* 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] Synthesis, 2009, # 8, p. 1305 - 1308
2
[ 4518-10-9 ]
[ 6942-37-6 ]
[ 46064-79-3 ]
[ 106896-48-4 ]
Reference：
[1] Synthesis, 2009, # 8, p. 1305 - 1308
3
[ 4518-10-9 ]
[ 6942-37-6 ]
[ 46064-79-3 ]
[ 106896-48-4 ]
Reference：
[1] Synthesis, 2009, # 8, p. 1305 - 1308
4
[ 67-56-1 ]
[ 106896-48-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 65℃; for 18 h;
(a) methyl 3-amino-2-bromobenzoate To a 100 mL RB flask was added 3-amino-2-bromobenzoic acid (1.75g, 8.10 mmol), concentrated H2S04 (2.159 mL, 40.5 mmol), and MeOH (80 mL). The reaction solution was heated to 65 °C for 18 h with stirring. The solvent was removed under vacuum and the residue slowly poured into iced saturated aqueous Na2C03 solution. The product was extracted from the aqueous solution with EtOAc, dried over Na2S04 and concentrated under vacuum to afford methyl 3-amino-2-bromobenzoate (1.8 g, 95percent) as a brown oil. LC-MS(ES) m/z = 230, 232 [M+H]+.
Reference：
[1] Patent: WO2014/195919, 2014, A1, . Location in patent: Page/Page column 79
[2] Journal of Organic Chemistry, 2018, vol. 83, # 10, p. 5791 - 5800
5
[ 5337-09-7 ]
[ 106896-48-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
With tin(ll) chloride In methanol; water for 2 h; Heating / reflux
2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 MMOL) (prepared from 2-amino-3-nitro- benzoic acid as described by Webber E. S. et AL., see patent application number WO 01/16136 A2) and SNCI2 (42 g, 223 MMOL) were REFLUXED in methanol (225 mL, 0.2 M) and H20 (5.3 G, 243 MMOL) for 2 hours. After cooling at ambient temperature, diatomaceous earth (20 G) and DICHLOROMETHANE (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) with vigorous stirring. The mixture was filtered and the organic phase was washed with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure to afford Intermediate 5 (a) (11.4 G) in 98percent yield. 1H-NMR (d6-DMSO) : o 7. 12 (dd, 1H, J = 8. 1,7. 5 Hz), 6.93 (dd, 1H, J = 8. 1,1. 6 Hz), 6.80 (dd, 1H, J = 7.4, 1.6 Hz), 5.57 (s, 2H), 3.81 (s, 3H).
99%
With sodium hydroxide; stannous chloride In hydrogenchloride; ethanol
b)' In an alternate procedure, Methyl 2-bromo-3-aminobenzoate may be prepared as follows: A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30 °C over 1 hour. The mixture was then heated at 50-60 °C for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35 °C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99percent) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
99%
With sodium hydroxide; stannous chloride In hydrogenchloride; ethanol
b) Methyl 2-bromo-3-aminobenzoate A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30° C. over 1 hour. The mixture was then heated at 50-60° C. for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35° C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99percent) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
With tin(ll) chloride; In methanol; water; for 2.0h;Heating / reflux;
2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 MMOL) (prepared from 2-amino-3-nitro- benzoic acid as described by Webber E. S. et AL., see patent application number WO 01/16136 A2) and SNCI2 (42 g, 223 MMOL) were REFLUXED in methanol (225 mL, 0.2 M) and H20 (5.3 G, 243 MMOL) for 2 hours. After cooling at ambient temperature, diatomaceous earth (20 G) and DICHLOROMETHANE (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) with vigorous stirring. The mixture was filtered and the organic phase was washed with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure to afford Intermediate 5 (a) (11.4 G) in 98% yield. 1H-NMR (d6-DMSO) : o 7. 12 (dd, 1H, J = 8. 1,7. 5 Hz), 6.93 (dd, 1H, J = 8. 1,1. 6 Hz), 6.80 (dd, 1H, J = 7.4, 1.6 Hz), 5.57 (s, 2H), 3.81 (s, 3H).
3.51 g (99%)
With sodium hydroxide; stannous chloride; In hydrogenchloride; ethanol;
b)' In an alternate procedure, Methyl 2-bromo-3-aminobenzoate may be prepared as follows: A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30 C over 1 hour. The mixture was then heated at 50-60 C for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35 C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
3.51 g (99%)
With sodium hydroxide; stannous chloride; In hydrogenchloride; ethanol;
b) Methyl 2-bromo-3-aminobenzoate A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30 C. over 1 hour. The mixture was then heated at 50-60 C. for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35 C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
With water; iron; ammonium chloride; In ethanol; at 80℃; for 1.0h;Product distribution / selectivity;
01382] Step 2: Synthesis of methyl 3-a obenzoate[01383] To a stirred solution of methyl 2-bromo-3-nitrobenzoate (4 g, 15.38 mmol) in ethanol (20 mL), ammonium chloride (4 g, 74.07 mmol) dissolved in water (20 mL) and iron powder (6.88 g, 123 mmol) were added under stirring. Resulting reaction mixture was heated at 80 C for 1 h. On completion, water was added to the mixture and filtered through celite. The filtrate was extracted with ethyl acetate and the combined organic layers washed with water and sodium bicarbonate solution, dried and concentrated under reduced pressure giving the desired methyl 3-amino-2-bromobenzoate (3 g, 85 %) which was used without further purification.
In acetic acid; at 25 - 80℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (2.39g, 10.0 mmol) and cyclohexane-1,3-dione (1.12g, 10.0 mmol) were dissolved in 10 mL of acetic acid at 25 C, under nitrogen. The mixture was stirred at 80C for 8 hours. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 2.46 g (76%) of methyl 2-bromo-3-((3- oxocyclohex-l-en-l-yl)amino)benzoate as a tan foam. 1H NMR (CDCl3-d) delta 7.53-7.55 (m, 2Eta), 7.37(dd, 1Eta, J=7.2, 8.4 Hz ), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H), 2.40- 2.42 (m, 2H), and 2.08-2.1 1 (m, 2H). MS (ESI) m/e [M+1]+ 324.0.
76%
With acetic acid; at 25 - 80℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and cyclohexane-1,3-dione (1.12 g, 10.0 mmol) were dissolved in 10 mL of acetic acid at 25 C., under nitrogen. The mixture was stirred at 80 C. for 8 hours. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 2.46 g (76%) of methyl 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoate as a tan foam. 1H NMR (CDCl3-d1) delta 7.53-7.55 (m, 2H), 7.37 (dd, 1H, J=7.2, 8.4 Hz), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.42 (m, 2H), and 2.08-2.11 (m, 2H). MS (ESI) m/e [M+1]+ 324.0.
76%
With acetic acid; at 25 - 80℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and cyclohexane-1,3-dione (1.12 g, 10.0 mmol) were dissolved in 10 mL acetic acid at 25 C. under nitrogen. The mixture was stirred at 80 C. for 8 h. The resulting solid was purified by chromatography column on silica gel eluting with hexane / ethyl acetate to give 2.46 g (76%) of 2-bromo-3 - ((3-oxocyclohex- 1 -en-1-yl ) Amino) benzoate as a yellow-brown foam.
76%
With acetic acid; at 25 - 80℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and 1,3-dioxocyclohexane (1.12 g, 10.0 mmol) at 25 C,Dissolved in acetic acid (10 mL) under nitrogen.The reaction mixture was reacted at 80 C for 8 hours.(Reaction mixture was spin-dried) The obtained solid was purified by chromatography (eluent: n-hexane and ethyl acetate)Methyl 2-bromo-3-((3-oxocyclohexyl-1-en-1-yl)amino)benzoate (2.46 g, 76%) was obtained as a tan foam.
17.2 g (88%)
c) 3- (3-Carbomethoxy-2-bromoanilino) cyclohex-2-en-1-one A mixture of <strong>[106896-48-4]methyl 2-bromo-3-aminobenzoate</strong> (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125 C under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) delta 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm-1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326.
17.2 g (88%)
c) 3-(3-Carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one A mixture of <strong>[106896-48-4]methyl 2-bromo-3-aminobenzoate</strong> (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125 C. under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) delta 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm-1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326. Elemental Analyses for C14H14NO3Br: Calculated: C, 51.85; H, 4.32; N, 4.32. Found: C, 53.60; H, 4.73; N, 4.09.
In acetic acid; at 80℃; for 8.0h;
Weigh 3.58 g of <strong>[106896-48-4]methyl 3-amino-2-bromobenzoate</strong>,1.68 g of cyclohexane-1,3-dione in a reaction flask,Add 20 ml of acetic acid to dissolve,Reaction at 80 C for 8 h,After completion of the reaction, the solvent was evaporated under reduced pressure.
b) Methyl 2-bromo-3-aminobenzoate Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) delta 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm-l) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232.
0.175 g (99%)
In ethyl acetate;
b) Methyl 2-bromo-3-aminobenzoate Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) delta 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm-1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232. Elemental Analyses for C8H8NO2Br: Calculated: C, 41.77; H, 3.51; N, 6.09. Found: C, 42.01; H, 3.29; N, 6.00.
0.175 g (99%)
In ethyl acetate;
b) Methyl 2-bromo-3-aminobenzoate Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) delta 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm-1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232. Elemental Analyses for C8H8NO2Br: Calculated: C, 41.77; H, 3.51; N, 6.09. Found: C, 42.01; H, 3.29; N, 6.00.
0.175 g (99%)
In ethyl acetate;
b) Methyl 2-bromo-3-aminobenzoate Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) delta 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm-1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232. Elemental Analyses for C8H8NO2Br: Calculated: C, 41.77; H, 3.51; N, 6.09. Found: C, 42.01; H, 3.29; N, 6.00.
3-(3-carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl)-cyclohex-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.18 g (74%)
c) 3-(3-Carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl-cyclohex-2-en-1-one A mixture of <strong>[106896-48-4]methyl 2-bromo-3-aminobenzoate</strong> (10.2 g, 44.3 mM) and 5-(4-trifluoromethylphenyl)-1,3-cyclohexanedione (1.77 g, 6.93 mM) was heated at 150 C. under a stream of nitrogen for 20 minutes. The resultant solid was triturated with 4:1 EtOAc/Et2O to afford 2.18 g (74%) of 3-(3-carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl)-cyclohex-2-en-1-one. 1H NMR (DMSO-d6) delta 8.9 (s, 1H), 7.75-7.5 (m, 7H), 3.9 (s, 3H), 3.5 (m, 1H), 2.9 (dd, J=14 and 9 Hz, 1H), 2.7 (dd, J=14 and 4 Hz, 1H), 2.55 (dd, J=14 and 9 Hz, 1H), 2.35 (dd, J=14 and 4 Hz, 1H). MS (ES) m/e 368, 370.
3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9.98 g (67%)
c) 3-(3-Carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one A mixture of <strong>[106896-48-4]methyl 2-bromo-3-aminobenzoate</strong> (10.2 g, 44.3 mM) and 5-methyl-1,3-cyclohexanedione (6.15 g, 48.7 mm) was heated at 125 C. under a stream of nitrogen for 1.5 hours. The resultant solid was triturated with ethyl acetate to afford 9.98 g (67%) of 3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one. 1H NMR (CDCl3) delta 7.55 (m, 2H), 7.35 (dd, J=8 and 8 Hz, 1H), 6.4 (bs, 1H), 5.55 (s, 1H), 3.95 (s, 3H), 2.6-2.0 (m, 5H), 1.15 (d, J=7 Hz, 3H). MS (ES) m/e 338, 340.
[01384] Step 3: Synthesis of methyl 2-b opentylamino) benzoate[01385] To a stirred solution of <strong>[106896-48-4]methyl 3-amino-2-bromobenzoate</strong> (3 g, 13.0 mmol) and cyclopentanone (5.4 g, 64.28 mmol) in methanol (20 mL), acetic acid (1.56 g, 26 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (2 g, 3 L7 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material purified by column chromatography to afford methyl 2-bromo-3-(cyclopentylamino) benzoate (1 .4 g, 36 %).
benzyl 3,5-dioxopiperidine-1-carboxylate[ No CAS ]
[ 106896-48-4 ]
[ 1446261-45-5 ]
Yield
Reaction Conditions
Operation in experiment
51%
In acetic acid; at 25 - 70℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (0.25g, 1.1 mmol) and benzyl 3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved in 10 mL of acetic acid at 25 C, under nitrogen. The mixture was stirred for 8 hours at 70C. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 0.13 g (51%) of benzyl 3-((2- bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate as a tan foam. 1H NMR (CDCl3-d1) delta 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H), 5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS (ESI) m/e [M+l]+ 459.0.
51%
With acetic acid; at 25 - 70℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved in 10 mL of acetic acid at 25 C., under nitrogen. The mixture was stirred for 8 hours at 70 C. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 0.13 g (51%) of benzyl 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate as a tan foam. 1H NMR (CDCl3-d1) delta 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H), 5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 459.0.
51%
With acetic acid; at 25 - 70℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved in 10 mL acetic acid at 25 C. under nitrogen did. The mixture was stirred at 70 C. for 8 hours. The resulting solid was purified by chromatography column on silica gel eluting with hexane / ethyl acetate to give 0.13 g (51%) of 3 - ((2-bromo-3- (methoxycarbonyl) phenyl) amino) -5- Oxo-5,6-dihydropyridine-1 (2H) -carboxylate as a yellow-brown foam.
51%
With acetic acid; at 25 - 70℃; for 8.0h;Inert atmosphere;
Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxy=opiperidine-1-carboxylate (0.13 g, 0.55 mmol) at 25 C,Dissolved in acetic acid (10 mL) under nitrogen. The mixture was stirred at 70 C for 8 hours.The obtained solid was purified by column chromatography (eluent: n-hexane and ethyl acetate).benzyl 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate 0.13 g (51%),It is a tan foamy substance.
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In toluene; at 100℃; for 18.0h;Inert atmosphere;
To a suspension of tetrakis(triphenylphosphine)palladium(0)(1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol) in 54 mL oftoluene were added <strong>[106896-48-4]methyl 3-amino-2-bromobenzoate</strong> (2.3 g, 10 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g,12 mmol), and TEA (7 mL, 50 mmol). The mixture was stirred for 18 h at 100 C under nitrogen atmosphere. After cooling, water (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL) and the combined organic layers were washed with brine (20 mL) and dried over MgSO4. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to provide 2.31 g of (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate.
2.31 g
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In toluene; at 100℃; for 18.0h;Inert atmosphere;
To a suspension of tetrakis(triphenylphosphine)palladium(0)(1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol) in 54 mL of toluene were added <strong>[106896-48-4]methyl 3-amino-2-bromobenzoate</strong> (2.3 g, 10 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), and TEA (7 mL, 50 mmol). The mixture was stirred for 18 h at 100 C. under nitrogen atmosphere. After cooling, water (20 mL) was added. The mixture was extracted with EtOAc (3*20 mL) and the combined organic layers were washed with brine (20 mL) and dried over MgSO4. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to provide 2.31 g of (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate. To a refluxing solution of (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (1.1 g, 2.8 mmol) and dibromoethane (5.21 g, 2.8 mmol) in ethanol (20 mL) was added zinc powder (1.43 g, 22 mmol) in one portion. After refluxing for 8 h, the reaction mixture was filtered and the filtrate was concentrated to 3 mL, which was poured into water (15 mL). The reaction mixture was extracted with EA (20 mL*3). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give pale brown oil, which was chromatographed over silica gelelution with hexane: ethyl acetate (5:1) to give the (R)-methyl 2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate and (307 mg, 0.78 mmol). 1H NMR (CDCl3-d) delta 10.3 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.29-7.35 (m, 5H), 7.16 (t, 1H, J=7.8 Hz), 6.96 (s, 1H), 5.15 (s, 2H), 3.95 (s, 3H), 3.56-3.59 (m, 2H), 2.83-2.85 (m, 1H), 2.03-2.07 (m, 2H), and 1.84-1.93 (m, 4H). MS (ESI) m/e [M+1]+ 393.0.
2.31 g
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In toluene; at 100℃; for 18.0h;Inert atmosphere;
To a suspension of tetrakis (triphenylphosphine) palladium (0) (1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol) in 54 mL of toluene was added <strong>[106896-48-4]methyl 3-amino-2-bromobenzoate</strong> (2.3 g 10 mmol) , Benzyl (R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), and TEA (7 mL, 50 mmol). The mixture was stirred under nitrogen atmosphere at 100 C. for 18 hours. After cooling, water (20 mL) was added. The mixture was extracted with EtOAc (3 × 20 mL) and the combined organic layers were washed with brine (20 mL) and dried over MgSO 4. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using CH 2 Cl 2 as eluent to give 2.31 g of (R) -2 - ((2-amino-6- (methoxycarbonyl) phenyl) ethynyl) -2-methylpyrrolidin- 1 -benzyl carboxylate.
2.31 g
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In toluene; at 100℃; for 18.0h;Inert atmosphere;
Tetrakis(triphenylphosphine)palladium(0) (1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol), toluene (54 mL) and methyl 3-amino-2-bromo-benzoate (2.3 g, 10mmol),(R)-Benzyl-2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), triethylamine (7 mL, 50 mmol).The mixture was heated to 100 C under nitrogen for a period of 18 hours.Cooled and added water (20 mL). (20mL × 3) and extracted with ethyl acetate, the organic phases were combined, saturated brine (20mL), dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated to dryness and the residue was purified using a silica gel column (mobile phase: dichloromethane).(R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate(2.31g)
(a) methyl 3-amino-2-bromobenzoate To a 100 mL RB flask was added 3-amino-2-bromobenzoic acid (1.75g, 8.10 mmol), concentrated H2S04 (2.159 mL, 40.5 mmol), and MeOH (80 mL). The reaction solution was heated to 65 C for 18 h with stirring. The solvent was removed under vacuum and the residue slowly poured into iced saturated aqueous Na2C03 solution. The product was extracted from the aqueous solution with EtOAc, dried over Na2S04 and concentrated under vacuum to afford methyl 3-amino-2-bromobenzoate (1.8 g, 95%) as a brown oil. LC-MS(ES) m/z = 230, 232 [M+H]+.
methyl 2-bromo-3-((4,4-difluorocyclohexyl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.2%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 2.0h;
(a) methyl 2-bromo-3-((4,4-difluorocyclohexyl)amino)benzoate To a solution of 4,4-difluorocyclohexanone (1.312 g, 9.78 mmol) and methyl 3- amino-2-bromobenzoate (1.5 g, 6.52 mmol) in DCM (30 mL), was added AcOH (0.560 mL, 9.78 mmol), then Na(OAc)3BH (4.15 g, 19.56 mmol) portionwise. The reaction solution was stirred at room temperature for 2 days. The reaction solution was quenched with saturated aqueous NaHC03 solution slowly and the layers were separated, then the aqueous layer was extracted with DCM. The combined organics were adsorbed onto silica, and purified by flash chromatography (CombiFlash, 40 g column, 0-10% EtOAc in hexane) to afford methyl 2-bromo-3-((4,4-difluorocyclohexyl)amino)benzoate (1.23g, 3.53 mmol, 54.2% yield) as a colorless oil. LC-MS(ES) m/z = 348.1, 350.1 [M+H]+.
tert-butyl 4-((2-bromo-3-(methoxycarbonyl)phenyl)amino)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.6%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 96.0h;
(a) tert-butyl 4-((2-bromo-3-(methoxycarbonyl)phenyl)amino)piperidine-l- carboxylate To a flask containing tert-butyl 4-oxopiperidine-l-carboxylate (10.59 g, 53.1 mmol) and <strong>[106896-48-4]methyl 3-amino-2-bromobenzoate</strong> (4.89 g, 21.26 mmol) in DCM (100 mL), was added AcOH (2.434 mL, 42.5 mmol), then Na(OAc)3BH (18.02 g, 85 mmol) portionwise, and the reaction solution was stirred at room temperature for 4 days. The reaction solution was quenched with saturated aqueous NaHC03 solution slowly and the layers separated. The aqueous layer was extracted with DCM (3x). The combined organics were washed with brine and adsorbed onto silica and purified by flash chromatography (CombiFlash, 120 g column, 0-20% EtOAc in hexane) to afford tert- butyl 4-((2-bromo-3-(methoxycarbonyl)phenyl)amino)piperidine-l-carboxylate (5.5 g, 13.31 mmol, 62.6% yield) as a yellow waxy solid. LC-MS(ES) m/z = 357.1, 359.1 [M+H- tBu]+ (major), 413.2 415.2 [M+H]+ (minor).
11-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-methoxy-3-methyl-7,8,9,10,16,17-hexahydrobenzo[h]pyrido[4,3-c][1,6]oxaazacyclotridecin-15(5H)-one[ No CAS ]
(E)-11-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-methoxy-3-methyl-6,7,16,17-tetrahydro-5H-benzo[c]pyrido[4,3-k][1]azacyclotridecin-15(10H)-one[ No CAS ]
(Z)-11-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-methoxy-3-methyl-6,7,16,17-tetrahydro-5H-benzo[c]pyrido[4,3-k][1]azacyclotridecin-15(10H)-one[ No CAS ]
(E)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-methoxy-3,5-dimethyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecin-14(9H)-one trifluoroacetate[ No CAS ]
(E)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-(hydroxymethyl)-1-methoxy-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecin-14(9H)-one trifluoroacetate[ No CAS ]
(Z)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-(hydroxymethyl)-1-methoxy-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecin-14(9H)-one trifluoroacetate[ No CAS ]
(E)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-(hydroxymethyl)-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecine-1,14(2H,9H)-dione[ No CAS ]
(Z)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-(hydroxymethyl)-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecine-1,14(2H,9H)-dione[ No CAS ]
10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-(hydroxymethyl)-3-methyl-6,7,8,9,15,16-hexahydrobenzo[c]pyrido[4,3-j][1]azacyclododecine-1,14(2H,5H)-dione[ No CAS ]
(E)-11-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-7-hydroxy-1-methoxy-3-methyl-6,7,16,17-tetrahydro-5H-benzo[c]pyrido[4,3-k][1]azacyclotridecin-15(10H)-one[ No CAS ]
11-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-7-hydroxy-1-methoxy-3-methyl-7,8,9,10,16,17-hexahydro-5H-benzo[c]pyrido[4,3-k][1]azacyclotridecin-15(6H)-one[ No CAS ]
11-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-7-hydroxy-3-methyl-5,6,7,8,9,10,16,17-octahydro-1H-benzo[c]pyrido[4,3-k][1]azacyclotridecine-1,15(2H)-dione[ No CAS ]
(E)-15-(2-((tert-butyldimethylsilyl)oxy)ethyl)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-methoxy-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecin-14(9H)-one[ No CAS ]
(E)-10-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-15-(2-hydroxyethyl)-3-methyl-5,6,15,16-tetrahydrobenzo[c]pyrido[4,3-j][1]azacyclododecine-1,14(2H,9H)-dione[ No CAS ]
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