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CAS No. : | 113211-94-2 | MDL No. : | MFCD00042488 |
Formula : | C7H5BrF2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FTBSGSZZESQDBM-UHFFFAOYSA-N |
M.W : | 207.02 | Pubchem ID : | 517984 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.19 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
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) : | -5.66 cm/s |
Log Po/w (iLOGP) : | 2.17 |
Log Po/w (XLOGP3) : | 2.68 |
Log Po/w (WLOGP) : | 3.55 |
Log Po/w (MLOGP) : | 3.95 |
Log Po/w (SILICOS-IT) : | 3.67 |
Consensus Log Po/w : | 3.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.19 |
Solubility : | 0.134 mg/ml ; 0.000646 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.33 |
Solubility : | 0.963 mg/ml ; 0.00465 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.22 |
Solubility : | 0.0125 mg/ml ; 0.0000604 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.72 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
20 g | With phosphorus tribromide In diethyl ether at -10℃; for 1.25 h; | Step 2 (MW-S2):Phosphorous tribromide (6.7 ml, 69.44 mmol) was added drop wise over 15 mm to a solution of MW-Si (20 g, 138.88 mmol) in diethylether (250 mL) at -10°C. The reaction mixture wasstirred for 1 h. The reaction was quenched with saturated sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to afford 20 g of MW-52 as a light brown liquid, further used without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 g | With phosphorus tribromide; In diethyl ether; at -10℃; for 1.25h; | Step 2 (MW-S2):Phosphorous tribromide (6.7 ml, 69.44 mmol) was added drop wise over 15 mm to a solution of MW-Si (20 g, 138.88 mmol) in diethylether (250 mL) at -10°C. The reaction mixture wasstirred for 1 h. The reaction was quenched with saturated sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to afford 20 g of MW-52 as a light brown liquid, further used without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ISOPROPYLAMIDE; at 100℃; for 3h; | A mixture of ethyl N-[(l-cyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4-tetrahydro-5- pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (255 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 1000C for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (x2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (x2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol- water gave the title compound (140 mg, 32%). IH NMR (400 MHz, DMSO-6) delta ppm 13.10 (br. s., 1 H), 10.11 (br. s., 1 H), 7.25 - 7.43 (m, 1 H), 7.08 - 7.23 (m, 1 H), 7.03 (t, J=7.07 Hz, 1 H), 5.08 (s, 2 H), 4.55 - 4.73 (m, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.12 - 2.35 (m, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.63 (s, 3 H), 1.20 - 1.38 (m, 2 H), 1.02 - 1.18 (m, I H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide; In acetone; for 6h;Heating / reflux; | 2,3-Difluorobenzyl bromide (2.07 g, 10 mmol) was added to a stirred suspension of 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine (1.28 g, 5 mmol), NaI (0.1 g) and acetone (50 ml). The mixture was stirred and heated at reflux for 6 h. After cooling, the solid was collected by filtration and then stirred with 0.88 aqueous ammonia- water (80 ml, 1:1) for 0.5 h. The resulting solid (ca.2 g) was removed by filtration and dried in vacuo. Recrystallisation from methanol gave the product (1.2 g) as a pale yellow solid, mp 208-209 0C. deltaH (500 MHz, dmso-de) 5.20 (2H, s, NCH2), 5.66 (IH, brpeak, NH), 6.63 (IH, brpeak, NH), 7.19 (2H, m, aromatic H), 7.35 (IH, m, aromatic H), 7.44 (2H, m, aromatic H), 7.72 (IH, brd, J= 7 Hz, aromatic H). m/z 383 (M+ + 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Using the procedure set forth in paragraph A, the following compounds were prepared |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Thiourea [(5.] 0g) was added to a solution of 3, 4-difluorobenzyl bromide [(13.] 6g) in ethanol [(100ML).] The mixture was heated at reflux for 3h before removal of the volatiles in [VACUA.] The crude solid was suspended in aqueous sodium hydroxide solution [(1.] 6M, 110ml) and heated at reflux for 3h before allowing to cool to room temperature. The reaction was acidified with concentrated hydrochloric acid and the organics extracted with ether [(200MOL).] The organic layer was washed with saturated sodium bicarbonate solution (2x50ml), brine (20ml), dried [(MGSO¢),] and concentrated [IN IACUO] to provide the subtitle product as a colourless oil. Yield ll. lg 'H [NMR No.(CDCL3) ] 7.00-7. 11 (3H, m), 3.78 (2H, d), and 1.90 [(1H,] t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; water; at 20 - 60℃; for 22h; | Sodium hydroxide (6. [1 G)] in ethanol [(20ML)] and water (20ml) was added to a suspension of 4, [6-DIHYDROXY-2-THIOPYRIMIDINE] in ethanol/water (120ml/120ml). <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (28.4g) was added dropwise to this solution. The mixture was heated at [60C] for 2h and stirred at room temperature for 20h. The solids were filtered and washed with water [(200ML),] isopropanol [(20ML)] and [DRIED IN VACUO] at [40C] for 24h to yield the subtitle compound. Yield 31.0g. MS APCI (+ve) 271 [[M+H] +] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 3h; | 5-Chlorosalicylaldehyde (10g, 63. [7MMOL),] 2, 3-difluorobenzyl bromide (8. 08ml, 63. 7mmol) and [K2C03] (17.6g, 127. 4mmol) were heated in DMF (64ml, 1 M) at [60C] for 3hrs. Upon cooling to room temperature, Et2O and [H20] were added. The layers were separated and the aqueous phase was extracted with [ET20.] The combined organic extracts were dried [(NA2SO4),] filtered and concentrated to give the title compound (13.4g, 74.3%). 1H NMR [(400MHZ,] [CDC13)] 5.27 (2H, s), 7.04 [(1H,] d, J=8.8Hz), 7.20 (3H, m's excess), 7.50 (1H, dd, J=2.8Hz, J=9. [OHZ),] 7.81 (1H, d, J=2.8Hz), 10.44 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 40h; | [6- {2- [5-TRIFLUOROMETHYL-2- (HYDROXY)-PHENYL]-5-METHYL-PYRROL-1-YL}-PICOLINIC ACID] (0. [1 OU,] 0. [28MOL),] 2, 3-difluorobenzyl bromide (0. 072ml, 0. [56MMOL)] and K2CO3 (0.85g, 0. 61mmol) were heated in DMF (1. [2MUT)] at [60C] for 16 hours. Further 2, 3-difluorobenzyl bromide (0. 072ml, 0. [56MMOL)] was added and heating continued for a further 24 hours. The mixture was cooled, diluted with [CH2CI2 (5ML)] and shaken with water (1ml). The organics were separated using a phase separator column with a [NA2SO4] cartridge attached and concentrated. The residue was purified by chromatography on silica gel, with iso-hexane/ EtOAc (15%) as eluant, to give the title compound (40mg, 24%). LC/MS t=4.21 min [MH+] 615. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; water; for 1h; | The subtitle product of Example 1 step i) [(5.] [0G)] was dissolved in ethanol [(100ML),] 1M aqueous sodium hydroxide (27. [4ML)] added followed by <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (5.7g). The mixture was stirred for 1h, the volatiles removed under reduced pressure and the residue purified by column chromatography (5% methanol/DCM) to yield the subtitle product as a white solid. Yield 4.3g. MS APCI (+ve) 328 [[M+H] +] [1H NMR No.(DMSO) ] 7.41-7. 28 (2H, [M),] 7.15 (1H, [M),] 6.86-6. 69 (1H, [M),] 5.10-4. 93 (1H, [M),] 4.71 [(1H,] t), 4.41 (2H, s), 3.40 [(1H,] [M),] 3.34-3. 23 (2H, [M),] 1.07 (3H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; at 70℃; for 24h; | Example 77: 1-[1-(4-Chlorophenylsulfonyl)-5-(methylsulfonyl)pentyl]-2,3-difluorobenzene To dimethoxyethane (5 ml) were added sodium 4-chlorobenzenesulfinate (45 mg, 0.227 mmol) and <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (29 mul, 0.227 mmol).. The resulting mixture was stirred at 70C for 24 hours.. After cooling at room temperature, the solvent was concentrated under reduced pressure.. ethyl acetate was added to the residue and from the mixture, the insoluble matter was filtered off.. The filtrate was concentrated under reduced pressure.. The residue was subjected to chromatography on a silica gel column.. The fraction obtained from the ether elude was concentrated under reduced pressure.. A toluene (10 ml) solution of the residue, the 4-(methylsulfonyl)-1-butanol (71 mg, 0.454 mmol) obtained in Referential Example 3 and cyanomethylenetri-n-butylphosphorane (110 mg, 0.454 mmol) was heated under reflux for 15 hours under an argon atmosphere.. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.. The residue was subjected to flash chromatography on a silica gel column.. The fraction obtained from the 55% ethyl acetate/hexane elude was concentrated under reduced pressure to give the title compound (37 mg, 37%) as a white solid.. The solid was washed with hexane-ether and filtered, whereby the title compound was obtained as a white powder. Melting point: 141-143C. IR (ATR) nu: 2948, 2867, 1625, 1575, 1484, 1396, 1317, 1272, 1230, 1199, 1149, 1124, 1085, 1012, 966, 935, 894, 808, 761, 717, 659, 628, 584, 547, 518, 472, 443 cm-1.1H-NMR (400MHz, CDCl3) delta: 1.37-1.60(2H,m), 1.81-1.96(2H,m), 2.11-2.25(1H,m), 2.45-2.57(1H,m), 2.88(3H,s), 2.96(2H,t,J=7.9Hz), 4.53(1H,dd,J=11.1,4.0Hz), 7.10-7.19(2H,m), 7.22-7.33(1H,m), 7.39-7.44(2H,m), 7.49-7.54 (2H,m). MS (m/z): 437(M++H). Element Analysis for C18H19ClF2O4S2 Calculated: C 49.48%; H 4.38%; Cl 8.11%; F 8.70%; S 14.68%. Found: C 49.38%; H 4.34%; Cl 8.13%; F 8.60%; S 14.56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,3-Difluorobenzyl bromide (0.95g) was added to an aliquot of the reaction solution of step iv) [(2ML)] containing the subtitle product of step iv) and the reaction stirred for 2h. The reaction was partitioned between EtOAc [(20ML)] and brine [(20ML).] The aqueous was extracted with EtOAc (2 x [20ML)] and the organics [CONCENTRATED IN VACUO.] The residue was purified by column chromatography (30% then 40% [ETOAC/ISO-HEXANE)] to afford the subtitle product as an oil that was diluted in acetonitrile [(5ML)] and 2M hydrochloric acid [(5ML)] and was stirred overnight before removal of the volatiles in vacuo. The crude material was purified by reverse phase HPLC (gradient 95% to 20% 0. 02M ammonium hydroxide/acetonitrile) to yield the title compound as a white solid. Yield: 0.17g. MS APCI (+ve) 476 [[M+H] +] [IH NMR A (DMSO) 10. 57 (1H,] bs), 7.40 [(1H,] bt), 7.32 (2H, m), 7.15 [(1H,] m), 5.90 [(1H,] s), 4.71 [(1H,] bs), 4.39 (2H, t), 4.02 [(1H,] bs), 3.60 (4H, t), 3.40 [(1H,] m), 3.30 [(1H,] m), 3.18 (4H, bs), 1.06 (3H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,3-Difluorobenzyl bromide (2.65g) was added to an aliquot of the reaction solution of step v) (12. [6ML)] containing the subtitle product of step v) and the reaction stirred for lh. The reaction was partitioned between EtOAc [(20ML)] and [HA0] [(20ML),] the organics were recovered, dried [(MGS04)] and concentrated in vacuo. The residue was purified by column chromatography (650: 350: 1 [ISO-HEXANE/ETOAC/ACOH)] to afford the subtitle compound as an oil that was diluted in trifluoroacetic acid [(2ML)] and was stirred for [12MIN] before quenching the reaction by the addition of 1M sodium hydroxide solution to pH >10. The aqueous was washed with Et20 before saturated ammonium chloride solution was added to acidify the aqueous to pH 4 followed by extracting with EtOAc (3 x [20ML).] The EtOAc extracts were combined, dried [(MGS04)] and concentrated in vacuo. The crude material was purified by reverse phase HPLC (gradient 95% to 20% 0.02M ammonium hydroxide/ acetonitrile) to yield the title compound as a white solid. Yield: 0.52g. MS APCI (+ve) 460 [M+H] [+] [IH] NMR [8] [(CDC13)] 7.25-7. 20 [(1H,] [M),] 7.08-6. 97 (2H, [M),] 5.95 [(1H,] s), 4.98 [(1H,] d), 4.34 (2H, s), 4.15-4. 01 [(1H,] [M),] 3.73-3. 69 (1H, [M),] 3.60-3. 55 [(1H,] [M),] 3.39 (4H, t), 1.93-1. 90 (4H, [M),] 1.21 (3H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In methanol; at 20℃; for 1h; | To a solution of potassium hydroxide powder (7.72 g) in methanol (250 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (10.9 g) followed by <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (22.5 g). The reaction mixture was stirred for one hour at room temperature then poured into water (500 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropanol and diethyl ether, to give the subtitled compound as a pale brown solid (15.0 g). MS (APCI) 427 (M+H, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | A solution of 31.8 mg (0.11 mmol) OF 3- [ (1-CYCLOPENTYL-3-ETHYLINDAZOL)-6-YL]-LH-- pyrazole in 1 mL of DMF was added to a flask containing 12.9 mg (0.32 mmol) of NaH (60% in mineral oil) and 1 mL of DMF. This was stirred at room temperature for 3 hours. Then, a solution of 43 I1L (0.33 mmol) of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in 1 mL of DMF was added and the reaction was stirred at room temperature overnight. The mixture was poured into a mixture of 10 ML of water and 10 mL of ethyl acetate. The organic layer was washed with 2 x 10 mL of water and 1 x 10 mL of brine. The organic layer was then dried over NA2SO4, filtered and the solvent was removed under reduced pressure. Purification via column chromatography over 4 g of silica using 5% ethyl acetate in hexanes to 10% ethyl acetate in hexanes gradient over 10 minutes to give 24 mg (0.06 mmol, 52% YIELD) of 3- [ (L-CYCLOPENTYL-3-ETHYLINDAZOL)-6-YL]-1- (2, 3- DIFLUOROBENZYL)-LH-PYRAZOLE as a clear OIL.. 1H-NMR (CDC13) 8 7.84 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.15-7. 04 (m, 3H), 6.68 (s, 1H), 5. 48 (s, 2H), 4.99 (p, J = 7.6 Hz, 1H), 3.01 (q, J = 7.4 Hz, 2H), 2.12 (s, 4H), 1.98 (s, 2H), 1.75- 1.72 (m, 2H), 1.40 (t, 7 : 4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 3- [4-METHOXY-3- (3R) TETRAHYDROFURANYLOXYPHENYL]-LH-PYRAZOLE (243 mg, 0.96 mmol) was dissolved in DMF (8 mL) at room temperature and treated with sodium hydride (75 mg, 1. 86MMOL) with stirring for 3 hours. The reaction mixture was treated with a solution of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (0.35 mL, 2.79 mmol) in DMF (1 mL) and stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water three times and brine once. The organic layer was dried over sodium sulfate and concentrated to an oil which was purified on a column of silica gel using a hexane/ethyl acetate gradient. Tubes containing the compound were pooled and evaporated under vacuum to afford 327mg (90%) of 1- (2, 3-difluorobenzyl)-3- [4- METHOXY-3-(3R)-TETRAHYDROFURANYLOXYPHENYL]-LH-PYRAZOLE as a colorless oil. MS [M+H] = 387 ; 1H NMR (CDC13,300 MHz) 8 2.23 (m, 2H), 3.8-4. 1 (M, 4H), 3.92 (s, 3H), 5.1 (m, 1H), 5.4 (s, 2H), 6.5 (s, 1H), 6.9 (M, 2H), 6.95-7. 11 (m, 2H), 7. 3 (m, 2H), 7.45 (s, LH). A minor product consisting of 1- (2, 3-DIFLUOROBENZYL)-5- [4-METHOXY-3- (3R)- TETRAHYDROFURANYLOXY-PHENYL]-LH-PYRAZOLE was also formed, which can be separated and- isolated by preparative HPLC (see, e. g. , Example 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Sodium hydride (20 mg, 0.5 mmol)was added, under an atmosphere of nitrogen at room temperature, to a mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-2- pyrrolidone (110 mg, 0.4 mmol) and 110 muL of 15-crown-5 in 2 mL of N, N- dimethylformamide. After 3 hours, the mixture was cooled to O0C and 2,3- difluorobenzyl bromide (166 mg, 0.8 mmol) in 2 mL of tetrahydrofuran was added. The resulting mixture was allowed to stir at room temperature for 6 hours. 100 mL of ethyl acetate was added, followed by the addition of 100 mL of ice cold water. After standard aqueous work up, the crude product was purified by flash column chromatography (ethyl acetate/hexane 2:1) to afford 112 mg (70%) of l-(2,3-difluorobenzyl)-4-(3- cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NuMR (300 MHz, CDCl3) delta 7.18- 6.98 (m, 3H), 6.79 (d, J= 8.1 Hz, IH), 6.90 (d, J= 8.1 Hz, IH), 6.68 (s, IH) 4.71-4.69 (m, IH), 4.60 (s, 2H), 3.81 (s, 3H), 3.68 (t, J= 9.0 Hz, IH), 3.66-3.54 (m, IH), 3.29 (dd, J= 9.6, 7.2 Hz, IH), 2.84 (dd, J= 16.8, 9.0 Hz, IH), 2.57 (dd, J= 16.8, 8.4 Hz, IH), 2.00-1.75 (b, 6H), 1.70-1.52 (b, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In DMF (N,N-dimethyl-formamide); for 6h; | EXAMPLE 7 2-{4-[(2,3-difluorobenzyl)oxy]phenyl}-N-[1-(2-pyrrolidin-1-ylethyl)-1H-indazol-4-yl]-acetamide A mixture of 2-(4-hydroxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-yl]-acetamide (45.0 mg, 0.124 mmol), 1-bromomethyl-2,3-difluoro-benzene (38.0 mg, 0.185 mmol), Cs2CO3 (60.0 mg, 0.184 mmol) in 2 mL of DMF was shaken for 6 hours after which the mixture was concentrated under reduced pressure. The residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.61 (m, 4H), 2.44 (m, 4H), 2.86 (t, 2H, J=6.78), 3.72 (s, 2H), 4.47 (t, 2H, J=6.78), 5.18 (s, 2H), 7.00 (m, 2H), 7.19-7.72 (m, 8H), 8.26 (s, 1H), 10.16 (s, 1H); MS (DCI/NH3) m/z 491 [M+H]+. | |
With caesium carbonate; In DMF (N,N-dimethyl-formamide); for 6h; | Example 7; 2-{4-[(2,3-difluorobenzyl)oxy]phenyl}-N-[1-(2-pyrrolidin-1-ylethyl)-1H-indazol-4-yl]acetamide; A mixture of 2-(4-hydroxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-yl]-acetamide (45.0 mg, 0.124 mmol), 1-bromomethyl-2,3-difluoro-benzene (38.0 mg, 0.185 mmol), Cs2CO3 (60.0 mg, 0.184 mmol) in 2 mL of DMF was shaken for 6 hours after which the mixture was concentrated under reduced pressure. The residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.61 (m, 4H), 2.44 (m, 4H), 2.86 (t, 2H, J=6.78), 3.72 (s, 2H), 4.47 (t, 2H, J=6.78), 5.18 (s, 2H), 7.00 (m, 2H), 7.19-7.72 (m, 8H), 8.26 (s, 1H), 10.16 (s, 1H); MS (DCI/NH3) m/z 491 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 3.91667h; | Example 1; 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1- methvlethvnaminolthiazolor4, 5-dlDvrimidin-2 (3H) -one; (a) 6-amino-2-[[(2, 3-diiluorophenyl) methyl] thio]-4-pyrimidinol; To a stirred suspension of 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (67.7g) in a mixture of water (920ml) and tetrahydrofuran (300ml) was added aqueous sodium hydroxide solution (46-48% w/w; 24mol) followed by water (40ml). The resulting hazy, pale yellow solution was cooled to 20 C before adding 2, 3-difluorobenzyl bromide (83. 0g) uniformly over 25 minutes, to yield a white precipitate. The mixture was stirred at ambient temperature for 3.5 hours, the product collected and washed twice with a mixture of water (68ml) and tetrahydrofuran (24ml), to afford the title compound as a white solid (101. 89g). 1H NMR: 8 (DMSO-d6) 11.45 (1H, br. s), 7.44 (1H, t), 7.34 (1H, m), 7.15 (1H, m), 6.58 (2H, br. s), 5.01 (1H, s), 4.39 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
i) (2, 3-difluorophenyl) methanethiol; Thiourea (6.7 g) was added to a stirred solution of 2, 3-difluorobenzylbromide (18.3 g), in ethanol (300 ml). The reaction mixture was heated at reflux for 2.5 hours and then evaporated, treated with 2N sodium hydroxide solution (440 ml) and heated at reflux for a further 4 hours and left stirring at ambient temperature overnight. The resulting mixture was ice-cooled, acidified to pH 6 using concentrated aqueous hydrochloric acid solution and then extracted with diethyl ether. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated to give (2,3- difluorophenyl) methanethiol (8.0 g). NMR Spectrum: (CDC13) 8 1.90 (t, 1H), 3.78 (d, 2H), 7.06 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With zinc;palladium diacetate; triphenylphosphine; In diethylene glycol dimethyl ether; at 0 - 20℃; for 1h;Product distribution / selectivity; | A benzyl compound of the present invention was prepared in the same manner as in Example 1 except for using 2,3-difluoro benzyl bromid as a starting material. Yield and selectivity of the objective benzyl ketone are shown in table 1.MS [m/z] 153 (Pr-Cyc-CO+), 127 (F2-Aryl-CH2+), 125 (Pr-Cyc+), 83 (C6H11+), 69 (C5H9+), 55 (C4H7+), 41 (C3H5+) |
Yield | Reaction Conditions | Operation in experiment |
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73% | With zinc;palladium diacetate; triphenylphosphine; In diethylene glycol dimethyl ether; at 0℃; for 5h; | 1.0 mmol of Pd-(II)-acetate, 2.0 mmol of triphenylphosphine and 88 mmol of zinc were placed in a reaction vessel. The contents were evacuated with a membrane pump, and were purged with N2. The procedure was repeated two times in order to remove oxygen completely. 80 ml of ethyleneglycol dimethylether, which was dried by refluxing in the presence of sodium and benzophenone until color changed to blue, and then distilled, was added. Then, the reaction vessel was cooled to 0C. A mixture of 65 mmol of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong>, and 55 mmol of 4'-propylcyclohexyl-4-cyclohexylcarbonyl chloride in 60 ml ethyleneglycol dimethyl-ether was slowly added, so that the temperature of the mixture was 0C. The mixture was stirred at the same temperature for 5 hours, then warmed to room temperature. Then, the mixture was quenched with diluted HCl and water and extracted into diethylether three times, then the layers were filtrated to remove excess zinc powder before separation of the layers. The organic layers were collected, dried (Na2SO4), some of the solvent removed and the product crystallized by cooling to -20C. The product was filtered off and washed with a little of cold diethylether and dried. The washings are collected, some of the solvent removed and again crystallized to obtain the objective benzyl ketone compound of the present invention. Yield and selectivity of the objective benzyl ketone were shown in table1.MS [m/z] (TMS deriv./TMS-enolether) 434 (M++TMS), 307 (C23H32F2+), 255 (C20H35O2+), 73 (TMS+, base peak)1H-NMR (300 MHz, CDCl3, delta.[ppm]): 0.80-1.20 (m, 20H, CH/CH2); 0.87 (t, 3H, 3JHH=7.1 Hz, CH3); 1.20-1.44 (m, 5H, CH2/CH); 1.64-1.90 (m, 8H, CH/CH2); 1.92-2.00 (m, 2H CH2); 2.37-2.46 (m, 1H, CH); 2.79 (d, 2H, 4JHF=1.46 Hz, CH2); 6.86-6.94 (m, 1H, CHar); 6.98-7.11 (m, 2H, CHar)13C-NMR (75.4 MHz, CDCl3, delta.[ppm]): 14.4 (CH3); 20.3 (CH2); 28.8 (2xCH2); 29.3 (2xCH2); 30.0 (2xCH2); 33.6 (2xCH2); 37.5 (CH2); 39.8 (CH); 40.5 (CH2, t, J=2.23 Hz); 42.6 (CH); 43.2 (CH); 51.0 (CH); 116.0 (CHar, d, J=17.1); 123.9 (CHar, dd); 124.3 (Car, d); 126.4 (CHar, dd); 148.1 (CFar, dd, 1JCF=120.4 Hz, 2JCF=13.2 Hz); 151.3 (CFar, dd, 1JCF=121.1 Hz, 2JCF=13.1 Hz); 209.3 (C=O)19F-NMR (282.2 MHz, CDCl3, delta.[ppm]): -149.6 (m); -153.5 (m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Aqueous sodium hydroxide solution (46-48% w/w; 24mL) followed by H2O (4OmL) was added to a stirred suspension of 4-arnino-6-hydroxy-2-mercaptopyrirnidirie monohydrate (67.7g) in a mixture of water (92OmL) and THF (30OmL). The resulting hazy, pale yellow solution was cooled to 200C before adding <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (83.Og) uniformly over 25 mins, to yield a white precipitate. The mixture was stirred at ambient temperature for 3.5 h, the product collected and washed twice with a mixture of H2O (68mL) and THF (24mL), to afford the subtitle compound as a white solid (101.89g). 1H NMR: delta (DMSO-d6) 4.39 (2H, s), 5.01 (IH, s), 6.58 (2H, br.s), 7.15 (IH, m), 7.34 (IH, m), 7.44 (IH, t), 11.45 (IH, br.s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | (b) 4-amino-2-[[(2,3-difluorophenyl)methyl]thio]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, To a suspension of 60% sodium hydride (125 mg) in dry DMF (5 ml) was added a solution of the product from example 3, step (a) (0.57 g) in DMF (10 ml). The mixture was allowed to stir for 30 mins. To the solution was added <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (0.39 ml) and the mixture stirred for 2 hours. Poured into water and the crude product extracted into ethyl acetate. Chromatography on silica eluding with 10% ethyl acetate/dichloromethane afforded the title compound (0.35 g). MS: APCI 309 (M+H) 1H NMR: delta (DMSO) 10.85 (1H, s), 7.45-10 (3H, m), 6.78 (2H, m), 4.36 (2H, s), 3.24 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | (b) 2-[[(2,3-Difluorophenyl)methyl]thio]-4,6-dihydroxy-5-pyrimidineacetic Acid, Ethyl Ester To a suspension of 60% sodium hydride in oil (1.37 g) in dry DMF (10 ml) was added a solution of the product from example 1, step (a) (7.9 g) in dry DMF (30 ml). After the addition the mixture was stirred at room temperature for 1 hour. To the solution was added <strong>[113211-94-2]2,3-difluorobenzylbromide</strong> (4.45 ml) and the mixture allowed to stir overnight. The mixture was poured into water (200 ml) and the product collected by filtration to give the subtitle compound (8.1 g). MS: APCI 355 (M-H), 357 (M+H) 1H NMR: delta (DMSO) 7.50-7.18 (3H, m), 4.47 (2H, s), 4.04 (2H, q), 3.97 (2H, s), 1.67 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In methanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; acetone; | g 2,4-bis[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone Sodium (3.96 g) was dissolved in methanol (150 ml), 5,6-diamino-2,4-pyrimidinedithiol (15 g) was added, then <strong>[113211-94-2]2,3-difluorobenzylbromide</strong> (30.9 g) slowly added and the reaction mixture was stirred at room temperature under nitrogen for 10 min. Ethyl glyoxalate (1 5 ml) was added followed by more sodium (2.5 g) and the reaction was left for a further 20 min. The reaction was then quenched with acetic acid (10 ml) and poured on to water (600 ml) with stirring. The resulting precipitate was filtered through celite and washed with water. The filtrate was discarded and the solid was washed through the celite using acetone. The solution was then evaporated to dryness and purified by silica gel column chromatography using 10% ethyl acetate in DCM to yield the sub-titled compound as a cream solid (8 g). MS: APCI (+ve) 465 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; | a 2-[[(2,3-Difluorophenyl)methyl]thio]-4,6-pyrimidinediamine 4,6-diamino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100 ml) at room temperature under an atmosphere of nitrogen. Potassium tert-butoxide (1 M in THF, 48.3 ml) was added followed by 2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and ammonium chloride. The organic phase was washed with ammonium chloride (3*) and brine, then dried over magnesium sulphate and evaporated to give the subtitled product as a white solid (12.2 g) MS: APCI (+ve) 269 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; | a 2-[[(2,3-Difluorophenyl)methyl]thio]-4,6-pyrimidinediamine 4,6-diarnino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100 ml) at room temperature under an atmosphere of nitrogen. Potassium tert-butoxide (1M in THF, 48.3 ml) was added followed by 2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and ammonium chloride. The organic phase was washed with ammonium chloride (3*) and brine, then dried over magnesium sulphate and evaporated to give the subtitled product as a white solid (12.2 g) MS: ADCI (+ve) 269 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
on carrying out the operation according to the procedure of Example 10 starting with 4.1 g of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> and 4.1 g of sodium methanesulfinate, 4 g of (2,3-difluoro-benzyl) methyl sulfone are obtained in the form of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.0% | With ammonium chloride; magnesium; | Example 57 1-(2,3-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride 0.41 g (16.8 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.47 g (16.8 mmole) of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.23 g (14.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.13 g of crude base (102% of theory) were obtained, from which 1.67 g of 1-(2,3-difluorobenzyl)-2-(dimethylamino-phenylmethyl)cyclohexanol, hydrochloride (30.0% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,O-bis-(trimethylsilyl)-acetamide; In 1,1-dichloroethane; | Step A 1-(2,6-Difluorobenzyl)-5-carbethoxyuracil 5-Carbethoxyuracil (5 g, 27.15 mmol) and N,O-bis(trimethylsilyl)acetamide (13.4 mL, 2 eq) in dichloroethane(35 mL) were heated at 80 C. for 2 hours. Difluorobenzyl bromide (8.4 g, 1.5 eq) was added and the reaction mixture was heated at 80 C. for 16 hours. The reaction was quenched with methanol and partitioned between methylene chloride and sodium bicarbonate solution. The organic layer was washed with brine, dried and concentrated in vacuo and the residue was triturated with ether to give compound 1 as a white solid (3.26 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | EXAMPLE 30 Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2,3-difluorophenyl)methyl]-1-piperazinyl]-cyclohexanol This compound was prepared from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinyl)cyclohexanol and <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in a manner similar to example 21. The crude product was recrystallized from isopropyl acetate to give a white solid (88.5%, mp: 159-160 C.). Calc'd. For C24 H28 F2 N2 O3.0.1H2 O: C, 66.68%; H, 6.58%; N, 6.48%. Found: 66.46%; H, 6.51%; N, 6.28%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 53 Synthesis of 1-(2,3-difluorobenzyl)indole-4-carbaldehyde STR60 The same procedures used in Example 1 were repeated except for using 580 mg of indole-4-carbaldehyde and 911 mg of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in place of the benzyl bromide used in Example 1 to give 841 mg of 1-(2,3-difluorobenzyl)indole-4-carbaldehyde as pale brown crystals. The yield thereof was found to be 76%. NMR (CDCl3) delta: 5.46 (2H,s), 6.59 (1H,dd,J=7.0 Hz, 7.0 Hz), 6.8~7.2 (2H,m), 7.2~7.4 (3H,m), 7.59 (1H,d,J=8.1 Hz), 7.65 (1H,dd,J=7.3 Hz, 1.1 Hz), 10.25 (1H,s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In water; acetonitrile; at 40℃; for 18h; | i)2-[(2,3-Difluorobenzyl)thio]pyrimidine-4,6-diol; To a slurry of 2-mercaptopyrimidine-4,6-diol (55.6g) in water (735ml) was added sodiumacetate (47.4g) with stirring forming a complete solution over 20 minutes. A solution of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (80g) in acetonitrile (73.5ml) was then added dropwise over 15minutes and the resulting mixture heated at 40C with stirring for 18h. After cooling toambient temperature the resulting precipitate was then filtered and washed with H^O (1L)before drying in vacua at 100C to afford the subtitle compound as a cream solid.Yield: 101.5g.JH NMR: 8 (DMSO) 7.74 (1H, s), 7.39 - 7.32 (2H, m), 7.21 - 7.15 (1H, m), 4.48 (2H, s). | |
A solution of potassium hydroxide (5.67g) was added dropwise to a suspension of 2- [MERCAPTOPYRIMIDINE-4,] 6-diol (14.56g) in DMF [(78ML)] and [H20] [(39ML)] and the mixture stirred for 30min. A solution of 2, 3-difluorobenzyl bromide (20.86g) in THF [(16ML)] was then added dropwise and the mixture stirred for 18h. The reaction was then cooled to [0C] and the precipitate was filtered and washed with H20 (4 x 100ml) before drying in vacuo to afford the subtitle compound as a cream solid. Yield: 22.4g. ['H NMR 8 (DMSO)] 7.74 [(1H,] s), 7.39-7. 32 (2H, m), 7.21-7. 15 [(1H,] m), 4.48 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;Product distribution / selectivity; | The title compound was prepared and isolated as a solid (55 mg, 30% yield) in analogy with Example 43B (the reaction was performed in a Radley carousel) using 2,3-difluor- benyl bromide as the alkylating agent instead of benzylbromide. 1R NMR (400 MHz, DMSOd6) delta ppm 1.18 (s, 9 H) 2.65 (s, 3 H) 3.85 (s, 2 H) 6.78 - 6.86 (m, 2 H) 6.99 - 7.06 (m, 1 H) 7.19 - 7.29 (m, 1 H); Mass Spectrum (ESI): M-H+ 365. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In ice-water; ethanol; ethyl acetate; | (a) 1.32 g of sodium are dissolved in 150 ml of ethanol. 6.72 g of <strong>[23785-21-9]imidazole-4-carboxylic acid ethyl ester</strong> and 9.9 g of 2,3-difluorobenzyl bromide are added and the whole is heated under reflux for 3.5 hours while stirring. The reaction mixture is concentrated by evaporation under reduced pressure and the residue is stirred with ice-water and extracted by shaking three times with 50 ml of ethyl acetate each time. The extracts are combined, washed with water and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-(2,3-difluorobenzyl)-imidazole-4(5)-carboxylic acid ethyl ester is obtained in the form of an isomeric mixture which can be separated into the components, 1-(2,3-difluorobenzyl)-<strong>[23785-21-9]imidazole-4-carboxylic acid ethyl ester</strong>, m.p. 95°-100° (from toluene/hexane) and 1-(2,3-difluorobenzyl)-imidazole-5-carboxylic acid ethyl ester (oil), by chromatography on silica gel as the stationary phase and toluene/isopropanol (9:1) as the mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dimethyl sulfoxide; | b) 2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one Potassium t-butoxide solution (0.45mL of 1M in tetrahydrofuran) was added to a stirred solution of the product of step a) (0.09g) and <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in dimethyl sulphoxide (2mL). After stirring for 3 days, the reaction mixture was poured onto water. The title compound was obtained. Yield 0.065g. m.p. 310-313C MS: APCI(+ve) 327 (M+1) 1H NMR: delta (DMSO) 4.48 (s,2H), 7.18-7.45 (m,3H), 8.20 (s,2H) and 12.62 (s,1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.04 g (70%) | With potassium carbonate; In N,N-dimethyl-formamide; | A. 9-[(2,3-Difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,3-difluorotoluene (1.01 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 73 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 1.04 g (70%) of the 9-[(2,3-difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) delta 7.4 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.15-6.9 (m, 5H), 6.35 (t, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm-1) 1719 and 1650. MS (ES) m/e 368, 370. Elemental Analyses for C21H17NO3F2: Calculated: C, 68.29; H, 4.64; N, 3.79. Found: C, 68.50; H, 4.62; N, 3.94. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; for 72h; | Potassium t-butoxide solution (0.45ml of 1M solution in tetrahydrofuran) was added to a stirred solution of 2-amino-5,6-dihydro-5-thioxo-thiazolo[4,5-d]pyrimidin-7(4H)-one (0.09g) [Cited: Indian J. Chem., Sect. B (1989), 28B(11), 964-5.] and <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in dimethyl sulphoxide (2ml). After stirring for 3 days, the reaction mixture was poured onto water to give and the subtitle compound, isolated by filtration. MS (APCI) 327 (M+H+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6-mercapto-1H-pyrazolo[3,4-d]pyrimidin-4-ol (5g) was added to a suspension of 60% NaH (1.42g) in dry DMF (50ml) and left to stir for 1hour. 2,3-Difluorobenzyl bromide was then added slowly and the reaction mixture stirred for 1-2 hours.. The resulting mixture was poured in to water whereupon the sub-titled product precipitated out.. It was then filtered, washed with water and dried over P2O5 at 50C for 10hrs (4.46g). MS: APCI (+ve) 295 (M+1)1H NMR: delta (DMSO) 4.52 (s, 2H), 7.14-7.21 (m, 1H), 7.32-7.43 (m, 2H), 8.11 (br s, 1H), 12.34 (br s, 1H), 13.64 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 65℃; for 3.5h; | b) 2-(2,3-Difluorobenzyl)-isothiourea hydrobromide: A suspension of 40.33 g of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> and 17.8 g of thiourea in 240 ml ofEtOH is heated at 65 for 3.5 hours. The reaction mixture obtained is cooled and solvent is evaporated. The evaporation residue obtained is triturated with ether. A solid obtained is filtered, washed with Et2O and dried.2-(2,3-Difluorobenzyl)-isothiourea hydrobromide is obtained; Intermediate A: 2-(2,3-Difluoro-benzyl)-isothiourea hydrobromide53.3 g of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> and 23.5 g of thiourea are suspended in 310 ml ofEtOH and the reaction mixture obtained is heated to 65 for 3.5 hours. After cooling to RT, solvent is evaporated and the residue obtained is triturated with EtOAc. The solid obtained is collected by filtration and dried. The title compound is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; water; at 20 - 60℃; | Step 1 : 2-(2,3-Difluoro-benzylsulfanyl)-pyrimidine-4,6-diol <n="32"/>To a suspension of 15.2 g of 2-thiobarbituric acid in 85 ml of EtOH and 85 ml of H2O are added a solution of 4.2 g of NaOH in 25 ml of EtOH and 25 ml of H2O. 21.74 g of Difluorobenzyl bromide are added dropwise and the reaction mixture obtained is heated at 60 for 2 hours and then stirred at RT overnight. A precipitate formed is collected by filtration, washed with 200 ml of H2O and 20 ml of iso-propanol and dried. The title compound is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With C13H30N4PPol; In N,N-dimethyl acetamide; at 70℃; | A 20 mL scintillation vial was charged with PS-BEMP resin (157 mg, 0.35 mmol.). To the resin was then added Example 1A (88 mg, 0.29 mmol) dissolved in DMA (1.0 mL). To the resin-suspension was then added <strong>[113211-94-2]1-(bromomethyl)-2,3-difluorobenzene</strong> (72 mg, 0.35 mmol) dissolved in DMA (0.9 mL). The vial was capped and heated at 70 C. overnight on a heater-shaker. The vial was removed from the heater-shaker and the resin-suspension was filtered out. The reaction mixture was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 41 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) delta ppm 1.40-1.47 (m, 6H) 3.52-3.56 (m, 2H) 3.76-3.80 (m, 3H) 4.87-4.97 (m, 2H) 7.10 (d, 1H) 7.18-7.28 (m, 2H) 7.35-7.43 (m, 1H) 7.47 (dd, 1H) 7.62 (d, 1H); MS (ESI) 425 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | 4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (7. [1G)] was added portion wise to a stirred suspension of 60% sodium hydride (2.4g) [IN DRY N, N-DIMETHYLFORMAMIDE (70ML).] After 1 hour a solution of 2, 3-Difluorobenzyl bromide [(LOG)] in [DRY N, N DIMETHYLFORMAMIDE] [(LOML)] was added. Stirred over weekend at room temperature. Poured on to ice/water and the precipitate was collected by filtration to give 9.6g of product. 81 % yield. MS [(APCI)] (+ve) 270 (M+H, 94%) | |
An aqueous solution of potassium hydroxide (4. [61G)] in H20 [(25ML)] was added to a suspension of 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate [(11.] 26g) in DMF [(50ML).] Stirring was maintained for 30min during which time a solution was obtained, before the dropwise addition of a solution of 2, 3-difluorobenzyl bromide (14.46g) in THF (lOml). After stirring for 20h the slurry was diluted with H20 [(500ML)] and stirred for 30min before filtering. The filtrate was washed with [H20] (4 x 100ml) and iso-hexane (4 x 100ml) before drying in vacuo for 24h to afford the subtitle compound as a white solid. Yield: 14. 1g. MS APCI (+ve) 309 [[M+CH3COO-] +] | ||
4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (7. 1 g) was added portion wise to a stirred suspension of 60% sodium hydride (2.4g) [IN DRY N, N DIMETHYLFORMAMIDE (70M1).] After 1 hour a solution of 2, 3-Difluorobenzyl bromide [(L OG) IN DRY N, N-DIMETHYLFORMAMIDE] [(LOML)] was added. The solution was stirred over weekend at room temperature, poured on to ice/water and the precipitate was collected by filtration to give 9.6g of the subtitle compound. MS [(APCI)] (+ve) 270 (M+H, 94%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In N,N-dimethyl-formamide; at 120℃; for 2.5h; | Phthalimide potassium salt (3.20 g, 17.3 mmol) was added to the solution of 2,3- difluorobenzylbromide (2.0 mL, 15.7 mmol) in DMF (anhydrous, 15 mL) with several portions. The mixture was stirred at 12O0C for 2.5 hours and cooled to room temperature. The reaction was quenched with ice and extracted with ethyl acetate (200 mL). Organic phase was washed with brine (6 x 30 mL) and dried by anhydrous sodium sulfate. The solution was filtered and concentrated and the residue was purified with silica gel column. 151D-88 (4.36 g, 92% yield) was afforded. 1H NMR (CDCl3): delta 7.78-7.76 (m, IH), 7.66-7.64 (m, 2H), 7.02- 6.92 (m, 3H), 4.86 (s, 2H). APCI-MS m/z: 274.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5-33 4-(N-(2,3-difluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and <strong>[113211-94-2]1-(bromomethyl)-2,3-difluorobenzene</strong>. 1H NMR (400 MHz, DMSO-d6): delta, ppm: 3.30 (s, 3H), 4.29 (s, 2H), 4.32 (s, 2H), 6.87 (d, 2H, J=8 Hz), 7.02-7.20 (m, 5H), 7.95 (d, 2H, J=8 Hz). 8.05 (d, 2H, J=8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2-butoxy-lambda/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 17) (200mg, 0.625mmole) in TetaF (3mL) was added Cs2CO3 (300mg 0.923mmol and <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (0.2mL, 1.57mmol). The reaction was heated at 6O0C for 2h, diluted with water (2mL). The mixture was extracted with ethyl acetate (2 X 5mL). The organic extracts were dried over MgSO4 and evaporated. The residue was purified by reverse phase chromatography [5-95% acetonitrile, water, 0.1 % TFA] to obtain the product as a TFA salt. 1eta NMR (300 MHz, DMSO-D6) delta ppm 0.89 (t, J=7.3 Hz, 3 H) 1.30 - 1.44 (m, 2 H) 1.57 - 1.70 (m, 2 H) 3.38 - 3.54 (m, 3 H) 3.61 - 3.72 (m, 3 H) 3.96 - 4.02 (m, 5 H) 4.23 (t, J=6.6 Hz, 2 H) 5.40 (s, 2 H) 7.14 - 7.28 (m, 1 H) 7.30 - 7.44 (m, 1 H) 7.59 - 7.73 (m, J=9.6 Hz, 1 H) 8.11 (s, 1 H) MS (ESP) m/z= 445 [M-H"] for C22H28F2N6O2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To hexane washed sodium hydride (7.45g, 60% in oil) under argon, was added N- methylpyrrolidone (NMP) (270ml) and the mixture cooled in an ice-salt bath. 2, 2-Dimethyl-1, 3-dioxane-4,6-dione (26.8g) was added portionwise over 20min keeping the temperature between 5-10C. Effervescence was noted during the addition. The mixture was stirred at room temperature for lh and phenylisothiocyanate (25.2g) added over 15min. The mixture was stirred at room temperature for 2. 5h and cooled to 15C in a cold water bath. 2,3-Difluorobenzyl bromide (38. 6g) was added over 10min and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1.2L) and water. The organic layer was washed with further water and then brine and dried over MgS04. The solvent was removed under reduced pressure and the residue triturated with 40-60C petrol and the solid collected by filtration. Crystallisation from methyl t. butyl ether gave the title compound as a pale yellow solid (51.4g). 1H-NMR (d6- DMSO) 8 1.64 (6H, s), 4.16 (2H, d), 7.1-7. 25 (2H, m), 7.25-7. 5 (6H, m), 12.12 (1H, br s); MS (APCI-) found (M-1) = 404; C2oHl7F2N04S requires 405. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Butyllithium (4. 76ml, 2. 5M in hexanes, 1 equiv) was added dropwise to a solution of 4-chloroquinaldine (2. 4ml, 1 equiv) in tetrahydrofuran (30ml) at- 78C and the reaction mixture stirred for 15min. 2,3-Difluorobenzyl bromide (1. 82ml, 1.2 equiv) was added dropwise and stirring was continued for lh. After warming to room temperature the solution was diluted with water and ethyl acetate and the organic phase dried and evaporated. Chromatography (silica, 10: 1 petrol/ethyl acetate) gave the title compound as a white solid (3. 16g).'H-NMR (CDCl3) 6 3.23 (4H, m), 6.89-6. 99 (3H, m), 7.33 (1H, s), 7.59 (1H, m), 7.74 (1H, m), 8.04 (1H, d), 8.15 (1H, d); MS (APCI+) found (M+1) = 304; Cl7Hl235ClF2N requires 303. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | To an ice cooled stirring suspension of sodium hydride (1.96 g, 49.1 mmol, 60% dispersion in oil) in dry tetrahydrofuran (100 ml) was added dropwise under an argon atmosphere tert-butylacetoacetate (7.4 ml, 44.6 mmol). After a further 15 min, n-butyllithium (18. 7 ml, 46.8 mmol, 2. 5M in hexanes) was added dropwise maintaining the reaction temperature below 10C. 2,3-Difluorobenzyl bromide (11.08 g, 53.5 mmol) was added dropwise 20 min later, then the mixture allowed to warm to ambient temperature. After a further 15 min the reaction mixture was poured onto a mixture of water (150 ml) and glacial acetic acid (10 ml), extracted 3 times with ethyl acetate and the combined extracts washed with saturated sodium hydrogen carbonate then brine, dried (MgS04) and evaporated to a yellow oil. Chromatography (fine silica, ethyl acetate-light petrol) gave the title compound as a yellow oil, yield 9.05 g (71%). 1H NMR (CDCl3) 8 1.45 (9H, s), 2.84-2. 91 (2H, m), 2.95-3. 00 (2H, m), 3.35 (2H, s), 6.92-7. 04 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Powdered KOH (0.50 g, 8.91 mmol) was added to a solution of methyl 2,3, 4,9- TETRAHYDRO-LH-CARBAZOLE-8-CARBOXYLATE (Example 28) (400 mg, 1.744 mmol) in DMSO (5 ml) and the yellow mixture stirred for 5 min at ambient temperature before 2,3- difluorobenzyl bromide (500 mul, 3.5 mmol) was added. The mixture was quenched with sat. NH4C1 after 20 min and extracted with ET2O. The combined ether layers were washed with water and brine and evaporated. The product was purified by flash chromatography using 2% EtOAc in hexanes. Yield 509 mg (82%); colorless oil. IH NMR (400 MHz, CDC13) 8 1.84-1. 93 (M, 4 H), 2.59-2. 60 (M, 2 H), 2.73-2. 76 (M, 2 H), 3.70 (s, 2 H), 5.59 (s, 2 H), 6.07-6. 10 (M, 1 H), 6.80-6. 81 (M, 1 H), 6.97-7. 11 (M, 3 H), 7.54 (dd, J=8, 1 Hz, 1 H), 7.66 (dd, J=8,1 Hz, 1 H). 13C NMR (100 MHz, CDC13) 8 20. 85, 22.27, 22.86, 23.23, 42.14, 42.17, 42.20, 42.23, 52.00, 111. 30, 115. 52, 115. 68, 115. 92, 118.29, 122.08, 122.13, 124.00, 124.05, 124.07, 124.12, 124.32, 128.59, 130.15, 133.46, 137.87, 168.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 4- (3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (110 mg, 0.4 mmol) in 2 ml OF N, N-DIMETHYLFORMAMIDE and 110 1LL of 15-crown-5 is treated with sodium hydride (20 mg, 0.5 mmol) under nitrogen at ambient temperature. After 3 hours, the mixture is cooled to 0C and treated with 2, 3-difluorobenzyl bromide (166 mg, 0.8 mmol) in 2 ml of tetrahydrofuran. The resulting mixture is allowed to stir at ambient temperature for 6 hours. 100 ml of ethyl acetate is added, followed by 100 ml of ice cold water. After usual aqueous work up, the crude product is purified by flash column chromatography (ethyl acetate/hexane 2: 1) to give 112 mg (70%) of 1- (2, 3-DIFLUOROBENZYL)-4- (3- CYCLOPENTYLOXY-4-METHOXYPHENYL) -2-PYRROLIDONE : 1H NMR (300 MHZ, CDCL3) 8 7.18- 6.98 (M, 3H), 6.79 (d, J= 8. 1 Hz, 1H), 6.90 (d, J= 8.1 Hz, 1H), 6. 68 (s, 1H) 4.71-4. 69 (M, 1H), 4.60 (s, 2H), 3.81 (s, 3H), 3.68 (t, J= 9.0 Hz, 1H), 3.66-3. 54 (M, 1H), 3.29 (dd, J= 9.6, 7.2 Hz, 1H), 2.84 (dd, J= 16. 8,9. 0 Hz, 1H), 2.57 (dd, J= 16.8, 8.4 Hz, 1H), 2.00-1. 75 (b, 6H), 1.70-1. 52 (b, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Example 4A; 1-(2,3-Difluorobenzyl)-<strong>[956010-88-1]1H-pyrazolo[3,4-b]pyridine-3-carbonitrile</strong>; Cesium carbonate (244 mg, 0.75 mmol) is added to a solution of <strong>[956010-88-1]1H-pyrazolo[3,4-b]pyridine-3-carbonitrile</strong> (90 mg, 0.62 mmol; Example 1A, stage b) and 2,3-difluorobenzyl bromide (142 mg, 0.69 mmol) in 1.8 ml of DMF under argon and at room temperature, and the reaction mixture is stirred for 16 h. For working up, 1.5 ml of 1 N hydrochloric acid and 3 ml of DMSO are added. The entire resulting solution is purified directly by preparative HPLC (method 5). 127 mg (75% of theory) of the title compound are obtained.1H-NMR (400 MHz, DMSO-d6): delta=5.93 (s, 2H), 7.12-7.23 (m, 2H), 7.43 (dd, 1H), 7.55 (dd, 1H), 8.51 (dd, 1H), 8.81 (dd, 1H).LC/MS (method 2): Rt=2.29 min.; MS (ESIpos): m/z=271 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | A solution of 31.8 mg (0.11 mmol) of 3-[(l-cyclopentyl-3-ethylindazol)-6-yl]-lH- pyrazole in 1 niL of DMF was added to a flask containing 12.9 mg (0.32 mmol) of NaH (60% in mineral oil) and 1 mL of DMF. This was stirred at room temperature for 3 hours. Then, a solution of 43 muL (0.33 mmol) of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in 1 mL of DMF was added and the reaction was stirred at room temperature overnight. The mixture was poured into a mixture of 10 mL of water and 10 mL of ethyl acetate. The organic layer was washed with 2 x 10 mL of water and 1 x 10 mL of brine. The organic layer was then dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification via column chromatography over 4 g of silica using 5% ethyl acetate in hexanes to 10% ethyl acetate in hexanes gradient over 10 minutes to give 24 mg (0.06 mmol, 52% yield) of 3-[(l-cyclopentyl-3-ethylindazol)-6-yl]-l-(2,3- difluorobenzyl)-lH-pyrazole as a clear oil. 1H-NMR (CDCl3) delta 7.84 (s, IH), 7.69 (d, J = 8.3 Hz, IH), 7.54 (d, J = 8.3 Hz, IH), 7.50 (s, IH), 7.15-7.04 (m, 3H), 6.68 (s, IH), 5.48 (s, 2H), 4.99 (p, J = 7.6 Hz, IH), 3.01 (q, J = 7.4 Hz, 2H), 2.12 (s, 4H), 1.98 (s, 2H), 1.75- 1.72 (m, 2H), 1.40 (t, 7.4 Hz, 3H). | |
52% | Example 9 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(2,3-difluorobenzyl)-1H-pyrazole A solution of 31.8 mg (0.11 mmol) of 3-[(1-cyclopentyl-3-ethylindazol)-6-yl]-1H-pyrazole in 1 mL of DMF was added to a flask containing 12.9 mg (0.32 mmol) of NaH (60% in mineral oil) and 1 mL of DMF. This was stirred at room temperature for 3 hours. Then, a solution of 43 muL (0.33 mmol) of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in 1 mL of DMF was added and the reaction was stirred at room temperature overnight. The mixture was poured into a mixture of 10 mL of water and 10 mL of ethyl acetate. The organic layer washed with 2×10 mL of water and 1×10 mL of brine. The organic layer was then dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification via column chromatography over 4 g of silica using 5% ethyl acetate in hexanes to 10% ethyl acetate in hexanes gradient over 10 minutes to give 24 mg (0.06 mmol, 52% yield) of 3-[(1-cyclopentyl-3-ethylindazol)-6-yl]-1-(2,3-difluorobenzyl)-1H-pyrazole as a clear oil. 1H-NMR (CDCl3) delta 7.84 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.50 (s, 1H), 7.15-7.04 (m, 3H), 6.68 (s, 1H), 5.48 (s, 2H), 4.99 (p, J=7.6 Hz, 1H), 3.01 (q, J=7.4 Hz, 2H), 2.12 (s, 4H), 1.98 (s, 2H), 1.75-1.72 (m, 2H), 1.40 (t, 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 3-[4-Methoxy-3-(3R)tetrahydrofuranyloxyphenyl]-lH-pyrazole (243 mg, 0.96 mmol) was dissolved in DMF (8 mL) at room temperature and treated with sodium hydride (75 mg, 1.86mmol) with stirring for 3 hours. The reaction mixture was treated with a solution of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> (0.35 mL, 2.79 mmol) in DMF ( 1 mL) and stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water three times and brine once. The organic layer was dried over sodium sulfate and concentrated to an oil which was purified on a column of silica gel using a hexane/ethyl acetate gradient. Tubes containing the compound were pooled and evaporated under vacuum to afford 327mg (90%) of l-(2,3-difluorobenzyl)-3-[4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole as a colorless oil. MS [M+H]= 387; 1H NMR (CDCl3, 300 MHz) delta 2.23 (m,2H), 3.8-4.1 (m, 4H), 3.92 (s, 3H), 5.1 (m, IH), 5.4 (s, 2H), 6.5 (s, IH), 6.9 (m,2H), 6.95-7.11 (m,2H), 7.3 (m,2H), 7.45 (s,lH). A minor product consisting of l-(2,3-difluorobenzyl)-5-[4-methoxy-3-(3R)- tetrahydrofuranyloxy-phenyl]-lH-pyrazole was also formed, which can be separated and isolated by preparative HPLC (see, e.g., Example 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | a) 2-(tert-Butyl-dimethyl-silanyl)-4-(2,3-difluoro-benzyl)-imidazole- 1-sulfonic acid dimethylamideTo a solution of 4.2 g (14.5 mmol) 2-(tert-butyl-dimethyl-silanyl)-imidazole- 1-sulfonic acid dimethylamide in 50 ml tetrahydrofuran were added 10.9 ml (17.4 mmol) of a 1.6M butyl lithium solution in hexane at -750C. After stirring for 20 min 3.6 g (17.4 mmol) 2,3- difluorobenzylbromide was added at -750C and the mixture was allowed to reach room temperature overnight. The mixture was partitioned between water and ethyl acetate, re- extracted with ethyl acetate and the combined organic layers are dried over MgSO4, <n="42"/>filtered and evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate = 4:1) to yield 3.Og (49%) of 2-(tert-butyl-dimethyl-silanyl)-4-(2,3- difluoro-benzyl)-imidazole-l-sulfonic acid dimethylamide as a light yellow solid; MS (ISP): 416.1 ((M+H)+ ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With caesium carbonate; In N,N-dimethyl-formamide; at 50.0℃; for 0.25h; | Step b : 5-Chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine Reaction of <strong>[40966-87-8]2-amino-5-chloropyridin-3-ol</strong> with 1.1 equivalents of 2,3-difluorobenzyl bromide and 2.2 equivalents of caesium carbonate in DMF (15 min at 50° C.), aqueous work-up, extraction with ethyl acetate and subsequent chromatography of the organic residue (gradient: cyclohexane/ethyl acetate 8:1 to pure ethyl acetate) to give 5-chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine; 10percent yield. LC-MS (Method 1): Rt=0.94 min MS (ESpos): m/z=271.0/273.0 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
650 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1.0h; | Preparation Example 1 (0258) A suspension of 500 mg of <strong>[173530-73-9]ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate</strong>, 0.35 ml of 2,3-difluorobenzylbromide, and 650 mg of potassium carbonate in 8.6 ml of N,N-dimethylformamide (DMF) was stirred at 60 C. for 1 hour. The reaction mixture was left to be cooled to room temperature and water was then added thereto. The resulting solid was collected by filtration and washed with water. The solid was washed with diisopropyl ether to obtain 650 mg of ethyl 8-[(2,3-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate. |
Tags: 113211-94-2 synthesis path| 113211-94-2 SDS| 113211-94-2 COA| 113211-94-2 purity| 113211-94-2 application| 113211-94-2 NMR| 113211-94-2 COA| 113211-94-2 structure
[ 446-48-0 ]
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[ 456-41-7 ]
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1-(Bromomethyl)-2-fluorobenzene
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[ 23915-07-3 ]
1-(Bromomethyl)-2,4-difluorobenzene
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[ 220141-72-0 ]
5-(Bromomethyl)-1,2,3-trifluorobenzene
Similarity: 0.83
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H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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