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CAS No. : | 85070-48-0 | MDL No. : | MFCD01631571 |
Formula : | C7H4ClFO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YAOZCMANASAVFN-UHFFFAOYSA-N |
M.W : | 158.56 | Pubchem ID : | 736335 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.8 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.77 cm/s |
Log Po/w (iLOGP) : | 1.68 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 2.48 |
Log Po/w (SILICOS-IT) : | 3.04 |
Consensus Log Po/w : | 2.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.53 |
Solubility : | 0.468 mg/ml ; 0.00295 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.1 |
Solubility : | 1.26 mg/ml ; 0.00796 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.0938 mg/ml ; 0.000592 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.25 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In dichloromethane at 0 - 5℃; for 1 h; | 1L four-necked flask, 36.3 g of sodium hydrogencarbonate, 500 g of dichloromethane, 0.5 g of ΤΕΜΡO, and the mixture was cooled to 0 to 5 ° C with stirring, 50 g of 2-fluoro-3-chlorobenzyl alcohol and 100 g of dichloromethane were added dropwise, and then add the sodium hypochlorite solution 230g, drop after the insulation reaction 1 h, sampling control, raw materials ≤ 1percent, stop the reaction, standing stratification, the oil layer of simple distillation of dichloromethane recovery, and then vacuum distillation that 2-fluoro-3-chlorobenzaldehyde 46.1 g, content 97.5percent, yield 91percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: With sodium chlorite In water; acetone for 0.0833333 h; Cooling with ice Stage #2: With aminosulfonic acid In water; acetone at 0℃; for 0.5 h; |
To an ice-cooled solution of sodium chlorite (6.81 g, 75.68 mmol) in water (30 mL) was added a solution of 3-Chloro-2-fluoro-benzaldehyde (3 g, 18.92 mmol) in acetone (75 mL) and the reaction mixture was stirred for 5 mm. To the resulting reaction mixture was added sulphamic acid (5.50 g, 56.76 1 mmol) in one lot at 0 °C and stirring continued for 30 mm. Progress of the reaction was monitored by TLC. After completion, the reaction mixture wasdiluted with water (5 mL) and filtered. Filtrate was extracted with ethyl acetate (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get 3-chloro-2-fluoro-benzoic acid (3.2 g, 97percent) as white solid. LC-MS:172.9(M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To an ice-cooled solution of sodium chlorite (6.81 g, 75.68 mmol) in water (30 mL) was added a solution of 3-Chloro-2-fluoro-benzaldehyde (3 g, 18.92 mmol) in acetone (75 mL) and the reaction mixture was stirred for 5 mm. To the resulting reaction mixture was added sulphamic acid (5.50 g, 56.76 1 mmol) in one lot at 0 C and stirring continued for 30 mm. Progress of the reaction was monitored by TLC. After completion, the reaction mixture wasdiluted with water (5 mL) and filtered. Filtrate was extracted with ethyl acetate (3 x 50 mL), combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get 3-chloro-2-fluoro-benzoic acid (3.2 g, 97%) as white solid. LC-MS:172.9(M-H). | |
3-Chloro-2-fiuorobenzaldehyde (15.9 g, 0.1 mol) was dissolved in tert-butanol (60 ml), stirred and heated under N2 at 50 0C. 2M aqueous NaOH (100 ml, 0.2 mol) was warmed to 50 0C and added to the solution of the aldehyde. Aqueous hydrogen peroxide solution (H2O2, 30%, 70 ml, 0.6 mol) was added over 45 min , maintaining the temperature at 55-60 0C. The mixture was stirred and heated under N2 for a further Ih, cooled and concentrated in vacuo. The residual slurry was filtered. The filtrate was washed with toluene (2 x xx ml) and acidified to pH 1 with 5N hydrochloric acid whilst stirring vigorously. The resulting solid was collected by filtration, washed with water and dried in vacuo at 50 0C. to give 11.1 g of product, mp 179-181 0C.A sample prepared by a different route [ J.Mortier et al, Tetrahedron Lett., 36, 881- 884 (1995)] is reported to have mp 179-181 0C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.1% | Compound 2 (20 g) was combined with 300 mL of THF and cooled to -20 0C. The mixture was treated successively with 75.93 g mL of butylethylmagnesium-butanol adduct (BEM-B) solution in heptane and 35.08 g of 28 wt% ?-butyllithium solution in heptane while maintaining the temperature at -20 0C. 3-Chloro-2-fluorobenzaldehyde (15.80 g) was added and the mixture allowed to warm to 0 0C. After 2 hours at that temperature the reaction was quenched by the addition of 2M hydrochloric acid. The phases were separated and the organic phase was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the product was precipitated by the addition of MTBE. The slurry was filtered and the product air dried to yield Compound 3 (18.0O g; 69.1 % yield): 1H NMR (DMSOd6, 400 MHz) delta 12.15 (br s, IH), 7.81 (s, IH), 7.42 (t, J= 7.2 Hz, IH), 7.26 (t, J= 6.8 Hz, IH), 7.15 (t, J= 7.8 Hz, IH), 6.77 (s, IH), 6.09 (d, J= 4.7 Hz, IH), 5.90 (d, J= 4.9 Hz, IH), 3.84 (s, 3H), 3.80 (s, 3H) | |
Compound 2 (10 g) was combined with 192 mL of THF and cooled to-20 0C. The mixture was treated successively with 21 mL of 1 M <n="16"/>dibutylmagnesium solution in heptane and 19.2 niL of 2.5 M H-butyllithium solution in hexane while maintaining the temperature at -20 0C. 3-Chloro-2-fluorobenzaldehyde (7.3 g) was added and the mixture allowed to warm to 0 0C. After 2 hours at that temperature the reaction was quenched by the addition of 55 mL of 2 M hydrochloric acid. The phases were separated and the organic phase was extracted with 92 mL of ethyl acetate. The combined organic layers were washed with 92 mL of saturated aqueous sodium chloride. The organic phase was concentrated and the product precipitated by the addition of 200 mL heptane. The slurry was filtered and the product air dried to yield Compound 3: 1HNMR (DMSO-d6, 400 MHz) delta l2.15 (br s, lH), 7.81 (s, lH), 7.42 (t, J= 7.2 Hz, IH), 7.26 (t, J = 6.8 Hz, IH), 7.15 (t, J= 7.8 Hz, IH), 6.77 (s, IH), 6.09 (d, J = 4.7 Hz, IH), 5.90 (d, J = 4.9 Hz, IH), 3.84 (s, 3H), 3.80 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Bisdimethylaminoethyl ether (2.84 g) was dissolved in 42 mL THF and cooled in an ice bath. Isopropylmagnesium chloride (8.9 mL of a 2 M solution in THF) followed by Compound 14 (5 g dissolved in 5 mL THF) were added slowly sequentially. The mixture was allowed to warm to ambient temperature and stirred overnight. Next, 2.1 mL of <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> was added. After stirring for ~ Ih, the mixture was quenched to pH ~ 7 with 2N HCl. The product was extracted into ethyl acetate and the organic phase was dried over sodium sulfate. The solvent was exchange to heptane to precipitate the product and a mixture of heptanes:MTBE (4:1) was added to form a slurry. After filtration the solid was slurried in toluene, filtered and vacuum dried to yield compound 15: 1H NMR (CD3CN, 400 MHz) delta 7.47 (s, IH), 7.41-7.35 (m, 2H), 7.15 (t, J = 7.4 Hz, IH), 6.66 (s, IH), 6.21 (br s, IH), 3.90 (s, 3H), 3.87 (br s, IH), 3.81 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 14 (5 g), isopropylmagnesium chloride (8.9 mL of 2M solution in THF) and THF (56 mL) were combined at ambient temperature and then warmed to 50 C for ~5 hours. After cooling to ambient temperature and stirring overnight, 2.1 mL of <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> was added dropwise to form a slurry. After stirring overnight the solid was isolated by filtration and washing with MTBE to yield compound 15a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In methanol; at -20 - 0℃; for 3h; | Methanol (20 mL) was added to sodium hydride (60% sodium hydride content, 1.6 g) under argon atmosphere at 0C, and the thus-obtained mixture was stirred for 10 minutes. After the reaction mixture was cooled to - 20C, a solution of the crude <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (5.5 g) and methyl 2-azidoacetate (5.0 g) in methanol (10 mL) was added thereto within 20 minutes. After the reaction mixture was heated to 0C, the mixture was stirred for 2.5 hours, and water (40 mL) was added thereto. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with a mixture of methylene chloride and ethyl acetate. The extract was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (toluene : hexane = 3:17), to thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g). | |
With methanol; sodium hydride; at -20 - 0℃; for 3h; | Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0C under an argon atmosphere, and the mixture was stirred for 10 minutes. After 2-nitropropane (11 ml) was added to the reaction mixture to stir the mixture for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir the resultant mixture at room temperature for 3.5 hours. Precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned in diethyl ether and water, and an organic layer was successively washed with a 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatagraphy on silica gel (ethyl acetate:hexane = 3:7) to obtain crude <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (5.5 g) as a pale yellow oil. Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0C under an argon atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to - 20C, and the crude <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (5.5 g) and a solution of methyl 2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes. The temperature of the reaction mixture was raised to 0C , and after the mixture was stirred for 2.5 hours, water (40 ml) was added thereto. The reaction mixture was concentrated under reduced pressure, the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatagraphy on silica gel (toluene:hexane = 3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product was dissolved in xylene (50 ml), and the solution was stirred at 130C to 140C for 3 hours. The reaction mixture was concentrated, and the resultant residue was purified by column chromatagraphy on silica gel (methylene chloride) and then crystallized from diethyl ether-hexane to obtain the title compound (440 mg).1H-NMR (DMSO-d6) delta: 4.08(3H,s), 7.20(1H,s), 7.31-7.38(2H,m). MS (FAB) m/z: 228(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 1h; | Under nitrogen at room temperature, to a solution of 2,2,2-trifluoro-N-[(1R)-2-(4-mercaptophenyl)-1-methylethyl]-acetamide (700 mg) in N,N-dimethylformamide (10 ml) were added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (464 mg) and potassium carbonate (404 mg), and the mixture was stirred at 60 C. for 1 hour.The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate.The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure.The residue was triturated with diisopropyl ether and collected by filtration followed by dryness to give N-[(1R)-2-[4-[(2-hloro-6-formylphenyl)-thio]phenyl]-1-methylethyl]-2,2,2-trifluoroacetamide (824 mg). (+)ESI-MS (m/z): 424 (M+Na)+ | |
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 1h; | Under nitrogen at room temperature, to a solution of 2,2, 2-trifluoro-N-[(1R)-2-(4-mercaptophenyl)-1-methylethyl]- acetamide (700 mg) in N, N-dimethylformamide (10 ml) were added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (464 mg) and potassium carbonate (404 mg), and the mixture was stirred at 60C for 1 hour. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration followed by dryness to give N- [ (LR)-2- [4- [ (2-HLORO-6-FORMYLPHENYL)- THIO] PHENYL]-1-METHYLETHYL]-2, 2,2-trifluoroacetamide (824 mg). (+) ESI-MS (m/z): 424 (M+Na) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 0.25 M stock solution of 2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2- yl)-acetamide was prepared in 1.0 M diisopropylethylamine in DMF. Benzaldehyde and other heterocyclic aldehydes were individually weighed and were dissolved to 0.25 M using a Tecan Genesis workstation. The Tecan was used to dispense 200 muL of template 1 to each reaction vessel then was used to dispense 400 L of aldehyde stock solutions to individual reaction vessels. The reaction vessels were sealed and were heated at 45-50 C, with agitation, for 18 hours. The reaction vessels were then cooled, unsealed, and 50 L of aminopropyl-functionalized silica gel (Aldrich) was dispensed to each reaction vessel. Activated 4 angstrom molecular sieves (powdered, 50 L) were then dispensed to each reaction. Reaction vessels were then sealed and were heated at 45-50 C with agitation for 3 h. Reactions were then unsealed and were filtered to remove solids. B. Sample solutions were dried in vacuo using a Genevac. Samples were dissolved in 500 pL of DMSO and 500 pL of methanol and purity was determined by LC-MS with using a combination of UV254, UV220, and ELSD detection [purity = (UV254+UV220/2)]. The HPLC conditions were: 4.6 mm x 50 mm C18 column, 10-90% acetonitrile gradient over 5 minutes (mobile phases were H20 with 0.05 % TFA and acetonitrile with 0.035 % TFA), with a flow rate of 3.5 ml/min. Samples which were <80% pure were purified using a mass directed LC-MS purification. Purified samples were concentrated in vacuo then were dissolved in DMSO and were reformatted into 96 well microtiter plates. Samples were tested for purity using LC-MS and quantity was estimated by correlating ELSD response to a standard concentration-ELSD response curve. Samples were then concentrated to dryness and were dissolved in DMSO to a final concentration of 10 uM based on ELSD quantitation. C. The following compounds were prepared in the manner described above in Steps A and B using the appropriate aldehyde in place of benzaldehyde: 2-Cyano-3- (3, 4-dimethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 345 (MH+) ; 3- (4-Benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES) : 391 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-phenyl)- acrylamide ; MS (ES): 301 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- phenyl ester; MS (ES): 343 (MH+); 2-Cyano-3- (2, 4-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Bromo-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 363 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-phenyl)- acrylamide ; MS (ES): 303 (MH+) ; 3- (4-tert-Butyl-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 341 (MH+) ; 3- (2-Chloro-4-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 337 (MH+) ; 2-Cyano-3- (2, 5-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-5- (4-methoxy-phenyl)-penta-2, 4-dienoic acid (5-ethyl- [1,3, 4] thiadiazol-2-yl)-amide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-hydroxy-3, 5-dimethoxy- phenyl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-iodo-5- methoxy-phenyl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3- (3, 4-dihydroxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 3-(4-Benzyloxy-3,5-dimethyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 419 (MH+) ; 2-Cyano-3- (3, 5-dibromo-2-methoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES) : 471 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (4-hexyloxy-phenyl)- acrylamide ; MS (ES): 385 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- 2, 6-dimethoxy-phenyl ester; MS (ES): 403 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-imidazol-1-yi-phenyl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-trifluoromethyl-phenyl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Chloro-3, 4-dimethoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 379 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- ( 1-methyl-1 H-indol-3-yl)- acrylamide ; MS (ES): 338 (MH+) ; 2-Cyano-3- (2, 6-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 2-Cyano-3-(4-dimethylamino-2-nitro-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (2-iodo-phe... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-nitropropane; sodium hydride; In ethanol; at 0 - 20℃; for 3.66667h; | Ethanol (100 mL) was added to sodium hydride (60% sodium hydride content, 4.7 g) at 0C under argon atmosphere, and the mixture was stirred for 10 minutes. 2-Nitropropane (11 mL) was added to the reaction mixture, and after the thus-obtained mixture was stirred for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The organic layer was sequentially washed with 1N aqueous sodium hydroxide, water, and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 3:7), to thereby give crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale-yellow oily compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a sol. of benzaldehyde (1 mmol) in MeOH (5 mL) was added cyclopropylamine (0.10 mL, 1.5 mmol). The sol. was stirred overnight. NaBH4 (0.031 g, 1.3 mmol) was added at 0 C, and then stirring was continued at rt for 4 h. A sol. of aq. 1M NaOH was added, andthe MeOH was evaporated. The residue was extracted with EtOAc (2x) and the org. layer was washed with brine, dried over Na2SO4, and filtered. The solvents were removed under reduced pressure. The amines are not further purified unless stated otherwise. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 0 - 20℃; for 4h; | 3-Chloro-2-fluorobenzaldehyde (1.80 ml, 15.8 mmol), D,L-<strong>[498-63-5]prolinol</strong> (1.55 ml, 15.8 mmol) and acetic acid (0.90 ml, 15.8 mmol) were dissolved in THF (40 ml) and the mixture was cooled to 0°C. Sodium triacetoxyborohydride (5.0 g, 23.7 mmol) was added portionwise.The mixture was stirred at room temperature for 4 h. Saturated aqueous sodium hydrogen carbonate was added until the gas evolution ceased. EtOAc (90 ml) was added and the mixture was washed with water. The organic phase was dried (MgSO4) and the solvent was evaporated to give a crude that was used directly in the next step. MS ESI m/z M+H4244, 246. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 0 - 20℃; for 20h; | 2-(z-Propylamine)ethanol (1.83 ml, 15.8 mmol) and acetic acid (0.90 ml, 15.8 mmol) were dissolved in anhydrous THF (40 ml) and the mixture was cooled to O0C. 3-Chloro-2- fluorobenzaldehyde (1.85 ml, 15.8 mmol) and sodium triacetoxyborohydride (5.0 g, 23.7 mmol) were added. The mixture was stirred at ambient temperature for 20 h. Saturated aqueous sodium hydrogen carbonate (8 ml) was added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4) and the solvent was evaporated to give the title compound (3.9 g). MS ESI m/z M+H1" 246, 248. | |
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 0 - 20℃; for 20h; | 2-(z-Propylamine)ethanol (1.83 ml, 15.8 mmol) and acetic acid (0.90 ml, 15.8 mmol) were 0 dissolved in anhydrous THF (40 ml) and the mixture was cooled to 0C. 3-Chloro-2- EPO <DP n="26"/>fluorobenzaldehyde (1.85 ml, 15.8 mmol) and sodium triacetoxyborohydride (5.0 g, 23.7 mmol) were added. The mixture was stirred at ambient temperature for 20 h. Saturated aqueous sodium hydrogen carbonate (8 ml) was added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4) and the solvent was evaporated to give the title compound (3.9 g) that was used without further purification. MS ESI m/z M+H+ 246, 248. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.7% | A solution of 4-iodo-l-tritylimidazole (commercially available, 5.1 g, 1 1.8 mmol) in dichloromethane (40 ?iL) at -10 0C was treated with ethyl magnesium bromide (3.9 mL, 1 1.8 mmol, 3M in ether) and allowed to react for 45 m. A solution of <strong>[85070-48-0]3-chloro-2-fluoro-benzaldehyde</strong>, (Intermediate 1) (1.5 g, 9.4 mmol) in dichloromethane was added via syringe at -10 0C and stirred for 16 hours at room temperature. The mixture was quenched with water (50 mL) and a saturated solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by MPLC with 3 to 5 % MeOHiCH2Cl2 to give (3-chloro-2-fluorophenyl)(l-trityl-l H-imidazol-4-yl) methanol, (Intermediate 2) as a solid, (3.5 g 78 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Bisdimethylaminoethyl ether (2.84 g) was dissolved in 42 mL THF and cooled in an ice bath. Isopropylmagnesium chloride (8.9 mL of a 2 M solution in THF) followed by Compound 14 (5 g dissolved in 5 mL THF) were added slowly <n="28"/>sequentially. The mixture was allowed to warm to ambient temperature and stirred overnight. Next, 2.1 mL of <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> was added. After stirring for ~ Ih, the mixture was quenched to pH ~ 7 with 2N HCl. The product was extracted into ethyl acetate and the organic phase was dried over sodium sulfate. The solvent was exchange to heptane to precipitate the product and a mixture of heptanes:MTBE (4:1) was added to form a slurry. After filtration the solid was slurried in toluene, filtered and vacuum dried to yield compound 15: 1U NMR (CD3CN, 400 MHz) delta 7.47 (s, IH), 7.41-7.35 (m, 2H), 7.15 (t, J = 7.4 Hz, IH), 6.66 (s, IH), 6.21 (br s, IH), 3.90 (s, 3H), 3.87 (br s, IH), 3.81 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 14 is combined with anhydrous tetrahydrofuran:dioxane (5:0.9), and the mixture is agitated under a nitrogen atmosphere until a homogeneous solution is achieved. The solution is cooled to -3 C and 1.3 eq. of /-PrMgCl-LiCl in tetrahydrofuran is added. The reaction mixture is agitated at 0 C until the formation of the mono-Grignard is complete as determined by HPLC analysis. Next, a solution of 1.1 eq. of 3-chloro-2-fluorobenzaldehyde in tetrahydrofuran is added. This mixture is allowed to stir at 0 0C until the formation of Compound 15a is complete by HPLC. Next, additional /-PrMgCl-LiCl solution in tetrahydrofuran (2.5 eq.) is added and the reaction mixture is warmed to about 20 C. After conversion to the second Grignard intermediate is complete, the reaction mixture is cooled to 3 C. Anhydrous CO2 <n="30"/>(g) is charged to the reaction mixture at about 5 0C. The reaction mixture is adjusted to about 20 C. After the carboxylation reaction is complete by HPLC, the reaction mixture is cooled to about 10 C and water is charged to quench the reaction followed by the addition of concentrated hydrochloric acid to adjust the pH to no more than 3. The reaction mixture is then warmed to about 20 C. The phases are separated. The organic phase is solvent exchanged to a mixture of isopropyl alcohol and water and the resulting slurry is cooled to about 0 0C. The product is isolated by filtration, washed with a mixture of isopropyl alcohol and water and dried at about 40 C to yield Compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With piperidine; for 6h;Reflux; | 6-chloroindolin-2-one (8.35 g, 50 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (8.295 g, 52.5 mmol) were stirred at reflux for 6 hours in the presence of piperidine (1 ml). Then filter the reaction suspension, The collected solid was washed with methanol and dried to give (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indol-2-one product (14.63 g, 47.5) as a yellow solid. Mmol), yield 95%. |
95% | With piperidine; for 6h;Reflux; | 6-Chloroindolin-2-one (8.35 g, 50 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (8.295 g, 52.5 mmol) were stirred at reflux in the presence of piperidine (1 ml) for 6 hours. The reaction suspension was then filtered, and the solid obtained was washed with methanol and dried to give a yellow solid product, (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indol2-one (14.63g, 47.5mmol). Yield: 95%. 1H NMR (400MHz, DMSO): delta 10.85 (s, 1 H), 7.70 (q, J=7.3Hz 2 H), 7.54 (s, 1 H), 7.36 (t, J=8Hz 1 H), 7.16 (d, J=8Hz 1 H), 6.92-6.86 (m, 2 H); MS: Calcd for C15H9Cl2FNO ([M+H]+): 308, found: 308.0. |
84% | With piperidine; In methanol; at 50℃; for 3h; | General procedure: To the mixture of optionally substituted 6-chlorooxindole (5.0 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was addedpiperidine (Aldrich) (1.7 g, 20 mmol) dropwise. The mixture was then heated at 50 Cfor 3 h. After cooled to 4 C, the mixture was filtered and resulting precipitate wascollected, washed with cold methanol, dried to give the desired product.(E)-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one 13.1 (R3a = H,R3b = H, R3c = H): a yellow solid (Yield, 84%); 1H NMR (300 MHz, DMSO-d6) 10.88 (br.s., 1H), 7.73 (q, J = 7.41 Hz, 2H), 7.56 (s, 1H), 7.34 - 7.43 (m, 1H), 7.17 (d, J = 8.10 Hz,1H), 6.87 - 6.97 (m, 2H) ppm. |
With piperidine; In methanol; | 3-Chloro-2-fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6-chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3) as a green solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium methylate; In methanol; at 45℃; for 5h; | To a solution of 4-chloro-2-fluoro-phenylacetonitrile (Oakwood) (5 g, 30 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood) (5 g, 32 mmol) in methanol (200 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (21 mL, 92 mmol). The reaction mixture was heated and stirred at 45 C. for 5 h. The mixture became cloudy, and was cooled to room temperature and filtered. The white precipitate was washed with water, cold methanol, and then dried in vacuo to give the first batch of desired product. The filtrate was concentrated, diluted with water, neutralized by aqueous HCl solution to ?pH? 7, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, then 1:10) to give the second batch of the desired product. The two batches were combined to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (9 g, 97%). |
93% | With sodium methylate; In methanol; at 0 - 45℃; for 5h;Inert atmosphere; | To a mixture of <strong>[85070-48-0]3-chloro-2-fluoro-benzaldehyde</strong> (13.7 g, 86.68 mmol, 1.05 eq) and 2- (4-chloro-2-fluoro-phenyl)acetonitrile (14 g, 82.56 mmol, 1 eq) in methanol (200 mL) was added the solution of sodium methoxide (13.4 g, 247.67 mmol, 3 eq) in methanol (40 mL) dropwise at 0 C under nitrogen atmosphere. The product begins to precipitate during the addition. The suspension was stirred at 45 C for 5 hours. The solid was filtered and washed with water (200 mL) and methanol (50 mL) and then was dried in vacuum to give (Z)-3-(3-chloro-2-fluoro- phenyl)-2-(4-chloro-2-fluoro-phenyl)prop-2-enenitrile (24 g, 77.39 mmol, 93% yield) as a white solid. 1H-NMR (400MHz, CDCL) d 8.20 - 8.10 (m, 1H), 7.81 (s, 1H), 7.64 - 7.49 (m, 2H), 7.33 - 7.20 (m, 3H). |
88.5% | With sodium hydroxide; In methanol; at 50℃; for 4.5h;Large scale; | A 250-L glass-lined reactor was charged with 2-(4-chloro-2-fluorophenyl)acetonitrile (15.0 kg, 88.5 mol, Eq: 0.988), <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (14.2 kg, 89.6 mol, Eq: 1.00), MeOH (140 L). In one portion, a solution of sodium hydroxide [prepared from 50 wt% solution (0.23 L, 4.4 mmol, Eq: 0.05) diluted in methanol (10 L)] was added. The resulting mixture was heated to 50 C for 4.5 h, and then the resulting thick slurry was cooled down to 20 C. Consumption of 3- chloro-2-fluorobenzaldehyde was monitored by HPLC analysis. The solid product was isolated by filtration via a 0.3 m filter/dryer and the cake washed with methanol (58 L). The product was dried under vacuum with N2 purge at 60C to provide the stilbene as a white powder, 24.2 kg (88.5% yield) with 99.87% purity by HPLC analysis. 1H NMR (300 MHz, CDC13) delta 8.10-8.15 (1H, m), 7.79 (1H, s), 7.48-7.59 (2H, m), 7.20-7.28 (3H, m). |
86% | With sodium methylate; In methanol; at 45℃; for 5h; | To a solution of 4-chloro-2-fluorophenylacetonitrile (Matrix) (5 g, 30 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood) (5 g, 32 mmol) in methanol (200 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (21 mL, 92 mmol). The reaction mixture was heated and stirred at 45 C. for 5 h. The mixture was cooled to room temperarure and filtered. The white precipitate was washed with water, cold methanol, and then dried under reduced pressure to afford (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (8 g, 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With piperidine; In methanol; at 20.0℃; for 3.0h; | Step 1 To a stirred solution of oxindole 1 (4.19 g, 25 mmol) in methanol (50 mL) was added aldehyde 2 (3.96 g, 25 mmol) and piperidine (2.45 mL, 25 mmol). The reaction mixture was stirred at room temperature for 3 h and the yellow precipitate was collected, washed successively with methanol, hexanes, and ethyl ether and dried to give compound 3 (6.25 g, 81% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With piperidine; In methanol; at 80℃; for 2h; | To the mixture of 6-bromo-2-oxindole (5 g, 24 mmol) (Combi-blocks) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (3.7 g, 24 mmol) (Oakwood) in methanol (200 mL) was added piperidine (2 g, 24 mmol) (Aldrich) dropwise. The mixture was then heated at 80 C. for 2 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.8 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With piperidine; In methanol; at 50.0℃; for 3.0h; | To the mixture of <strong>[100487-74-9]6-chloro-5-fluoroindolin-2-one</strong> (Natrochem) (2.88 g, 15.5 mmol) and 3-chloro-2-fluorobenzaldehyde (3.69 g, 23.3 mmol) (Aldrich) in methanol (140 mL) was added piperidine (3.96 g, 46.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 4.4 g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With piperidine; In methanol; at 50℃; for 3h; | To the mixture of 6-chloro-4-fluoroindolin-2-one (Natrochem, 85% purity) (1.1 g, 5.0 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was added piperidine (1.7 g, 20 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, washed with cold methanol, dried to give the first batch of desired product (1.22 g). The filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (20-35% EtOAc in hexanes) to give the second batch of desired product (0.32 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-4-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.54 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine; In methanol; at 50℃; for 3h; | To the mixture of 6-chloro-7-fluoroindolin-2-one (1.1 g, 5.9 mmol) (Natrochem) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (1.4 g, 8.9 mmol) (Aldrich) in methanol (50 mL) was added piperidine (1.5 g, 17.8 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to half its volume. The'mixture was filtered and resulting precipitate was collected, dried to give the first batch of desired product (1.4 g). The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product (0.44 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.84 g, 89%). |
89% | With piperidine; In methanol; at 50℃; for 3h; | Example 6 Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one; To the mixture of 6-chloro-7-fluoroindolin-2-one (1.1 g, 5.9 mmol) (Natrochem) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (1.4 g, 8.9 mmol) (Aldrich) in methanol (50 mL) was added piperidine (1.5 g, 17.8 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to half its volume. The mixture was filtered and resulting precipitate was collected, dried to give the first batch of desired product (1.4 g). The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product (0.44 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.84 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine; In methanol; at 50℃; for 3h; | To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In dichloromethane; at 20℃; for 3h; | Example 5 Preparation of intermediate [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in dichloromethane (50 mL) was added <strong>[85070-48-0]3-chloro-2-fluoro-benzaldehyde</strong> (Oakwood) (1.6 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (2.4 g, 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With pyridine; at 100℃; for 2h; | Method B. To a solution of racemic 3-(1-aminomethyl-3,3-dimethyl-butyl)-6-chloro-1,3-dihydro-indol-2-one prepared in Example 3 (1.2 g, 4.3 mmol) in pyridine (50 mL) was added <strong>[85070-48-0]3-chloro-2-fluoro-benzaldehyde</strong> (Oakwood) (0.68 g, 4.3 mmol). The reaction mixture was heated at 100 C. for 2 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved into ethyl acetate, washed with aqueous saturated CuSO4 solution, and brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2'S,3'S,4'S)-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-4'-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a white solid (Yield, 0.29 g, 16%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | toluene-4-sulfonic acid; In toluene; at 130℃; for 2h; | Example 40 Preparation of intermediate rac-(2'S,3'S,4'S)-4'-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one To a solution of racemic 3-[1-aminomethyl-5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 3.5 mmol) in toluene (30 mL) was added <strong>[85070-48-0]3-chloro-2-fluoro-benzaldehyde</strong> (Oakwood) (0.56 g, 3.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (67 mg, 0.35 mmol). The reaction mixture was heated at 130 C. for 2 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and aqueous NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2'S,3'S,4'S)-4'-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one as a white solid (0.12 g, 6%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine; In methanol; at 50℃; for 3h; | Example 2 Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one; To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With piperidine; In methanol; at 50℃; | Example 20 Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To a suspension of <strong>[32501-05-6]1H-pyrrolo[3,2-b]pyridin-2(3H)-one</strong> (Sinova. 933 mg, 6.96 mmol) in MeOH (35 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 3.58 g, 22.6 mmol) giving a clear solution. Piperidine (Lancaster, 2.58 g, 30.30 mmol) was added slowly. After stirred for a few minutes, the reaction mixture was heated at 50 C. for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light yellow crystalline solid (1.22 g, 64%). MS (ES+) m/z [(M+H)+]: 275 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With piperidine; In methanol; at 50℃; | Example 12 Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3b]pyridin-2-one To a suspension of <strong>[5654-97-7]1H-pyrrolo[2,3-b]pyridin-2(3H)-one</strong> (Chemgenx, 926 mg, 6.91 mmol) in MeOH (55 mL), was added 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 3.29 g, 20.70 mmol). Piperidine (Lancaster, 2.41 g, 2.8 mL, 28.30 mmol) was added slowly. After stirring a few minutes, the reaction mixture was heated at 50 C. for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a light yellow crystalline solid (1.18 g, 62%). MS (ES+) m/z [(M+H)+]: 275 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With piperidine; In methanol; at 50℃; | Example 40 Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To a mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1.5 g, 8.9 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 1.4 g, 8.9 mmol) in methanol (65 mL) was added piperidine (Aldrich, 0.76 g, 8.9 mmol) dropwise. The reaction mixture was heated at 50 C. and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (1.8 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In methanol; for 18h;Reflux; | N,N-diisopropylethylamine (0.10 ml) was added to a methanol (30 ml) solution of 6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (633 mg, 3.75 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (0.45 ml, 3.83 mmol) and the resulting mixture was heated to reflux for 18 hours. After cooling, the precipitate was collected by filtration, washed with cold methanol, and dried to give 920 mg (79%) of the title compound as a yellow solid.1H-NMR (400 MHz, DMSO-d5) delta: 7.02 (1H, d, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 7.53 (1H, d, J=7.8 Hz), 7.66-7.78 (3H, m), 11.4 (1H, s). |
52% | With piperidine; In methanol; at 50℃; | Example 34 Preparation of intermediate E/Z-6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one To a suspension of 6-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Sinova, 501.5 mg, 2.83 mmol) in MeOH (25 mL) was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 1.35 g, 8.51 mmol). Piperidine (Aldrich, 1.03 g, 12.0 mmol) was added slowly, giving a clear brown solution. After stirred for a few minutes, the reaction mixture was heated at 50 C. overnight, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a grey solid (457 mg, 52%). MS (ES+) m/z [(M+H)+]: 309 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With piperidine; In methanol; at 50℃; | Example 45 Preparation of intermediate E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To a suspension of 5-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 815.5 mg, 4.84 mmol) in MeOH (45 mL) was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 2.3 g, 14.5 mmol). Piperidine (Aldrich, 1.63 g, 19.2 mmol) was added slowly. After stirring a few minutes, the mixture was heated at 50 C. for 6 h resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (1.38 g, 92%). MS (ES+) m/z [(M+H)+]: 309 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With piperidine; In methanol; at 50℃; | Example 4 Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2c]pyridin-2-one To a suspension of 1H-pyrrolo[3,2-c]pyridin-2(3H)-one (1.00 g, 7.46 mmol, prepared according to the method described in J. Org. Chem., 1991, 56, 4805-4808) in MeOH (55 mL) in a 100-mL round-bottomed flask, was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood Products, 3.55 g, 22.40 mmol), giving a clear solution. Piperidine (Lancaster, 2.66 g, 31.20 mmol) was added slowly. After stirred for 10 min, the reaction mixture was heated at 50 C. for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light yellow crystalline solid (1.38 g, 67%). MS (ES+) m/z [(M+H)+]: 275 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With piperidine; In methanol; at 20℃; | Example 82 Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To the mixture of 6-fluoro-4-aza-2-oxindole (Sinova, 1 g, 4.6 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood Products, 1.2 g, 7.6 mmol) in methanol (50 mL) was added piperidine (Aldrich, 2 g, 24 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 h. Then the mixture was filtered. The resulting precipitate was collected to give the first batch of desired product. The filtrate was concentrated. The residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desire product. The two batches were combined to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (Yield 1.1 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With piperidine; In methanol; at 50℃; | Example 76 Preparation of intermediate E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To the mixture of 6-bromo-4-aza-2-oxindole (Sinova, 0.3 g, 1.4 mmol) and 3-chloro-2-fluorobenzaldehyde (Oakwood, 0.45 g, 2.8 mmol) in methanol (20 mL) was added piperidine (Aldrich, 0.36 g, 4.2 mmol) dropwise. The reaction mixture was heated at 50 C. and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (25-50% EtOAc in hexanes) to give the second batch of product. The two batches were combined to give E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (0.35 g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With piperidine; In methanol; at 50℃; for 5h; | Example 23 Preparation of intermediate E/Z-6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one To a suspension of 6-chloro-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (Sinova, 689 mg, 4.09 mmol) in MeOH (50 mL) was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 1.89 g, 11.9 mmol). Piperidine (1.46 g, 17.2 mmol) was added slowly, giving a clear brown solution. After stirred for a few minutes, the reaction mixture was heated at 50 C. for 5 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light brown solid (1.07 g, 85%). MS (ES+) m/z [(M+H)+]: 309 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Example 88 Preparation of intermediate E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one To a mixture of 2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (Molbridge, 0.5 g, 3.0 mmol) in acetic acid (8 mL) and aqueous concentrated HCl solution (37%, 2 mL) was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 0.9 g, 5.7 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was neutralized to "pH? 7-8 by aqueous saturated NaHCO3 solution, then extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to a small volume. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product. The two batches were combined to give E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a yellow solid (0.51 g, 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With piperidine; In methanol; at 50℃; for 4h; | Example 29 Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To a suspension of 6-methyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 500 mg, 3.37 mmol) in MeOH (20 mL) was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 1.60 g, 10.1 mmol) giving a clear solution. Piperidine (Lancaster, 1.2 g, 14.1 mmol) was added slowly. After stirred for a few minutes, the reaction mixture was heated at 50 C. for 4 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light yellow crystalline solid (946 mg, 97%). MS (ES+) m/z [(M+H)+]: 289 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With piperidine; In methanol; at 50.0℃; | Example 48 Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one To a suspension of <strong>[56057-25-1]7-methyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one</strong> (Sinova, 818.0 mg, 5.52 mmol) in MeOH (30 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 2.60 g, 16.4 mmol) in MeOH (2 mL) to give a clear solution. Piperidine (Aldrich, 1.89 g, 22.2 mmol) was added slowly and a light yellow precipitation started to form shortly. After stirring a few minutes, the reaction mixture was heated at 50 C. for 12 h. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (939 mg, 58%). MS (ES+) m/z [(M+H)+]: 288 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetic acid; at 20℃; for 24h; | Example 95 Preparation of intermediate E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one To a mixture of 2-chloro-4,6-dihydro-thieno[3,2-b]pyrrol-5-one (Example 94, 4.2 g, 24 mmol) in acetic acid (60 mL) and aqueous concentrated HCl solution (37%, 15 mL) was added <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (Oakwood, 7.5 g, 47 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered, and the resulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desire product. The filtrate was concentrated, and the residue was neutralized to "pH? 7-8 by aqueous saturated NaHCO3 solution, then extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product. The two batches were combined to give E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one as a brown solid (5.1 g, 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine; In methanol; at 50℃; for 3h; | To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dichloromethane; at 20℃; for 2.16667h; | Intermediate 6 A. (R,E)-N-(3-Chloro-2-fluorobenzylidene)-2-methylpropane- 2-sulfmamide: (Ref: Angew. Chem. Int. Ed., 48:914-917 (2009)). To a stirred suspension of <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (1.308 g, 8.25 mmol) and Cs2C03 (4.03 g, 12.38 mmol) in DCM (10 mL) was added a solution of (i?)-2-methylpropane-2- sulfmamide (1 g, 8.25 mmol) in DCM (50 mL) dropwise for 10 min. The solution was then stirred for 2 h at rt. LC/MS indicated that the reaction was complete. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (20 mL x 3). The organic layers were dried over Na2S04 and concentrated in vacuo to give (R,E)-N-(3- chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.3 g, 107%) as a clear oil. MS (ESI) m/z: 262.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 20℃; for 4h; | [00419] Intermediate 46A. (E)-3-Chloro-2-fluorobenzaldehyde oxime: To the solution of <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (1.3 g, 8.20 mmol) and hydroxylamine hydrochloride (0.695 g, 10.00 mmol) in EtOH (6.83 mL)/water (6.83 mL) was added 1 N NaOH (10.00 mL, 10.00 mmol). The reaction was stirred at rt for 4 h, then it was acidified to pH 6 with 1 N HCl which gave a white suspension. The reaction mixture was filtered, and the solid was rinsed with water, and air-dried to afford the desired product (1.31 g, 92%) as a white solid. MS(ESI) m/z: 174.0 (M+H)+. 1H NMR (500 MHz, CDC13) delta 8.36 (s, 1H), 7.74 (s, 1H), 7.66 (ddd, J = 7.8, 6.3, 1.7 Hz, 1H), 7.42 (ddd, J = 8.0, 7.2, 1.7 Hz, 1H), 7.13 - 7.07 (m, 1H) ppm. |
71% | With hydroxylamine hydrochloride; triethylamine; In tetrahydrofuran; for 24h; | Intermediate 18A. (£)-3-Chloro-2-fluorobenzaldehyde oxime: To a solution of 3- chloro-2-fluorobenzaldehyde (9.61 grams, 60.6 mmol) in THF (50 mL), hydroxylamine hydrochloride (4.21 grams, 60.6 mmol) was added followed by TEA (8.45 mL, 60.6 mmol). After 24h. the reaction was quenched with water(200 mL), extracted organics with EtOAc (2 x lOOmL), dried and evaporated. Purified by normal phase chromatography to give 18A (7.5 grams, 71%) as a colorless solid. MS (ESI) m/z: 174.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In tetrahydrofuran; at -78℃; for 2h; | [00422] Intermediate 47A. l-(3-Chloro-2-fluorophenyl)propan-l-ol: To the solution of <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (2.8 g, 17.66 mmol) in THF (88 mL) at -78 C was added dropwise ethylmagnesium bromide (1 M in THF) (21.19 mL, 21.19 mmol). After 2 h, the reaction was warmed to 0 C and it was carefully quenched with saturated NH4C1 solution. The reaction mixture was diluted with water and extracted with EtOAc (3x). The organic layers were combined and washed with water, brine, dried over MgS04, filtered and concentrated. Purification by silica gel chromatography yielded the desired product (2.04 g, 61%) as a colorless oil. MS(ESI) m/z: 211.0 (M+Na)+. 1H NMR (500 MHz, CDC13) delta 7.37 (td, J = 7.0, 1.7 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.09 (td, J = 7.8, 1.1 Hz, 1H), 4.99 - 4.94 (m, 1H), 1.92 (d, J = 4.4 Hz, 1H), 1.85 - 1.77 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In tetrahydrofuran; at 20℃; for 0.5h;Inert atmosphere; | To a solution of <strong>[85070-48-0]2-fluoro-3-chloro-benzaldehyde</strong> (4.74 g, 30 mmol) in THF (20 mL) was added NaBH4 (1.48 g, 40 mmol). The resulting mixture was stirred at room temperature for 30 min before diluting with DCM. The organic layer was washed with water and brine The combined organic layers were dried over anhy. Na2S04, filtered and concentrated in vacuo to give desired product without further purification (4.8g, 100%). MS: 161.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 3h; | A 100 mL round-bottom flask was charged with <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (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]+. |
33% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 3h; | Step 1: Preparation o -chloro-2-(morpholin-4-yl)benzaldehyde [00238] A 100-mL round-bottom flask was charged with <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (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 h at 100 C in an oil bath and diluted with Iota0 (30 mL). The resulting solution was extracted with dichloromethane (3 x 20 mL), and the organic layers were combined and 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 column with 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]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol; for 1h;Reflux; | General procedure: A mixture of 6-methylpyridine-3-carbohydrazide 3 (0.003 mmol) and appropriate aldehyde/acetophenone (0.033 mmol) in ethanol (5 mL) were refluxed for 1 hr. The reaction mass was cooled. The precipitated solid was filtered, washed with chilled ethanol and dried. The crude product was recrystallized from hot ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In N,N-dimethyl-formamide; for 4h;Reflux; | General procedure: A mixture of a 6-(arylamino)pyrimidine-2,4(1H,3H)-dione 3a (1 equiv) and a 2-halo- or 2-tosyl-benzaldehyde 4 (X = F, Cl, or OTs; 1.2 equiv) in DMF (10 mL/mmol 3a) was heated under reflux for 4 h. After cooling, the solution was evaporated under reduced pressure and the residue was purified by flash chromatography (5:95 MeOH-CH2Cl2) to afford the product. 5.27 9-Chloro-10-(3-fluorophenyl)-2H,3H,4H,10H-pyrimido-[4,5-b]quinoline-2,4-dione (27) Prepared using general method 5.7 from 3a (R5,7 = H, R6 = F; 65 mg, 0.29 mmol) 8 and 4 (R1-3 = H, R4 = Cl, X = F; 55 mg, 0.35 mmol). Yellow solid (71.0 mg, 71%). Mp > 365 C; IR (KBr): 3.417 (NH), 1.717 (C=O), 1.658 (C=O), 1.614 (C=C) cm-1; 1H NMR: delta 7.28 (1H, d, J = 7.8 Hz, Ph 6-H), 7.38-7.45 (2H, m, Ph-H), 7.49 (1H, t, J = 7.8 Hz, C7-H), 7.53-7.60 (1H, m, Ph-H), 7.86 (1H, dd, 4J = 1.3 Hz, 3J = 7.8 Hz, C8-H), 8.25 (1H, dd, 4J = 1.3 Hz, 3J = 7.8 Hz, C6-H), 9.10 (1H, s, C5-H), 11.21 (1H, s, N3-H); 13C NMR: delta 116.38 (Cq), 116.59 (CH, d, J = 21.2 Hz), 118.11 (CH, d, J = 23.8 Hz), 120.94 (Cq), 124.55 (Cq), 125.82 (CH), 126.86 (CH, d, J = 2.9 Hz), 130.58 (CH, d, J = 8.8 Hz), 132.45 (CH), 137.43 (Cq), 139.33 (CH), 140.88 (Cq, d, J = 10.9 Hz), 143.42 (CH), 156.64 (Cq), 160.73 (Cq), 161.96 (Cq), 162.35 (Cq, d, J = 243.7 Hz); anal. RP-HPLC: tR 1.63 min (97.0%; A), 19.62 min (98.1%; B); HRMS (ESI+): calcd for C17H10ClFN3O2 [M+H]+ 342.0446, found 342.0453. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With piperidine; In methanol; at 50℃; for 3h; | General procedure: To the mixture of optionally substituted 6-chlorooxindole (5.0 mmol) and <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was addedpiperidine (Aldrich) (1.7 g, 20 mmol) dropwise. The mixture was then heated at 50 Cfor 3 h. After cooled to 4 C, the mixture was filtered and resulting precipitate wascollected, washed with cold methanol, dried to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With piperidine; In methanol; at 50.0℃; for 3.0h; | General procedure: To the mixture of optionally substituted 6-chlorooxindole (5.0 mmol) and 3-chloro-2-fluorobenzaldehyde (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was addedpiperidine (Aldrich) (1.7 g, 20 mmol) dropwise. The mixture was then heated at 50 Cfor 3 h. After cooled to 4 C, the mixture was filtered and resulting precipitate wascollected, washed with cold methanol, dried to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: A mixture of 2-hydroxyacetophenone (1 equiv) and the corresponding aldehyde (1 equiv) in ethanol (40 mL) and 1,4-dioxane (20 mL) was cooled to 0-10 C, 40% w/v KOH (5 equiv) solution was added dropwise. Then the reaction mixture was stirred at room temperature and monitored by TLC until the reaction completion. HCl (10%) was added to neutralize the reaction mixture. Ethyl acetate (50 mL) was then added, organic layer was separated and washed with H2O (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was dissolved in 1,4-dioxane (50 mL) and ethanol (30 mL), cooled in an ice-water bath, NaOH (5.4% w/v) solution (5 equiv), 35% H2O2(8 equiv) was added dropwise. The reaction mixture was stirred in an ice bath for 2 h and subsequently at room temperature overnight, resulting in a yellow suspension. After acidification with 2 M HCl to neutrality, ethyl acetate (3*50 mL) was used to extract the product, and the organic layer was washed with H2O (50 mL) and brine (50 mL), then dried over anhydrous sodium sulfate and concentrated in vacuum. The product was purified by column chromatography.The total yields for the two steps were varied from 40%to 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | To a solution of ethyl 2-hydroxyacetate (1.6 g, 15 mmol) in tetrahydrofuran (25 mL) at 0 o C, was added sodium hydride (0.61 g, 15 mmol). The reaction was stirred for 0.5 hour, and 3-chloro- 2-fluorobenzaldehyde (2.0 g, 13 mmol) was added. The mixture was stirred at 25 C for 4.5 hours, then quenched with water (5 mL) and extracted with ethyl acetate (2 chi 40 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate =15: 1] to give compound B-291 (0.80 g, 28% yield) as a yellow solid. LCMS (J): tR=1.551 min., (ES+) m/z (M+H)+ =225.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; In dichloromethane; at 0 - 5℃; for 1h; | 1L four-necked flask, 36.3 g of sodium hydrogencarbonate, 500 g of dichloromethane, 0.5 g of TauEpsilonMuRhoO, and the mixture was cooled to 0 to 5 C with stirring, 50 g of 2-fluoro-3-chlorobenzyl alcohol and 100 g of dichloromethane were added dropwise, and then add the sodium hypochlorite solution 230g, drop after the insulation reaction 1 h, sampling control, raw materials ? 1%, stop the reaction, standing stratification, the oil layer of simple distillation of dichloromethane recovery, and then vacuum distillation that 2-fluoro-3-chlorobenzaldehyde 46.1 g, content 97.5%, yield 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 1h; | To a stirred solution of tert-butyl 5-fluoro-2-sulfanylbenzoate (2g, 8.76 immol) and 3- chloro-2-fluoro-benzaldehyde (1.38g, 8.76 immol) in DMF (l2mL) was added K2C03 (2.4g,17.522mmo1) and reaction mass was stuffed at 25C for lh. Reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude thus obtained was purified by normal silica column using 0-2% ethyl acetate in hexane to get tertbutyl 2- (2-chloro-6-formyl-phenyl) sulfanyl-5-fluoro-benzoate (1. 8g, 56%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 22 - 70℃; for 0.5h; | To a solution of methyl 4-bromo-2-mercaptobenzoate (1.29 g, 5.22 mmol, Eq: 1) in DMF(25.8 ml) was added at 22 C <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (1.24 g, 7.83 mmol, Eq: 1.5)followed by potassium carbonate (721 mg, 5.22 mmol, Eq: 1), warmed to 70 C and stirred at 70C for 30 mm to give nearly conversion complete. The suspension was cooled to 22 C, the precipitated solid was filtered off (dicalite) and washed with ether (1 x 15 ml). The filtrate was evaporated in HV and the yellow oil was purified by flash chromatography (silica gel, 80 g,EtOAc in heptane 0% to 20% to 60%) to give methyl 4-bromo-2-((2-chloro-6- formylphenyl)thio)benzoate (1.73 g, 86%) as a light yellow solid.LC-MS: mlz = 385.0 (M + H)+ (monoisotopic mass 383.92) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.17% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a suspension of 3-Chloro-2-fluoro-benzaldehyde (2.8 g, 16.64 mmol) and K2C03 (4.5 g, 33.29 mmol) in DMF (15 mL) was added 2-Mercapto-benzoic acid methyl ester (7.9 g, 49.93mmol) and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with (3 x 100 mL) ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by silica gel column chromatography (20 % ethyl acetate and hexane) to afford methyl 2-(2-chloro-6-formyl-phenyl)sulfanylbenzoate (4.4 g, 86.17%) as white solid. LC-MS: 307.2 [M+H]. |
86.17% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a suspension of 3-Chloro-2-fluoro-benzaldehyde (2.8 g, 16.64 mmol) and K2CO3 (4.5 g, 33.29 mmol) in DMF (15 mL) was added 2-Mercapto-benzoic acid methyl ester (7.9 g, 49.93 mmol) and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with (3 x 100 mL) ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by silica gel column chromatography (20 % ethyl acetate and hexane) to afford methyl 2-(2- chloro-6-formyl-phenyl)sulfanylbenzoate (4.4 g, 86.17%) as white solid. LC-MS: 307.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | Example 64: 1,1,1,3,3,3-Hexafluoropropan-2-yl 2-(3-chloro-2-(4,4-difluoropiperidin-1- yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate Step 1: Preparation of 3-chloro-2-(4-hydroxypiperidin-1-yl)benzaldehyde A flask was charged with <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (3.00 g, 18.9 mmol, 1.00 equiv), piperidin-4-ol (2.86 g, 28.3 mmol, 1.49 equiv), potassium carbonate (7.81 g, 56.5 mmol, 2.99 equiv), and DMSO (30 mL) under nitrogen. The resulting solution was stirred overnight at 120 ^C and diluted with H2O (15 mL). The resulting solution was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on a silica gel column (27:63 EtOAc/petroleum ether) to provide 3.20 g (71% yield) of 3-chloro-2-(4-hydroxypiperidin-1-yl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 240 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | (3-Chloro-2-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanol To a -78 C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40 mL), under argon was added a solution of 2,6-dichloropyrazine (1.648 g, 11.0 mmol) in THF (10 mL). After addition was completed, the resulting mixture was stirred at -78 C. for an additional 1 h, then <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (2.61 g, 16.5 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred for another hour, then quenched with hydrochloric acid (1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL) mixture, and warmed to RT The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc=4:1) to give the title compound as a yellow solid (700 mg, 20%). MS (ES+) C11H6Cl3FN2O requires: 306, found: 307 [M+H]+. 1H NMR (500 MHz, DMSO-d6) delta 8.80 (s, 1H), 7.61 (t, J=6.6 Hz, 1H), 7.59-7.45 (m, 1H), 7.29 (t, J=7.9 Hz, 1H), 6.66 (d, J=6.0 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium phosphate; triphenylphosphine; copper dichloride; In 1-methyl-pyrrolidin-2-one; at 25 - 120℃; for 16h; | To a solution of <strong>[85070-48-0]3-chloro-2-fluoro-benzaldehyde</strong> (10.0 g, 63.29 mmol) in NMP (100 mL) was added 3-bromophenol (13.1 g, 75.95 mmol), CuCl2 (0.42 g, 3.165 mmol), K3P04 (26.8 g, 126.6 mmol) and PPh3 (1.24 g, 4.747 mmol) at 25C, then the mixture was stirred at 120 C for 16 h. The reaction was quenched by addition of water (500 mL) and the resulting mixture was extracted with EtOAc (500 mL) for three times. The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution with PE: EtOAc =20: 1) to give 2-(3- bromophenoxy)-3-chloro-benzaldehyde (14.1 g, 71%) as oil. MS obsd. (ESI+) [(M+H)+]: 311.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | With hydroxylamine hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; | 3-Chloro-2-fluorobenzaldehyde (50.0 g, 0.32 mol) and hydroxylamine hydrochloride (22.2 g, 0.32 mol)Dissolved in THF (400 mL), added Et3N (32.3 g, 0.32 mol) and stirred overnight.The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed twice with saturated aqueous NaCl solution.Dry over anhydrous magnesium sulfate, filter, and concentrate the concentrated crude product on a silica gel column to give the desired <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> oxime as a white solid.(29.1g, 53.2%) |
53.2% | With hydroxylamine hydrochloride; triethylamine; In tetrahydrofuran; | The compound <strong>[85070-48-0]3-chloro-2-fluorobenzaldehyde</strong> (50.0 g, 0.32 mol) and hydroxylamine hydrochloride (22.2 g, 0.32 mol) were dissolved in THF (400 mL), and Et3N (32.3 g, 0.32 mol) was added and stirred overnight.The reaction solution was quenched with water and ethyl acetate.The organic phase was washed twice with saturated aqueous NaCl and dried over anhydrous magnesium sulfate.Filtration, the concentrated crude product was purified by silica gel column to obtain the titleCompound (29.1 g, 53.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 24h; | 3-Chloro-2-fluorobenzaldehyde (0.014 mmol) was weighed, and K2CO3 (0.02 mol) was added to a 250 mL two-neck round bottom flask together with solvent DMF (40 mL to 50 mL).Heating at 150 C under reflux; pyrrolidine (0.02 mol) was slowly added dropwise to the above system,The nucleophilic substitution reaction of the aromatic ring was continued for 24 hours by reflux heating at 150 C, and the reaction was completed.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-o-pyrrolidinobenzaldehyde raw material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | General procedure: To a suspension of NaH (592 mg, ca. 60%in mineral oil, washed with hexane, ca. 15 mmol) in N,N-dimethylformamide (DMF, 13 mL) was added1-adamantanethiol (2.17 g, 12.9 mmol) in DMF (20 mL) at 0 C under N2. The reaction mixture wasstirred at 0 C for 1.5 h, and a solution of 1a (2.97 g, 10.5 mmol) in DMF (20 mL) was added at -40 C.The reaction mixture was stirred at -40 C for 2 h. The reaction mixture was poured into water, andextracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The filtratewas concentrated under reduced pressure, and purified by silica gel column chromatography(hexane-EtOAc, 4:1) to give 4.27 g (9.93 mmol) of 2a. |
Tags: 85070-48-0 synthesis path| 85070-48-0 SDS| 85070-48-0 COA| 85070-48-0 purity| 85070-48-0 application| 85070-48-0 NMR| 85070-48-0 COA| 85070-48-0 structure
[ 695187-29-2 ]
5-Chloro-2,4-difluorobenzaldehyde
Similarity: 0.96
[ 190011-87-1 ]
3-Chloro-2,6-difluorobenzaldehyde
Similarity: 0.94
[ 695187-29-2 ]
5-Chloro-2,4-difluorobenzaldehyde
Similarity: 0.96
[ 190011-87-1 ]
3-Chloro-2,6-difluorobenzaldehyde
Similarity: 0.94
[ 695187-29-2 ]
5-Chloro-2,4-difluorobenzaldehyde
Similarity: 0.96
[ 190011-87-1 ]
3-Chloro-2,6-difluorobenzaldehyde
Similarity: 0.94
[ 695187-29-2 ]
5-Chloro-2,4-difluorobenzaldehyde
Similarity: 0.96
[ 190011-87-1 ]
3-Chloro-2,6-difluorobenzaldehyde
Similarity: 0.94
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