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2-bromo-N-((dimethylamino)methylene)-5-fluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
at 120℃; for 1.5h;
A mixture of 2-bromo-5-fluorobenzamide (9.50 g, 43.57 mmol) and N,N-dimethylformamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed during the reaction was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylformamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (75 ml) and hexane (50 ml) to give 8.55 g (72% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.21 (3H, s, CH3), 3.24 (3H, s, CH3), 7.0 (1H, m, aromatic), 7.58 (1H, dd, J=5.0 Hz and J=8.5 Hz, aromatic), 7.64 (1H, dd, J=3.0 Hz and J=9.1 Hz, aromatic), 8.64 (1H, s, CH).
2-bromo-N-(1-(dimethylamino)ethylidene)-5-fluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
at 120℃; for 1.5h;
A mixture of 2-bromo-5-fluorobenzamide (9.57 g, 43.89 mmol) and N,N-dimethylacetamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylacetamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (30 ml) and hexane (50 ml) to give 9.51 g (75% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.43 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.19 (3H, s, NCH3), 6.90-6.97 (1H, m, aromatic), 7.46 (1H, dd, J=3.1 Hz and J=9.1 Hz, aromatic), 7.53 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic). MS (ESI+) m/e 287 [M+H+].
With ammonium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 25℃; for 20h;
A solution of 2-bromo-5-fluorobenzoic acid (10.0 g, 45.66 mmol) in dichloromethane (100 ml) was treated at 25° C. with oxalyl chloride (8.0 ml, 91.3 mmol) followed by a drop of N,N-dimethylformamide. The resulting mixture was then stirred for 4 h. The solvent and excess reagent were evaporated in vacuo and the residual oil was dissolved in tetrahydrofuran (100 ml) and added to a mixture of tetrahydrofuran (200 ml ), water (100 ml ) and concentrated ammonium hydroxide (10 ml ). The resulting mixture was then stirred at 25° C. for 20 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 9.51 g (96% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.9-6.3 (2H, broad, NH2), 7.05 (1H, m, aromatic), 7.42 (1H, dd, J=3.2 Hz and J=8.3 Hz, aromatic), 7.61 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic).
With ammonium hydroxide In dichloromethane at 0 - 20℃; for 1h;
To a RB flask equipped with an addition funnel is charged acid 7, 2-Me-THF and DMF. The solution is then cooled to 70C and oxalyl chloride is added dropwise over 30 min at < 15 0C.After the addition is complete, the reaction mixture is warmed to it and aged for 45 min. Upon complete consumption of the acid, the reaction mixture is then charged dropwise into another flask containing cold (9 0C) mixture of concentrated NH4OH and 2-Me-THF over 1.5 h, while maintaining the temperature around 20-250C. To the reaction mixture is added water (100 mL)15 to dissolve some solids and the resulting biphasic layer is transferred to a separatory funnel. The aqueous layer is separated and the organic layer is washed with 1 N HCl (50 mL) and with brine (100 mL). The final organic layer is then solvent switched to toluene to give a final slurry concentration of 15 vol. The slurry is then hheated to 110 0C to get a clear solution, which is then cooled slowly to RT. Crystallization is typically observed to occur at 1000C and after aging at rt overnight, heptane (10 vol) is then added, followed by a Ih of age. The suspension is then filtered and the wet cake is washed with cold 1 :1 heptane :toluene and dried under a stream of N2 to give the product in 46.9 g (94.7%).
94.7%
To a RB flask equipped with an addition funnel is charged acid 7a, 2-Me-THF and DMF. The solution is then cooled to 70C and oxalyl chloride is added dropwise over 30 min at < 15 0C. After the addition is complete, the reaction mixture is warmed to rt and aged for 45 min. Upon complete consumption of the acid, the reaction mixture is then charged dropwise into another flask containing cold (9 0C) mixture of concentrated NH4OH and 2-Me-THF over 1.5 h, while maintaining the temperature around 20-250C. To the reaction mixture is added water (100 mL) to dissolve some solids and the resulting biphasic layer is transferred to a separatory funnel. The aqueous layer is separated and the organic layer is washed with 1 N HCl (50 mL) and with brine (100 mL). The final organic layer is then solvent switched to toluene to give a final slurry concentration of 15 vol. The slurry is then hheated to 1 10 0C to get a clear solution, which is then <n="17"/>cooled slowly to RT. Crystallization is typically observed to occur at 1000C and after aging at rt overnight, heptane (10 vol) is then added, followed by a Ih of age. The suspension is then filtered and the wet cake is washed with cold 1 :1 heptane:toluene and dried under a stream of N2 to give the product in 46.9 g (94.7%).
With piperidine; tri tert-butylphosphoniumtetrafluoroborate In acetonitrile at 80℃; for 3 - 4h;
1.3
Alkyne 4a, bromide 5a, acetonitrile (PvM Table, line 6), and piperidine are charged successively to a round bottom flask equipped with a thermocouple, stir bar, and reflux condenser. The reagents are stirred until a reddish-brown solution is formed and the solution is degassed by 5 vacuum and nitrogen refill cycles. The phosphine ligand and palladium catalyst are then added successively and the resulting solution is degassed again. The solution is then heated to 80 °C and aged until a 99% conversion by HPLC analysis is achieved (typically 1 h). The solution is diluted with 100 mL of toluene and is then washed successively with HOAc (1.5 equiv) in 15 wt% aqueous NaCl (48 mL), saturated KHCO3 solution (40 mL), and saturated NaCl solution (40 mL). Ecosorb 941 (2.53 g) and trithiocyanuric acid (127 mg) are added to the solution and the solution was stirred between 23-25 °C for 1 hour. The black slurry is then filtered over Solka flock (10 g) through a 15-20 micron fritted funnel. The wet cake is washed with 130 mL of 2:1 toluene: CH3 CN. The solution is transferred to a separatory funnel and washed with 15 wt%K2CO3 aqueous solution (38 mL) and then diluted with toluene (26.7 mL) and CH3CN (53 mL). The organic layer is washed with saturated aqueous NaCl (38 mL) and transferred to a round bottom flask. The organic layer is assayed to contain 12.76 gA of product 6a by HPLC analysis.
92%
With piperidine In acetonitrile at 80℃; for 3 - 4h;
159.3; 159.4
Alkyne 4, bromide 5, acetonitrile (RM Table, line 6), and piperidine are charged successively to a round bottom flask equipped with a thermocouple, stir bar, and reflux condenser. The reagents are stirred until a reddish-brown solution is formed and the solution is degassed by 5 vacuum and nitrogen refill cycles. The phosphine ligand and palladium catalyst are then added successively and the resulting solution is degassed again. The solution is then heated to 80 0C and aged until a 99% conversion by HPLC analysis is achieved (typically 1 h). The solution is diluted with 100 mL of toluene and is then washed successively with HOAc (1.5 equiv) in 15 wt% aqueous NaCl (48 mL), saturated KHCO3 solution (40 mL), and saturated NaCl solution (40 mL). Ecosorb 941 (2.53 g) and trithiocyanuric acid (127 mg) are added to the solution and the solution was stirred between 23-25 °C for 1 hour. The black slurry is then filtered over Solka flock (10 g) through a 15-20 micron fritted funnel. The wet cake is washed with 130 mL of 2:1 toluene:CH3CN. The solution is transferred to a separatory funnel and washed with 15 wt% K2CO3 aqueous solution (38 mL) and then diluted with toluene (26.7 mL) and CH3CN (53 mL). The organic layer is washed with saturated aqueous NaCl (38 mL) and transferred to a round bottom flask. The organic layer is assayed to contain 12.76 gA of product 6 by HPLC analysis. The crude solution of 6 (12.6 g) in PhMe/MeCN is concentrated under reduced pressure to remove MeCN, while maintaining the total volume of lOvol and the batch temperature at 20-25 0C. Total of 6-vol of PhMe is used during this process. At the end of the solvent switch, the resulting slurry is heated up to 90 0C and cooled slowly to 720C. After appropriate seeding, the product started to crystallize to give a slurry which is then aged overnight. Heptane (3.3 vol) is then added and the resulting mixture is aged until 6-8% of product remained in the mother liquor. At this point, the slurry is then filtered and the wetcake is washed with cold PhMe/Heptane (3/1, 6 vol) followed by heptane (3 vol) and dried under stream of N2 overnight. The product is isolated as pale yellow solid in 13.67 g (84.4 wt%) in 92% recovery or 81% overall yield.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 120℃; for 3h; Microwave irradiation; Inert atmosphere;
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 120℃; for 3h; Microwave irradiation; Inert atmosphere;
With potassium carbonate In dimethyl sulfoxide at 120℃; for 8h;
4.3. General procedure for the heterogeneous copper(I)-catalyzedsynthesis of quinazolinone derivatives
General procedure: To a 10 mL reaction tube were added MCM-41-L-Proline-CuBr(135 mg, 0.1 mmol), 2-halobenzamide 1 (1.0 mmol), benzylamine derivative 2 (2.0 mmol), K2CO3 (3.0 mmol), and DMSO (3 mL). The reaction mixture was stirred at 110 or 120 °C under air for 6-12 h.After being cooled to room temperature, the reaction mixture was diluted with 20 mL of EtOAc, and filtered. The MCM-41-L-Proline-CuBr complex was washed with distilled water (2 5 mL) and ethanol (2 5 mL), and reused in the next run. The filtrate was washed with water (2 10 mL) and dried over MgSO4. After being concentrated in vacuo, the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 3:1 to 2:1)to afford the target product 3.
With Rhodococcus rhodochrous ATCC BAA 870 cobalt nitrile hydratase; In aq. buffer; at 30℃;pH 7.6;Enzymatic reaction;
General procedure: 1800 muL (90%) Tris buffer (50 mM, pH 7.6) and 200 muL(10%) of methanol or acetone. In a 2 mL Eppendorf, NHase (10 mg) was added followed by Trisbuffer. Nitrile substrate (10 mg dissolved in 200 muL methanol or acetone) was added to the 2 mLEppendorf tube. (If an amine group was present on the nitrile substrate a Tris buffer of pH 9 wasused). The reaction mixture was incubated at 30 C on an ESCO Provocell microplateshaker/incubator (Esco Technologies, Halfway House, South Africa) (199 rpm). The reaction wasallowed to proceed for 24 h, 48 h or 5 d, depending on conversion, as monitored by TLC analysis.Ethyl acetate and water were added to the reaction mixture, and after separation, the organic layerwas concentrated under reduced pressure, and the resulting mixture was then purified by silica gelcolumn chromatography eluting with 20% to 90% ethyl acetate/ hexane.
With potassium carbonate; sulphur In N,N-dimethyl-formamide at 110℃; Inert atmosphere;
1.2 General procedure for preparing 3
General procedure: To a solution of corresponding compound 2 (1.0 eq), S powder (2.0 eq) and K2CO3 (1.5 eq) in DMF was stirred at 110 °C under an argon (N2) atmosphere overnight. The solvent was removed under vacuum and the residue was dissolved with DCM/MeOH and then filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography to afford the title compounds. 6-fluorobenzo[d]isothiazol-3(2H)-one (3a) White solid; yield 42%;
15%
With potassium carbonate; sulphur In N,N-dimethyl-formamide at 110℃; Inert atmosphere;
1.2 General procedure for preparing 3
General procedure: To a solution of corresponding compound 2 (1.0 eq), S powder (2.0 eq) and K2CO3 (1.5 eq) in DMF was stirred at 110 °C under an argon (N2) atmosphere overnight. The solvent was removed under vacuum and the residue was dissolved with DCM/MeOH and then filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography to afford the title compounds. 6-fluorobenzo[d]isothiazol-3(2H)-one (3a) White solid; yield 42%;