the above solution (0.3 mmol), was added (S)-tert-butyl 1-aminopropan- 2-ylcarbamate (0.5 mmol) and DIEA (2 mmol). After stirred at 60 C for 16 h, concentration, extraction with ethyl acetate and treated with HC1 in dioxane gave (S)-4-(m-toluidino)-2-(2- aminopropylamino)-6-(2-hydroxyethoxy)pyrimidine-5-carboxamide. MS found forC17H24N603 as (M+H)+ 361.3, lambda=260.9.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 21h;
A mixture of 4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)-2-chloropyrimidine (2.0 g, 4.5 mmol; Example 6, Step 4), (S)-tert-butyl-1-aminopropan-2-ylcarbamate (1.0 g, 5.8 mmol; Example 23, Step 2), and diisopropylethyl amine (2.4 mL, 13.5 mmol) in dry acetonitrile was heated at 85 C. for 16 h. An additional charge of (S)-tert-butyl-1-aminopropan-2-ylcarbamate (145 mg, 0.8 mmol) was added and the reaction was maintained at 85 C. for 5 h. After allowing to cool to rt, the reaction was diluted with EtOAc (40 mL), washed with water (2*15 mL), dried (Na2SO4), and concentrated to provide 2.6 g of (S)-tert-butyl 1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate which was carried forward without further purification: LCMS (m/z): 585.0 (MH+), tR=1.07 min.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 2h;
1.58 g (7.18 mmol) in ACN was added 920 mg (8.6 mmol) p-toluidine and ~2 mL DIE A. The reaction was stirred at room temperature for ~1 hour. The ACN was removed in vacuo until solid precipitated. At this point water (-50 mL) was added and the solid was filtered. The solid (B6.2) was dried and massed to be 1.85 g (89% yield). To 1.01 g (3.47 mmol) of B6.2 in a 50/50 mixture of THF/H20 was added 4.16 mmol of LiOH in H20 (1.2 eq). The reaction was stirred at room temperature for 30 minutes and then was acidified to pH~2 with 1 M HCl (aq). The volatiles were removed and the resulting solid was filtered to give 613 mg B6.2. To B6.2 in DMF was added 662 mg HOBt H20 and 708 mg EDC HCl. After stirring for 2 hours and additional 0.5 eq of EDC HCl was added. The reaction was stirred for 1 hour and then NH3 in dioxane (excess) was added. The reaction was stirred for 45 minutes and then the dioxane was removed in vacuo. Water was added which led to a precipitate. The solid (B6.3) was filtered, washed with water and dried. To -200 mg B6.3 in ~2 mL NMP and 0.3 mL DIEA was added 240 mg (S)-tert-butyl 1 -aminopropan-2-ylcarbamate. The reaction mixture was stirred at 90C for 2 hours and was then cooled. Water was added, solid precipitated and was filtered. Similar to Scheme 2 (example 73), a Boc-deprotection utilizing DCM/TFA afforded the title compound. MS found for C15H2ON6O as (M+H)+301.2.
In dichloromethane; at 20℃; for 2h;Cooling with ice;
General procedure: To an ice-cooled solution of the Boc-protected amine dissolved in anhydrous CH2Cl2, was added DSC (1.20 eq) previously dissolved in CH2Cl2 and the mixture was stirred for 2 h at room temperature. The mixture was diluted in CH2Cl2, the insoluble compounds were filtered off and washed with CH2Cl2. Then the organic layer was washed with saturated Na2SO4 and concentrated under reduced pressure. The desired activated building block was crystallised in a mixture of Et2O and pentane and recovered by filtration
(S)-tert-butyl (1-(2-chloroacetamido)propan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium carbonate; In ethyl acetate; at -5 - 20℃;
(S)-Tert-butyl1-aminopropan-2-ylcarbamate (33.0 g, 0.19 mol) was dissolved in EtOAc (540 mL).Aqueous Na2CO3 (2 M, 190 mL, 0.4 mol) was added. Themixture was cooled to -5 to 0 C and 2-chloroacetyl chloride (30.2 mL, 0.38mol) was added dropwise over 1 h. The resulting mixture was allowed to warm tor.t. and stirred for 2 h. Water (500 mL) was added to quench the reaction. Thelayers were separated and the aqueous layer was extracted with EtOAc (300 mL × 3).The combined organic layers were washed with brine (300 mL × 3), dried over Na2SO4,and concentrated to dryness to give (S)-tert-butyl1-(2-chloroacetamido)propan-2-ylcarbamate (50.5 g, quantitative yield)as a white solid, which was used in the next step without further purification.1H NMR (300 Hz, CDCl3) delta ppm 4.61 (br s, 1H), 4.05 (d, J = 1.5 Hz, 2H), 3.88 (m, 1H), 3.41 (m,1H), 3.24 (m, 1H), 1.46 (s, 9H), 1.20 (d, J= 6.9 Hz, 3H). MS m/z (ES+)[M+Na]+ = 273.
2-((S)-2-aminopropyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
General procedure: 2-((R)-2-aminopropyl)-3a,4,7,7a-tetrahydro-lH-4,7-epoxyisoindole-l,3(2H)-dione (DD tert-butyl (R)-(l-aminopropan-2-yl)carbamate hydrochloride (1 eq) in a microwave tube was solved in MeOH. Na2C03 (2 eq) and TBAB (0.26 eq) was added and the mixture was stirred in an ice-water-bath. 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-l,3-dione (1 eq) in a flask, suspended in MeOH was also stirred in an ice-water-bath for 10 minutes and then slowly added to the reaction mixture. The mixture was allowed to warm up to room temperature and stirred for 1 h. DMS (1.5 eq) was added, the tube sealed and the mixture was stirred at 70 C overnight. Then the mixture was allowed to cool to room temperature, chloroform and 0.1 N NaOH was added, the layers separated and the aqueous phase washed with chloroform. Combined organic layers were washed with 0.1 N NaOH, 0.1 N HCl and brine and the dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was solved in dichloromethane/TFA (10: 1) at 0 C. The mixture was allowed to warm up to room temperature and then stirred for 3 h. It was diluted with MeOH and the solvent evaporated. The residue was solved in sat. NaHC03 solution, the pH adjusted with NH3conc. to 10 and extracted with chloroform (lOx). Combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Yield: 52%
10%
tert-butyl (R)-(1-aminopropan-2-yl)carbamate hydrochloride (1 eq) in a microwave tube was solved in MeOH. Na2CO3 (2 eq) and TBAB (0.26 eq) was added and the mixture was stirred in an ice-water-bath. 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione (1 eq) in a flask, suspended in MeOH was also stirred in an ice-water-bath for 10 minutes and then slowly added to the reaction mixture. The mixture was allowed to warm up to room temperature and stirred for 1 h. DMS (1.5 eq) was added, the tube sealed and the mixture was stirred at 70 CC ovemight. Then the mixture was allowed to cool to room temperature, chloroform and 0.1 N NaOH was added, the layers separated and the aqueous phase washed with chloroform. Combined organic layers were washed with 0.1 N NaOH, 0.1 N HC1 and brine and the dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was solved in dichloromethane/TFA (10:1) at 0 C. The mixture was allowed to warm up to room temperature and then stirred for 3 h. It was diluted with MeOH and the solvent evaporated. The residue was solved in sat. NaHCO3 solution, the pH adjusted with NH30. to 10 and extracted with chloroform (lOx). Combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Yield: 52%
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid[ No CAS ]
[ 146552-71-8 ]
(R)-tert-butyl (1-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Intoa 50 mL round bottom flask, 1-chloropyrrolidine-2,5-dione (0.15 g, 1.160 mmol) was added to a stirred mixtureof2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4- methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid (0.45g, 0.580 mmol) in THF (20 ml) at room temperature. After the reaction mixture was stirred at room temperature for 1 hr, (S)-tertbutyl (1-aminopropan-2-yl)carbamate (0.15 g, 0.870 mmol) was added at room temperature. The resulting mixture was stirred at room temperature overnight and then diluted with water (50 mL) and extracted with ethyl acetate (3x lOOmL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether(1/5) to give the title compound as a solid. LCMS (ESI) calc?d for C39H461N709S2 [M + H]:948,found:948. ?H NMR (300 MHz, CDC13): 8.23-8.12 (m, 6H), 7.33-7.26 (m, 4H), 6.96-6.86 (m, 4H), 5.80 (s, 2H), 4.10-3. 70 (m, 4H), 3.79 (s, 9H), 3.70-3.68 (m, 3H), 1.47 (s, 9H),1.16 (d,J= 3.0Hz, 3H).
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid[ No CAS ]
[ 146552-71-8 ]
(R)-tert-butyl (1-(4-(2-amino-1H-benzo[d]imidazol-4-yl)-2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propan-2-yl)carbamate[ No CAS ]
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid[ No CAS ]
[ 146552-71-8 ]
(S)-tert-butyl (1-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Into a 50 mL round bottom flask, 1 -chloropyrrolidine-2,5-dione (0.15 g, 1.160 mmol) was added to a stirred mixture of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2- (4-methoxybenzyl)-2H-tetrazol-5 -yl)benzenesulfinic acid(0 .45 g, 0.580 mmol) in tetrahydrofuran (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. Triethymine (2 ml), ()-tert-butyl (1-aminopropan-2-yl)carbamate (0.15 g, 0.870 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature 2 hr and then it was diluted with water (50 mL) and extracted with ethyl acetate (3x lOOmL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether (1/5) to give the title compound as a solid. LCMS (ESI) calc?d for C42H441N70952 [M + H]:982,found:982;?H NMR (300 MHz, CDC13): oe8.40-7.91(m, 7H), 7.34-7.28 (m, 6H), 6.98- 6.71 (m, 6H), 5.91(s,2H),5. 19-5. 12(m,2H), 4.21-4. 13(m,2H),3.94-3.89(m, 1H), 3.77(s,9 H), 3.68-3.51(m,2H),3.31-3.28(m,2H), 0.91(d, J=6.6 Hz, 3H).
6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile[ No CAS ]
[ 146552-71-8 ]
C23H25FN6O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50 mg
With potassium carbonate; In 1,4-dioxane; for 13h;Reflux;
tert-Butyl((2S)-1-aminopropan-2-yl)carbamate (63 mg) and potassium carbonate (139 mg) were added to a1,4-dioxane (2 ml) solution containing 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (60 mg), followed by refluxfor 13 hours. The reaction mixture was cooled to room temperature. Ethyl acetate and a saturated aqueous sodiumhydrogen carbonate solution were added. The resultant was subjected to extraction with ethyl acetate three times. Theextracts were combined and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure.The obtained residue was purified by silica gel chromatography, and colorless oily matter (50 mg) was thus obtained.
Tert-Butyl (S)-(1-aminopropan-2-yl) carbamate(3.60 g) and benzaldehyde (2.64 mL) were mixed in ethanol (50 mL).The mixture was stirred at 60 C. for 1 hour.Sodium borohydride in the reaction mixture under ice cooling(1.51 g)Stir at room temperature for 15 minutes.Under ice cooling, a saturated aqueous ammonium chloride solution and then 1N hydrochloric acid were added to the reaction mixture until the pH reached 9. The reaction mixture was concentrated under reduced pressure.A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform.The organic layer was dried with sodium sulfate.After filtering off the sodium sulfate,The filtrate was concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to chloroform: methanol = 25: 1),The title compound (4.47 g) was obtained.
6,6'-(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(2-methoxynicotinic acid)[ No CAS ]
[ 146552-71-8 ]
C42H50Cl2N6O8[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
To an oven-dried 20 mL vial was added 6,6?-(2,2?-dichloro-[l,l?-biphenyl]-3,3?-diyl)bis(2- methoxynicotinic acid), HATU (2.1 equiv.), N,N-diisopropylethylamine (3.0 equiv.), and tert-butyl (S)- (l-aminopropan-2-yl)carbamate (2.1 equiv.) at room temperature. After stirring for 30 minutes the mixture was purified directly by silica gel chromatography to yield di-tert-butyl ((2S,2?S)-((6,6?-(2,2?- dichloro-[l,r-biphenyl]-3,3?-diyl)bis(2-methoxynicotinoyl))bis(azanediyl))bis(propane-l,2- diyl))dicarbamate.
tert-butyl (S)-(1-((4-(methylsulfonyl)-2-nitrophenyl)amino)propan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.8%
With potassium carbonate Heating;
4.1.7. General procedure for the synthesis of 10a-10b
General procedure: fluoro-3-nitrophenyl)ethan-1-one or 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (19.8 mmol) and K2CO3 (3.73 g, 27.0 mmol) in THF (50mL) were heated at 40 C for 4 h. After the reaction was completed, thereaction mixture was cooled to room temperature, concentrated under vacuum, and diluted with EtOAc (150 mL). The organic layer waswashed with brine, dried with anhydrous Na2SO4, filtered, andconcentrated under vacuum. The crude product was purified by flashchromatography (PE:EtOAc = 7:1) to provide the desired product asyellow solid.
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