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Structure of 50637-83-7 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Intermediate 4: 2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (Scheme 1); To the l-(6-bromo-2-naphthalenyl)ethanone (lg, 4.01 mmol) dissolved in acetic acid (5ml) was added pyridinium tribromide (1.28 g, 4.01 mmol) and stirred for lOmin. HBr (33percent in acetic acid, 1.321 ml, 8.03 mmol) was added slowly and the solution was stirred for 4h. Yellow precipitation was noticed. The reaction mixture was quenched by adding cold sat NaHC03 solution and the precipitate formed was filtered and washed with water and dried.Yield : 76.0percent'H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.50 (s, 1 H), 8.03 - 8.13 (m, 2 H), 7.79 - 7.91 (m, 2 H), 7.67(dd, J=8.8, 1.5 Hz, 1 H), 4.57 (s, 2 H).
73%
at 20℃;
Bromine (3.32 g, 1.07 ml, 20.8 mmol) was added to a heated solution of 1-(6-bromonaphthalen-2-yl)ethanone (5.18 g, 20.8 mmol) in acetic acid (100 mL). Left to cool to rt overnight. The precipitate was filtered, washed with Et2O and dried under vacuum to give 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (5.02 g, 73percent).
70%
With copper bromide In chloroform; ethyl acetate at 10℃; Reflux
S2 (249.1 mg, 1.0 mmol) andCopper bromide (223.4 mg, 1.5 mmol)Add 25mL dried egg-shaped bottle,Add 5mL ethyl acetate and 5mL chloroform solution at room temperature to make the raw material completely dissolved,Then refluxed overnight. TLC tracking until the conversion of raw materials is completed,Remove the solvent after stopping heating to room temperature.Ethyl acetate was added to the bottle to dissolve it, followed by saturated brine and waterThe combined organic phases were dried over anhydrous sodium sulfate.After concentration under reduced pressure, the crude product was purified by column chromatography (petroleum ether → petroleum ether:Ethyl acetate = 20: 1) to give S3 (230.1 mg, 70percent yield) as a white solid.
67%
With bromine In dichloromethane at 15℃;
Step A - Synthesis of compound Int-39b Compound Int-39a (6 g, 24.09 mmol) in CH2C12 (80 mL) was treated dropwise with Br2 (1.253 mL, 24.33 mmol). The mixture was allowed to stir for about 15 hours then concentrated in vacuo. The residue obtained was recrystalhzed from THF to provide compound Int-39b, which was dried in vacuo (5.3g; 67percent).
37.82%
at 20℃; for 1 h;
Compound AA_072-2 (3.5 g, 14.06 mmol) was dissolved in acetic acid (30 mL), liquid bromine (2.2 g, 14.06 mmol) was dripped slowly. After dripping, the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete as detected by TLC, H2O (80 mL) was added. The reaction mixture was filtrated and the solid was collected to deliver the target compound AA_072-3 (white solid, 1.74 g, yield 37.82percent). The product was directly used for the next step without purification. 1H NMR (CDCl3, 400 MHz): δ 8.12-8.05 (m, 2H), 7.88-7.85 (m, 3H), 7.83-7.68 (m, 1H), 4.56 (s, 2H).
7 g
With bromine In 1,4-dioxane; dichloromethane at 10℃; for 2 h;
To a solution of bromide B-la (5.0 g, 20.07 mmol) in DCM (150 mL) was added B (0.827 mL, 16.06 mmol) in dioxane (50 mL) over 10 minutes at 10 °C and the reaction mixture was stirred at 10 °C for 2 h. The reaction mixture was quenched with 10percent aHC03and extracted with DCM. The organic layer was dried over Na2S04and concentrated to obtain crude dibromide B-lb (7.0 g) as a yellow solid. NMR (CDC13), δ = 7.26 ppm, 400 MHz): δ 8.48 (s, 1 H), 8.07- 8.04 (m, 2 H), 7.85 (d, J = 8.8, 1 H), 7.84 (d, J = 8.8, 1 H), 7.66 (dd, J = 8.8, 2.0, 1 H), 4.55 (s, 2 H).
Reference：
[1] Patent: WO2011/91446, 2011, A1, . Location in patent: Page/Page column 7; 11
[2] Patent: US2012/230951, 2012, A1, . Location in patent: Page/Page column 85
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2011, vol. 50, # 4, p. 593 - 604
[4] Patent: CN107286150, 2017, A, . Location in patent: Paragraph 0132; 0133; 0134; 0135
[5] Patent: WO2013/39878, 2013, A1, . Location in patent: Page/Page column 109; 110
[6] Patent: US2017/253614, 2017, A1, . Location in patent: Paragraph 0574; 0576
[7] Justus Liebigs Annalen der Chemie, 1973, p. 1112 - 1140
[8] Journal of Medicinal Chemistry, 1981, vol. 24, # 1, p. 67 - 74
[9] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1984, vol. 23, # 12, p. 1008 - 1010
[10] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1984, vol. 23, # 12, p. 1008 - 1010
[11] Patent: US2011/64695, 2011, A1, . Location in patent: Page/Page column 94
[12] Patent: US2011/64697, 2011, A1, . Location in patent: Page/Page column 85
[13] Patent: US2011/64698, 2011, A1, . Location in patent: Page/Page column 87
[14] Patent: WO2011/54834, 2011, A1,
[15] Patent: WO2012/13643, 2012, A1, . Location in patent: Page/Page column 26
[16] Patent: US2012/219594, 2012, A1,
[17] Patent: US2015/23913, 2015, A1, . Location in patent: Paragraph 0995-0996
[18] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 370
[19] Patent: US9127021, 2015, B2, . Location in patent: Page/Page column 153
[20] Patent: WO2010/99527, 2010, A1, . Location in patent: Page/Page column 118
2
[ 1256387-44-6 ]
[ 50637-83-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 2033 - 2046
[2] Patent: WO2010/132601, 2010, A1, . Location in patent: Page/Page column 594-595
3
[ 1303533-76-7 ]
[ 50637-83-7 ]
Yield
Reaction Conditions
Operation in experiment
50%
With triethylamine; phosphonic acid diethyl ester In tetrahydrofuran
1- (6-bromonaphthalen-2-yl)ethanone (55.6 g, 223 mmol, 1.0 equiv.) was dissolved in dichloromethane (1.3 L). Dibromine (78.3 g, 490 mmol, 2.2 equiv.) was added drop wise during 30 minutes. The reaction mixture was stirred 1 hour and concentrated to afford 2,2-dibromo-l-(6-bromonaphthalen-2-yl)ethanone as a solid which was used as such in next step.2,2-dibromo-l-(6-bromonaphthalen-2-yl)ethanone (90.0 g, 221 mmol, 1.00) was dissolved in tetrahydrofurane (800 mL), triethylamine (27.67 mL, 199 mmol,0.9 equiv.) was added followed by diethyl phosphite (45.8 g, 332 mmol, 1.50 equiv.). The reaction mixture was stirred overnight. The reaction mixture was filtrated and the solvent was removed in vacuum. The obtained residue was dissolved in ethyl acetate (1.2 L) and washed with water. The organic layer was separated, dried over sodium sulphate, filtrated and concentrated to yield crude 2-bromo-l-(6-bromonaphthalen-2- yl)ethanone (70.3 g). Recrystallization from acetonitrile gave 30 g (first batch) and 6.5 g (second batch) of 2-bromo-l-(6-bromonaphthalen-2-yl)ethanone (50 percent)
Intermediate 4: 2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (Scheme 1); To the l-(6-bromo-2-naphthalenyl)ethanone (lg, 4.01 mmol) dissolved in acetic acid (5ml) was added pyridinium tribromide (1.28 g, 4.01 mmol) and stirred for lOmin. HBr (33% in acetic acid, 1.321 ml, 8.03 mmol) was added slowly and the solution was stirred for 4h. Yellow precipitation was noticed. The reaction mixture was quenched by adding cold sat NaHC03 solution and the precipitate formed was filtered and washed with water and dried.Yield : 76.0%'H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.50 (s, 1 H), 8.03 - 8.13 (m, 2 H), 7.79 - 7.91 (m, 2 H), 7.67(dd, J=8.8, 1.5 Hz, 1 H), 4.57 (s, 2 H).
73%
With bromine; acetic acid; at 20℃;
Bromine (3.32 g, 1.07 ml, 20.8 mmol) was added to a heated solution of 1-(6-bromonaphthalen-2-yl)ethanone (5.18 g, 20.8 mmol) in acetic acid (100 mL). Left to cool to rt overnight. The precipitate was filtered, washed with Et2O and dried under vacuum to give 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (5.02 g, 73%).
70%
With copper bromide; In chloroform; ethyl acetate; at 10℃;Reflux;
S2 (249.1 mg, 1.0 mmol) andCopper bromide (223.4 mg, 1.5 mmol)Add 25mL dried egg-shaped bottle,Add 5mL ethyl acetate and 5mL chloroform solution at room temperature to make the raw material completely dissolved,Then refluxed overnight. TLC tracking until the conversion of raw materials is completed,Remove the solvent after stopping heating to room temperature.Ethyl acetate was added to the bottle to dissolve it, followed by saturated brine and waterThe combined organic phases were dried over anhydrous sodium sulfate.After concentration under reduced pressure, the crude product was purified by column chromatography (petroleum ether ? petroleum ether:Ethyl acetate = 20: 1) to give S3 (230.1 mg, 70% yield) as a white solid.
67%
With bromine; In dichloromethane; at 15℃;
Step A - Synthesis of compound Int-39b Compound Int-39a (6 g, 24.09 mmol) in CH2C12 (80 mL) was treated dropwise with Br2 (1.253 mL, 24.33 mmol). The mixture was allowed to stir for about 15 hours then concentrated in vacuo. The residue obtained was recrystalhzed from THF to provide compound Int-39b, which was dried in vacuo (5.3g; 67%).
37.82%
With bromine; acetic acid; at 20℃; for 1h;
Compound AA_072-2 (3.5 g, 14.06 mmol) was dissolved in acetic acid (30 mL), liquid bromine (2.2 g, 14.06 mmol) was dripped slowly. After dripping, the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete as detected by TLC, H2O (80 mL) was added. The reaction mixture was filtrated and the solid was collected to deliver the target compound AA_072-3 (white solid, 1.74 g, yield 37.82%). The product was directly used for the next step without purification. 1H NMR (CDCl3, 400 MHz): delta 8.12-8.05 (m, 2H), 7.88-7.85 (m, 3H), 7.83-7.68 (m, 1H), 4.56 (s, 2H).
With bromine; acetic acid; for 1h;
Step 356c. The compound from step 356b (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc-saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).
With bromine; In acetic acid; for 1h;
Example 1 Step 1a. A mixture of 5-bromo-2-chloropyrimidine (0.101 g, 0.524 mmol) and (S)-2-(aminomethyl)-1-N-Boc-pyrrolidine (0.105 g, 0.524 mmol) in 1,4-dioxane (2 mL) were heated up to 100 C. for 5 h. The mixture was cooled down and the volatiles were evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (75.5 mg, 40%). ESIMS m/z=357.25, 359.25 [M+H]+.Step 1b. 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et2O, 8.09 mL, 24.3 mmol) slowly at 0 C. for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH4Cl. The volatiles were removed and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).Step 1c. The compound from step 1b (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc-saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).Step 1d. A mixture of the compound from step 1c (at most 11.6 mmol) and N-Boc-L-proline (3.75 g, 17.4 mmol) in CH3CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearance of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z=462.03, 464.02 [M+H]+.Step 1e. A mixture of the compound from step 1d (0.200 g, 0.452 mmol), bis(pinacolato)diboron (0.144 g, 0.565 mmol), PdCl2(dppf)2 (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80 C. under N2 for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc-water). The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow solid (0.188 g, 85%). ESIMS m/z=490.12 [M+H]+.Step 1f. A mixture of the compound from step 1a (30.2 mg, 84.5 mumol), the compound from step 1e (53.7 mg, 0.110 mmol) and NaHCO3 (28.4 mg, 0.338 mmol) in DME (6 mL) and H2O (2 mL) was added Pd(PPh3)4 (4.9 mg, 4.2 mumol). The resultant mixture were degassed and heated to 85 C. under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc-H2O). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow oil (47.1 mg, 87%). ESIMS m/z=640.61 [M+H]+.
With bromine; In acetic acid; for 1h;
Step 349b. The compound from step 349a (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc-saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).
With N-Bromosuccinimide; trimethylsilyl trifluoromethanesulfonate; In acetonitrile; at 30℃; for 24h;
TMSOTf (13.4 g, 60.2 mmol) was added to a stirred solution of l-(6-bromonaphthalen- 2-yl)ethanone (300 g, 1204 mmol) and BS (235.8 g, 1324 mmol) in CH3CN(6000 mL). The mixture was stirred for 24 h at 30C. The reaction mixture was diluted with ether, washed with H20, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue of crude 2-bromo-l-(6-bromonaphthalen-2-yl)ethanone (526 g) was used in the next step without further purification.
With bromine; In 1,4-dioxane; dichloromethane; at 10℃; for 2h;
To a solution of bromide B-1a (5.0 g, 20.07 mmol) in DCM (150 mL) was added Br2(0.827 mL, 16.06 mmol) in dioxane (50 mL) over 10 minutes at 10 C. and the reaction mixture was stirred at 10 C. for 2 h. The reaction mixture was quenched with 10% NaHCO3and extracted with DCM. The organic layer was dried over Na2SO4and concentrated to obtain crude dibromide B-1b (7.0 g) as a yellow solid.1H NMR (CDCl3), delta=7.26 ppm, 400 MHz): delta 8.48 (s, 1H), 8.07-8.04 (m, 2H), 7.85 (d, J=8.8, 1H), 7.84 (d, J=8.8, 1H), 7.66 (dd, J=8.8, 2.0, 1H), 4.55 (s, 2H).
7 g
With bromine; In 1,4-dioxane; dichloromethane; at 10℃; for 2h;
To a solution of bromide B-la (5.0 g, 20.07 mmol) in DCM (150 mL) was added B (0.827 mL, 16.06 mmol) in dioxane (50 mL) over 10 minutes at 10 C and the reaction mixture was stirred at 10 C for 2 h. The reaction mixture was quenched with 10% aHC03and extracted with DCM. The organic layer was dried over Na2S04and concentrated to obtain crude dibromide B-lb (7.0 g) as a yellow solid. NMR (CDC13), delta = 7.26 ppm, 400 MHz): delta 8.48 (s, 1 H), 8.07- 8.04 (m, 2 H), 7.85 (d, J = 8.8, 1 H), 7.84 (d, J = 8.8, 1 H), 7.66 (dd, J = 8.8, 2.0, 1 H), 4.55 (s, 2 H).
With bromine; acetic acid; for 1h;
Step 348i. The compound from step 348h (2.89 g, 11.6 mmol) in acetic acid (60 mE) was treated with bromine (0.59 mE, 11.6 mmol) dropwise for 1 hout The volatiles were evaporated and the residue was partitioned (EtOAc-saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2504), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).
With bromine; acetic acid; for 1h;
Step l-458b. The compound from step l-458a (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 12h;
(S)-2-(2-f6-bromonaphthalen-2-yl -2-oxoethyQ 1-tert-butyl pyrrolidine- 1 ,2-dicarboxylate; 2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (lg, 3.05 mmol), DIEA (0.8 ml,4.57 mmol)and N-[(methyloxy)carbonyl]-L-valyl-L-proline (787 mg, 3.66 mmol) were dissolved in acetonitrile (10 ml) and the reaction was stirred at RT for 12h, afterwards solution was concentrated and product purified on silica to provide pure title compound. Yield : 85%; ES LC-MS m/z = 463 (M+H)+;1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.40 (s, 1 H), 8.08 (br. s., 1 H), 7.99 (dd, J=8.6, 3.0 Hz, 1 H), 7.85 (d, J=8.8 Hz, 2 H), 7.61 - 7.77 (m, 1 H), 5.29 - 5.73 (m, 2 H), 4.41 - 4.55 (m, 1 H), 3.55 - 3.68 (m, 1 H),3.37 - 3.54 (m, 1 H), 2.30 - 2.38 (m, 2 H), 2.05 - 2.17 (m, 1 H), 1.87 - 2.01 (m, 1 H), 1.47 (d, J=6.4 Hz, 9 H).
64%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 25℃; for 4h;
Step B - Synthesis of compound Int-39c Compound Int-39b (5.3 g, 16.16 mmol) and BOC-PRO-OH (3.65 g, 16.97 mmol) in Acetonitrile (50 mL) was cooled to 20 C and DIPEA (3.39 mL,19.39 mmol) was added dropwise. The mixture was allowed to warm to 25^C and allowed to stir for 4 hours. The reaction was diluted with 100 mL ethyl acetate washed with 1 x 50 mL aq. 1 N HCl; 2x 50 mL brine, filtered and the solvent was evaporated in vacuo. The material was recrystalhzed from ethyl acetate to provide compound Int-39c (4.8 g; 64%).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
Step 356d. A mixture of the compound from step 356c (at most 11.6 mmol) and N-Boc-L-proline (3.75 g, 17.4 mmol) in CH3CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearance of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z=462.03, 464.02 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
Example 1 Step 1a. A mixture of 5-bromo-2-chloropyrimidine (0.101 g, 0.524 mmol) and (S)-2-(aminomethyl)-1-N-Boc-pyrrolidine (0.105 g, 0.524 mmol) in 1,4-dioxane (2 mL) were heated up to 100 C. for 5 h. The mixture was cooled down and the volatiles were evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (75.5 mg, 40%). ESIMS m/z=357.25, 359.25 [M+H]+.Step 1b. 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et2O, 8.09 mL, 24.3 mmol) slowly at 0 C. for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH4Cl. The volatiles were removed and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).Step 1c. The compound from step 1b (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc-saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).Step 1d. A mixture of the compound from step 1c (at most 11.6 mmol) and N-Boc-L-proline (3.75 g, 17.4 mmol) in CH3CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearance of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z=462.03, 464.02 [M+H]+.Step 1e. A mixture of the compound from step 1d (0.200 g, 0.452 mmol), bis(pinacolato)diboron (0.144 g, 0.565 mmol), PdCl2(dppf)2 (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80 C. under N2 for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc-water). The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow solid (0.188 g, 85%). ESIMS m/z=490.12 [M+H]+.Step 1f. A mixture of the compound from step 1a (30.2 mg, 84.5 mumol), the compound from step 1e (53.7 mg, 0.110 mmol) and NaHCO3 (28.4 mg, 0.338 mmol) in DME (6 mL) and H2O (2 mL) was added Pd(PPh3)4 (4.9 mg, 4.2 mumol). The resultant mixture were degassed and heated to 85 C. under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc-H2O). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow oil (47.1 mg, 87%). ESIMS m/z=640.61 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
Step 349c. To a mixture of the compound from step 349b (at most 11.6 mmol) and N-Boc-L-proline (3.75 g, 17.4 mmol) in CH3CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z=462.03, 464.02 [M+H]+.
2-Bromo-l-(6-bromonaphthalen-2-yl)ethanone (526.5 g, 1204. mmol) was dissolved in CH3CN (6000 mL). Boc-J-proline (284 g, 1325 mmol) was added to the solution and the reaction mixture was stirred for 20 min at room temperature. Et3N (480 mL, 3612 mmol) was added dropwise to the solution. The reaction mixture was stirred for 15 h at room temperature. The solvent was removed under vacuum and crude 5 (794 g) was used in the next step without further purification. Method Al; Rt: 1.68 min. m/z : 484.1 (M+Na)+ Exact mass: 461.1
SC-1 2-Bromo-l-(6-bromonaphthalen-2-yl)ethanone (526.5 g, 1204. mmol) was dissolved in CH3CN (6000 mL). Boc-Z-proline (284 g, 1325 mmol) was added to the solution and the reaction mixture was stirred for 20 minutes at room temperature. Et3N (480 mL, 3612 mmol) was added drop wise to the solution. The reaction mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and crude SC-1 (794 g) was used in the next step without further purification. Method Al; Rt: 1.68 min. m/z : 484.1 (M+Na)+ Exact mass: 461.1
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
Step 348j. A mixture of the compound from step 348i (at most 11.6 mmol) andN-l3oc-E-proline (3.75 g, 17.4 mmol) in CH3CN (60 mE) was added DIPEA (2.89 mE, 23.2 mmol) slowly. The mixture was stirred at it until the disappearance of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2504), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS mlz=462.03, 464.02 [M+H].
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
Step l-458c. A mixture of the compound from step 1-458b (at most 11.6 mmol) and 7V-Boc-L-proline (3.75 g, 17.4 mmol) in CH3CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearencePAGE 118 OF 222 of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SOzI), filtered and evaporated to give the crude desired compound as a yellow- white foam (4.762 g). ESIMS m/z = 462.03, 464.02 [M+H]+
pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine; In acetonitrile; for 72h;
Pyrrolidine- 1 ,2-dicarboxylic acid l-tert-butyl ester (24.0 g) was dissolved in acetonitrile (330 mL), and triethylamine (15.6 mL) was added. A solution of 2-bromo-l -(6- brornonaphthalen-2-yl)-ethanone (33.0 g) in acetonitrile (170 mL) were added. Reaction mixture was stirred over 3 days and evaporated under vacuum. Oil was dissolved in dichloromethane (100 mL), extracted with water (50 mL) and with NaHCO3 solution (50 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-30% ethyl acetate :hexane) and evaporated under vacuum, giving pyrrolidine- 1 ,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl] ester l-tert-butyl ester (39.2 g, 84%) as a tan solid.
1 -(6-Bromonaphthalen-2-yl)-2- diazoethanone (34.7 g) were dissolved in ethyl acetate (500 mL), and hydrobromic acid solution (21.1 mL, 5.7 M in acetic acid) was added at 0C. Reaction mixture was stirred 3 hours, NaHCtheta3 solution (200 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum, giving 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g, crude) as a tan solid.
Step; 2-bromo-l-(6-bromonaphthalen-2-yl)ethanone (4.9 g, 14.9 mmol, 1 equiv.) was suspended in acetonitrile (150 mL) at 20. (L^-^oc-Proline (3.22g, 14.9 mmol, 1 equiv.) was added followed by N-ethyl-N-isopropylpropan-2-amine (2.83 mL, 16.4 mmol, 1.10 equiv.) The reaction mixture was stirred at 20C for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in dichloromethane and washed successively with aqueous hydrochloric acid (1 %, 100 mL) and aqueous NaHC03 solution. After drying over sodium sulphate, filtration and concentration, the residual oil (6.52 g, 94%) was used as such in the next step.Ammonium acetate (16.3 g, 212 mmol, 15 equiv.) was added to the compound obtained above (6.52 g, 14.1 mmol, 1.00 equiv.) dissolved in toluene (150 mL) and the mixture was refluxed overnight. The reaction mixture was concentrated and the residue was crystallized from acetonitrile (100 mL). The crystals were filtered off and dried in vacuum at 40C to afford VHIb (3.2 g, 51 %).
To a solution of 2-bromo-l-(6-bromonaphthalen-2-yl)ethanone (57.7 g, 175.9 mmol, 80% pure) in acetonitrile (1 L), L-Cte-Proline (43.8 g, 175.9 mmol) was added, followed by diisopropylethylamine (33.4 mL, 193.5 mmol) and the reaction was stirred 40 minutes at room temperature. The solvent then was removed under reduced pressure and the obtained residue was redissolved in dichloromethane (500 mL), washed with 1%) HC1 (500 mL) and aqueous saturated NaHC03 (500 ml). The organic phase was dried with MgSC^, filtrated and the solvent was removed under reduced pressure resulting in a brown oily residue (80 g) which was used as such in next step.Part of the above residue (69.8 g, 140.6 mmol) and ammoniumacetate (162.6 g, 2.11 mol) were stirred in toluene and refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The obtained residue was stirred in a mixture of dichloromethane and water (1/1, 1500 mL) to precipitate compound VIIIc. After filtering and rinsing with water, compound VIIIc (61.3 g, 92 %) was obtained as a white powder.1H NMR (400 MHz, DMSO-de) delta ppm 1.84 - 2.38 (m, 4 H), 3.42 - 3.56 (m, 1 H), 3.58 - 3.73 (m, 1 H), 4.84 - 5.20 (m, 3 H), 6.97 - 7.46 (m, 5 H), 7.54-7.60(m, 1 H), 7.63-7.71 (m, 1 H), 7.83 - 7.91 (m, 2 H), 7.95-8.05 (m, 1 H), 8.10-8.16 (m, 1 H), 8.22-8.37 (m, 1 H), 11.92 - 12.44 (m, 1 H)
With triethylamine; phosphonic acid diethyl ester; In tetrahydrofuran;
1- (6-bromonaphthalen-2-yl)ethanone (55.6 g, 223 mmol, 1.0 equiv.) was dissolved in dichloromethane (1.3 L). Dibromine (78.3 g, 490 mmol, 2.2 equiv.) was added drop wise during 30 minutes. The reaction mixture was stirred 1 hour and concentrated to afford 2,2-dibromo-l-(6-bromonaphthalen-2-yl)ethanone as a solid which was used as such in next step.2,2-dibromo-l-(6-bromonaphthalen-2-yl)ethanone (90.0 g, 221 mmol, 1.00) was dissolved in tetrahydrofurane (800 mL), triethylamine (27.67 mL, 199 mmol,0.9 equiv.) was added followed by diethyl phosphite (45.8 g, 332 mmol, 1.50 equiv.). The reaction mixture was stirred overnight. The reaction mixture was filtrated and the solvent was removed in vacuum. The obtained residue was dissolved in ethyl acetate (1.2 L) and washed with water. The organic layer was separated, dried over sodium sulphate, filtrated and concentrated to yield crude 2-bromo-l-(6-bromonaphthalen-2- yl)ethanone (70.3 g). Recrystallization from acetonitrile gave 30 g (first batch) and 6.5 g (second batch) of 2-bromo-l-(6-bromonaphthalen-2-yl)ethanone (50 %)
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Example VII-XVIPreparation of Compound 222General Procedure VII-BPA mixture of compound VIII-XIVh (300 mg, 0.914 mmol), compound I-XXIIIc (300 mg, 1.37 mmol) and Cs2CO3 (892 mg, 7.74 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The mixture was then diluted with EtOAc (30 mL), and washed with brine. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give crude compound VII-XVIa (400 mg, yield 82%). MS (ESI) m/z (M+H)+ 533.
In dichloromethane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
6-Bromonaphthalene-2-carbonyl chloride (27.0 g, crude) was dissolved in dichloromethane (330 mL) and cooled to 0 C. TMS diazomethane solution (100 mL, 2 M in DCM) was added, and ice bath was removed. Reaction mixture was stirred for 16 hours and evaporated under vacuum, giving 1-(6-bromonaphthalen-2-yl)-2-diazoethanone (34.7 g, crude) as an orange solid. 2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone:
4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester[ No CAS ]
[ 108-88-3 ]
(1-{2-[4-(6-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-ylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate; triethylamine; In ethyl acetate; acetonitrile;
<strong>[50637-83-7]2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone</strong> (1 g, 3.07 mmol) and 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (849 mg, 3.38 mmol) were suspended in MeCN (15 mL) and treated with Et3N (0.45 mL, 3.22 mmol). After stirring o/n, the reaction mixture was concentrated. The resulting residue was dissolved in EtOAc and washed with water, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (0% to 20% EtOAc/Hex) to provide the title compound (1.27 g, 83%). 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester: 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (1.2 g, 2.41 mmol) was treated with NH4OAc (3.72 g, 96.4 mmol) and PhMe (48 mL). The reaction mixture was refluxed with stirring for 18 h. After this period, it was cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. Filtration and concentration provided a crude residue that was purified by silica column chromatography (20% to 60% EtOAc/Hex) to provide the title compound (803 mg, 70%). (1-{2-[4-(6-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-ylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester:
2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester[ No CAS ]
pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine; In dichloromethane; acetonitrile;
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (24.0 g) was dissolved in acetonitrile (330 mL), and triethylamine (15.6 mL) was added. A solution of 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g) in acetonitrile (170 mL) were added. Reaction mixture was stirred over 3 days and evaporated under vacuum. Oil was dissolved in dichloromethane (100 mL), extracted with water (50 mL) and with NaHCO3 solution (50 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-30% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (39.2 g, 84%) as a tan solid. 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester:
(1-{2-[5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
[2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester[ No CAS ]
pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen bromide; sodium hydrogencarbonate; In acetic acid; ethyl acetate;
1-(6-Bromonaphthalen-2-yl)-2-diazoethanone (34.7 g) were dissolved in ethyl acetate (500 mL), and hydrobromic acid solution (21.1 mL, 5.7 M in acetic acid) was added at 0 C. Reaction mixture was stirred 3 hours, NaHCO3 solution (200 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum, giving 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g, crude) as a tan solid. Pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester:
With triethylamine; In tetrahydrofuran; ethyl acetate;
2,2-dibromo-1-(6-bromonaphthalen-2-yl)ethanone (90.0 g, 221 mmol, 1.00) was dissolved in tetrahydrofurane (800 mL), triethylamine (27.67 mL, 199 mmol, 0.9 equiv.) was added followed by diethyl phosphite (45.8 g, 332 mmol, 1.50 equiv.). The reaction mixture was stirred overnight. The reaction mixture was filtrated and the solvent was removed in vacuum. The obtained residue was dissolved in ethyl acetate (1.2 L) and washed with water. The organic layer was separated, dried over sodium sulphate, filtrated and concentrated to yield crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (70.3 g). Recrystallization from acetonitrile gave 30 g (first batch) and 6.5 g (second batch) of 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (50%)
Diisopropylethylamine (1.72 mL, 9.86 mmol) was added to a flask containing <strong>[50637-83-7]2-bromo-1-(6-bromonaphthalen-2-yl)ethanone</strong> (2.16 g, 6.57 mmol) and (2S,5S)-5-(methoxycarbonylamino)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxylic acid (2 g, 6.57 mmol) in acetonitrile (50 mL). It was left to stir at room temperature. After stirring for 24 h, the reaction mixture was evaporated to dryness, diluted with EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was dissolved in dioxane (15 mL) and placed in a 20 mL tube containing ammonium acetate (839 mg, 10.9 mmol). The tube was sealed and then heated at 140 C. in a microwave for 60 min. The cooled mixture was evaporated to dryness under reduced pressure and the residue dissolved in EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was crystallized from EtOAc and MeOH, filtered, washed with Et2O and dried under vacuum to afford methyl (2S,5S)-2-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-5-ylcarbamate as a white solid (0.86 g, 45%): ESI-LRMS m/z calcd for C27H23BrN4O3 [M+]531, found 532 [M+H+].
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 12h;
Intermediate 5: 2-(6-Bromo-2-naphthalenyl)-2-oxoethyl N-[(methyloxy)carbonyl]-L- valyl-L-prolinate (Scheme 1); 2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (lg, 3.05 mmol), DIEA (0.481 ml, 2.75 mmol)and N-[(methyloxy)carbonyl]-L-valyl-L-proline 9 (500 mg, 1.836 mmol) were dissolved in acetonitrile (2ml) and the reaction was stirred at RT for 12h. It became clear solution and the reaction was concentrated, impregnated on silica gel and subjected to silica gel purification to provide pure compound.Yield : 84.0%*H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.31 - 8.41 (m, 1 H), 8.02 - 8.12 (m, 1 H), 7.91 - 8.03 (m, 1 H), 7.84 (d, J=8.7 Hz, 2 H), 7.58 - 7.71 (m, 1 H), 5.60 - 5.72 (m, 1 H), 5.28 - 5.41 (m, 2 H), 4.60 - 4.81 (m, 1 H), 4.29 - 4.43 (m, 1 H), 3.79 - 3.90 (m, 1 H), 3.70 - 3.79 (m, 1 H), 3.64 - 3.70 (m, 3 H), 2.30 - 2.47 (m, 2 H), 2.15 - 2.29 (m, 1 H), 2.06 - 2.13 (m, 2 H),0.90 - 1.09 (m, 6 H).ES LC-MS m/z = 520.1 (M+H)+;
71%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 24h;
Diisopropylethylamine (962 muL, 5.51 mmol) was added to a flask containing <strong>[50637-83-7]2-bromo-1-(6-bromonaphthalen-2-yl)ethanone</strong> (1.2 g, 3.67 mmol) and (S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (1 g, 3.67 mmol) in Acetonitrile (50 mL). After stirring for 24 h, the reaction mixture was evaporated to dryness, diluted with EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness to give (S)-2-(6-bromonaphthalen-2-yl)-2-oxoethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate (1.59 g, 71%) as a light grey solid: ESI-LRMS m/z calculated for C24H27BrN2O6 [M+] 519, found 521 [M+2H+].
lJ-dimethylethvK2S.4SV2-r4-r6-bromo-2-naplithalenvn-lH-imidazol-2-yll-4-methyl-l- pyrrolidinecarboxylate 21-A1; To 2-bromo-l-(6-bromo-2-naphthalenyl)ethanone (1.6 g, 4.88 mmol) in dry acetonitrile (30 mL) was added DIPEA (0.852 mL, 4.88 mmol) and (4S)-1-[(1,1- dimethylethyl)oxy]carbonyl}-4-methyl-L-proline (1.118 g, 4.88 mmol). The reaction was stirred at room temp overnight, solvents removed. The residue was dissolved in 1,4- dioxane (40 mL), added to a sealed reaction vessel containing ammonium acetate (3.76 g, 48.8 mmol) and stirred at 110 °C overnight. The solvent was removed and product purified on silica, eluted with 40-100percent ethyl acetate in cyclohexane to furnish product as an off white foam/pale yellow gum in 35percent yield. ES LC-MS m/z = 456/458 (M+H)+
methyl [(1S)-2-methyl-1-({(2S,4S)-4-methyl-2-[5-(6-{2-[(2S,4S)-4-methyl-2-pyrrolidinyl]-1H-imidazol-4-yl}-2-naphthalenyl)-1H-benzimidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate dihydrochloride[ No CAS ]
methyl ((1S)-2-methyl-1-[(2S,3aS,6aS)-2-[5-(6-{2-[(2S,4S)-4-methyl-2-pyrrolidinyl]-1H-imidazol-4-yl}-2-naphthalenyl)-1H-benzimidazol-2-yl]hexahydrocyclopenta[b]pyrrol-1(2H)-yl]carbonyl}propyl)carbamate dihydrochloride[ No CAS ]
((2S,5S)-2-{4-[6-(5-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-pyridin-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-carbamic acid methyl ester di-trifluoroacetic acid[ No CAS ]
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 5h;
To a solution of dibromide B-1b (7.0 g, 21.34 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (4.94 g, 21.34 mmol) in ACN was added DIPEA (7.45 mL, 42.7 mmol) dropwise at 0 C. and the reaction mixture was stirred at rt for 5 h. Then the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with 10% NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude was purified by Combiflash Isco (Silica gel, 120 g, Redisep, EtOAc: petroleum ether, 20:80) to obtain ketoester B-1c (9.2 g) as a yellow solid. LC/MS (Condition B-10): Rt=2.43 min.1H NMR (CDCl3, delta=7.26 ppm, 400 MHz): delta 8.40 (s, 1H), 8.06 (d, J=1.6, 1H), 7.99 (dd, J=8.8, 1.6, 1H), 7.83 (d, J=8.8, 2H), 7.65 (dd, J=8.8, 1.6, 1H), 5.60 (d, J=16.0, 1H), 5.4 (d, J=16.0, 1H), 5.13 (d, J=9.2, 1H), 4.27 (d, J=9.6, 1H), 1.46 (s, 9H), 1.12 (s, 9H). LC/MS: Anal. Calcd. for [M-H]-C23H27BrNO5: 477.38; found 478.0.
9.2 g
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 5h;
To a solution of dibromide B-lb (7.0 g, 21.34 mmol) and (S)-2-((tert- butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (4.94 g, 21.34 mmol) in ACN was added DIPEA (7.45 mL, 42.7 mmol) dropwise at 0 C and the reaction mixture was stirred at rt for 5 h. Then the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with 10% aHC03, brine, dried over a2S04, filtered and concentrated. The crude was purified by Combiflash Isco (Silica gel, 120 g, Redisep, EtOAc: petroleum ether, 20:80) to obtain ketoester B-lc (9.2 g) as a yellow solid. LC/MS (Condition B-10): Rt= 2.43 min.XH NMR (CDC13, delta = 7.26 ppm, 400 MHz): delta 8.40 (s, 1 H), 8.06 (d, J = 1.6, 1 H), 7.99 (dd, J = 8.8, 1.6, 1 H), 7.83 (d, J = 8.8, 2 H), 7.65 (dd, J = 8.8, 1.6, 1 H), 5.60 (d, J = 16.0, 1 H), 5.4 (d, J = 16.0, 1 H), 5.13 (d, J = 9.2, 1 H), 4.27 (d, J = 9.6, 1 H), 1.46 (s, 9 H), 1.12 (s, 9 H). LC/MS: Anal. Calcd. for [M-H]"477.38; found 478.0
S3 (164.0 mg, 0.5 mmol) and potassium thiocyanate (97.2 mg, 1 mmol)Add 25mL dried egg-shaped bottle,Then add 3mL anhydrous ethanol solution to dissolve, stir at room temperature overnight,TLC tracking until the conversion of raw materials is completed. Stop the reaction,A portion of the ethanol solution was distilled off under reduced pressure, washed with water,Extract three times with ethyl acetate, combine the organic phases,Drying over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by column chromatography(Petroleum ether: ethyl acetate = 20: 1 ? petroleum ether:Ethyl acetate = 4: 1) to give S4 (107.0 mg, 70% yield) as a white solid.
cis-1,2-cyclohexane dicarboxylic anhydride[ No CAS ]
[ 50637-83-7 ]
[ 31457-71-3 ]
C25H29BrN2O6[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2 g
Compound BB-22 (1 g, 7.6 mmol) was dissolved in THF (10 mL), cis-1,2-cyclohexane-dicarboxylic anhydride (AA_013-1, 1 g, 6.5 mmol) was added at 10 C. The reaction mixture was stirred at 10 C. for 14 h. After the reaction was complete as detected by TLC, the solvent was removed by a rotary evaporator thereby giving colorless jelly (1.8 g). The colorless jelly (1.8 g, 6.3 mmol) and K2CO3 (1.7 g, 12.6 mmol) were suspended in DMF (20 mL), compound AA_072-3 (1.74 g, 6.3 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete as detected by TLC, the reaction was quenched with H2O (10 mL) and extracted with ethyl acetate (100 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by a rotary evaporator to remove the solvent thereby obtaining yellow oil (3.8 g, yield 88.4%). The product was directly used for the next step without purification. At room temperature, the yellow oil (2 g, 4.28 mmol) was dissolved in toluene (100 mL), ammonium acetate (4.9 g, 63 mmol) was added. The reaction mixture was heated to reflux and stirred for 15 h under nitrogen gas atmosphere. After the reaction was complete as detected by TLC, the reaction mixture was cooled to room temperature, and then quenched with H2O (100 mL) and extracted with ethyl acetate (300 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (PE/EA=10:1?3:1) to deliver the target compound AA_072-4 (yellow solid, 1.0 g, yield 30.3%). LCMS m/z: 514.8 [M+H]+
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