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Structure of 452-77-7 * 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.
Preparation of 3-fluoro-4-methylphenol: 3-Fluoro-4-methylaniline (5g, 39.95 lmmol) was dissolved in 10percent sulfuric acid aqueous solution (100ml). Thereafter, the temperature was lowered to O°C. thereto sodium nitrate (5.5g, 79.902mmol) was added, and the reaction mixture was stirred at same temperature for 30 minutes. Then the reaction mixture was stirred at 500C for 30 minutes, and the last time, stirred at 8O°C for 5 hours. Ice water was added to quench the reaction, and aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate = 8:1) to give 2.26g (yield: 44.8percent, colorless oil) of the target compound.1H NMR(400MHz, CDCl3): 6.98(t, J=8.6Hz, IH), 6.52(m, 2H), 5.82(br, IH),2.12(s, 3H).
Reference:
[1] Patent: WO2007/8037, 2007, A1, . Location in patent: Page/Page column 34-35
[2] Journal of the Chemical Society, 1949, p. Spl. 113
[3] Journal of the American Chemical Society, 1950, vol. 72, p. 1806
2
[ 372-19-0 ]
[ 593-53-3 ]
[ 443-86-7 ]
[ 367-29-3 ]
[ 452-77-7 ]
Reference:
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 1556 - 1561
3
[ 452-77-7 ]
[ 405-06-1 ]
Reference:
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 1806
4
[ 106-49-0 ]
[ 452-80-2 ]
[ 452-77-7 ]
Reference:
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
5
[ 372-19-0 ]
[ 593-53-3 ]
[ 443-86-7 ]
[ 367-29-3 ]
[ 452-77-7 ]
Reference:
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 1556 - 1561
6
[ 1427-07-2 ]
[ 452-77-7 ]
Yield
Reaction Conditions
Operation in experiment
74%
With indium (III) iodide; 1,1,3,3-Tetramethyldisiloxane In toluene at 60℃; for 6 h; Inert atmosphere; Sealed tube
General procedure: To a screw top vial (5 mL) under N2 containing freshly distilled toluene (0.6 mL) were successively added an aromatic nitro compound (0.60 mmol), InI3 (14.9 mg, 0.030 mmol), and TMDS (318 μL, 1.80 mmol). After the vial was sealed with a cap that contained a PTFE septum, the mixture was stirred at 60 °C (bath temperature), and monitored via TLC analysis. Sat. aq NaHCO3 solution (5 mL) was added to the resultant mixture, which was then extracted with EtOAc (3 × 6 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane–EtOAc, 9:1 to 4:1) to afford the corresponding aniline derivative.
Reference:
[1] Tetrahedron Letters, 2003, vol. 44, # 42, p. 7783 - 7787
[2] Synthesis (Germany), 2015, vol. 47, # 20, p. 3179 - 3185
[3] Journal of the American Chemical Society, 1950, vol. 72, p. 1806
[4] Monatshefte fuer Chemie, 1959, vol. 90, p. 683,687
[5] Journal of the Chemical Society, 1949, p. Spl. 113
[6] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[7] Tetrahedron Letters, 2010, vol. 51, # 32, p. 4250 - 4252
7
[ 88-72-2 ]
[ 452-77-7 ]
Reference:
[1] Patent: US6020379, 2000, A,
8
[ 452-75-5 ]
[ 452-77-7 ]
Reference:
[1] Chemistry - A European Journal, 2013, vol. 19, # 6, p. 2131 - 2141
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 24, p. 4071 - 4074
9
[ 372-19-0 ]
[ 593-53-3 ]
[ 443-86-7 ]
[ 367-29-3 ]
[ 452-77-7 ]
Reference:
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 1556 - 1561
10
[ 106-49-0 ]
[ 452-80-2 ]
[ 452-77-7 ]
Reference:
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
11
[ 452-77-7 ]
[ 446-31-1 ]
Reference:
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
12
[ 452-77-7 ]
[ 394-42-3 ]
Reference:
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 1806
13
[ 452-77-7 ]
[ 202865-78-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With bromine; potassium carbonate In dichloromethane at -15℃; for 1 h;
Example 28; Preparation of Intermediate Compound 28G; 28G; Step A - Synthesis of Compound 9B; 28A 28B; A mixture of compound 28A (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound 28B (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate In dichloromethane at -15℃; for 1 h;
Example 9; Preparation of Intermediate Compound 9G; 9G; Step A - Synthesis of Compound 9B; A mixture of compound 9A (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound 9B (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate In dichloromethane at -15℃; for 1 h;
Example 28; Preparation of Intermediate Compound 28G <n="200"/>; 28G; Step A - Synthesis of Compound 28B; 28A 28B; A mixture of compound 28 A (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound 28B (11.0 g, quant.), which was used without further purification.
100%
With bromine In dichloromethane at -15℃; for 1 h; Cooling with salt-ice
A mixture of compound SA (6,00 g, 47.9 mrnol) and anhydrous potassium carbonate (6.70 g, 48.5 mmoi) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound SB (1 1.0 g. quant. ). which was used without further purification.
100%
With bromine; potassium carbonate In dichloromethane at -15℃; for 1 h;
Example 9; Preparation of Intermediate Compound AA7; Step A - Synthesis of Compound AA2; A mixture of compound AAl (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound AA2 (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate In dichloromethane at -15℃; for 1 h;
Example 19; Preparation of Intermediate Compound AA7; Step A - Synthesis of Compound AA2; A mixture of compound AAl (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound AA2 (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate In dichloromethane at -15℃;
A mixture of compound AA1 (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15° C. in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15° C. for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2.x.100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound AA2 (11.0 g, quant.), which was used without further purification.
33%
With bromine; potassium carbonate In dichloromethane at -15℃; for 1 h;
To a suspension of 3-fluoro-4-methylaniline (6.0 g, 48mmol) and K2C03 (6.6 g, 48 mmol) in DCM (80 mL) at -15 °C was added Br2 (2.4 mL, 48mmol) in DCM (20 mL) slowly. The reaction mixture was stirred at -15 °C for 1 h. Themixture was then quenched with ice water (30 mL), diluted with water (80 mL), andextracted with DCM (3 x 50 mL), dried and concentrated. The residue was purified via silica gel chromatography (0 - 10 percent EtOAc in petroleum ether) to give the title compound (3.2 g, 33percent) as a white solid. MS (ES+) C7H7BrFN requires: 203, found: 204 [M+Hf’
Reference:
[1] Patent: WO2009/32123, 2009, A2, . Location in patent: Page/Page column 158
[2] Patent: WO2009/32125, 2009, A1, . Location in patent: Page/Page column 98
[3] Patent: WO2009/32124, 2009, A1, . Location in patent: Page/Page column 198-199
[4] Patent: WO2009/152200, 2009, A1, . Location in patent: Page/Page column 65
[5] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 3, p. 244 - 248
[6] Patent: WO2008/82488, 2008, A1, . Location in patent: Page/Page column 153
[7] Patent: WO2008/82484, 2008, A1, . Location in patent: Page/Page column 194-195
[8] Patent: US2010/322901, 2010, A1, . Location in patent: Page/Page column 64
[9] Patent: WO2018/81276, 2018, A1, . Location in patent: Page/Page column 159
[10] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
With indium (III) iodide; 1,1,3,3-Tetramethyldisiloxane; In toluene; at 60℃; for 6h;Inert atmosphere; Sealed tube;
General procedure: To a screw top vial (5 mL) under N2 containing freshly distilled toluene (0.6 mL) were successively added an aromatic nitro compound (0.60 mmol), InI3 (14.9 mg, 0.030 mmol), and TMDS (318 muL, 1.80 mmol). After the vial was sealed with a cap that contained a PTFE septum, the mixture was stirred at 60 C (bath temperature), and monitored via TLC analysis. Sat. aq NaHCO3 solution (5 mL) was added to the resultant mixture, which was then extracted with EtOAc (3 × 6 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane-EtOAc, 9:1 to 4:1) to afford the corresponding aniline derivative.
With sodium nitrate; sulfuric acid; water; at 0 - 80℃; for 6h;
Preparation of 3-fluoro-4-methylphenol: 3-Fluoro-4-methylaniline (5g, 39.95 lmmol) was dissolved in 10% sulfuric acid aqueous solution (100ml). Thereafter, the temperature was lowered to OC. thereto sodium nitrate (5.5g, 79.902mmol) was added, and the reaction mixture was stirred at same temperature for 30 minutes. Then the reaction mixture was stirred at 500C for 30 minutes, and the last time, stirred at 8OC for 5 hours. Ice water was added to quench the reaction, and aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate = 8:1) to give 2.26g (yield: 44.8%, colorless oil) of the target compound.1H NMR(400MHz, CDCl3): 6.98(t, J=8.6Hz, IH), 6.52(m, 2H), 5.82(br, IH),2.12(s, 3H).
(3-fluoro-4-methyl-phenyl)-acetamide (26): 5.00 g of <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (25) (40.0 mmol) and 500 mg 4-dimethylaminopyridine (4.0 mmol, 0.1 eq) were dissolved in 16 mL pyridine. To the solution was added 23 mL Ac2O (240 mmol, 6 eq). Cooling in an ice bath was necessary immediately following addition to moderate the initial rise in temperature. After the initial cooling period, the reaction was stirred at room temperature for 4 hours, and the pyridine solution was then diluted with EtOAc/H2O. The organic phase was washed twice more with deionized H2O, three times with 10% aqueous CuSO4, and two further times with deionized H2O. The extract was dried over anhydrous Na2SO4, filtered, and reduced to a white solid after rotary evaporation. Yield=6.69 g (100%).
93%
With N,N,N-trimethyl-2-(sulfooxy)ethanaminium chloride; In neat (no solvent); at 20℃; for 0.2h;Milling; Green chemistry;
General procedure: A mixture of amine (1 mmol), acetic anhydride (1 mmol) and 3.5 mol% SCIL was systematically mixed in a mortar followed by grinding at room temperature. The sticky mixture got solidified within 10-20 min. The mixture was powdered till the completion of reaction as indicated by TLC. The product was dissolved in ethyl acetate to recover the insoluble catalyst. The filtered catalyst was dried at 60oC under vaccum for 1 h after thoroughly washing with ethyl acetate. The recovered SCIL was recycled in the model reaction for six times to check its catalytic efficiency. The products were recrystallized from hot methanol.
2-[(3-fluoro-4-methylphenyl)amino]-N-(7-hydroxy-1-naphthyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With triethylamine; In methanol; for 15h;Heating / reflux;
Bromoacetyl bromide (0. 6 mmol, 53 1LL) was added under stirring to a solution of 8-amino- 2-naphthol (0.6 mmol, 95 mg in 10 ml dioxane) at 4C. Triethylamine (0.55 mmol, 56 mg) was added and the reaction stirred at room temperature for 1 h. Solvent was evaporated and the crude 2-Bromo-N-(7-hydrox-1-naphthyl)-acetamide obtained was used in Examples 2 tol2 without further purification. MW (calcd) 280.1, MW (found) [M+1] : 281.1, 281. 9 2-BROMO-N-(7-HYDROXY-NAPHTHALEN-1-YL)-ACETAMIDE (56 mg, 0.2 mmol) and triethylamine (0.18 mmol, 26 UL) dissolved in MEOH (3 ml) were added to 3-fluoro-4-methyl- phenylarnine (0.3 mmol, 38 mg) at room temperature. The reaction mixture was refluxed for 15 H. THE VOLATILES were removed in vacuo and the residue was purified on a PREPARATIVE HPLC (XTerra C8 column 19* 100 mm, CH3CN/H20). After concentration of the eluate, the residue was dissolved in EtOAc. The organic phase was washed with water, brine, and dried over NA2S04. Evaporation of the solvent afforded the title compound (38 mg, 60 %). MW (calcd) 324.36, MW (found) [M+1] : 325; 1H NMR (400 MHz, acetone) No. ppm 2.1 (s, 3H), 3. 98 (s, 2H), 5. 68 (s, 1H), 6.44 (d, J=7. 1 Hz, 2H), 6. 46 (s, 1H) 6. 95 (T, J=8. 6 Hz, 1 H), 7.09 (dd, J=2. 3, 8. 8, Hz, 1H) 7.18 (m, 2H) 7.55 (d, J=8. 1 Hz, 1H) 7.70 (d, J=8. 6 Hz, 1H) 7.79 (d, J=7.1 Hz, 1H) 9.19 (s, 1H).
3-fluoro-4-methyl-phenylhydrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
<strong>[452-77-7]3-Fluoro-4-methylaniline</strong> (5.0 g, 40 mmol) was combined with a mixture of acetic acid; (125 mL), water (50 mL), and concentrated (50 mL) hydrochloric acid;. The resulting solution was cooled in an ice bath and treated portion-wise with NaNO2 (3.1 g, 45 mmol) in water (50 mL). After the reaction mixture had stirred at low temperature for 15 minutes, it was added to a solution of tin chloride (45 g, 200 mmol) in 100 ml concentrated hydrochloric acid; that was also cooled in an ice bath. The reaction mixture was then allowed to warm to room temperature and stirred for 30 minutes. The resulting slurry was extracted with ethyl acetate (400 mL), and the organic layer was washed with brine and dried over magnesium sulfate. The solution was then filtered and the solvent removed under reduced pressure. The yellow solid thus obtained was partitioned between 1 M sodium hydroxide (200 mL) and ethyl acetate (600 mL)and the two-phase mixture filtered and separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was taken up in diethyl ether and treated with hydrogen chloride gas. The resulting slurry was filtered and the precipitate dried under vacuum to give the hydrochloride salt of the desired product as a white solid (3.25 g, 50%). 1H NMR (300 MHz, d6-DMSO) delta 10.3 (br s, 1H), 8.4 (br s, 1H), 7.17 (t, J=8.6 Hz, 1H), 6.83 (dd, J=2.2 Hz, 8.2 Hz, 2H), 2.14 (s, 3H).
With hydrogenchloride; sodium sulfate; In water; at 45 - 75℃; for 3h;
Example 125 Synthesis of (+/-)-5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-6-fluoro-7-methyl- 2,3, 4,5-tetrahydro-benzo [b] azepine-1-carboxylic acid isopropyl ester Step 1. Preparation of N- (3-Fluoro-4-methyl-phenyl)-2-hydroxyimino-acetamide To a solution of chloral hydrate (2.97 g, 17.98 mmol) and anhydrous sodium sulfate (15.20 g, 107 mmol) in water (50 mL) add a mixture of hydroxylamine sulfate (13.67 g, 83.23 mmol), 3-Fluoro-4-methyl-phenylamine (2 g, 15.98 mmol), concentrated hydrochloric acid (1.67 mL) in water (17 mL). Heat the mixture at 45 C for 2 h and at 75C for 1 hr. Cool the mixture to room temperature and filter the solid. Wash the solid with water and ethyl ether. Dry the solid under vacuum to yield the title compound (2.96 g, 94%).'H NMR (DMSO-d6, 300 MHz) S 2.08 (d, J = 1.0 Hz, 3H), 7.12 (t, J = 8.8 Hz, 1H), 7.25 (dd, J = 2. 1,8. 2 Hz, 1H), 7.36 (dd, J = 1.6, 12.4 Hz, 1H), 10.18 (s, 1H), 12.11 (s, 1H). MS (ES-): 195 (M-H).
With caesium carbonate; In diethyl ether; hexane; ethyl acetate; toluene;
a) Methyl 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate To an oven-dried glass vial with stir bar was added a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 70 mg (0.56 mmol) of <strong>[452-77-7]3-fluoro-4-methylaniline</strong>. The vial was transferred to a glove bag, flushed with dry argon and anhydrous toluene (0.9 mL) was added. The vial was capped with a Teflon-lined screw cap and heated at 100 C. for 48 h. To the cooled suspension was added ethyl acetate (4 mL), the mixture filtered (Celite) washing with ethyl acetate (2*2 mL), and the solvents removed in vacuo. The resulting residue was purified by silica gel preparative thin layer chromatography (10% Et2O in hexane) to afford 103 mg (78%) of the title compound as a yellow oil. 1H-NMR (CDCl3, 400 MHz) delta2.22 (d, 3 H, J=1.6 Hz), 2.40 (s, 3 H), 3.89 (s, 3 H), 6.09 (s, 1 H), 6.68 (m, 1 H), 6.71 (s, 1 H), 7.08 (m, 1 H), 7.72 (s, 1 H).
103 mg (78%)
With caesium carbonate; In diethyl ether; hexane; ethyl acetate; toluene;
a) Methyl 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate To an oven-dried glass vial with stir bar was added a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 70 mg (0.56 mmol) of <strong>[452-77-7]3-fluoro-4-methylaniline</strong>. The vial was transferred to a glove bag, flushed with dry argon and anhydrous toluene (0.9 mL) was added. The vial was capped with a Teflon-lined screw cap and heated at 100 C. for 48 h. To the cooled suspension was added ethyl acetate (4 mL), the mixture filtered (Celite) washing with ethyl acetate (2*2 mL), and the solvents removed in vacuo. The resulting residue was purified by silica gel preparative thin layer chromatography (10% Et2O in hexane) to afford 103 mg (78%) of the title compound as a yellow oil. 1H-NMR (CDCl3, 400 MHz) delta 2.22 (d, 3H, J=1.6 Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 (s, 1H), 6.68 (m, 1H), 6.71 (s, 1H), 7.08 (m, 1H), 7.72 (s, 1H).
Example 248 Synthesis of N-(3-fluoro-4-methylphenyl)phthalimide A mixture of <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated under reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the resulting residue and the insoluble matter was filtered off whereas the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=98:2) to give 18.7 g of the titled compound (yield, 73%). 1H-NMR(CDCl3) delta: 2.33(3H,s), 7.14(1H,s), 7.18(1H,s), 7.28-7.34(1H,m), 7.79-7.82(2H,m), 7.94-7.98(2H,m)
7-Fluoro-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 619, Structure 102 of Scheme XIX, Where R1=R3=H, R2=Methyl, R4=Fluoro) This compound was prepared in a similar fashion as that described in Example 1, General Procedure I but using 3-fluoro-4-methylaniline (Structure 101 of Scheme XIX, where R3=H, R2=methyl, R4=fluoro) and <strong>[400-36-2]4,4,4-trifluoroacetoacetate</strong> in place of Compound 200. Compound 619 was isolated as a white solid: 1H NMR (400 MHz, acetone-d6) 11.22 (s, 1H), 7.67 (d, J=7.3, 1H), 7.20 (d, J=10.6, 1H), 6.86 (s, 1H), 2.35 (d, J=1.4, 3H).
B. 5-Fluorotoluidine The above nitrotoluene is hydrogenated in ethanol (200 ml) over one teaspoonifl of Raney Nickel catalyst with hydrogen at 42 p.s.i. and room temperature. When the theoretical amount of hydrogen has been taken up, the hydrogenation is stopped, and the catalyst carefully filtered off. The filtrate is evaporated to dryness to yield an oil which is distilled.
3-fluoro-4-methyl-phenylhydrazine hydrochloride[ No CAS ]
4-fluoro-5-methyltryptamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 13 Preparation of (+/-) 5-fluoro-6-methyl-1-(1-naphthalenyl methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole STR47 3-fluoro-4-methyl-phenylhydrazine hydrochloride (21.4 g -) was prepared as described for 2-bromo-4 methyl phenylhydrazine hydrochloride in Example 7, except using <strong>[452-77-7]3-fluoro-4-methylaniline</strong> as starting material. STR48 4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 3-fluoro-4-methylphenylhydrazine hydrochloride (6.00 g) as starting material. STR49 A suspension of azalactone (prepared as described in Example 5) (2.3 g, 9.6 mmol) and 4-fluoro-5-methyltryptamine hydrochloride (2.2 g, 9.6 mmol) in 1N HCl (40 mL was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0.2% NH4 OH as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (520 mg) by filtration.
EXAMPLE 13 Preparation of (+-) 5-fluoro-6-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole STR48 3-fluoro-4-methyl-phenylhydrazine hydrochloride (21.4 g-) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 7, except using <strong>[452-77-7]3-fluoro-4-methylaniline</strong> as starting material. STR49 4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 3-fluoro-4-methylphenylhydrazine hydrochloride (6.00 g) as starting material. STR50 A suspension of azalactone (prepared as described in Example 5) (2.3 g, 9.6 mmol) and 4-fluoro-5-methyltryptamine hydrochloride (2.2 g, 9.6 mmol) in 1N HCl (40 mL was heated to reflux for 24 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with chloroform. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (ethyl acetate/0.2% NH4 OH as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate containing 1% methanol and treated with maleic acid. The product was isolated as the maleate salt (520 mg) by filtration.
Preparation 12: 2-Fluoro-4-methanesulfonylbenzoic acid: A mixture of 3-fluoro-4-methylphenylamine (3.67 g, 29.3 mmol), dimethyl disulfide (39.6 mL, 440 mmol) and tert-butyl nitrite (4.70 mL, 39.2 mmol) in 1,2-dichloroethane (400 mL) was heated at 6O0C for 10 min. A solution of 3-fluoro-4-methylphenylamine (33.0 g, 264 mmol) in 1,2-dichloroethane (100 mL) was added dropwise, whilst simultaneously adding tert- butyl nitrite (38.0 mL, 317 mmol) and maintaining the temperature at around 6O0C. Following addition of reactants, the heat source was removed and the reaction stirred for 1 h. Water (200 mL) was added and the reaction mixture stirred vigorously for 10 min. The organic phase was separated and washed with water (100 mL) and 1 M aqueous HCl (200 mL) then dried (MgSO4) and evaporated. 2-Fluoro-l-methyl-4-methylsulfanylbenzene was isolated by distillation (5O0C / 0.9 Torr) and used immediately as follows: a mixture of the thioether (10.0 g, 64.1 mmol) in water (200 mL) was heated to 1000C with vigorous stirring. Potassium permanganate (45.6 g, 289 mmol) was introduced portionwise over 20 min and heating continued for 35 min then filtered through a sinter. The filtrate was cooled and extracted with EtOAc (3 x 200 mL), the aqueous phase acidified to pH 1 using cone HCl and extracted with EtOAc (4 x 150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. Et2O was added and the precipitate collected by filtration and air-dried to give the title compound: deltaH (CD3OD) 3.19 (3H, s), 7.81-7.86 (2H, m), 8.14-8.18 (IH, m).
With aluminium trichloride; In chloroform; at 23 - 140℃; for 14.5h;
Step 1: 2-bromo-N-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-2) Solid aluminum chloride (3.66 g, 27.5 mmol, 1 equiv) was added to a neat mixture of 2-bromobenzonitrile (1-1, 5.0 g, 27.5 mmol, 1.0 equiv) and <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (3.44 g, 27.5 mmol, 1.00 equiv) at 80 C., and the resulting mixture was heated at 140 C. for 30 min. The reaction mixture was cooled to 23 C., allowed to stand for 14 h, then dissolved in chloroform (35 mL). The solution was washed with aqueous NaHCO3 solution (40 mL) and concentrated to afford 2-bromo-N-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-2) as a dark oil. LRMS m/z: Calc'd for C14H12BrFN2 (M+H) 308.2, found 308.2.
With sodium hydroxide; In water; acetone; at 0 - 5℃; for 1h;
(4,6-Dichloro-[1,3,5]triazin-2-yl)-(3-fluoro-4-methyl-phenyl)-amine (156a) To cyanuric chloride (1.4821 g, 8 mmol) dissolved in acetone (115 mL) stiffing at 0-5 C., was added a solution of <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (1.0017 g, 8 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (3.2 mL, 8 mmol). The reaction mixture was allowed to stir at 0-5 C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (156a, 1.88 g, 86%), mp 130 C.; HPLC: Inertsil ODS-3V C 18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH:CH3CN], 264 nm, Rt 36.8 min, 99.1% purity; MS (TOF MS ES+): m/z 344 (31.0), 275 (66.6), 273 (M+H, 1100).
cis-4-hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanecarboxylic acid[ No CAS ]
[ 452-77-7 ]
4-hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanecarboxylic acid (3-fluoro-4-methyl-phenyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 1.5h;
Example 37: 4-hydroxy-4-[2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- cyclohexanecarboxylic acid (3-fluoro-4-methyl-phenyl)-amide:A solution of intermediate 7.vi (0.1 g, 0.303 mmol) and <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (0.04 g, 0.303 mmol) in DMF (1.5 mL) was treated with DIPEA (3 eq.) and propylphosphonic anhydride solution (50% in EA, 1.1 eq.). The mixture was stirred at rt for 1.5 h, partitioned between EA and water. The org. phase was washed several times with water and brine, dried over MgSO4 and concentrated. Chromatography on SiO2 (EA) gave the title compound as a colourless solid (0.035 g, 26% yield).1H NMR (DMSO d6) delta: 9.87 (m, IH), 8.65 (m, IH), 8.22 (m, IH), 7.53 (m, 2H), 7.19 (m, 3H), 4.06 (m, 4H), 3.23 (m, 3H), 2.19 (m, 3H), 1.80 (m, 5H), 1.59 (m, 2H), 1.39 (m, 2H). MS (ESI, m/z): 438.3 [M+H+].
26%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 1.5h;
A solution of intermediate 7.vi (0.1 g, 0.303 mmol) and <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (0.04 g, 0.303 mmol) in DMF (1.5 mL) was treated with DIPEA (3 eq.) and propylphosphonic anhydride solution (50% in EA, 1.1 eq.). The mixture was stirred at rt for 1.5 h, partitioned between EA and water. The org. phase was washed several times with water and brine, dried over MgSO4 and concentrated. Chromatography on SiO2 (EA) gave the title compound as a colourless solid (0.035 g, 26% yield). 1H NMR (DMSO d6) delta: 9.87 (m, 1H), 8.65 (m, 1H), 8.22 (m, 1H), 7.53 (m, 2H), 7.19 (m, 3H), 4.06 (m, 4H), 3.23 (m, 3H), 2.19 (m, 3H), 1.80 (m, 5H), 1.59 (m, 2H), 1.39 (m, 2H). MS (ESI, m/z): 438.3 [M+H+].
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1h;
Example 28; Preparation of Intermediate Compound 28G; 28G; Step A - Synthesis of Compound 9B; 28A 28B; A mixture of compound 28A (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound 28B (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1h;
Example 9; Preparation of Intermediate Compound 9G; 9G; Step A - Synthesis of Compound 9B; A mixture of compound 9A (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound 9B (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1h;
Example 28; Preparation of Intermediate Compound 28G <n="200"/>; 28G; Step A - Synthesis of Compound 28B; 28A 28B; A mixture of compound 28 A (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound 28B (11.0 g, quant.), which was used without further purification.
100%
With bromine; In dichloromethane; at -15℃; for 1h;Cooling with salt-ice;
A mixture of compound SA (6,00 g, 47.9 mrnol) and anhydrous potassium carbonate (6.70 g, 48.5 mmoi) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound SB (1 1.0 g. quant. ). which was used without further purification.
100%
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1h;
Example 9; Preparation of Intermediate Compound AA7; Step A - Synthesis of Compound AA2; A mixture of compound AAl (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound AA2 (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1h;
Example 19; Preparation of Intermediate Compound AA7; Step A - Synthesis of Compound AA2; A mixture of compound AAl (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 0C in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 0C for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound AA2 (11.0 g, quant.), which was used without further purification.
100%
With bromine; potassium carbonate; In dichloromethane; at -15℃;
A mixture of compound AA1 (6.00 g, 47.9 mmol) and anhydrous potassium carbonate (6.70 g, 48.5 mmol) in anhydrous dichloromethane (130 mL) was cooled to -15 C. in a salt-ice bath and then added dropwise to a solution of bromine (7.70 g, 48.2 mmol) in anhydrous dichloromethane (80 mL). After addition was complete, the reaction was allowed to stir at -15 C. for 1 hour. Ice water (100 mL) was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to provide compound AA2 (11.0 g, quant.), which was used without further purification.
33%
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1h;
To a suspension of 3-fluoro-4-methylaniline (6.0 g, 48mmol) and K2C03 (6.6 g, 48 mmol) in DCM (80 mL) at -15 C was added Br2 (2.4 mL, 48mmol) in DCM (20 mL) slowly. The reaction mixture was stirred at -15 C for 1 h. Themixture was then quenched with ice water (30 mL), diluted with water (80 mL), andextracted with DCM (3 x 50 mL), dried and concentrated. The residue was purified via silica gel chromatography (0 - 10 % EtOAc in petroleum ether) to give the title compound (3.2 g, 33%) as a white solid. MS (ES+) C7H7BrFN requires: 203, found: 204 [M+Hf?
With lithium perchlorate; In acetonitrile; at 50℃; for 5h;
149.i) (RS)-4-(tert-Butyl-dimethyl-silanyloxy)-1-(3-fluoro-4-methyl-phenylamino)-butan-2-olLiClO4 (6.31 g, 60 mmol) was added to a solution of (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (4 g, 20 mmol, prepared according to Heterocycles (1987), 25(1), 329-32) in MeCN (60 mL). <strong>[452-77-7]3-Fluoro-4-methylaniline</strong> (2.28 g, 18 mmol) was added and the mixture was stirred at 50 C. for 5 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as brown oil (5.56 g, 86%).LCMS (ESI, m/z): 328.4 [M+H+].
86%
With lithium perchlorate; In acetonitrile; at 50℃; for 5h;
149. i) (RS)-4-(tert-Butyl-dimethyl-silanyloxy)-l-(3-fluoro-4-methyl-phenylamino)-butan-2- olLiClO4 (6.31 g, 60 mmol) was added to a solution of (7?USD-tert-butyl-dimethyl-(2-oxiranyl- ethoxy)-silane (4 g, 20 mmol, prepared according to Heterocycles (1987), 25(1), 329-32) inMeCN (60 mL). <strong>[452-77-7]3-Fluoro-4-methylaniline</strong> (2.28 g, 18 mmol) was added and the mixture was stirred at 50 0C for 5 h. The solvent was removed under reduced pressure and the <n="157"/>residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as brown oil (5.56 g, 86%).MS (ESI, m/z): 328.4 [M+H+].
86%
With lithium perchlorate; In acetonitrile; at 50℃; for 5h;
To a solution of (7?^)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (4.4 g, 200 mmol; prepared as in J. Org. Chem. (2008), 73, 1093) in MeCN (6O mL) was added LiClO4 (6.31 g, 3 eq.). <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (commercial; 2.28 g, 0.92 eq.) was added and the mixture was stirred at 500C for 5 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as a brown oil (5.56 g, 86% yield). MS (ESI, m/z): 328.4 [M+H+].
4-(6-methoxy-[1,5]naphthyridin-4-yl)-1-(R/S)-1-oxiranylmethyl-piperazin-2-one[ No CAS ]
[ 452-77-7 ]
1-[(R/S)-3-(3-fluoro-4-methyl-phenylamino)-2-hydroxy-propyl]-4-(6-methoxy-[1,5]naphthyridin-4-yl)-piperazin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
In ethanol; water; at 80℃; for 3h;
100.iii) 1-[(R)-3-(3-Fluoro-4-methyl-phenylamino)-2-hydroxy-propyl]-4-(6-methoxy-[1,5]-naphthyridin-4-yl)-piperazin-2-one or 1-[(S)-3-(3-Fluoro-4-methyl-phenylamino)-2-hydroxy-propyl]-4-(6-methoxy-[1,5]-naphthyridin-4-yl)-piperazin-2-oneA solution of intermediate 100.ii) (26 mg, 0.083 mmol) and <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (10.4 mg, 0.083 mmol) in EtOH/water 9:1 (0.5 mL) was heated at 80 C. for 3 h. The mixture was concentrated under reduced pressure and the residue was chromatographed over SiO2 (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a colorless oil (10 mg, 3%).LCMS (ESI, m/z): 440.5 [M+H+].
3%
In ethanol; water; at 80℃; for 3h;
lOO.iii) l-[(R)-3-(3-Fluoro-4-methyl-phenylamino)-2-hydroxy-propyl]-4-(6-methoxy-[1, 5]naphthyridin-4-yl)-piperazin-2-one or l-[(S)-3-(3-Fluoro-4-methyl-phenylamino)-2- hydroxy-propyl]-4-(6-methoxy-[l,5]naphthyridin-4-yl)-piperazin-2-oneA solution of intermediate 100. U) (26 mg, 0.083 mmol) and <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (10.4 mg, 0.083 mmol) in EtOH/water 9:1 (0.5 mL) was heated at 80 0C for 3 h. The mixture was concentrated under reduced pressure and the residue was chromatographed over SiO2(DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a colorless oil (10 mg,3%).MS (ESI, m/z): 440.5 [M+H+].
With sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 5h;
To a stirred light brown solution of 10.0 g (80 mmol) 3-Fluoro-4-methyl aniline in 80 ml DCM was added rapidly a solution of 7.05 g (84 mmol, 1.05 eq.) NaHCO3 in 100 ml of water. To the resulting biphasic mixture was added under vigorous stirring 9.22 ml (120 mmol, 1.5 eq.) methyl chloroformate over a period of 30 min. The light brown reaction mixture was stirred for 4.5h at RT. The organic phase was separated and washed twice with a total amount of 50 ml water, and the combined aqueous phases were washed twice with a total amount of 100 ml DCM. The combined organic phases were dried over 5 g Na2SO4 and filtered with suction on a funnel with a fritted disk. The cake was washed in total with 50 ml DCM. The DCM was partially removed under reduced pressure to about 1/3 of its original volume and then 70 ml heptane was added dropwise under stirring within 30 min, whereby the product precipitated. From this suspension, DCM was completely removed under reduced pressure. Finally, the suspension was stirred in an ice bath for 1h, the crystals were filtered off with suction on a funnel with a fritted disk and washed with three 10 ml portions, in total with 30 ml ice cold heptane. The wet off-white crystals were dried at 50C in vacuo to yield the product 14.20 g (92.0% of theory) of the title compound as off-white crystals (m.p. = 84.8-85.1C) 1H-NMR data (CDCl3, 300 MHz): delta 7.23 (m, 1H), 7.08 (dd, 1H), 6.91 (dd, 1H), 6.57 (br s, 1H), 3.77 (s, 3H), 2.21 (s, 3H). MS m/e (%): 184 ([M+H]+, 100).
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate; In methanol; dichloromethane; at 0 - 20℃; for 17h;
Example 12; Preparation of Compound 160, 161 and 162; Step 1 - Synthesis of Compound 12B <n="170"/>; 12A 12B; <strong>[452-77-7]3-Fluoro-4-methylaniline</strong> (94.5 g, 755 mmol), dichloromethane (3 L), and methanol (1 L) were charged into a 5000 ml three-necked flask equipped with mechanic stirrer. The resulting solution was cooled to 0 0C using an ice-water bath and to the cooled solution was added calcium carbonate powder (151 g, 1509 mmol) followed by iodate salt 12A (275 g, 790 mmol). The resulting suspension was maintained at ~ 0 0C for 2 hours then the cool bath was removed and the reaction mixture warmed to room temperature while stirring for an additional 15 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (1 L), washed sequentially with water (500 mL), saturated sodium carbonate solution (500 mL) and water (500 mL), then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting brown oil residue was dried under house vacuum to provide compound 12B (179 g, 95% yield, >90% purity by NMR) which was used without further purification.
87%
With benzyl dimethyl ammonium dichloroiodate; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1h;
To a solution of 3-Fluoro-4-methyl-phenylamine (1A)(8.O g, 64 mmol) in dicholoromethane (500 mL) and MeOH (100 mL) was added benzyltrimethylammonium dichloroiodate (23.8 g, 67.4 mmol) and calcium carbonate (12.8g, 133 mmol). The suspension was allowed to stir at room temperature for Ih, the solids were removed by filtration and the filtrate was concentrated. The concentrated crude was redissolved in CH2Cl2, washed successively with 5% NaHSO4, saturated NaHCO3, water, brine and dried over MgSO4. The organic layer was concentrated and the crude was purified using chromatography over SiO2 (330 g, flash column) using 0 to 20 % ethyl acetate in hexane to provide compound IB (13.4g, 87%). 1H NMR (400 MHz, CDCl3): delta 2.12 (s, 3H), 4.2 (broad S, 2H), 6.51 (d, J= 10.8 Hz, IH), 7.43 (d, J= 8.4 Hz, IH).
87%
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate; In methanol; dichloromethane; at 20℃; for 1h;
Example 13; Preparation of Compound 126 and 127; Step 1: 13A 13B; To a solution of 3-Fluoro-4-methyl-phenylamine (13A) (8.0 g, 64 mmol) in dicholoromethane (500 mL) and MeOH (100 mL) was added benzyltrimethylammonium dichloroiodate (23.8 g, 67.4 mmol) and calcium carbonate (12.8g, 133 mmol). The suspension was stirred at room temperature for Ih, the solids were removed by filtration and the filtrate was concentrated. The concentrated crude was redissolved in CH2Cl2, washed successively with 5% NaHSO4, saturated NaHCO3, water, brine and dried over MgSO4. The organic layer was concentrated and the crude was purified by chromatography over SiO2 (330 g, flash column) using 0 to 20 % ethyl acetate in hexane to give a brown oil 5-fluoro-2-iodo-4-methyl- phenylamine 13B (13.4g, 87%). 1H NMR (400 MHz, CDCl3): delta 2.12 (s, 3H), 4.2 (broad S, 2H), 6.51 (d, J= 10.8 Hz, IH), 7.43 (d, J= 8.4 Hz, IH).
<strong>[452-77-7]3-Fluoro-4-methylaniline</strong> (5.0 g, 40 mmol) and KSCN (15.5 g, 160 mmol) in AcOH (50 mL) was cooled to 0 C and Br2 (6.7 g, 42 mmol) in AcOH (20 mL) was added slowly. The mixture was then stirred at rt for 3 h. The reaction mixture was quenched with ice-cold NH4OH (100 mL). The resulting solid was filtered, washed with water, and dried under vacuum to give the title compound (6.0 g, 99%)as a yellow solid. MS (ES+) C8H7FN2S requires: 182, found: 183 [M+Hf?.
98%
To a stirred solution of <strong>[452-77-7]3-fluoro-4-methyl-phenylamine</strong> (10.0 g, 79.9 mmol) and potassium thiocyanide (31.06 g, 319.62 mmol) in acetic acid (130 mL) was added a solution of bromine (12.77 g, 79.9 mmol) in acetic acid (20 mL) over 20 min. The reaction mixture was stirred at room temperature for 20 h, poured on to crushed ice-water (800 mL). Ammonium hydroxide solution (28%) was added to pH 8, stirred for 2 h. Filtered, washed with water, dried to afford (42) 14.27 g (98%) as light yellow solid.
A mixture of 3-fluoro-4-methyl-aniline (commercial; 1.25 g, 10 mmol), sat. aq. NaHCO3 (1O mL) and acetone (1O mL) was treated dropwise with benzyl chloroformate (1.7O g, 1.41 mL, 1 eq.). After CO2 evolution ceased, the mixture was partitioned between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The resulting benzyl carbamate was dissolved in THF (50 mL) and cooled under argon to -78 C. n-BuLi (2.5M in hexanes, 6.45 mL, 1.1 eq.) was added dropwise, and the resulting solution was stirred for 1 h at that temperature. The reaction was then allowed to warm to -15C at which (5)-glycidyl butyrate (1.69 mL, 1.1 eq.) was added dropwise. The mixture was stirred at rt overnight. A tip of a spatula of Cs2CO3 was added, and the mixture was stirred at rt for 3 h. NH4Cl and EA were added and the phases were separated. The aq. phase was extracted once more with EA and the combined org. extracts were washed several times with sat. aq. NH4Cl, then with brine, dried over Na2SO4 and concentrated. The resulting orange solid was triturated with EA to afford the title intermediate as a pale yellow solid (1.18 g, 53% yield). MS (ESI, mix): 226.3 [M+H+].
With sodium hydrogencarbonate; In acetone;
A mixture of 3-fluoro-4-methyl-aniline (commercial; 1.25 g, lO mmol), sat. aq. NaHCO3 (1O mL) and acetone (1O mL) was treated dropwise with benzyl chloroformate (1.7O g, 1.41 mL, 1 eq.). After CO2 evolution ceased, the mixture was partitioned between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The resulting benzyl carbamate was dissolved in THF (50 mL) and cooled under argon to -78 C. n-BuLi (2.5M in Hex, 6.45 mL, 1.1 eq.) was added dropwise, and the resulting solution was stirred for 1 h at that temperature. The reaction was then allowed to warm to -15C at which (5)-glycidyl butyrate (1.69 mL, 1.1 eq.) was added dropwise. The mixture was stirred at rt overnight. A tip of a spatula of Cs2CO3 was added, and the mixture was stirred at rt for 3 h. NH4Cl and EA were added and the phases were separated. The aq. phase was extracted once more with EA and the combined org. extracts were washed several times with sat. aq. NH4Cl, then with brine, dried over Na2SO4 and concentrated. The orange solid obtained was triturated with EA to afford the title intermediate as a pale yellow solid (1.18 g, 53% yield). MS (ESI, m/z): 226.3 [M+H+].
Ethyl 2-bromo-2-phenylacetate (0.29 mL, 1.64 mmol), 3-fluoro-4- methylaniline (247 mg, 1.97 mmol) and DIPEA (0.37 mL, 2.14 mmol) are dissolved in acetonitrile (8 mL). The reaction is heated in a microwave oven at1000C for Ih and 15 min. Then, a solution of lithium hydroxide hydrate (207 mg, 4.94 mmol) in water (5 mL) is added and the mixture is stirred at RT for 2h. Acetonitrile is evaporated under vacuum, the remaining aqueous solution is cooled at 0 and the pH is adjusted to 2 with 4M HCl in dioxane. The resulting white solid is recovered by filtration and dried at 45C under vacuum overnight (367 mg, 75% yield).
4-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrole bishydrochloride[ No CAS ]
[ 452-77-7 ]
(3-fluoro-4-methyl-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrol-4-yl)-amine bishydrochloride salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2%
With potassium hydroxide; XPhos;palladium diacetate; In tert-butyl alcohol; at 100℃;
Example 50 (3-Fluoro-4-methyl-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-dlpyrrol-4-yl)-amine ? Bishydrochloride Salt (50) 4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3',4'-d]pyrrole» bishydrochloride (200 mg, 0.71 mmol), <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (0.10 mL, 0.86 mmol), Pd(OAc)2 (8 mg, 0.04 mmol), X-Phos (34 mg, 0.07 mmol), and KOH (240 mg, 4.28 mmol) were suspended in tert-butanol (3 mL), and stirred overnight at 100 0C. The reaction was concentrated, and the reaction mixture was suspended in DMSO (ImL) and H2O (15mL). The resulting precipitate was filtered, and dissolved in MeOH (2mL) and 2M HCl in ether (3 equiv). Ether (10 mL) was added dropwise to the solution to induce precipitate formation. The resulting precipitate was filtered to provide 50 (6 mg, 2% yield) as a grey solid. LC-MS (M+H = 297, obsd. = 297).
SiO2/Al2O3 pellets; In toluene; at 45℃; for 24h;Molecular sieve;
10 g mole sieves (4A) and 0.5 g of catalytically active SiO2/Al2O3 pellets were added to a solution of 0.49 g (3.0 mmol) diacetylpyridine in toluene. After addition of 7.0 mmol of the respective aniline, the solution was heated at 45 C. for 24 hours. After filtration over Na2SO4 and evaporation to dryness, the products were precipitated as yellow solids from methanol overnight at -20 C. (73-94%).Spectroscopic data: 1a: 1H NMR (400 MHz, CDCl3): 8.30 (d, 2H, Py-Hm), 7.85 (t, 1H, Py-Hp), 7.15 (t, 2H, Ph-H), 6.53 (m, 4H, Ph-H), 2.39 (s, 6H, NCMe), 2.26 (s, 6H, Ph-CH3). 13C {1H} (100.5 MHz, CDCl3): 167.9 (Cq), 163.1 (Cq), 159.9 (Cq), 155.3 (Cq), 150.4 (Cq), 136.9 (CH), 131.6 (CH), 122.4 (CH), 114.8 (CH), 106.6 (CH), 16.2 (CH3), 14.1 (CH3). MS data: 377 (M?+) (88), 362 (12), 150 (100).
General Procedure: 4-Aminoquinazolines were prepared according to literature methods with a slight procedural modification. A typical procedure utilized is demonstrated for compound 10 as a representative example. In a 25 mL seal-tube reaction vessel equipped with a magnetic stirrer, 100.0 mg (0.445 mmol) of 4-chloro-6,7-dimethoxy-quinazoline was added followed by 2.0 mL of acetonitrile and 62.5 mg (0.490 mmol) of 4-chloroaniline. The vessel was sealed and heated to 100 C. After stirring at said temperature for a period of one day, the reaction was cooled,solvent evaporated via speed-vac, and tritiated three times with cold acetonitrile. Any remaining solvent was evaporated in vacuo to afford 140 mg (quantitative yield) of 10 as a white crystalline solid.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 1h;Inert atmosphere;
General procedure: Method A: 2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride (.2 g, 0.814 mmol) was dissolved in DMF (2 ml) and 3,4-dimethylaniline (0.118 g, 0.977 mmol) was added followed by the dropwise addition of DIPEA (0.213 ml, 1.221 mmol). The reaction was stirred at RT for 1 h then purified by directly injecting to a Waters reverse phase purification system.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 6h;
General procedure: To a stirred solution of 3,4-dichloroaniline 4b (1.94 g, 12.0 mmol) in THF (20.0 mL) were added ethyl chloroglyoxylate (1.11 mL, 10.0 mmol) and Et3N (15.2 mL, 11.0 mmol) at 0 C. The mixture was stirred at room temperature for 6 h. After the precipitate was filtrated off, the filtrate solution was concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with 1.0 M HCl, saturated NaHCO3 and brine, then dried over MgSO4. Concentration under reduced pressure to provide the title compound 6b (1.58 g, 95% yield) as white powder, which was used without further purification.
General procedure: 4-Methyl-1,2,3-thiadiazole-5-carbaldehyde 3 (0.21 g, 1.6 mmol) and substituted amine (1.6 mmol) were stirred in 8mL methanol at room temperature. The imine was pre-condensated for 0.5-1 h and then cyclohexyl isocyanide (0.21 g, 1.9 mmol) and TMSN3 (0.28 g, 2.4 mmol) were added. The reaction mixture was stirred for 12-24 h at room temperature until the reaction was completed (indicated by TLC). Then the organic solvent was evaporated in vacuo. The crude products were purified by a silica gel column using ethyl acetate/petroleum ether (1:2-1:3 (v/v), 60-90 C) as an eluent to give 4a-4m as white or pale yellow solids in moderate yields.
N-(3-fluoro-4-methylphenyl)-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In dimethyl sulfoxide; at 140℃; for 0.666667h;
Step 1. Synthesis of N-(3-fluoro-4-methylphenyl)-3-nitropyridin-2-amine (C1) A mixture of 2-chloro-3-nitropyridine (4.76 g, 30.0 mmol), <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (3.75 g, 30.0 mmol) and potassium carbonate (8.29 g, 60.0 mmol) in dimethyl sulfoxide (30 mL) was stirred at 140 C. for 40 minutes. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a black solid. Yield: 6.78 g, 27.4 mmol, 91%. 1H NMR (400 MHz, CDCl3) delta 10.11 (br s, 1H), 8.54 (dd, J=8.3, 1.8 Hz, 1H), 8.51 (dd, J=4.6, 1.8 Hz, 1H), 7.59-7.64 (m, 1H), 7.15-7.21 (m, 2H), 6.86 (dd, J=8.4, 4.6 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H).
With triethylamine; In dichloromethane; at 20℃; for 5h;Inert atmosphere;
General procedure: A catalytic amount of DMF was added to a stirred solution of 2-chloro-5-nitrobenzoic acid (2) (4.00 g, 19.85 mmol) and oxalyl chloride (8.65 mL, 99.19 mmol) in DCM (50 mL) at 0 C under nitrogen atmosphere. After 20 min, the reaction was allowed to warm to room temperature and to proceed for a further 2 h. The reaction mixture was concentrated, re-dissolved in DCM and concentrated again. Triethylamine (13.83 mL, 99.22 mmol) and p-toluidine (2.13 g, 19.85 mmol) were added to the crude product dissolved in DCM (50 mL). The reaction was stirred for 5 h at room temperature under nitrogen atmosphere. After completion, the reaction mixture was diluted with DCM and successively washed with HCl (aq., 1 M), NaHCO3 (aq., sat.), water and brine. The organic phase was dried over MgSO4, filtered, and concentrated to dryness. The crude amide was purified by column chromatography (SiO2, EtOAc/n-heptane, 7:3 / 9:1) to give 3 in 90% yield
3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.6 g
To a solution of 2,4-dibromobutanoyl chloride (10 g, 38 mmol) in 100 mL of DCM at 0 C. under nitrogen was added <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (5.21 g, 42 mmol) followed by Et3N (6.3 mL, 45 mmol). The mixture was stirred at rt for 2 h, then concentrated in vacuo. The residue was dissolved in diethyl ether, then hexanes was added and a solid precipitated. The solid was removed by filtration and discarded. The filtrate was then concentrated in vacuo to give a dry residue. To a solution of this residue in 100 mL DMF at 0 C. under nitrogen was slowly added 60% NaH (1.82 g, 45 mmol). The mixture was stirred and allowed to warm up to rt over 30 min. The reaction mixture was slowly poured into 400 mL of ice water and allowed to stand overnight. A solid formed, and was filtered off and dried, then purified via silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to give racemic 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (5.6 g, 20.6 mmol). LCMS (method U) RT 3.41 min, m/z 273.97 (M+H+). 1H NMR (500 MHz, chloroform-d) delta 7.50 (dd, J=11.7, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (dd, J=7.0, 2.9 Hz, 1H), 4.03 (ddd, J=9.8, 7.9, 6.8 Hz, 1H), 3.82 (ddd, J=10.0, 7.7, 2.7 Hz, 1H), 2.75 (dq, J=14.6, 7.5 Hz, 1H), 2.48 (ddt, J=14.3, 6.7, 2.7 Hz, 1H), 2.28 (d, J=1.7 Hz, 3H).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 2h;
Synthesis of compound 238.1. To a solution of 57.4 (0.125g, 0.290 mmol, l .Oeq.) in DMSO (2 mL), 3-fiuoro-4-methylaniline (0.036g, 0.290 mmol, l .Oeq) and DIPEA (0.14 mL, 0.870 mmol, 3.0eq) were added at room temperature. Reaction mixture was heated at 90 C for 2 hours. After completion of the reaction, mixture was poured into cold water and extracted using ethyl acetate (20 mL x 2). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude was purified by column chromatography to afford 238.1 (0.063g, 41.81%). MS (ES): m/z 520.5 [M+H]+.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;
2-Chloro-<strong>[452-77-7]3-fluoro-4-methylaniline</strong> To a cooled (0 C.) solution of <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (1 equiv.) in DMF (1.6 M) was added NCS (1 equiv.). After the addition was finished, the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was diluted with ethyl acetate, washed with saturated Na2SO3, dried over Na2SO4, filtered and concentrated. The resulting residue was purified via silica gel column chromatography providing 2-chloro-<strong>[452-77-7]3-fluoro-4-methylaniline</strong> (8%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm: 6.87 (t, J=8.1 Hz, 1H), 6.49 (dd, J=1.2, 8.2 Hz, 1H), 4.02 (s, 2H), 2.20 (d, J=1.8 Hz, 3H).
diethyl 1-(2-ethoxy-1-((3-fluoro-4-methylphenyl)amino)-2-oxoethyl)hydrazine-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With tris(p-bromophenylammoniumyl) hexachloroantimonate; In nitromethane; at 20℃;Inert atmosphere;
General procedure: To a stirred mixture of anilines (1, 1.0mmol), diazoacetates (2, 1.0mmol) and azodicarboxylates (3, 1.0mmol) in MeNO2 (2.0mL) under argon atmosphere, TBPA+SbCl6- (5mol%) were added. The reactions were performed at room temperature and completed within 12-26h as monitored by TLC. The products 5 were isolated by column chromatographic separation.
With trifluorormethanesulfonic acid; at 100℃; for 16h;
General procedure: Aromatic amine derivatives (1a-1p) (5.0g, 45mmol), ethyl acrylate (68mmol) and TfOH as catalyst (10mol% with respect to amine) were mixed, and the reaction mixture was heated under reflux temperature overnight. The reaction was detected by TLC. The solvent was concentrated via reduced-pressure distillation. The residue was purified by column chromatography on silica gel eluted with PE/EtOAc=(10:1-5:1). Compounds 2a-2p were obtained. Yield: 75%-85%.
7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
<strong>[452-77-7]3-Fluoro-4-methylaniline</strong> (1.247 g, 9.96 mmol), 3-chlo- ropropionyl chloride (1.269 g, 9.99 mmol), and K2C03 (1.450 g, 10.5 mmol) in MeCN (10 mE) were stirred at 40 C. for 3 h. The reaction mixture was quenched with 4M HC1 and the product extracted into CH2C12. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue (1.168 g) was heated to 145 C. and small portions of A1C13 (3.538 g, 26.5 mmol) were added over a period of 30 mm. The reaction mixture was then cooled and 4M HC1 added under stirring followed by extraction of the product into CH2C12. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash CC (Si02 CH2C12/MeOH 40:1) to give the title compound (97KK40) (0.201 g, total yield 11%). ?H NMR (CDC13) oe 8.15 (br s, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H),2.91-2.87 (m, 2H), 2.62-2.60 (m, 2H), 2.19 (d, J=1.8 Hz, CH3).
N-(3-fluoro-4-methylphenyl)ethanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.8%
With pyridine; In dichloromethane; at 20℃; for 18h;
A solution of <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (0.457 mL, 3.995 mmol), pyridine (0.483 mL, 5.993 mmol) and ethanesulfonyl chloride (0.453 mL, 4.794 mmol) in dichloromethane (10 mL) was stirred at the room temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous 1M-hydrochloric acid solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 80 %) to give N(3-fluoro-4-methylphenyl)ethanesulfonamide as yellow solid (0.623 g, 71.8 %).
5-methyl-11-(3-fluoro-4-methylphenylamino)benzoindolo[3,2-b]quinolin-5-ium iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In 2-ethoxy-ethanol; at 120℃; for 0.5h;
General procedure: A suspension of 4a or 4b (0.1mmol), substituted aniline (0.15mmol), and 2-ethoxyethanol (10mL) was heated at 120C for 30min. When the reaction mixture was cooled to room temperature, anhydrous diethyl ether (10mL) was then added to the flask to precipitate the products. The resulting solution was kept steady at 4C for overnight. A yellow precipitate was formed, which was filtered and washed thoroughly with anhydrous ethyl acetate to afford A or B as a yellow solid. Further purification was carried out by recrystallization from methanol-diethyl ether (1:3).
N-(3-fluoro-4-methylphenyl)[1,1'-biphenyl]-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 125℃; for 22h;Inert atmosphere;
STEP 1: Synthesis of N-(3-fluoro-4-methylphenyl)[1,1?-biphenyl]-4-amine (0049) 4 4-Bromobiphenyl (20.0 g, 85.8 mmol), 5 <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (11.3 g, 90.1 mmol), 6 Pd(OAc)2 (578 mg, 2.57 mmol, 3 mol. %), 2,2?-bis(diphenylphosphino)-1,1?-binaphtalene ((BINAP) 2.40 g, 3.86 mmol, 4.5 mol. %), and 7 Cs2CO3 (39.13 g, 0.12 mol, 1.4 eq.), were charged in a flask under nitrogen atmosphere. The solids were suspended in anhydrous 8 1,4-dioxane, and the suspension was refluxed for 22 h at 125 C. After cooling to room temperature, it was filtered over silica and the pad was rinsed with dichloromethane. The filtrate was evaporated to dryness and purified by chromatography (silica, elution with hexane/dichloromethane 2:1, Rf in the corresponding TLC system 0.35). The 9 product was isolated in two main fractions: (-1) 7.55 g (32% yield) with 99.73% purity according to HPLC; (-2) 3.75 g (16% yield) with 99.33% purity according to HPLC. Both fractions were mixed together for the next step. (0050) 1H NMR (CD2Cl2, 400 MHz): 7.58 (2H, dd, J=8.24 and 1.10 Hz), 7.54 (2H; m-AB; J=8.57 Hz), 7.43 (2H, t, J=7.75 Hz), 7.31 (2H, t, J=7.38 Hz), 7.14 (2H; m-AB; J=8.57 Hz), 7.09 (1H, t, J=8.47 Hz), 6.81 (2H, m), 5.86 (1H, bs), 2.22 (3H, s) ppm. (0051) 13C NMR (CD2Cl2, 100 MHz): 164.18, 163.29, 161.36, 143.03, 142.95, 142.86, 141.21, 134.34, 132.43, 132.37, 129.31, 128.44, 127.22, 126.95, 118.42, 117.52, 117.38, 114.02 (d, J=2.93 Hz), 105.10, 104.89, 14.12 (d, J=3.24 Hz) ppm.
2-(imidazo[1,2-a]pyridin-5-yl)acetic acid[ No CAS ]
[ 452-77-7 ]
N-(3-fluoro-4-methylphenyl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45 mg
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
Example 15 N-(3-fluoro-4-methylphenyl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamide (0293) To a mixture of 2-(imidazo[1,2-a]pyridin-5-yl)acetic acid (50 mg) and anhydrous DMF (2.0 mL) were added <strong>[452-77-7]3-fluoro-4-methylaniline</strong> (0.039 mL), HATU (130 mg) and DIPEA (0.074 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate-hexane to give the title compound (45 mg). 1H NMR (300 MHz, DMSO-d6) delta2.17 (3H, d, J = 1.5 Hz), 4.14 (2H, s), 6.88 (1H, d, J = 6.8 Hz), 7.16-7.30 (3H, m), 7.46-7.58 (2H, m), 7.61 (1H, d, J = 1.1 Hz), 7.87 (1H, s), 10.52 (1H, s).
4-cyclopropyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid[ No CAS ]
4-cyclopropyl-N-(3-fluoro-4-methylphenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
General procedure: To a solution of compound 65 (0.20g, 0.77mmol) in anhydrous DMF (1mL) was added HATU (0.29g, 0.77mmol), the mixture was stirred at rt for 30min, then DIPEA (0.13mL, 0.77mmol) and p-toluidine (0.083g, 0.77mmol) was added. The mixture was stirred at rt for another 12h and monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc (3*20mL). The combined organic fractions were washed with brine, dried over Na2SO4, concentrated by evaporation under reduced pressure. Purification by silica gel column chromatography (gradient elution, gradient 0-25% EtOAc/60-90C petroleum ether) gave compound 7 (0.15g, 0.43mmol, 56% yield) as a white solid.
N-((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)(1-tert-butyl-1H-tetrazol-5-yl)methyl)-3-fluoro-4-methylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: In a round bottom flask containing aromaticamine (1.0 equiv) in MeOH, synthesized aldehyde (1.0 equiv) were added at roomtemperature. After 10 minsazidotrimethylsilane (1.0 equiv) andisocyanide (1.0 equiv) were added sequentially. The reaction mixture wasstirred for 6h at rt. Reaction proceeding was measured by TLC. After completionof reaction, solvent was concentrated under vacuum and the crude was purifiedby silica-gel column chromatography using a mixture of hexane withEtOActo afford the desired Ugi-azide product in good yield.
N-((3-(benzofuran-2-yl)-1-p-tolyl-1H-pyrazol-4-yl)(1-tert-butyl-1H-tetrazol-5-yl)methyl)-3-fluoro-4-methylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
General procedure: In a round bottom flask containing aromaticamine (1.0 equiv) in MeOH, synthesized aldehyde (1.0 equiv) were added at roomtemperature. After 10 minsazidotrimethylsilane (1.0 equiv) andisocyanide (1.0 equiv) were added sequentially. The reaction mixture wasstirred for 6h at rt. Reaction proceeding was measured by TLC. After completionof reaction, solvent was concentrated under vacuum and the crude was purifiedby silica-gel column chromatography using a mixture of hexane withEtOActo afford the desired Ugi-azide product in good yield.
3-(2-(4-(ethoxycarbonyl)thiazol-2-yl)-1H-benzo[d]imidazol-1-yl)propanoic acid[ No CAS ]
C23H21FN4O3S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;
General procedure: To a mixtureof compounds 12 (500 mg, 1.45 mmol), 4-methylmorpholine (0.8 mL, 4.25 mmol) and aniline (161 mg,1.74 mmol) in dried DCM was added HOBt (389 mg, 2.90 mmol) at 0 C, and then EDCI (557 mg,2.90 mmol) was added in batches. The resulting solution was warmed to room temperature afterstirring for 30 min at 0 C. The reaction mixture was washed with water three times and saturatedNaCl solution once. The organic layer was dried over anhydrous sodium sulfate, concentrated andpurified by flash silica gel column chromatography (PE/EA = 4/1, v/v), and then the residue wasre-dissolved in THF (15 mL), and lithium hydroxide solution (3.5 mmol/mL, 5 mL) was addeddropwise. The resulting solution was stirred at room temperature for 6 h. After the reaction wascompleted, the reaction mixture was concentrated in vacuo, and the residue dissolved in water andacidified with 2 N HCl to pH 5 at 0 C, filtered and dried to obtain the desired compound 13a as awhite solid in 56.1% yield.
2-chloro-N-(3-fluoro-4-methylphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 8h;
General procedure: The appropriate fluorinated aniline (<strong>[452-77-7]3-fluoro-4-methylaniline</strong>, 2-fluoro-4-iodoaniline and/or 2,4,5-trifluoaniline) 1a-c (10 mmol),triethylamine (12 mmol), chloroacetyl chloride (12 mmol) in dichloromethane(40 mL) were allowed to stir at 0 C for 2 h. The reaction wasstirred at room temperature for 6 h, until the consumption of thestarting materials. The resulting solid was filtered off, washed withwater and re-crystallized with ethanol to afford the corresponding 2-chloro-N-(substituted phenyl)acetamides 2a-c.
N<SUP>1</SUP>,N<SUP>3</SUP>-bis(3-fluoro-4-methylphenyl)-4-methoxybenzene-1,3-isophthalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.5%
General procedure: The solution of 4-methoxy-1,3-benzenedichloride (6)(0.93 g, 4.0 mmol) in anhydrous THF (15 mL) was added to3-bromine-4-methylaniline (1.48 g, 8.0 mmol). This solutionwas stirred rapidly at room temperature for about 1 hand then pyridine (1 mL) was added. The solution wasrefluxed for 4-8 h. The residue was recrystallized frommethanol-water to terminal compound 1a (1.81 g, yield85.2%). The other compounds (1b-1i) were prepared with thesimilar method of preparing compound 1a.
N<SUP>1</SUP>,N<SUP>3</SUP>-bis(3-fluoro-4-methylphenyl)-4-methoxybenzene-1,3-disulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.6%
With pyridine; In tetrahydrofuran; at 20℃; for 12h;Reflux;
General procedure: The solution of 4-methoxybenzene-1,3-disulfonyldichloride(8) (0.87 g, 2.9 mmol) in anhydrous THF (15 mL) wasadded to pyridine (1 mL) and 3-bromine-4-methylanilin(1.07 g,5.8 mmol). This solution was stirred rapidly at roomtemperature for about 2 h and then was refluxed for 10 h.The resulting solution was concentrated in vacuo and thesolvent was removed. The residue was recrystallized frommethanol-water to terminal compound 2a (1.20 g, yield68.5%).The other compounds (2b-2i) were prepared with thesimilar method of preparing compound 2a.
With dihydrogen peroxide; potassium carbonate; In water; acetonitrile; at 20℃;
General procedure: To a solution of p-toluidine (1.0 mmol) and potassium carbonate (1.0 mmol) in CH3CN (3 mL) were added a solution of 50% aqueous H2O2 (3.0 mmol) and the mixture was stirred at room temerature for 10-15 min. The mixture was then dried to vacuum and extracted three times with ethyl acetate followed by washing with brine,and dried over anhydrous Na2SO4. Evaporation of the solvent under vacuum afforded the crude product, which was furthur purified by column chromatography using hexane/ethyl acetate mixture and then analyzed by spectroscopy.
5-chloro-2-(3-fluoro-4-methylphenyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With acetic acid; at 110℃; for 4h;
General procedure: The starting materials 1 and 2 were commercially available (Energy Chemical, Shanghai, China).Compound 2 (3.72 mmol) was added to a stirred solution of compound 1 (3.38 mmol) in glacial aceticacid (10 mL). The reaction mixture was then stirred at 110 C for 4 h. After completion of the reaction,the solvent was evaporated, and the residue was purified on a silica gel column chromatography andeluted with ethyl acetate/petroleum ether (bp 60-90 C) (1:3, v/v) to give compounds 3.
4-chloro-2-(3-fluoro-4-methylphenyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With acetic acid; at 110℃; for 4h;
General procedure: The starting materials 1 and 2 were commercially available (Energy Chemical, Shanghai, China).Compound 2 (3.72 mmol) was added to a stirred solution of compound 1 (3.38 mmol) in glacial aceticacid (10 mL). The reaction mixture was then stirred at 110 C for 4 h. After completion of the reaction,the solvent was evaporated, and the residue was purified on a silica gel column chromatography andeluted with ethyl acetate/petroleum ether (bp 60-90 C) (1:3, v/v) to give compounds 3.
General procedure: 4-amino-6-chloropyrimidine (200 mg, 1.54 mmol) and KI(127.82 mg, 0.77 mmol) was dissolved in ethanol (35 mL). Trifluoroaceticacid (200 mL) was added after stirring and heating10 min for activating pyrimidine. Then to a stirred solution ofsubstituted aniline (1.23 mmol) in ethanol (15 mL) was added byway of drip for 1 h. The resulting mixture was heated to reflux for36 h, allowed to cool to room temperature, and concentrated invacuo. Then the solid residue was diluted with ethyl acetate and asaturated aqueous solution of NaHCO3. The aqueous layer wasseparated and extracted with ethyl acetate. The organic phase waswashed with brine, dried (Na2SO4), filtered, and concentrated. Purificationof the crude product by silica gel column chromatography(ethyl acetate/light petroleum, 2:1 and 1:1), provided the desiredproduct (batch1). Substituted aniline (2,6-dichloro and 3,5-dimethoxy) (200 mg) was dissolved in CH2Cl2 (15 mL) was addedby way of drip phosgene which dissolved in CH2Cl2 (20 mL)(batch1/phosgene, 2:1 (mol)) at 0 C for 0.5 h. The resulting mixturewas heated to reflux for 3e6 h, allowed to cool to room temperature,and concentrated in vacuo. Then the solid residue was dilutedwith ethyl acetate and a saturated aqueous solution of NaHCO3. Theaqueous layer was separated and extracted with ethyl acetate. Theorganic phase was washed with brine, dried (Na2SO4), filtered, andconcentrated. Purification of the crude product by silica gel columnchromatography (CH2Cl2/MeOH/aqueous NH3, 96:3:1), providedthe desired product (batch2). Batch1 and batch2 (batch1/batch2,5:6 (mol)) were dissolved in toluene (10 mL,18.89 mmol), theresulting mixture was heated to reflux for 8e10 h, allowed to coolto room temperature, then filtered by toluene to provide the endproduct(the residue).