* 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.
6-Chloroindazole. A solution of 4-chloro-2-fluorobenzaldehyde (5.0 g, 31.6 mmol) in 12 mL of pyridine was treated with hydrazine hydrate (10 eq., 10 mL) and DMAP (3.85 g, 31.6 mmol) and the mixture heated to 100 °C for several hours. The mixture was allowed to cool to RT and was diluted with EtOAc and washed several times with dilute acid. The EtOAc solution was dried over MgS04 and concentrated in vacuo to give 6-chloroindazole as an off white solid (3.86 g).
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
4
[ 61072-56-8 ]
[ 124-41-4 ]
[ 53581-86-5 ]
Yield
Reaction Conditions
Operation in experiment
77.5%
at 50℃; for 3 h;
4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 μL, 1.89 mmol) (solution in methanol), heated to 500C and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5percent ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5 percent yield).
Reference：
[1] Patent: WO2009/158426, 2009, A1, . Location in patent: Page/Page column 140
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 18, p. 5037 - 5041[3] Angew. Chem., 2018, vol. 130, # 18, p. 5131 - 5135,5
5
[ 874-42-0 ]
[ 1550-35-2 ]
[ 84194-36-5 ]
[ 61072-56-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
Reference：
[1] Journal of Fluorine Chemistry, 1996, vol. 80, # 2, p. 117 - 124
12
[ 452-66-4 ]
[ 61072-56-8 ]
[ 96515-79-6 ]
Reference：
[1] Patent: US5502073, 1996, A,
13
[ 61072-56-8 ]
[ 56456-49-6 ]
Yield
Reaction Conditions
Operation in experiment
78.7%
at 0 - 20℃; for 1 h;
Example 1 1-(5-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (1)1-(Bromomethyl)-4-chloro-2-fluorobenzene was prepared using the following two-step procedure. To a stirred solution of 4-chloro-2-fluorobenzaldehyde (1.0 g, 6.31 mmol) in methyl alcohol (CH3OH; 15 mL) was added sodium borohydride (NaBH4; 0.47 g, 12.6 mmol) at 0° C. The reaction mixture was stirred at RT for 1 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice pieces, and the volatiles were evaporated under reduced pressure. The residue was diluted with H2O (25 mL) and extracted with EtOAc (2.x.50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (SiO2, 100-200 mesh) to afford the corresponding alcohol (0.8 g, 5.0 mmol, 78.7percent) as a semi solid. 1H NMR (200 MHz, CDCl3): δ 7.41 (q, J=8.0, 15.6 Hz, 1H), 7.17-7.05 (m, 2H), 4.73 (d, J=6.2 Hz, 2H), 1.83 (t, J=6.2 Hz, 1H).
Reference：
[1] Patent: US2012/329788, 2012, A1, . Location in patent: Page/Page column 22
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 13, p. 3463 - 3468
[3] Patent: US6100257, 2000, A,
[4] Patent: EP1577290, 2005, A1, . Location in patent: Page/Page column 107
14
[ 61072-56-8 ]
[ 2365-48-2 ]
[ 104795-85-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4793 - 4807
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6463 - 6466
[3] Patent: WO2016/100184, 2016, A1, . Location in patent: Paragraph 00268
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
Example 1 1-(5-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (1)1-(Bromomethyl)-4-chloro-2-fluorobenzene was prepared using the following two-step procedure. To a stirred solution of 4-chloro-2-fluorobenzaldehyde (1.0 g, 6.31 mmol) in methyl alcohol (CH3OH; 15 mL) was added sodium borohydride (NaBH4; 0.47 g, 12.6 mmol) at 0 C. The reaction mixture was stirred at RT for 1 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice pieces, and the volatiles were evaporated under reduced pressure. The residue was diluted with H2O (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (SiO2, 100-200 mesh) to afford the corresponding alcohol (0.8 g, 5.0 mmol, 78.7%) as a semi solid. 1H NMR (200 MHz, CDCl3): delta 7.41 (q, J=8.0, 15.6 Hz, 1H), 7.17-7.05 (m, 2H), 4.73 (d, J=6.2 Hz, 2H), 1.83 (t, J=6.2 Hz, 1H).
With hydrogenchloride; sodium borohydrid; In 1,4-dioxane; methanol;
(1) First, 25 g of 4-chloro-2-fluorobenzaldehyde was dissolved in a mixed solvent consisting of 250 ml of 1,4-dioxane and 25 ml of methanol, to which 2.4 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, a small amount of diluted aqueous hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 25 g of 4-chloro-2-fluorobenzyl alcohol. 1 H--NMR (300 MHz, CDCl3): delta (ppm) 1.82 (1 H, t, J=6.1 Hz), 4.72 (2 H, d, J=6.1 Hz), 7.08 (1 H, dd, J=2.1, 9.8 Hz), 7.15 (1 H, dd, J=2.1, 8.2 Hz), 7.37 (1 H, dd, J=8.2, 8.2 Hz)
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1.5h;
4.75 g of 4-chloro-2-fluorobanzaldehyde and 30 ml of methanol were mixed. It was cooled to 0 C, and 0.57 g of sodium borohydride was added to it, and stirred at 0 C for 30 minutes and at room temperature for 1 hour. Water was added to the reaction mixture, and concentrated under reduced pressure. The obtained residue was extracted with chloroform. The organic layer was washed successively with 5 % hydrochloric acid, saturated aqueous solution of sodium chloride, dried by magnesium salfate, and concentrated under reduced pressure to obtain 4.57 g of (4-chloro-2-fluorophenyl)methanol.1H-NMR (CDCl3, TMS) delta (ppm): 7.37 (1H, t, J=8.0 Hz), 7.12-7.17 (1H, m), 7.08 (1H, dd, J=9.7 Hz, 1.9 Hz), 4.73 (2H, s), 2.04 (1H, br.s)
With caesium carbonate; In ISOPROPYLAMIDE; at 20℃; for 48h;
A stirred solution of <strong>[61072-56-8]4-chloro-2-fluoro-benzaldehyde</strong> (3.58g, 25.23 mmol) and 2- fluoro-6-methoxy phenol (4.0 g, 25 mmol) in DMA (25 mL) was treated with cesium carbonate (8.22g, 25.23 mmol). The mixture was stirred at room temperature for a total of 48 hours. The reaction mixture was poured into about 150 mL of ice water and stirred for 6 hours. The resulting solid was removed by filtration, washed with water and dried at 450C in a vacuum oven for 18 hours to give 6.8g (97%) of the title compound.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 15.0h;
General procedure: To a stirred solution of compound 1a-1n (9.90 mmol) in DMF (20 mL) were added methyl thioglycolate (10.9 mmol) and potassium carbonate (39.6 mmol). The resulting mixture was stirred at 60 C for 15 h. The DMF was removed under reduced pressure,water (50 mL) was added and the mixture was extracted with ethylacetate (2 x 40 mL). The combined organic layers were dried withsodium sulfate, filtered, and the solvents were removed under reduced pressure to afford the title compound 2a-2n [31,34].
With triethylamine; In dimethyl sulfoxide; at 80℃; for 1.0h;
To a mixture of 4-chloro-2-fluorobenzaldehyde (50 g, 0.32 mol) and methyl 2- mercaptoacetate (40 g, 0.38 mol) in dimethylsulfoxide (500 mL) was added triethylamine (96 g, 0.95 mol) at room temperature. The mixture was stirred at 80 C for 1 hour. On completion, the reaction mixture was cooled to room temperature and poured into ice water (4 L), resulting in formation of a solid. The mixture was stirred for half an hour, and the solid was collected by filtration, washed with water and dried in vacuo to give compound B-101 (80 g, crude) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 227.0.
With tert.-butyl lithium; In diethyl ether; pentane; at -78℃; for 1h;
Step B: Compound 3f (132 mg, 0.521 mmol) in 1 ML of ether was cooled to -78 C. To the solution was added t-BuLi (1.70 M in pentane, 0.64 ML, 1.10 mmol).After 1 hour at -78 C., a solution <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (86.8 mg, 0.548 mmol) in 1 ML of ether was added and the mixture was slowly warmed to room temperature.The mixture was quenched with water (5 ML) and layers were separated.The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over anhydrous MgSO4, filtered through Celite, and concentrated under reduced pressure.The crude was purified by chromatography with 1:2 ether/hexanes to provide 43.7 mg of compound 4f-7 as a pale yellow solid (25.2% yield). MS ESI (+) m/z 333 and 335 (M+1) detected. 1H-NMR (400 MHz, CDCl3) delta 7.96 (s, 1H), 7.72 (s, 1H), 7.56 (m, 1H), 7.39~7.35 (m, 2H), 7.18 (m, 1H), 7.05 (m, 1H), 6.21 (m, 1H), 4.15 (m, 2H), 2.37~2.27 (m, 2H, overlapped with -OH), 0.91 (m, 6H).
With potassium carbonate; In Isopropyl acetate; at 80℃; for 3.5h;
A mixture of the product from Part A (5.81 g, 11.9 mmol), K2CO3 (1.80 g, 13.0 mmol), and <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.83 g, 11.6 mmol) in IPA (37 mL) were combined and heated for 3.5 hr at 80 C. The resulting mixture was then cooled to ambient temperature, diluted with water (300 mL), and extracted with hexane (3*100 mL). The organic layer was washed with water (2*100 mL), dried over MgSO4, and concentrated in vacuo to afford 2.26 g (82% yield) of the desired compound in the form of a clear, colorless liquid. Proton NMR in CDCl3 was consistent with the desired product in the form of a mixture of cis and trans isomers.
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Heating;
Step B 4-Chloro-2- (2-fluoro-phenoxy)-benzaldehyde A solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.0 g, 6.3 mmol) and 2- fluorophenol (0. 78 g, 6.9 mmol) in DMSO (10 mL) is treated with potassium carbonate (1.04 g, 7.6 mmol). The reaction is heated to 100 C and stirred overnight. The reaction is cooled to room temperature and quenched with 1N aqueous hydrochloric acid to pH=6. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 4: 1 hexanes: acetone to elute the pure product. The solvent is removed to afford about 0. 8 g (51%) of product. 1H NMR (400 MHz, CDC13), TLC (1: 1 hexanes: EtOAc) Rf=0. 8
1,3:2,4-bis(4'-chloro-2'-fluorobenzylidene)sorbitol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
hydrogenchloride; In methanol; water; at 20℃; for 48h;
EXAMPLE 11 1,3:2,4-Bis(4'-chloro-2'-fluorobenzylidene) Sorbitol To a white slurry of D-sorbitol (14.4 g, 76.5 mmol) and <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (25.0 g, 153 mmol) in methanol (200 mL) at room temperature was added concentrated HCl aqueous solution (1.2 mL, 14 mmol). After mechanically stirring for 48 h, the viscous white slurry was suction filtered, and the residue was washed sequentially with boiling water (1000 mL*2), cyclohexane (1000 mL*2) and boiling water (1000 mL*4). After drying in vacuum oven at 110 C. for 12 h, 1,3:2,4-bis(4'-chloro-2'-fluorobenzylidene) sorbitol (27.6 g, 78%) was obtained as a white powder. The product was properly characterized using 1H and 13C NMR, IR and GC/MS.
Step 1. (4-Chloro-2-fluoro-phenyl)-trimethylsilanyloxyacetonitrile; EPO <DP n="114"/>[00421] To a solution of <strong>[61072-56-8]4-chloro-2-fluoro-benzaldehyde</strong> (5.0g, 31.55 mmol) in CH2Cl2 (20 mL) at O0C, was added TMSCN (3.12g, 31.55 mmol) and Cat. ZnI2 (50 mg). The mixture was stirred at RT for overnight. After concentrating, the desired product was obtained (8.12g, 100% yield) as a brown oil. 1H NMR (CDCl3) deltatheta.1 (s, 9H), 5.6 (s, IH), 7.0 (d, IH), 7.15 (d, IH), 7.55 (t, IH).
With potassium acetate; In dimethyl sulfoxide; at 80℃; for 16h;
A mixture of 4-(methyloxy)benzenecarboximidamide (3.0 g, 20.0 mmol), <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (2.22 g, 14.3 mmol), methyl acetoacetate (2.0 g, 17.2 mmol), and potassium acetate (1.4 g, 14.3 mmol) was dissolved in DMSO (100 mL) with stirring, and heated at 80 C for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with brine (3 x 100 mL), and dried (MgS04). The solvent was removed via rotovap and the residue was purified by ISCO silica column to afford a greenish solid product (2.0 g, 36 %). MS (ES+) m/z 390 [M+H]+.
4-chloro-2-fluorobenzaldehyde and 5-chloro-2-fluorobenzaldehyde were prepared in an analogous manner from 4-chloro-2-fluorotoluene and <strong>[452-66-4]5-chloro-2-fluorotoluene</strong> respectively (both supplied by Lancaster Synthesis).
Intermediate 5To <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (30.64 g, 193.2 mmol, 1.0 eq) in DCM (460 ml) was added (S)-(-)-2-methyl-2-propane sulfinamide (23.41 g, 193.2 mmol, 1.0 eq) followed by titanium (IV) ethoxide (88.1 g, 386 mmol, 2.0 eq). The reaction was stirred overnight before addition of DCM (1 L) and sodium sulfate decahydrate (310 g). After 30 min vigorous stirring, the mixture was filtered through Celite (500 g) and the cake washed with DCM (2 x 1 L). The organic liquors were dried (MgS04), filtered and concentrated in vacuo. The crude compound was dissolved in DCM (500 ml), washed with 10% aq citric acid (200 ml), and saturated brine (100 ml), dried (MgS04), filtered and concentrated in vacuo to give (S)-2-methyl-propane-2-sulfinic acid 1-(4- chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (49.7 g, 1 H NMR >95% excluding solvent, 46.7 g active, 178 mmol, 92% yield). 1 H NMR (270 MHz, CDCI3): 8.82 (1 H, s), 7.96-7.90 (1 H, dd), 7.24-7.16 (2H, m), 1.25 (9H, s).
92%
With titanium(IV) tetraethanolate; In dichloromethane;
Synthesis of Key Intermediate 3cf(RH4-Chloro-2-fluoro-phenyl)-cvclopropyl-methyl1-carbamic acid tert-butyl esterStep 1 To <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (30.64 g, 193.2 mmol, 1.0 eq) in DCM (460 ml) was added (S)-(-)-2-methyl-2-propane sulfinamide (23.41 g, 193.2 mmol, 1.0 eq) followed by titanium (IV) ethoxide (88.1 g, 386 mmol, 2.0 eq). The reaction was stirred overnight before addition of DCM (1 L) and sodium sulfate decahydrate (310 g). After 30 min vigorous stirring, the mixture was filtered through Celite (500 g) and the cake washed with DCM (2 x 1 L). The organic liquors were dried (MgS04), filtered and concentrated in vacuo. The crude compound was dissolved in DCM (500 ml), washed with 10% aq citric acid (200 ml), and saturated brine (100 ml), dried (MgS04), filtered and concentrated in vacuo to give (S)-2-methyl-propane-2- sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (49.7 g, 1H NMR >95% excluding solvent, 46.7 g active, 178 mmol, 92% yield). 1H NMR (270 MHz, CDCI3): 8.82 ( H, s), 7.96-7.90 (1 H, dd), 7.24-7.16 (2H, m), 1.25 (9H, s).
With titanium(IV) tetraethanolate; In tetrahydrofuran; at 20℃; for 2.5h;Heating / reflux;
Reference example 72; (1); To <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (26.2g) and (S)(-)-2-methyl-2-propanesulfonamide (21.0g) in THF (940ml) was gradually dropped titanium ethoxide (IV) (80.9g) at room temperature, and the mixture was stirred under reflux for 2.5 hours. After being cooled, the reaction mixture was gradually poured into cooled saturated brine under stirring and the insoluble materials were filtered off over Celite. To the filtrate was added methylene chloride (1800ml) and the mixture was separated by a separating funnel, followed by dry. The solvent was removed to give compound (2) (42.3g) as a colorless solid. APCI-MS (m/e): 262/264 (M+H)+
A solution of potassium t-butoxide (3.55g) was stirred in THF (40MI) at 0C. Methyl triphenylphosphonium bromide (11. 4g) was added and the mixture was stirred for 10 min at 0C then at room temperature for 1 hour. After cooling to 10 C, 4-CHLORO-2- fluorobenzaldehyde (4.2g) was added in THF (30ml) over 10 minutes and the mixture was stirred at room temperature for 3 hours. Toluene (20ML) was added and solvent volume reduced by half in vacuo. After addition of petroleum ether, the mixture was filtered and solvent removed in vacuo. The residue was purified by silica gel chromatography (toluene : petroleum ether 3: 7) to give the title compound. RT 3.52min
Step 1: 4-Chloro-2-fluoro-1 -vinylbenzeneA solution of KOt-Bu (19.5 g, 174 mmol) in dry THF (300 mL) was cooled with an ice/water bath. Portionwise addition of MePPh3Br (62.2 g, 174 mmol) resulted in a suspension, which was stirred for 5 mm at 0 C and for I h at 15 C. Subsequently, the temperature was lowered to 0C and a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (25.1 g, 158 mmol) in dry THF (100 mL) was added dropwise. The temperature was raised to room temperature slowly. The reaction mixture was stirred at room temperature for 20 h. Addition of brine (100 mL) resulted in a clear two phase system and a white solid. The combination of layers was decanted from the solid. The layers were separated, the aqueous layer was combined with the solid residue and Et20 (200 mL). The combination of layers was decanted from the solid. The layers were separated, the combination of organic layers was dried (Na2SO4) and concentrated at a controlled vacuum of 100 mbar. The residual oil was combined with pentane (300 mL) and Na2SO4. The suspension was triturated. Filtration and pentane washing provided a filtrate, which was concentrated at a controlled vacuum of 100 mbar to arrive at 26.76 g (97%, 90% purity) of impure title compound as a yellow oil.
4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 muL, 1.89 mmol) (solution in methanol), heated to 500C and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5 % yield).
Example 1Preparation of (E)-4-(4-chloro-2-fluorophenyl)-but-3-en-2-one (1)To a mechanically stirred solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (23.8 grams (g), 0.15 mole (mol)) in acetone (100 milliliters (mL)) at room temperature was added over 20 minutes (min) a solution of sodium hydroxide (NaOH, 6.6 g, 0.165 mol) in water (H2O, 400 mL). After stirring the reaction mixture overnight, dichloromethane (CH2Cl2, 100 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (100 mL), and the combined organic extracts were washed with brine and dried over magnesium sulfate (MgSO4). Solvent removal followed by Kugelrohr distillation gave 4-(4-chloro-2-fluorophenyl)-3-buten-2-one (1; 22.5 g, 76%) as a colorless liquid, which solidified upon standing: by 70-80 C., 0.1 mmHg (13.33 pascals (Pa)); 1H NMR (400 MHz, CDCl3) delta 7.59 (d, J=16.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.22-7.12 (m, 2H), 6.76 (d, J=16.5 Hz, 1H), 2.39 (s, 3H); HRMS-ESI (m/z): calcd for C10H8ClFO, 198.024; found 198.025.
76%
With sodium hydroxide; In water; at 20℃;
Preparation of (E)-4-(4-chloro-2-fluorophenyl)-but-3-en-2-one (1) To a mechanically stirred solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (23.8 grams (g), 0.15 mole (mol)) in acetone (100 milliliters (mL)) at room temperature was added over 20 minutes (min) a solution of sodium hydroxide (NaOH, 6.6 g, 0.165 mol) in water (H2O, 400 mL). After stirring the reaction mixture overnight, dichloromethane (CH2Cl2, 100 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (100 mL), and the combined organic extracts were washed with brine and dried over magnesium sulfate (MgSO4). Solvent removal followed by Kugelrohr distillation gave 4-(4-chloro-2-fluorophenyl)-3-buten-2-one (1; 22.5 g, 76%) as a colorless liquid, which solidified upon standing: by 70-80 C., 0.1 mmHg (13.33 pascals (Pa)); 1H NMR (400 MHz, CDCl3) delta 7.59 (d, J=16.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.22-7.12 (m, 2H), 6.76 (d, J=16.5 Hz, 1H), 2.39 (s, 3H); HRMS-ESI (m/z): calcd for C10H8ClFO, 198.024. found 198.025.
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 8h;Sealed tube;
A thick walled flask was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (4) (1.00 g, 6.31 mmol) and tert-butyl-l-piperazinecarboxylate (1.17 g, 6.31 mmol). DMSO was added (10 mL) followed by potassium carbonate (870 mg, 6.31 mmol), the reaction was sealed, and was heated to 120 C for 8 h. The reaction was cooled to rt, then diluted with EtOAc (200 mL). The organic layer was washed with brine (3 x 100 mL) and sat NH4C1 (1 x 100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a solid. The solid was purified on silica gel by flash column chromatography (0 to 20% EtOAc in hexane) to afford tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-l-carboxylate (5) (1.50 g, 73% yield). 1H NMR (400 MHz, Chloroform-i ) delta 10.25 (s, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.18 - 7.05 (m, 2H), 3.69 - 3.61 (m, 4H), 3.09 - 3.02 (m, 4H), 1.51 (s, 9H). LCMS (ESI, m/z): 325.1 [M + H]
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 20h;Sealed tube;
General procedure: Example 16: 1,1,1,3,3,3-Hexafluoropropan-2-yl 1-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)-4- (trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate Step 1: Preparation of 1-(2-formyl-5-(trifluoromethyl)phenyl)-N,N-dimethylpiperidine-4- carboxamide A sealed tube was charged with 2-fluoro-4-(trifluoromethyl)benzaldehyde (520 mg, 2.71 mmol), N,N-dimethylpiperidine-4-carboxamide (507 mg, 73.2 mmol), and potassium carbonate (1.2 g, 8.66 mmol). DMA (4 mL) was added and the mixture was stirred at 140 C for 20 h. The reaction was cooled to rt, then diluted with EtOAc (200 mL). The organic layer was washed with brine (3x) and with sat. NH4Cl (1x). The organic layer was dried over Na2SO4, filtered and concentrated to yield a solid. The solid was purified by flash column chromatography to afford 1- (2-formyl-5-(trifluoromethyl)phenyl)-N,N-dimethylpiperidine-4-carboxamide as a yellow solid (489 mg, 55% yield).1H NMR (400 MHz, Chloroform-d) delta 10.31 (s, 1H), 7.90 (s, 1H), 7.40- 7.32 (m, 2H), 3.47- 3.38 (m, 2H), 3.12 (s, 3H), 3.08- 2.96 (m, 5H), 2.80- 2.66 (m, 1H), 2.19- 2.05 (m, 2H), 1.96- 1.85 (m, 2H).
With hydrazine hydrate; In ISOPROPYLAMIDE; at 18 - 100℃; for 17.5h;Inert atmosphere;Product distribution / selectivity;
A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaIdehyde (50 g, 315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for 30 minutes at room temperature. The solution was then stirred at 100 C for 17 hours. The reaction mixture, which was a thick white slurry, was cooled to room temperature. The solid was collected by filtration, washed with water and dried under vacuum to give the indicated product.
3.86 g
With pyridine; dmap; hydrazine hydrate; at 100℃;
6-Chloroindazole. A solution of 4-chloro-2-fluorobenzaldehyde (5.0 g, 31.6 mmol) in 12 mL of pyridine was treated with hydrazine hydrate (10 eq., 10 mL) and DMAP (3.85 g, 31.6 mmol) and the mixture heated to 100 C for several hours. The mixture was allowed to cool to RT and was diluted with EtOAc and washed several times with dilute acid. The EtOAc solution was dried over MgS04 and concentrated in vacuo to give 6-chloroindazole as an off white solid (3.86 g).
With potassium acetate; hydrazine hydrate; In N,N-dimethyl acetamide; at 20 - 100℃; for 17.5h;
A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaldehyde (50 g, 315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for 30 minutes at RT. The solution was then stirred at 100 C. for 17 hours. The reaction mixture, which was a thick white slurry, was cooled to RT. The solid was collected by filtration, washed with water and dried under vacuum to give the title product.
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 24h;
Weigh <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (0.014 mmol), K2CO3 (0.02 mol) and solvent DMF (40 mL to 50 mL)Add together to a 250 mL two-neck round bottom flask.Heating under reflux at 150 C, pyrrolidine (0.02 mol) was slowly added dropwise to the above system,The nucleophilic substitution reaction of the aromatic ring was continued by reflux heating at 150 C, and the reaction was completed in 24 hours.After cooling the reaction system, it was extracted 3-4 times with ethyl acetate and saturated brine, respectively.The organic phase was then evaporated under reduced pressure to give a crude material.The resulting oil was separated by column chromatography to give the desired desired compound of 2-fluoro-tetrahydropyrrolidine benzaldehyde.
With sodium tert-pentoxide; In N,N-dimethyl-formamide; at 20℃; for 1h;
General procedure: To a solution of benzaldehydes (1.2 equiv) and 26 (1.0 equiv) in DMF was added sodium tert-pentoxide (2.0 equiv). The mixture was stirred at room temperature for 1 h. Two workup procedures were used. Procedure A: Saturated aqueous solution of NH4Cl was added to the reaction mixture, and the resulting precipitate was filtered, washed with water, and dried in vacuo to give the desired products 27a-c, 27e-f, 27i-l, 27n-p, 27r. Procedure B: The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc) to give the desired products 27d, 27g-h, 27m, 27q, 27s-u.
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h;
To a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.43 g, 9.04 mmol) and diethyl 4-chloro-2-cyanobenzylphosphonate (2.6 g, 9.04 mmo) in THF (50 mL) was added potassium tertbutoxide (2.03 g, 18.1 mmol) at room temperature, the reaction was stirred for 3 hours. The mixture was then poured into water and extracted with ethyl acetate. After removing the solvent under vacuum, the crude product was purified by crystallization with methanol (2.6 g, 9.04 mmol). [0141] 1H NMR (400 MHz, CDCl3) delta 7.76 (1H, d), 7.67 - 7.53 (3H, m), 7.39 (2H, dd), 7.22-7.11 (2H, m).
2.6 g
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h;
c) (E)-5-Chloro-2-(4-chloro-2-fluorostyryl)benzonitrileTo a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1 .43 g, 9.04 mmol) and diethyl 4- chloro-2-cyanobenzylphosphonate (2.6 g, 9.04 mmo) in THF (50 mL) was added potassium tertbutoxide (2.03 g, 18.1 mmol) at room temperature, the reaction was stirred for 3 hours. The mixture was then poured into water and extracted with ethyl acetate. After removing the solvent under vacuum, the crude product was purified by crystallization with methanol (2.6 g, 9.04 mmol).1 H NMR (400 MHz, CDCI3) ? 7.76 (1 H, d), 7.67 - 7.53 (3H, m), 7.39 (2H, dd), 7.22 - 7.1 1 (2H, m).
General procedure: A solution of 5-bromopyrimidine (67.7g, 0.42mmol) in tetrahydrofuran (1.6L) and diethyl ether (anhydrous, 1L) in a 5L reactor was cooled to -105C with liquid nitrogen. A solution of nBuLi in hexanes (1.6M, 210mL) was added drop wise and the reaction mixture was kept below -100C throughout the addition. After all the nBuLi was added the mixture was stirred for 30 mins, then a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (45g, 0.28mmol) in tetrahydrofuran (200mL) was added and the mixture left to stir for 1 h at -100?C and allowed to come to room temperature overnight. The mixture was concentrated, diluted with dichloromethane (1L), washed with water (800mL), dried, and concentrated. Purification by flash column chromatography (eluting with hexanes 1L, 20% ethyl acetate in hexanes increasing to 66% ethyl acetate in hexanes) gave 83 as an orange oil (37g, 54%). 1H NMR (300 MHz, CHLOROFORM-d) d 9.13 (s, 1H), 8.74 (s, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.20-7.24 (m, 1H), 7.11 (dd, J = 10.2, 2.1 Hz, 1H), 6.17 (d, J = 3.6 Hz, 1H), 2.93 (d, J = 3.6 Hz, 1H).
Intermediate 1To a solution of <strong>[61072-56-8]4-chloro-2-fluoro-benzaldehyde</strong> (198.9 g, 1.254 mol, 1.0 eq) in DCM (2.5 ml) was added (R)-(+)-2-methyl-2-propanesulfinamide (159.6 g, 1.317 mol, 1.1 eq). To this was added a solution of titanium (IV) ethoxide (571.8 g, 2.008 mol, 1.6 eq) in DCM (500 ml) and the reaction was stirred at room temperature overnight. The reaction was diluted with DCM (2 L), Na2SO4.10H2O (2.00 Kg, 6.21 mol, 5.0 eq) was added and the mixture was stirred for 1 h. The mixture was filtered through Celite (1 Kg), eluting with DCM (2 x 2 L). The filtrate was concentrated in vacuo and the sample dissolved in DCM (2 L). The solution was washed with 10% citric acid solution (2 x 500 ml) and water (500 ml), dried over MgS04, filtered and concentrated in vacuo. The residue was slurried in heptanes (200 ml) at 40 C for 1 hour and then cooled to room temperature and stirred overnight. The stirred suspension was cooled to 0 C for 1 hour then filtered, washed with cold heptanes (50 ml) and dried in an oven at 40 C under vacuum overnight to give 237 g of material. The filtrate was concentrated in vacuo, the residue recrystallised from refluxing heptanes (100 ml), cooled to 0 C, filtered and washed with cold heptanes (20 ml). The solids were dried in an oven at 40 C under vacuum overnight to give 14.1 g of material which was blended with the 237 g previously isolated to give (R)-(+)-2- methyl-propane-2-sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (256.7 g, 1H NMR >95%, 0.981 mol, 78% yield). 1H NMR (270 MHz, CDCI3): 8.82 (1 H, s), 7.96-7.90 (1 H, m), 7.25-7.17 (2H, m), 1.25 (9H, s).
78%
With titanium(IV) tetraethanolate; In dichloromethane; at 20℃;
Synthesis of Key Intermediate 3dr(R)-1-(4-Chloro-2-fluoro-phenyl)-propyl1-carbamic acid tert-butyl esterStep 1 To a solution of <strong>[61072-56-8]4-chloro-2-fluoro-benzaldehyde</strong> (198.9 g, 1.254 mol, 1.0 eq) inDCM (2.5 ml) was added (R)-(+)-2-methyl-2-propanesulfinamide (159.6 g, 1.317 mol, 1.1 eq). To this was added a solution of titanium (IV) ethoxide (571.8 g, 2.008 mol, 1.6 eq) in DCM (500 ml) and the reaction was stirred at room temperature overnight. The reaction was diluted with DCM (2 L), Na2SO4.10H2O (2.00 Kg, 6.21 mol, 5.0 eq) was added and the mixture was stirred for 1 h. The mixture was filtered through Celite (1 Kg), eluting with DCM (2 x 2 L). The filtrate was concentrated in vacuo and the sample dissolved in DCM (2 L). The solution was washed with 10% citric acid solution (2 x 500 ml) and water (500 ml), dried over MgS04, filtered and concentrated in vacuo. The residue was slurried in heptanes (200 ml) at 40 C for 1 hour and then cooled to room temperature and stirred overnight. The stirred suspension was cooled to 0 C for 1 hour then filtered, washed with cold heptanes (50 ml) and dried in an oven at 40 C under vacuum overnight to give 237 g of material. The filtrate was concentrated in vacuo, the residue recrystallised from refluxing heptanes (100 ml), cooled to 0 C, filtered and washed with cold heptanes (20 ml). The solids were dried in an oven at 40 C under vacuum overnight to give 14.1 g of material which was blended with the 237 g previously isolated to give (R)-(+)-2- methyl-propane-2-sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-yIideneam'tde (256.7 g, 1H NMR >95%, 0.981 mol, 78% yield). 1 H NMR (270 MHz, CDCI3): 8.82 (1 H, s), 7.96-7.90 (1 H, m), 7.25-7.17 (2H, m), 1.25 (9H, s).
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 3.5h;
A 100 mL round-bottom flask was charged with 3-chloro-2-fluorobenzaldehyde (3.00 g, 18.9 mmol, 1.00 equiv), morpholine (2.50 g, 28.7 mmol, 1.52 equiv), potassium carbonate (6.50 g, 47.0 mmol, 2.49 equiv), and dimethyl sulfoxide (30 mL). The resulting solution was stirred for 3 hours at 100 C in an oil bath and diluted with 0 (30 mL). The resulting solution was extracted with dichloromethane (3 x 20 mL) and the organic layers were combined, washed with H20 (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel columnwith ethyl acetate/petroleum ether (1/20) to provide 1.40 g (33% yield) of 3-chloro-2- (morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere;
Step 1: Preparation of 2-(4-acetylpiperazin-l-yl)-4-chlorobenzaldehyde [00311] A 100-mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen and was then charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), l-(piperazin-l-yl)ethan-l-one (0.970 g, 7.57 mmol, 1.20 equiv), potassium carbonate (2.20 g, 16.0 mmol, 2.52 equiv), and DMSO (15 mL). The resulting solution was stirred overnight at 90 C and was then diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (60/40). This resulted in 1.20 g (71% yield) of 2-(4-acetylpiperazin- 1 -yl)-4-chlorobenzaldehyde as a yellow oil. LCMS (ESI, m/z): 267 [M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere;
Step 1: Preparation of 4-chloro-2- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]benzaldehyde [00307] A 100-mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen and was then charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), 5H,6H,7H-pyrrolo[3,4-b]pyridine (1.20 g, 10.00 mmol, 1.58 equiv), potassium carbonate (3.06 g, 22.1 mmol, 3.51 equiv), and DMSO (20 mL). The resulting solution was stirred overnight at 90 C and was then diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 0.400 g (25% yield) of 4-chloro-2-[5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]benzaldehyde as a brown solid. LCMS (ESI, m/z): 259 [M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 100℃;
Step 1: Preparation of 4-chloro-2-[4-[(pyrrolidin-l-yl)carbonyl]piperidin-l- yl]benzaldehyde [00315] A 20-mL round-bottom flask was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), 4-[(pyrrolidin-l-yl)carbonyl]piperidine hydrochloride (1.65 g, 7.54 mmol, 1.20 equiv), potassium carbonate (3.47 g, 25.1 mmol, 3.98 equiv), and DMSO (10 mL). The resulting solution was stirred overnight at 100 C and then diluted with H20 (10 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined, washed with H20 (3 x 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 1.50 g (74% yield) of 4- chloro-2- [4- [(pyrrolidin- 1 -yl)carbonyl]piperidin- 1 -yljbenzaldehyde as a yellow solid. XH NMR (300 MHz, Chloroform-if): delta 10.26 (s, 1H), 7.70-7.75 (m, 1H), 7.05-7.08 (m, 2H), 3.38-3.53 (m, 6H), 2.90-2.99 (m, 2H), 1.86-2.16 (m, 8H). LCMS (ESI, m/z): 321 [M+H]+.
74%
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Inert atmosphere;
[00176] A flask was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), 4-[(pyrrolidin-1-yl)carbonyl]piperidine hydrochloride (1.65 g, 7.54 mmol, 1.20 equiv), K2CO3 (3.47 g, 25.1 mmol, 3.98 equiv), DMSO (10 mL) under nitrogen. The resulting solution was stirred overnight at 100 C and then diluted with H2O (10 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with H2O (3 x 5 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column (1:3 EtOAc/petroleum ether) to provide of 4-chloro-2-[4-[(pyrrolidin-1- yl)carbonyl]piperidin-1-yl]benzaldehyde (1.50 g, 74% yield) as a yellow solid.1H NMR (300 MHz, Chloroform-d) 10.26 (s, 1H), 7.70 - 7.75 (m, 1H), 7.05 - 7.08 (m, 2H), 3.38 - 3.53 (m, 6H), 2.90 - 2.99 (m, 2H), 1.86 - 2.16 (m, 8H). LCMS (ESI, m/z): 321 [M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Inert atmosphere;
Step 1: Preparation of 2-[(8aR)-octahydropyrrolo[l,2-a]piperazin-2-yl]-4- chlorobenzaldehyde [00338] A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), (8aR)-octahydropyrrolo[l,2-a]piperazine (0.950 mg, 7.53 mmol, 1.19 equiv), potassium carbonate (2.17 g, 15.7 mmol, 2.49 equiv), and DMSO (20 mL). The resulting solution was stirred overnight at 100 C and diluted with H20 (15 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined, washed with H20 (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 0.700 g (42% yield) of 2-[(8aR)-octahydropyrrolo[l,2- a]piperazin-2-yl]-4-chlorobenzaldehyde as a light yellow oil. XH NMR (300 MHz, Chloroform-if): delta 10.21 (s, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.02-7.09 (m, 2H), 3.34-3.38 (m, 1H), 3.13-3.26 (m, 4H), 2.71-2.84 (m, 1H), 2.52 (br, 1H), 2.18-2.29 (m, 2H), 1.68-1.97 (m, 3H), 1.41-1.50 (m, 1H). LCMS (ESI, m/z): 265 [M+H]+.
Step 1: (E)-4-Chloro-2-fluoro-1-(2-nitroprop-1-enyl)benzene <strong>[61072-56-8]4-Chloro-2-fluorobenzaldehyde</strong> (10 g, 63.1 mmol), nitroethane (54.6 mL, 757 mmol) and piperidine (1.869 mL, 18.92 mmol) were dissolved in toluene (150 mL) and refluxed under Dean Stark conditions overnight. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was purified by column chromatography (silica, heptane/EtOAc 98:2) to give the desired product (10.4 g, 76%) as a yellow solid.
76%
With piperidine; In toluene;Reflux; Dean-Stark;
Step 1: (E)-4-Chloro-2-fluoro-1 -(2-nitroprop-1 -enyl)benzene <strong>[61072-56-8]4-Chloro-2-fluorobenzaldehyde</strong> (lOg, 63.1 mmol), nitroethane (54.6 mL, 757 mmol) and piperidine (1.869 mL, 18.92 mmol) were dissolved in toluene (150 mL) and refluxed under Dean Stark conditions overnight. The reaction mixture was cooled to room temperature and the solvents were evaporated. The crude product was purified by column chromatography (silica, heptane/EtOAc 98:2) to give the desired product (10.4 g, 76%) as a yellow solid.
44%
With methylamine hydrochloride; potassium acetate; trimethyl orthoformate; In methanol; for 18h;Reflux;
<strong>[61072-56-8]4-Chloro-2-fluorobenzaldehyde</strong> (25 g, 157.6 mmol), nitroethane (i2.43 mL, 173.35 mmol), trimethyl orthoformate (38 mL, 346.62 mrnol), methyiamineHCl (8.3 g, 122.9 mmol) & potassium acetate (10.8 g, 98.14 mmol) in MeOH (i25 mL) was heated at reflux for 18 h. The reaction mixture was cooled toRT and diluted with H20 (200 mL) and extracted with Et20 (3 x 100 mL). The combined organic layer was successively washed with H20 (200 mL), brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue upon trituration with MeOH (30m L) gave yellow solid. It was filtered off and washed with chilled MeOH (25 mL) to afford 15 g (44 %) of the desired product as a yellow solid.
44%
With methylamine hydrochloride; potassium acetate; trimethyl orthoformate; In methanol; for 18h;Reflux;
Step 1 : (E)-4-Chloro-2-fluoro-1-(2-nitroprop-1-enyl)benzene<strong>[61072-56-8]4-Chloro-2-fluorobenzaldehyde</strong> (25 g, 157.6 mmol), nitroethane (12.43 mL, 173.35 mmol), trimethyl orthoformate (38 mL, 346.62 mmol), methylamine-HCI (8.3 g, 122.9 mmol) and potassium acetate (10.8g, 98.14 mmol) in MeOH (125mL) was heated at reflux for 18 h. The reaction mixture was cooled to RT and diluted with H20 (200 mL) and extracted with Et2O (3x 100mL). The combined organic layer was successively washed with H20 (200 mL), brine (200 mL), dried (Na2S04), filtered and concentrated. The residue upon trituration with MeOH (30 mL) gave yellow solid. It was filtered off and washed with chilled MeOH (25 mL) to afford 15g (44%) of the desired product as a yellow solid. (TLC system: EtOAc : Petroleum ether; 1 :9; Rf: 0.56).
2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 4h;
A round bottom flask was charged with 8-oxa-3-azabicyclo[3.2.1]octane (495 mg,3.32 mmol), K2 C03 (436 mg, 3.16 mmol) and <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (500 mg, 3.15 mmol), and the contents were dissolved in DMSO (10 mL) and heated to 120 C. After 4 h, the reaction mixture was diluted in DCM (200 mL) and washed 3X with brine. The organics were dried over anhydrous Na2 S04 and concentrated. The resulting orange oil was chromatographed on a silica column with a gradient (100% hexanes to 80% Hexanes/20% EtOAc) to provide 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde as a yellow solid (336 mg, 43 %). 1H NMR(400 MHz, Chloroform-d) 810.32 (s, lH), 7.72 (s, lH), 7.46 (ddd,J= 8.7, 3.3, 1.7 Hz, 1H), 7.08 (dd, J= 8.7, 1.3 Hz, 1H), 4.47-4.41 (m, 2H), 3.21 (d, J= 11.5 Hz, 2H), 2.91 (d, J= 11.7 Hz, 2H),2.19-2.06 (m, 2H), 2.06-1.96 (m, 2H). LCMS (ESI, m/z): 252.1 [M+Ht.
4-chloro-2-(2,5-dihydro-1H-pyrrol-1-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; for 7h;
General procedure: To a solution of 2-fluorobenzaldehyde 4a (1.8 g, 14.5 mmol, 1.0 equiv) in DMF wasadded K2CO3 (2.0 g, 14.5 mmol, 1.0 equiv) and 3-pyrroline 5 (1.0 g, 14.5 mmol, 1.0equiv) at rt, then the mixture was heated to 90 oC and stirred for 7 h. The mixture wasfiltered and the filtrate was concentrated and the residue was purified by columnchromatography (PE/EA 25:1) to give the title compound 1 (1.55 g, 62% yield).
5-(4-chloro-2-fluorobenzylidene)-2-thioxothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium hydroxide; In ethanol;Reflux;
General procedure: The 2-thioxo-4-thiazolidinone (1mmol), benzaldehydes (1 mmol) and NaOH (1.0 mmol) were added to ethanol withtotal volume of 15 mL. The reaction mixture was heated to reflux and stirredfor 2-24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, neutralized to pH 7.0 with dilute hydrochloric, and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was recrystallization from ethanol.
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;
To a solution of 4- chloro--2--fluorobenzaldehyde (10.0 g, 63.0 mmol) in DMF (100 ml) wasadded ethyl thioglycolate (11.3 g, 94.6 mmol) followed by addition of K2C03 (26.1 g, 189mmol). The reaction mixture was heated at 70C for 16h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was diluted with H20 (300 ml)10 and extracted with EtOAc (2 x 300 ml). The organic layer was separated, dried overanhydrous Na2S04 and concentrated under vacuum to afford ethyl 6-chlorobenzothiophene-2-carboxylate Xl-9a (9.1 0 g) as an off-white solid.This compound was used as such for the next reaction without further purification.Yield: 60%15 1H NMR (400 MHz, DMSO-d5) o 1.33 (t, J=7.09 Hz, 3H) 4.35 (q, J=7.01 Hz, 2H) 7.51 (dd,J=8.56, 1.71 Hz, 1 H) 8.04 (d, J=8.80 Hz, 1 H) 8.20 (s, 1 H) 8.25 (d, J=0.98 Hz, 1 H).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 60℃; for 22.5h;
[000922] Compound 242A (2.44 g, 15.4 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were suspended in dry DMF (15 mL) and the resulting mixture was cooled to 0 C. Ethyl thioglycolate (1.7 mL, 15.5 mmol) was added in portions over 1 h and the reaction mixture was warmed slowly to room temperature and stirred at 25 C for 16 h. The reaction was heated at 60 C for 5.5 h before cooling and adding water (30 mL). The resulting mixture was stirred at room temperature for 30 min and filtered. The residue was washed with water (5 mL x 2) and dried to afford the Compound 242B.
With manganese(IV) oxide; In acetonitrile; for 24h;
To a solution of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (222mg) in MeCN (20m1) was addedMnO (480mg). The mixture was stirred for 24h. The mixture was filtered over celite, theorg. layer was dried over MgSO4 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): tR = 0.76 mm; [M+H]: not visible.
With manganese(IV) oxide; In acetonitrile; at 20℃; for 24h;Inert atmosphere;
To a solution of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (222 mg) in MeCN (20 mL) was added MnC>2 (480 mg). The mixture was stirred for 24h. The mixture was filtered over celite, the org. layer was dried over MgS04 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): tR = 0.76 min; [M+H]+: not visible.
With manganese(IV) oxide; In acetonitrile; for 24h;
To a solution of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (222mg) in MeCN (20ml) was added Mn02 (480mg). The mixture was stirred for 24h. The mixture was filtered over celite, the org. layer was dried over MgS04 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): tR = 0.76min; [M+H]+: not visible.
3-chloro-11H-indolo[1,2-a]benzimidazol-11-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With iron(III) chloride; potassium phosphate; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere;
General procedure: FeCl3 (8 mg, 0.05 mmol, 10 mol%), K3PO4 (212 mg, 1 mmol), N-heterocycles 1 (0.50 mmol), and o-fluorobenzaldehydes 2(0.50 mmol) were added to an oven-dried Schlenk tube (with a magnetic stirrer bar within) equipped with a Teflon valve. The tube was repeatedly evacuated and back-filled with N2 (3 times). Under a counter flow of N2, DMF (2.0 mL) was added by a syringe, and the mixture was stirred for about 16 h at 130 C. When the reaction was complete, the mixture was extracted with ethyl acetate (3 15 mL), and the organic layer was washed with brine(3 10 mL) and dried over anhydrous Na2SO4. Subsequently,the solvent was removed and the product was purified by column chromatography on silica gel (PE:EA = 5:1-1:1, v/v) to give the desired product 3.
81%
With potassium phosphate; iron(III) chloride hexahydrate; In N,N-dimethyl-formamide; at 110℃; for 15h;Sealed tube; Schlenk technique;
In a Schlenk reaction tube, was added <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (0.5mmol), benzo imidazole (0.5mmol),FeCl3·6H 2 O (8mg, 0.05mmol), potassium phosphate (212mg, 0.1mmol) and DMF (2mL), thereaction Sealed tube, under an air atmosphere, 110 C, reacted for 15 hours. After completion of the reaction,and extracted with dichloromethane three Times, and then the organic layer was washed three times withsaturated brine, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reducedpressure, Purified by column chromatography to give the product 3, the structure and characterization data areas follows: 3-chloro-11H-indolo [1,2-a] benzimidazol-11-one (3) .an orange solid (103.2mg, 81%).
With iron(III) chloride; potassium phosphate; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere;
General procedure: FeCl3 (8 mg, 0.05 mmol, 10 mol%), K3PO4 (212 mg, 1 mmol), N-heterocycles 1 (0.50 mmol), and o-fluorobenzaldehydes 2(0.50 mmol) were added to an oven-dried Schlenk tube (with a magnetic stirrer bar within) equipped with a Teflon valve. The tube was repeatedly evacuated and back-filled with N2 (3 times). Under a counter flow of N2, DMF (2.0 mL) was added by a syringe, and the mixture was stirred for about 16 h at 130 C. When the reaction was complete, the mixture was extracted with ethyl acetate (3 15 mL), and the organic layer was washed with brine(3 10 mL) and dried over anhydrous Na2SO4. Subsequently,the solvent was removed and the product was purified by column chromatography on silica gel (PE:EA = 5:1-1:1, v/v) to give the desired product 3.
80%
With potassium phosphate; iron(III) chloride hexahydrate; In N,N-dimethyl-formamide; at 110℃; for 15h;Sealed tube; Schlenk technique;
In a Schlenk reaction tube, was added <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (0.5mmol), imidazole (0.5mmol), FeCl 3· 6H 2 O (8mg, 0.05mmol), potassium phosphate (212mg, 0.1mmol) and DMF (2mL), trans Should besealed tube, under an air atmosphere, 110 C, reacted for 15 hours. After completion of the reaction, andextracted with dichloromethane Three times, and then the organic layer was washed three times with saturatedbrine, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure,Purified by column chromatography to give the product 10, the structure and characterization data are asfollows: 6-chloro-9H-imidazo [l, 2-a] indol-9-one (10) an orange solid (82.0mg, 80%)
6-chloro-2-methyl-9H-imidazo[1,2-a]indol-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With iron(III) chloride; potassium phosphate; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere;
General procedure: FeCl3 (8 mg, 0.05 mmol, 10 mol%), K3PO4 (212 mg, 1 mmol), N-heterocycles 1 (0.50 mmol), and o-fluorobenzaldehydes 2(0.50 mmol) were added to an oven-dried Schlenk tube (with a magnetic stirrer bar within) equipped with a Teflon valve. The tube was repeatedly evacuated and back-filled with N2 (3 times). Under a counter flow of N2, DMF (2.0 mL) was added by a syringe, and the mixture was stirred for about 16 h at 130 C. When the reaction was complete, the mixture was extracted with ethyl acetate (3 15 mL), and the organic layer was washed with brine(3 10 mL) and dried over anhydrous Na2SO4. Subsequently,the solvent was removed and the product was purified by column chromatography on silica gel (PE:EA = 5:1-1:1, v/v) to give the desired product 3.
1-(5-chloro-2-formylphenyl)piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 20h;Sealed tube;
[00170] A sealed tube was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1 g, 6.30 mmol), piperidine-4-carboxamide (0.970 g, 7.57 mmol), and K2CO3 (2.78 g, 20.2 mmol). DMA (8 mL) was added and the mixture was stirred at 140 C for 20 h. The reaction was cooled to rt, then diluted with EtOAc (200 mL). The organic layer was washed with brine (3x) and with sat. NH4Cl (1x). The organic layers were dried over Na2SO4, filtered and concentrated to yield a solid. The solid was purified on silica gel by flash column chromatography to afford 1-(5-chloro-2- formylphenyl)piperidine-4-carboxamide as a yellow solid (703 mg, 41 % yield). 1H NMR (400 MHz, DMSO-d67.19- 7.10 (m, 1H), 6.85 (s, 1H), 3.33- 3.21 (m, 2H), 2.96- 2.81 (m, 2H), 2.31- 2.20 (m, 1H), 1.89- 1.71 (m, 4H).
With potassium carbonate; In dimethyl sulfoxide; at 90℃;
[00181] A flask was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (2.00 g, 12.6 mmol, 1.00 equiv), tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (2.10 g, 11.3 mmol, 0.89 equiv), K2CO3 (4.00 g, 28.9 mmol, 2.29 equiv), and DMSO (20 mL). The resulting solution was stirred overnight at 90 C and then diluted with H2O (30 mL). The resulting solution was extracted with DCM (3 x 20 mL) and the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column (17:83 EtOAc/petroleum ether) to provide tert-butyl N-[(3R)-1-(5-chloro-2-formylphenyl)pyrrolidin-3-yl]carbamate (3.00 g, 73% yield) as a yellow solid. LCMS (ESI, m/z): 325 [M+H]+.
tert-butyl 5-(5-chloro-2-formylphenyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In dimethyl sulfoxide; at 80℃;
[00241] A flask was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (0.791 g, 4.98 mmol, 1.00 equiv), tert-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (1.27 g, 5.98 mmol, 1.50 equiv), DMSO (10 mL) and K2CO3 (2.00 g, 14.5 mmol, 2.00 equiv). The mixture was stirred overnight at 80 C and diluted with H2O (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with H2O (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column (1:1 EtOAc/petroleum ether) to provide tert-butyl 5-(5-chloro-2-formylphenyl)-octahydropyrrolo[3,4- c]pyrrole-2-carboxylate (1.40 g, 80% yield) as a yellow solid. LCMS (ESI, m/z): 351 [M+H]+.
6-chloro-2-methyl-9H-imidazo[1,2-a]indol-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium phosphate; iron(III) chloride hexahydrate; In N,N-dimethyl-formamide; at 110℃; for 15h;Sealed tube; Schlenk technique;
In a Schlenk reaction tube, was added <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (0.5mmol), 3- methyl-imidazole(0.5mmol), FeCl 3 6H 2 O (8mg, 0.05mmol), potassium phosphate (212mg, 0.1mmol) and DMF(2mL), trans Should be sealed tube, under an air atmosphere, 110 C, reacted for 15 hours. After completion ofthe reaction, and extracted with dichloromethane Three times, and then the organic layer was washed three timeswith saturated brine, the organic layer was dried over anhydrous sodium sulfate, and concentrated underreduced pressure, Purified by column chromatography to give the product 14, the structure and characterizationdata are as follows: 6-chloro-2-methyl-9H-imidazo [l, 2-a] indol-9-one (14) an orange solid (76.5mg, 70%)
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 1h;
To a solution of aldehyde in ethanol/water (8/1, v/v) at room temperature was added hydroxylamine hydrochloride (2 eq.) and sodium acetate (3 eq.). The reaction was stirred for 1-2 hour until TLC showed the reaction was complete. The mixture was concentrated in vacuo, and the residue was triturated from water, collected by filtration, washed with water and dried in vacuo to afford the oxime product, which was used as such in the next step; Following general procedure A2, compound A-107 was prepared from 4-chloro-2- fluorobenzaldehyde : [00404] Compound A-106 (2.7 g, 96% yield) was prepared as a white solid from 4-chloro-2- fluorobenzaldehyde (2.6 g, 16.4 mmol) using 45 mL of ethanol/water and a reaction time of 1 hour. LCMS (2): tR=1.856 min., (ES+) m/z (M+H)+ = 174.0. NMR (300 MHz, DMSO-d6) delta 11.83 (s, IH), 8.16 (s, IH), 7.87 - 7.63 (m, IH), 7.62 - 7.41 (m, IH), 7.31 (d, J= 7.9 Hz, IH). [00405] Compound A-107 (2.7 g, 84% yield) was prepared as a white solid from A-106 (2.7 g, 15.6 mmol) using 25 mL of N,N-dimethylformamide and a reaction time of 1.5 hours. 1H NMR (300 MHz, DMSO-d6) delta 12.73 (s, 1H), 7.75 - 7.65 (m, 1H), 7.65 - 7.57 (m, 1H), 7.47 - 7.37 (m, 1H).
96%
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 1h;
To a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (2.6 g, 16.4 mmol) in ethanol/water (45 mL, 8/1, v/v) at room temperature was added hydroxylamine hydrochloride (2.3 g, 32.8 mmol) and sodium acetate (4.0 g, 49.2 mmol). The reaction was stirred for 1 hour until TLC showed the reaction was complete. The mixture was concentrated in vacuo, and the residue was triturated from water, collected by filtration, washed with water and dried in vacuo to afford compound B-2 (2.7 g, white solid, 96% yield), which was used as such in the next step. LCMS (2): tR=1.856 mi, (ES) m/z (M+H)= 174.0. ?H NMR (300 MHz, DMSO-d6) 11.83 (s, 1H), 8.16 (s, 1H), 7.87-7.63 (m, 1H), 7.62-7.41(m, 1H),7.31(d,J7.9Hz, 1H).
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water; at 20℃; for 2h;
General procedure: Hydroxylamine hydrochloride (2.0 mmol) was dissolved in water (10.0 mL) and neutralized with aqueous sodium hydrogen carbonate (10%). This mixture was added to the solution of the substituted benzaldehyde (compound 1) (2.0 mmol) in methanol and stirred in room temperature for 2 hours until the starting material disappeared (monitored by TLC with EtOAc/petroleum ether = 1/10, V/V). The reaction mixture was added in water to precipitate crude white product compound 2.
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water; at 20℃; for 2h;
<strong>[61072-56-8]4-Chloro-2-fluorobenzaldehyde</strong> (1 mmol) was dissolved in methanol (10 mL)NaHCO3 (1.1 mmol)And an aqueous solution of NH2OH.HCl (1.1 mmoL) (10 mL)Stirred at room temperature for 2 h,Add water to the white solid precipitation,filter,Dried to give the compound <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> oxime.
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 0.833333h;
To a stined mixture of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (lOg, 0.063mo1) in conc.H2S04 (100 mL) at 0C was added KNO3 (7.03g, 0.069mo1) portion wise over 20mm and stined at RT for 30 mm. After completion of reaction, the reaction mixture was cooled to 0C and quenchedwith ice water. The solid was filtered and dried under vacuum to give the title compound (12.5 g,99 %).
5.1 g
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 1.5h;
To a solution, cooled to 0 C., of 2.81 g of potassium nitrate in 21 ml of sulphuric acid were added 4.0 g of 4-chioro-2-fluorobenzaldehyde, and the mixture was stirred at 0 C. for 0.5 hand at room temperature for 1 h. The mixture was added to ice-water and extracted twice with dichioromethane. The combined organic phases were washed with saturated sodium hydrogencarbonate solution, and the organic phase was removed and concentrated. This gave 5.1 g of the title compound.j0405] ?H-NMR (300 MHz, CDC13): oe=7.47 (d, 1H), 8.46 (d, 1H), 10.31 (s, 1H)
With 1,3-dimethyl-2-imidazolidinone; potassium carbonate; at 100℃; for 15h;
(1) A suspension of Compound 1 (10.0 g), Compound 2 (14.0 g), and potassium carbonate (13.1 g) in 1,3-dimethyl-2-imidazolidinone (80 mL) was stirred at 100°C for 15 hours. The reaction mixture was cooled to room temperature, then water was added thereto, and extracted with ethyl acetate. The resultant organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=99:1-90:10) to give Compound 3 (19.0 g) as a yellow viscous material. MS (APCI) : m/z 324/326 [M+H]+
ethyl 1-(5-chloro-2-formylphenyl) piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate; In dimethyl sulfoxide; at 90℃;
Example 118: 1-(5-Chloro-2-((8-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-2,8- diazaspiro[4.5]decan-2-yl)methyl)phenyl)piperidine-4-carboxylic acid Step 1: Preparation of ethyl 1-(5-chloro-2-formylph nyl) piperidine-4-carboxylate A flask was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (2.40 g, 15.1 mmol, 1.00 equiv), ethyl piperidine-4-carboxylate (2.60 g, 16.5 mmol, 1.20 equiv), potassium carbonate (6.20 g, 44.9 mmol, 3.00 equiv), and DMSO (25 mL). The resulting solution was stirred overnight at 90 ^C and then diluted with H2O (20 mL). The mixture was extracted with DCM (3 x 50 mL), and the organic layers were combined, washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (2:8 EtOAc/petroleum ether) to provide 4.00 g (89% yield) of ethyl 1-(5-chloro-2-formylphenyl) piperidine-4-carboxylate as a yellow oil. LCMS (ESI, m/z): 296 [M+H]+.
2-chloroindolo[1,2-a]quinoline-7-carboxaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 16h;Inert atmosphere;
General procedure: To a suspension of 2-methylindole-3-carboxaldehyde (7a) (200 mg, 1.26 mmol) and Cs2CO3 (1.34 g, 3.80 mmol) in N,N-dimethylformamide (4 mL) was added 2-fluorobenzaldehyde (210 muL, 1.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 140 C until the indole substrate was all consumed (monitored by TLC), and then allowed to cool down to room temperature. The resulting mixture was filtered and washed with ethyl acetate (80 mL). The filtrate was washed with water (3 X 80 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexanes = 1:3) to afford the desired indolo[1,2-a]quinoline.
2-chloro-9-methoxyindolo[1,2-a]quinoline-7-carboxaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 6h;Inert atmosphere;
General procedure: To a suspension of 2-methylindole-3-carboxaldehyde (7a) (200 mg, 1.26 mmol) and Cs2CO3 (1.34 g, 3.80 mmol) in N,N-dimethylformamide (4 mL) was added 2-fluorobenzaldehyde (210 muL, 1.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 140 C until the indole substrate was all consumed (monitored by TLC), and then allowed to cool down to room temperature. The resulting mixture was filtered and washed with ethyl acetate (80 mL). The filtrate was washed with water (3 X 80 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexanes = 1:3) to afford the desired indolo[1,2-a]quinoline.
tert-butyl 4-((5-chloro-2-formylphenyl)(4-methoxybenzyl)amino)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 110℃;
Step 2: Preparation of tert-butyl 4-((5-chloro-2-formylphenyl)(4-methoxybenzyl)amino)butanoate A flask was charged with tert-butyl 4-((4-methoxybenzyl)amino)butanoate (400 mg, 1.43 mmol, 1.00 equiv), DMSO (10 mL), DIPEA (553 mg, 4.28 mmol, 3.00 equiv), and <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (225 mg, 1.42 mmol, 1.00 equiv) under nitrogen. The reaction mixture was stirred overnight at 110 C. and quenched with water (30 mL). The resulting solution was extracted with DCM (2*50 mL) and the organic layers were combined. The combined organic layers were washed with brine (2*30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/6) to provide 184 mg (31% yield) of tert-butyl 4-((5-chloro-2-formylphenyl)(4-methoxybenzyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z): 418 [M+H]+.
diethyl (4-chloro-2-fluorophenyl)(6-chloropyridin-3-ylamino)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium dithionite; In dimethyl sulfoxide; at 120℃;
General procedure: Typical procedure for one-pot synthesis of alpha-aminophosphonates: A mixture of nitro compound (1.0 mmol), aldehyde (1.0 mmol), DEP (1.0 mmol), and sodium dithionite (1.0 mmol) in DMSO (1.0 mL) were stirred at 120 C for the appropriate amount of time (3-4 h). After completion of the reaction as indicated by the TLC and LCMS, the reaction mixture was poured into water (5 mL), and then extracted with ethyl acetate (2 10 mL). The combined organic extracts were washed with saturated brine solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from diethyl ether (solid products) or purified by column chromatography using silica gel (100-200 mesh size) and eluting with hexane/ethyl acetate of increasing polarity to obtain the pure compound. When the above reaction was performed with 5-nitrobenzofuran (entry 16 in Table 2), the double bond between 2 and 3 carbons gets reduced by the sodium dithionite.
[amino-(4-chloro-2-fluorophenyl)methyl]phosphonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
General procedure: Synthetic procedure was based on this elaborated earlier byOleksyszyn and Soroka [34-36]. Thus, acetamide 1.18 g (0.02 mol)was dissolved in glacial acetic acid (4 mL, 4.20 g, 0.07 mol). Thesolution was cooled in an ice-bath at 0 C and acetyl chloride(0.71 mL, 0.78 g, 0.01 mol) was added observing the formation of acrystalline by-product. After a few minutes appropriate aldehyde(0.01 mol) was added, and the mixture was kept in ice-bath for30 min and then left for 1 day at room temperature with constantstirring. Then the mixturewas cooled again to 0 C and phosphorustrichloride was added dropwise (0.87 mL, 1.37 g, 0.01 mol). Afterstirring for 30 min the mixture was allowed to warm to roomtemperature, and finally heated for 1-1.5 h at 75-80 C. Evaporationof the volatile components of the reaction mixture resulted inan oily product, which was refluxed for 8 h in concentrated hydrochloricacid (50 mL). After the removal of volatile components ofthe reaction mixture oily product was dissolved in ethanol (10 mL)and left for crystallization. Resulting aminobenzylphosphonic acidwas then recrystallized from ethanol or ethanol-water.
methyl 1-(5-chloro-2-formylphenoxy)cyclopropane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
A vial was charged with <strong>[33689-29-1]methyl 1-hydroxycyclopropane-1-carboxylate</strong> (1.28 g, 11.0 mmol, 1.10 equiv) and THF (20 mL). Sodium hydride (60% in oil, 600 mg, 15.0 mmol, 1.50 equiv) was added dropwise at 0 C. The resulting solution was stirred for 0.5 h at room temperature. Then 4- chloro-2-fluorobenzaldehyde (1.59 g, 10.0 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (20 mL). The mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 500 mg (20% yield) of methyl 1-(5- chloro-2-formylphenoxy)cyclopropane-1-carboxylate as a white solid. LCMS (ESI, m/z): 255 [M+H].
4-(4-chloro-2-fluorophenyl)-2-(1H-indol-3-yl)-1,4,5,6,7,8,9,10,11,12,13,14-dodecahydrocyclododeca[b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With ammonium acetate; In ethanol; for 2h;Reflux;
General procedure: A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile 3 (0.1 g, 0.543 mmol), aromaticaldehyde 4 (0.543 mmol), cycloalkanone 5 (0.543 mmol) and ammonium acetate (6, 0.1 g, 1.1mmol) was dissolved in ethanol (10 mL) and heated to reflux on a heating mantle for 2 h. Aftercompletion of the reaction as evident from TLC, the reaction mixture was set aside at ambienttemperature for 6-7 h. The precipitate formed was filtered and dried to get the pure indole-cycloalkyl[b]pyridine-3-carbonitriles. The unaromatized product was obtained in the cases wherethe product was precipitated within 2 h.
4-(4-chloro-2-fluorophenyl)-2-(1H-indol-3-yl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With ammonium acetate; In ethanol; for 2h;Reflux;
General procedure: A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile 3 (0.1 g, 0.543 mmol), aromaticaldehyde 4 (0.543 mmol), cycloalkanone 5 (0.543 mmol) and ammonium acetate (6, 0.1 g, 1.1mmol) was dissolved in ethanol (10 mL) and heated to reflux on a heating mantle for 2 h. Aftercompletion of the reaction as evident from TLC, the reaction mixture was set aside at ambienttemperature for 6-7 h. The precipitate formed was filtered and dried to get the pure indole-cycloalkyl[b]pyridine-3-carbonitriles. The unaromatized product was obtained in the cases wherethe product was precipitated within 2 h.
2-(5-bromo-1H-indol-3-yl)-4-(4-chloro-2-fluorophenyl)-5,6,7,8,9, 10,11,12,13,14-decahydrocyclododeca[b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With ammonium acetate; In ethanol; for 2h;Reflux;
General procedure: A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile 3 (0.1 g, 0.543 mmol), aromaticaldehyde 4 (0.543 mmol), cycloalkanone 5 (0.543 mmol) and ammonium acetate (6, 0.1 g, 1.1mmol) was dissolved in ethanol (10 mL) and heated to reflux on a heating mantle for 2 h. Aftercompletion of the reaction as evident from TLC, the reaction mixture was set aside at ambienttemperature for 6-7 h. The precipitate formed was filtered and dried to get the pure indole-cycloalkyl[b]pyridine-3-carbonitriles. The unaromatized product was obtained in the cases wherethe product was precipitated within 2 h.
2-(5-bromo-1H-indol-3-yl)-4-(4-chloro-2-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With ammonium acetate; In ethanol; for 2h;Reflux;
General procedure: A mixture of 3-(1H-indol-3-yl)-3-oxopropanenitrile 3 (0.1 g, 0.543 mmol), aromaticaldehyde 4 (0.543 mmol), cycloalkanone 5 (0.543 mmol) and ammonium acetate (6, 0.1 g, 1.1mmol) was dissolved in ethanol (10 mL) and heated to reflux on a heating mantle for 2 h. Aftercompletion of the reaction as evident from TLC, the reaction mixture was set aside at ambienttemperature for 6-7 h. The precipitate formed was filtered and dried to get the pure indole-cycloalkyl[b]pyridine-3-carbonitriles. The unaromatized product was obtained in the cases wherethe product was precipitated within 2 h.
2,4-bis(3,4-dichlorophenylthio)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;
[00443] A mixture of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (2 g, 12.7 mmol), 3,4-dichlorobenzenethiol (5 g, 27.8 mmol) and K2C03 (8.74 g, 63.3 mmol) in DMF (50 mL) was stirred for 18 h at 110 C. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (160 mL). The organic phase was washed water (40 mL x 2), and brine (40 mL), dried (Na2S04), filtered and concentrated in vacuo and the residue was purified by chromatography (silica, ethyl acetate/petroleum ether =1/20) to afford 2,4-bis(3,4-dichlorophenylthio)benzaldehyde (3.2 g, 7 mmol, 55%) as a light yellow solid. 1H NMR (500 MHz, CDC13) delta 10.17 (s, 1H) , 7.74 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 12.5 Hz, J = 2.5 Hz, 2H), 7.41 (t, J= 8.5 Hz, 2H), 7.21-7.16 (m, 2H), 7.11 (dd, J= 8.5 Hz, J = 1.5 Hz, 1H), 6.51 (d, J= 1.5 Hz, 1H).
4-chloro-2-(3,4-dichlorophenoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42.06%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;
[00391] To a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (5.0 g, 31.53 mmol) and 3,4-dichlorophenol (5.65 g, 34.69 mmol) in DMF(50 mL), was added K2C03(5.67g, 40.99 mmol), this mixture was stirred at 80 C for 18 h. Then reaction solution was cooled to rt and extracted with EtOAc, washed with brine and concentrated to afford the crude product. Purification by column chromatography on silica gel with PE:EtOAc=l :0 afforded 4-chloro-2-(3,4-dichlorophenoxy)benzaldehyde (3.94 g, 13.06 mmol, purity: 100%, yield: 42.06 %) as a yellow solid. ESI-MS (EI+, m/z): 303.0 [M+H]+.
4-chloro-2-(4-cyclohexylphenoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h;
[00469] To a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (2.0 g, 12.66 mmol) and 4-cyclohexylphenol (2.23 g, 12.66 mmol) in DMF (20 mL) was added K2C03 (3.5 g, 25.32 mmol). The mixture was stirred at 90 C for 12h. The reaction was diluted with water (100ml), extracted by EtOAc(200 mi). The organic layer was dried, concentrated to give the crude product , purified by SGC (eluting with 0-50% EtOAc in PE) to afford 4-chloro-2-(4-cyclohexylphenoxy)benzaldehyde (3.2 g, 80%) as a white solid. ESI-MS (EI+, m/z): 315.0[M+H]+.
4-chloro-2-(4-fluoropiperidin-1-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 24h;
To a sealed tube vial was added <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (424 mg, 2.67 mmol, 1 equiv), 4-fluoropiperidine (330 mg, 3.21 mmol, 1.2 equiv), K2C03 (1180 mg, 8.56 mmol, 3.2 equiv) and DMA (4 mL). The reaction was heated to 140 C for 24 h. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (3 x 10 mL), and once with saturated ammonium chloride (10 mL). The organic layers were dried over Na2 SO4, filtered and concentrated under reduced pressure to afford an oil which was purified by flash column chomatography to provide 4-chloro-2-(4-fluoropiperidin-1-yl)benzaldehyde as an oil (435 mg, 67% yield). ?HNMR (400 MHz, Chloroform-d) (510.22 (s, 1H), 7.81 - 7.71 (m, 1H), 7.14-7.06 (m, 2H), 5.02- 4.81 (m, 1H), 3.36 -3.21 (m, 2H), 3.12-3.00 (m, 2H), 2.22- 1.99 (m, 4H). LCMS (ESI, m/z): 242 [M+H].
2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium carbonate; In N,N-dimethyl acetamide; at 140℃;
Commercially available 4-chloro-2-fluorobenzaldehyde (500 mg, 3.15 mmol, 1 equiv) and 8-oxa-3-azabicyclo[3.2.1]octanehydrochloride (566 mg, 3.78 mmol, 1.2 equiv) were combined in a high pressure glass vial with4 mL DMA and stirred until dissolved. Potassium carbonate (K2CO3, 1392 mg, 10.1 mmol, 3.2equiv) was added and the vial was stirred at 140 C overnight. The reaction was cooled, dilutedwith EtOAc (20 mL), and washed with water (4 x 5 mL). Aqueous layers were combined andextracted with EtOAc (3 x 10 mL). The organic layers were combined and dried over Na2SO4,decanted and concentrated under reduced pressure to yield an oil which was purified by flashcolumn chromatography to yield 568 mg (71% yield) of 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde as a yellow oil. 1H NMR (400 MHz, Chloroform-d) delta 10.26 (s, 1H),7.80 - 7.55 (m, 1H), 7.21 - 6.88 (m, 2H), 4.54 - 4.30 (m, 2H), 3.26 - 3.12 (m, 2H), 3.06 - 2.83(m, 2H), 2.21 - 1.85 (m, 4H). LCMS (ES, m/z): 252 [M+H]+.
t-butyl 2-(1-(5-chloro-2-formylphenyl)piperidin-4-yl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With potassium carbonate; In dimethyl sulfoxide; at 80℃;
A flask was charged with t-butyl 2-(piperidin-4-yl)pyrrolidine-1-carboxylate (156 mg, 0.610 mmol, 1.00 equiv), DMSO (5 mL), potassium carbonate (255 mg, 1.85 mmol, 3.00 equiv), and <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (146 mg, 0.920 mmol, 1.50 equiv). The resulting solution was stirred overnight at 80 C. and quenched with water (10 mL), as described in Example 15, Step 3. The residue was chromatographed on a silica gel column to provide 150 mg (62% yield) of t-butyl 2-(1-(5-chloro-2-formylphenyl)piperidin-4-yl)pyrrolidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 393 [M+H]+.
With sodium azide; In N,N-dimethyl-formamide; at 60℃; for 12h;
To a solution of <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1 g, 6.3 mmol) in dimethylformamide (10 ml) was added sodium azide (620 mg, 10 mmol). The mixture was heated to 60 C. for 12 h. The reaction solution was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. After the solvent had been removed, the crude product was used in the subsequent reaction without further purification.
Example 234 Synthesis of ethyl 5-bromobenzo[b]thiophene-2-carboxylate. To a solution of 4-chloro-2-fluorobenzaldehyde (2 g, 12.6 mmol) and ethyl 2-mercaptoacetate (1.58 g, 12.6 mmol) in EtOH (40 mL) was added Na2CO3 (1.58 g, 15.1 mmol). The reaction mixture was stirred at reflux for 14 h. Then the mixture was concentrated in vacuo. Water (30 mL) was added and the mixture was extracted with DCM (50 mL*3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc=1/1) to give the ethyl 5-bromobenzo[b]thiophene-2-carboxylate as a yellow solid (2.36 g, yield: 78%). ESI-MS [M+H]+: 240.9.
2-(2-fluoro-4-chlorophenyl)-4,5-dihydro-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With iodine; potassium carbonate; In tert-butyl alcohol; at 70℃; for 3.5h;
General procedure: To a solution of the aldehyde 1aev (1 eq.) in tert-butanol(9.0 ml/mmol) the diamine (1.1 eq.)was added and the solutionwasstirred at 70 C for 30 min K2CO3 (4 eq.) and I2 (1.25 eq.) was addedat 70 C and the mixture was stirred at this temperature for further3 h. The mixture was cooled down to rt and Na2S2O3 was addeduntil the iodine color almost disappear. The organic layer wasseparated and the solvent was removed in vacuo. The received solid was dissolved in water (7.5 ml/mmol) and 2 N NaOHaq was addeduntil pH 12e14. The aqueous layer was separated with CHCl3(3 3.75 ml/mmol), the combined organic layers were dried(Na2SO4) and the solvent was removed in vacuo. The product can beused without further purification.
2-(4-chloro-2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With iodine; potassium carbonate; In tert-butyl alcohol; at 70℃; for 3.5h;
General procedure: To a solution of the aldehyde 1aev (1 eq.) in tert-butanol(9.0 ml/mmol) the diamine (1.1 eq.)was added and the solutionwasstirred at 70 C for 30 min K2CO3 (4 eq.) and I2 (1.25 eq.) was addedat 70 C and the mixture was stirred at this temperature for further3 h. The mixture was cooled down to rt and Na2S2O3 was addeduntil the iodine color almost disappear. The organic layer wasseparated and the solvent was removed in vacuo. The received solid was dissolved in water (7.5 ml/mmol) and 2 N NaOHaq was addeduntil pH 12e14. The aqueous layer was separated with CHCl3(3 3.75 ml/mmol), the combined organic layers were dried(Na2SO4) and the solvent was removed in vacuo. The product can beused without further purification.
2‑((5‑((1R,3R)‑2,2‑dimethyl‑3‑(2‑methylprop‑1‑en‑1‑yl)cyclopropyl)‑1,3,4‑oxadiazol‑2‑yl)thio)acetohydrazide[ No CAS ]
[ 61072-56-8 ]
(E)-N'-(4-chloro-2-fluorobenzylidene)-2-((5-(2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxadiazol-2-yl)thio)acetohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.3%
In ethanol; at 90℃;Sealed tube; Microwave irradiation;
General procedure: To a 50mL round-bottom flask fitted with a magnetic stirringbar, intermediate 5 (3.0 g, 1 mmol) and the solution of substituted benzaldehyde (1.2 mmol) in anhydrous ethanol (10 mL) were added in order, then the round-bottom flask was sealed and placed in the synthetic reactor and reacted under microwave irradiation at 90 C with 150 W for 20 min. Upon completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum and purified after recrystallization from ethanol to obtain the target compounds 6a-6u. The physical characteristics, IR, 1H NMR, 13C NMR, ESI-MS, and elemental analysis datafor all the target compounds 6a-6u are shown in Supplementary Materials, and the data for the representative compound 6s are shown below.
4.1 General procedure of synthesis of 4-(benzylideneamino)-N-(6-methoxypyridazin-3-yl) benzenesulfonamide (Schiff bases) 3(a-r)
General procedure: Compound 1 was mixed with absolute ethanol, and then different substituted aldehydes 2 were added along with concentrated acetic acid as a catalyst. The mixture was refluxed for 3h (Scheme 1 ). The solids formed under room temperature were subject to filtration and recrystallized from methanol to obtain compounds 3(a-r) in better yields. The final compounds were dried using a VacuumTherm (Thermo Scientific) vacuum oven overnight. All the solvents and reagents are of high purity and have been purchased from Sigma-Aldrich, Fluorochem, Alfa Aesar and Fisher Scientific. Melting points were recorded using a Gallen kamp melting point apparatus and are uncorrected. 1H and 13C nuclei nuclear magnetic (NMR) analyses were performed on a Spectrospin 400MHz spectrometer (Bruker) equipped with a SampleXpress (from Bruker) auto sampler system, using deuterated solvents for the preparation of the samples. The obtained spectra were analyzed using Topspin 7.1 software (Bruker). The chemical shifts were reported relative to trimethylsilane (TMS), used as a standard (0.00ppm). Signals were identified and described as singlet (s), doublet (d), triplet (t). Coupling constants were reported in Hertz (Hz). Fourier transform Infrared (FTIR) spectrum of samples was recorded using KBr pellet press method by Bruker TENSOR 27 FTIR spectrophotometer. Mass Spectra (ESI), HRMS Agilent technologies 6890N and an inert mass selective detector 5973 mass spectrometer Technologies. The yields (%) given are on the basis of 1.0mM of each reactant used. The compounds 3(a-r) were characterized as given below
Stage #1: methyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate With isopropylmagnesium chloride In tetrahydrofuran at -70℃; for 0.5h;
Stage #2: 4-chloro-2-fluorobenzaldehyde In tetrahydrofuran at -40℃; for 1h;
To a solution of compound 20 (3.00 g, 12.7 mmol, 1.00 eq) in THF (20 mL) was added i- PrMgBr (1.00 M, 19.2 mL, 1.51 eq). The mixture was stirred at -70 °C for 0.5 hr, then compound e (3.00 g, 18.9 mmol, 1.49 eq) was added, the mixture was stirred at -40 °C for 1 hr. The reaction mixture was quenched by addition NH4Cl 30 mL at -40 °C, and then diluted with water 100 mL and extracted with ethyl acetate 150 mL (50 mL x 3). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient, 60 mL/min) to give compound 21 (1.50 g, 4.75 mmol, 37.3% yield) as a yellow solid. LCMS: RT = 0.907 min, m/z = 298.1 (M+1)+.
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