Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 19064-24-5 | MDL No. : | MFCD00192035 |
Formula : | C6H3F2NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SSNCMIDZGFCTST-UHFFFAOYSA-N |
M.W : | 159.09 | Pubchem ID : | 87922 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 35.18 |
TPSA : | 45.82 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.89 cm/s |
Log Po/w (iLOGP) : | 1.13 |
Log Po/w (XLOGP3) : | 1.95 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 1.73 |
Log Po/w (SILICOS-IT) : | 0.55 |
Consensus Log Po/w : | 1.62 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.39 |
Solubility : | 0.644 mg/ml ; 0.00405 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.54 |
Solubility : | 0.462 mg/ml ; 0.0029 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.33 |
Solubility : | 0.753 mg/ml ; 0.00473 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.64 |
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 |
---|---|---|
61% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 18.5 h; | A solution of potassium TERT-BUTOXIDE (1.23 g, 11 mmol) in 25 mL of anhydrous DMSO was stirred at room temperature for 30 minutes and treated with 1, 3-difluoro-2-nitrobenzene (1.59 g, 10 mmol). After 18 hours, the mixture was diluted with 150 mL of 1 N aqueous sulfuric acid and extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 50 mL of trifluoroacetic acid. After 30 minutes at room temperature, the mixture was concentrated in vacuo, treated with 50 mL of 1 N aqueous sodium hydroxide, and extracted with three 30 mL portions of diethyl ether. The aqueous layer was acidified with 1 N aqueous sulfuric acid and extracted with two 50 mL portions of dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 g of 3-fluoro-2-nitrophenol as orange oil (61percent yield). An solution of 3-fluoro-2-nitrophenol (1.13 g, 7.2 mmol) and pyridine (0.65 mL, 8 mmol) in 15 mL of anhydrous dichloromethane was cooled in an ice bath and treated with a solution of triflic anhydride (1.33 mL, 7.9 mmol) in 3 mL of anhydrous dichloromethane. After 4 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with two 30 mL portions of saturated aqueous sodium bicarbonate, two 30 mL portions of 1 N aqueous sulfuric acid, and two 30 mL portions of water, dried over sodium sulfate, filtered, and concentrated in VACUA TAO give 2 g of the title product as a light brown oil (96percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium perborate In acetic acid at 80 - 90℃; for 1 h; | Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80° C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10percent THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52percent). MS (ESI) m/z 160 ([M+H]+). |
52% | With sodium perborate In acetic acid at 80 - 90℃; for 1 h; | Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80° C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10percent THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52percent). MS (ESI) m/z 160 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | for 3 h; Heating / reflux | To a solution of 2,6-difluoronitrobenzene (5 g, 32 mmol) in methanol (50 mL) was added potassium hydroxide (1.8 g, 32.5 mmol), and the mixture was heated to reflux for 3 hr. Water was added, and the mixture was extracted with dichloromethane. The organic layer was separated, dried, filtered, and evaporated to yield 5.1 g (95percent) of 1-fluoro-3-methoxy-2-nitrobenzene, 1e. MS m/z (MH+) 172. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium perborate; In acetic acid; at 80 - 90℃; for 1h; | Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80 C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10% THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m/z 160 ([M+H]+). |
52% | With sodium perborate; In acetic acid; at 80 - 90℃; for 1h; | Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80 C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10% THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m/z 160 ([M+H]+). |
With sodium perborate; acetic acid; at 80 - 90℃; for 1h; | 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to a stirred suspension of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) at 80 C. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethylether and the combined organic layers were washed with a dilute solution of sodium bicarbonate, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (Hexane:THF, 9:1) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) which was used without further examination. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 18.5h; | A solution of potassium TERT-BUTOXIDE (1.23 g, 11 mmol) in 25 mL of anhydrous DMSO was stirred at room temperature for 30 minutes and treated with 1, 3-difluoro-2-nitrobenzene (1.59 g, 10 mmol). After 18 hours, the mixture was diluted with 150 mL of 1 N aqueous sulfuric acid and extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 50 mL of trifluoroacetic acid. After 30 minutes at room temperature, the mixture was concentrated in vacuo, treated with 50 mL of 1 N aqueous sodium hydroxide, and extracted with three 30 mL portions of diethyl ether. The aqueous layer was acidified with 1 N aqueous sulfuric acid and extracted with two 50 mL portions of dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 g of 3-fluoro-2-nitrophenol as orange oil (61percent yield). An solution of 3-fluoro-2-nitrophenol (1.13 g, 7.2 mmol) and pyridine (0.65 mL, 8 mmol) in 15 mL of anhydrous dichloromethane was cooled in an ice bath and treated with a solution of triflic anhydride (1.33 mL, 7.9 mmol) in 3 mL of anhydrous dichloromethane. After 4 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with two 30 mL portions of saturated aqueous sodium bicarbonate, two 30 mL portions of 1 N aqueous sulfuric acid, and two 30 mL portions of water, dried over sodium sulfate, filtered, and concentrated in VACUA TAO give 2 g of the title product as a light brown oil (96percent yield). |
To a mixture of potassium tert-butoxide (7.76 g) in dimethyl sulfoxide (150 ml) was added 1,3-difluoro-2-nitrobenzene (10 g), and stirred at room temperature for 18 h. The reaction mixture was diluted with 1N hydrochloric acid, and extracted with 1,1'-oxydiethane. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in trifluoroacetic acid (100 ml), and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was diluted with 1N sodium hydroxide, washed with 1,1'-oxydiethane. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with 1,1'-oxydiethane. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give the title compound (7.59 g) as crude. The crude compound was used to next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 0 - 20℃; for 15h; | To a 0 C solution of l,3-difluoro-2-nitrobenzene (100 g, 0.63 mol) in MeOH (1.3L) was slowly added a solution of MeONa (0.69 mol, in MeOH, freshly prepared from 15.9 g of sodium metal and 200 mL of MeOH). The resulting reaction was allowed to stir for about 15 hours at room temperature, then the reaction mixture was concentrated and diluted with EtOAc. The organic phase was washed sequentially with water and brine, dried over Na2S04, then filtered and concentrated in vacuo to provide l-fluoro-3-methoxy-2-nitrobenzene (98 g, yield: 91.4%), which was used without further purification. 1H-NMR (CDC13, 400 MHz) delta 7.38-7.44 (m, 1H), 6.72-6.88 (m, 2H), 3.95 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; | Compound 44.1 (230 mg, 1.53 mmol) and 2,6-difluronitrobenzene (252 mg, 1.58 mmol) were dissolved in 8 ml dry DMF and 1.6 ml of 1 M potassium t-butoxide in THF was added. The reaction was stirred at room temperature overnight, then flooded with 50 ml EtOAC, rinsed with 2 x 25 ml saturated sodium bicarbonate, 25 ml brine, dried over sodium sulfate, filtered, and evaporated partially to dryness. The solid was resuspended in 5 ml dry THF and filtered to yield 58 mg of yellow solid. The remaining solution was purified by column chromatography using a 15.5 x 2.5 cm column and eluting with 95 : 5 DCM : methanol to yield an additional 43 mg of off-white solid. Both of these were combined to yield a total of 92 mg (0.318 mmol, 21%). ES (+) MS m/e = 290 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; boron tribromide; In methanol; n-heptane; dichloromethane; water; | i 2-Amino-3-fluorophenol To a stirred solution of 2,6-difluoronitrobenzene (1100 mg, 6.9 mmol) in dry methanol (20 ml) was added a solution of sodium (180 mg, 7.8 mmol) in dry methanol (8 ml). The solution was stirred overnight. After concentration, water was added and the solution was extracted with ether, dried over MgSO4, filtered and concentrated to a yellow residue (870 mg.5.08 mmol). To the solution of the yellow residue in dichloromethane (10 ml) boron tribromide (1M in dichloromethane, 10 ml) was added and stirred at room temperature overnight. Water was then added and the solution stirred for further 60 min. The organic phase was separated and the water phase was extracted with ether. The combined organic phase were dried over MgSO4, filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and neutralised with 6M HCl and extracted with ether, dried over MgSO4 and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with EtOAc:Heptane: 1:3 as eluant to give the product (720 mg, 4.6 mmol) which was directly suspended with palladium-charcoal (140 mg) in water-ethanol (30 ml). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In DMF (N,N-dimethyl-formamide); for 18h; | To a 0.1 M DMF solution of 1, 3-difluoro-2-nitrobenzene was added Et3N (2 equivalents) followed by an amine (1 equivalent), e. g. morpholine. The mixture was stirred for 18 hours and then diluted with water and extracted with ethyl acetate. LC/MS M/Z 227.2 (MH+), RT2. 522 minutes. The combined organic layers were dried over MGS04, filtered, and concentrated. Ammonia was condensed into a pressure vessel containing the crude product. The pressure vessel was sealed and heated to 100 C (over 400 psi). After 72 hours, the pressure vessel was allowed to cool and the ammonia was evaporated to provide a reddish solid. The nitroamine was reduced as in Method 1 to provide the crude product which was used without FURTHERPURIFICATION. LC/MS M/Z194. 1 (MH+), RT1. 199 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 24h; | To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+). |
54% | Step 2: To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+). | |
54% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h; | To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine; In water; | 3-Fluoro-1,2-diaminobenzene is obtained as an oily amorphous product by hydrogenation of 3-fluoro-2-nitrophenyl hydrazine (prepared by reaction of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> with hydrazine hydrate) using hydrogen and 10% palladium on carbon catalyst in methanol at room temperature and atmospheric pressure. | |
With hydrazine hydrate; In tetrahydrofuran; di-isopropyl ether; | a 3-Fluoro-2-nitro-phenylhydrazine A mixture of 0.01 M <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> and 0.01 M hydrazine hydrate (99% strength) in 30 ml of THF was stirred overnight at RT (exothermic reaction) and the residue was brought to crystallization after distilling off the solvent by treating with diisopropyl ether. Crystalline substance, m.p.: 93-95 C. MS (Cl+, M+H+): 172.1 | |
With hydrazine hydrate; In tetrahydrofuran; at 20℃; | INTERMEDIATE: (5-Fluoro-3-methyl-quinoxalin-2-yl)-hydrazine (lib). l,3-Difluoro-2- nitrobenzene (5 g) was dissolved in THF (180 mL) and treated with hydrazine hydrate (1.57 g) at ambient temperature overnight. The volatiles were removed in vacuo to afford (3-fluoro-2-nitro- phenyl)-hydrazine (3.0 g). 2.0 g of this material was dissolved in methanol (15 mL). 10% Palladium on charcoal (0.3 g) was added and the mixture was treated with hydrogen (1 bar) for 12h at ambient temperature. The catalyst was filtered off, and the filtrate was concentrated in vacuo to afford 3- fluoro-benzene-l,2-diamine (1.4 g). This material was dissolved in methanol, ethyl pyruvate (1.2 g) was added and the mixture was stirred at ambient temperature for 2h. The precipitated solid was filtered off to afford an approximate 1 :1 mixture of 5-fluoro-3 -methyl- lH-quinoxalin-2-one and 8- fluoro-3-methyl-lH-quinoxalin-2-one (1.6 g in total). 1.2 g of this mixture was refluxed in phosphoryl chloride (20 mL) for 2h. The volatiles were removed in vacuo. The residue was basified with aq NaHCOs and extracted with DCM. The organic layer was dried over Na2SO i, filtered, and concentrated in vacuo to afford an approximate 1 :1 mixture of 2-chloro-5-fluoro-3-methyl- quinoxaline and 3-chloro-5-fluoro-2-methyl-quinoxaline (1.1 g in total). This mixture was reacted with hydrazine hydrate (10 mL) at 110 C for 2h. The precipitated solid was filtered off to afford an approximate 1 :1 mixture of lib and its regioisomer (8-fluoro-3-methyl-quinoxalin-2-yl)-hydrazine (0.4 g in total). This mixture was applied in the next step. |
With hydrazine hydrate; In tetrahydrofuran; at 20℃; | INTERMEDIATE (8-fluoro-3-methyl-quinoxalin-2-yl)-hydrazine (lie). l,3-Difluoro-2- nitrobenzene (5 g) was dissolved in THF (180 mL) and treated with hydrazine hydrate (1.57 g) at ambient temperature overnight. The volatiles were removed in vacuo to afford (3-fluoro-2-nitro- phenyl)-hydrazine (3 g). 2 g of this material was dissolved in methanol (15 mL). 10% Palladium on charcoal (0.3 g) was added and the mixture was treated with hydrogen (1 bar) for 12h at ambient temperature. The catalyst was filtered off, and the filtrate was concentrated in vacuo to afford 3-fluoro-benzene-l,2-diamine (1.4 g). This material was dissolved in methanol, ethyl pyruvate (1.2 g) was added and the mixture was stirred at ambient temperature for 2h. The precipitated solid was filtered off to afford an approximate 1:1 mixture of 5-fluoro-3-methyl-lH- quinoxalin-2-one and 8-fluoro-3-methyl-lH-quinoxalin-2-one (1.6 g in total). 1.2g of this mixture was refluxed in phosphoryl chloride (20 rriL) for 2h. The volatiles were removed in vacuo. The residue was basified with aq NaHCC>3 and extracted with DCM. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford an approximate 1:1 mixture of 2-chloro-5- fluoro-3-methyl-quinoxaline and 3-chloro-5-fluoro-2-methyl-quinoxaline (1.1 g in total). This mixture was reacted with hydrazine hydrate (10 rriL) at 110 C for 2h. The precipitated solid was filtered off to afford an approximate 1:1 mixture of lie and its regioisomer (5-fiuoro-3-methyl- quinoxalin-2-yl)-hydrazine (0.4 g in total). This mixture was applied in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of NaH (60% dispersion in mineral oil, 4.0 g, 100 mmol) in THF (200 mL) was added dropwise 4-methoxybenzyl alcohol (12 mL, 96.2 mmol) with stirring at 0 C. The mixture was stirred at room temperature for 15 min and <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (15.26 g, 100 mmol, Aldrich) was then added. The resulting red solution was heated to 65 C. with stirring and the progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in MeOH, evaporated onto SiO2 and eluted through a SiO2 plug with 25% EtOAc/hexane. Evaporation of the solvent under reduced pressure gave the crude product as a yellow amorphous solid, which was used in the next step without additional purification. MS (ESI, neg. ion.) m/z: 274.1 [M-1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | To a solution of methylsyringate (1.0 g; 4.72 mmol) in DMF (50 mL) were added Cs2CO3 (1.85 g; 5.66 mmol) and 2,6-difluoronitrobezene (0.5 mL; 4.72 mmol). The reaction mixture was heated to 80 C. for 16 h. The mixture was cooled and poured into water, then extracted with EtOAc (3×). The organic layers were combined and washed with water (1×) then brine (1×). The organic phase was dried (MgSO4), filtered and concentrated in vacuo giving 1.64 g (99%) of 1-1 which was used in the next reaction without further purification. |
99% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | Preparation of Intermediate 1-5; Step l; [0051] To a solution of methylsyringate (1.Og; 4.72 mmol) in DMF (50 niL) were added Cs2CO3 (1.85 g; 5.66 mmol) and 2,6-difluoronitrobezene (0.5 niL; 4.72 mmol). The reaction mixture was heated to 80 0C for 16 h. The mixture was cooled and poured into water, then extracted with EtOAc (3X). The organic layers were combined and washed with water (IX) then brine (IX). The organic phase was dried (MgSO4), filtered and concentrated in vacuo giving 1.64 g (99%) of 1-1 which was used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | To a solution of phenol 7-3 (0.39 g; 1.66 mmol) in DMF (16 mL) were added <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.18 mL; 1.66 mmol) and Cs2CO3 (541 mg; 1.66 mmol). The reaction mixture was heated to 80 C. for 16 h. The mixture was cooled, diluted with EtOAc (100 mL) and washed with water (1×50 mL) and brine (1×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 5:1 hexanes:EtOAc) giving 210 mg of 7-4 (34%). |
34% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | [0082] To a solution of phenol 7-3 (0.39 g; 1.66 mmol) in DMF (16 mL) were added <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.18 mL; 1.66 mmol) and Cs2CO3 (541 mg; 1.66 mmol). The reaction mixture was heated to 80 C for 16 h. The mixture was cooled, diluted with EtOAc (100 mL) and washed with water (1 X 50 mL) and brine (1 X 50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 5:1 hexanes:EtOAc) giving 210 mg of 7-4 (34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | To a solution of 8-2 (123 mg; 0.522 mmol) in DMF (5 mL) were added <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (55 μL; 0.522 mmol) and Cs2CO3 (170 mg; 0.522 mmol). The reaction mixture was heated to 80 IC for 16 h. The mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3×). The organic phases were combined and washed with water (1×) and brine (1×). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, elution with 3:1 EtOAc:hexanes) giving 91 mg (47% for 2 steps) of 8-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 18h; | A mixture of 18-2 (0.24 g, 0.9 mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.24 g, 1.5 mmol), and K2CO3 (0.28 g, 2 mmol) was stirred at 80 C. in 10 ml DMF for 18 hours. The mixture was then filtered and concentrated in vacuo to yield 18-3 (0.27 g, 0.67 mmol, 74%) as an oil which was used without further purification |
74% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;Product distribution / selectivity; | [00163] A mixture of 18-2 (0.24g, 0.9mtnol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.24g, 1.5mmol), and K2CO3 (0.28g, 2mmol) was stirred at 80C in 10ml DMF for 18 hours. The mixture was then filtered and concentrated in vacuo to yield 18-3 (0.27g, 0.67mmol, 74%) as an oil which was used without further purification. |
70% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 5h; | A solution of 11-4 (0.32 g, 1.2 mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.23 g, 1.4 mmol), and Cs2CO3 (0.86 g, 2.6 mmol) in 10 ml DMF was stirred at 60 C. for 5 hours. The mixture was cooled to room temp, filtered and concentrated in vacuo. The residue was chromatagraphed on a silica gel column, eluting with 5% MeOH/DCM to yield 11-5 as an oil (0.34 g, 0.84 mmol, 70%). |
70% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5h;Product distribution / selectivity; | Step 5; [00111] A solution of 11-4 (0.32g, 1.2mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.23g, 1.4mmo), and Cs2CO3 (0.86g, 2.6mrnol) in 10ml DMF was stirred at 6O0C for 5 hours. The mixture was cooled to room temp, filtered and concentrated in vacuo. EPO <DP n="56"/>The residue was chromatagraphed on a silica gel column, eluting with 5% MeOH/DCM to yield 11-5 as an oil (0.34g, 0.84mmol, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | 17-2 (187 mg; 0.407 mmol) was debenzylated by hydrogenation in MeOH in the presence of a catalytic amount of 10% Pd/C (1 small scoop) under 1 atm of H2 (g) (balloon) for 3 d. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude phenol was taken up in DMF (4 mL) and 2,6 difluoronitrobenzene (43 μL; 0.407 mmol) and Cs2CO3 (133 mg; 0.407 mmol) were added. The mixture was heated to 80 C. for 16 h. After cooling to room temperature the mixture was filtered through a pad of Celite, concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 3:1 hexanes:EtOAc) to afford 139 mg (67% for 2 steps) of 17-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium azide; In dimethyl sulfoxide; at 20℃; for 18h; | Preparation of 1-Azido-3-fluoro-2-nitrobenzene To a stirred solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.0 g, 12.6 mmol) in DMSO (6.0 mL) at room temperature, was added sodium azide (0.82 g; 12.6 mmol). After 18 hours the solution was poured into 200 mL of ice-cold water. The precipitate, 1-azido-3-fluoro-2-nitrobenzene, was collected and dried under vacuum (2.26 g; 99%); 1H NMR (CDCl3, 400 MHz) δ 7.00 (t, J=8.8 Hz, 1H); 7.07 (d, J=8.35 Hz, 1H); 7.47 (dt, J=8.35, 5.68 Hz, 1H). MS (ES) m/z 182.1 |
98% | With sodium azide; In dimethyl sulfoxide; | To a solution of 1 ,3-difluoro-2-nitrobenzene (4.80 g, 30.2 mmol) in DMSO (35 mL) was added sodium azide (2.26 g, 34.7 mmol). After stirring overnight, the reaction was diluted with EtOAc (150 mL), washed with water (2 X 150 mL), dried over Na2S04, filtered and concentrated to give the title compound (5.40 g, 98%) as a pale yellow solid. 1H NMR (CDCI3) δ 6.99-7.1 1 (m, 2 H), 7.46-7.52 (m, 1 H). |
96% | With sodium azide; In dimethyl sulfoxide; for 2h; | A solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (10 g, 63 mMol) in DMSO (70 mL) was treated with sodium azide (4.5 g, 69 mMol) and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (500 mL), washed (water, 3*500 mL; brine, 100 mL), dried (MgSO4) and evaporated under reduced pressure to leave the product as a tan oil that crystallized on standing (11 g, 96%). A solution of 1-(2-hydroxyethyl)piperazine (5.7 g, 43 mMol) in THF (40 mL) under nitrogen was cooled in an ice bath and treated with sodium hydride (60% mineral oil dispersion, 1.7 g, 43 mMol) portion wise over 15 mins. The mixture stirred an additional hour and was then cooled to -78 C. A solution of 2-azido-6-fluoronitrobenzene (6.0 g, 33 mMol) in THF (40 mL) was added to the reaction mixture drop wise over 15 mins. The mixture stirred an additional 2 h while warming to 20 C. then diluted with 1N HCl (50 mL) and water (500 mL). The mixture was washed with ethyl acetate (2*500 mL) and the combined organic layers were further extracted with 1 N HCl (2*100 mL) and water (200 mL). All aqueous layers were combined, neutralized (solid sodium carbonate) and extracted with chloroform (3*200 mL). The extract was dried (MgSO4) and evaporated to leave the product as an oil (7.1 g, 24 mMol, 74%). It was dissolved in DCM (100 mL), treated with di-(t-butyl)dicarbonate and stirred for 30 mins. Aminomethylpolystyrene (1% DVB, 3.2 mMol/g, 7.5 g, 24 mMol) was added and stirring continued for 1 h. The resin was filtered, washed (DCM, 2*25 mL) and the combined organic washes were evaporated under reduced pressure to leave the product as a brown gum (9.4 g, 100%). LC/MS (method A); Rt=1.11 mins, purity=85%, [M+H]+=393. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 0.5h; | To a solution of piperazine-1-carboxylic acid tert-butyl ester (0.204 g, 1.1 mmol) in 1 mL dimethylsulfoxide was added potassium carbonate (0.303 g, 2.2 mmol) followed by 1,3-difluoro-2-nitro-benzene (0.159 g, 1 mmol). The solution was stirred 30 minutes at room temperature, and was then diluted with 50 mL ethyl ether. The organic phase was washed three times with 50 mL water and once with 50 mL brine, dried over sodium sulfated, and concentrated in vacuo to give 0.314 g (0.965 mmol, 96.5%) of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. MS: 226 (M-BOC+H)+. |
83% | With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 2.5h; | To a 1L flask equipped with mechanical stirrer, <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (16.5 g, 104 mmol) was added and flask was filled with DMSO (170 mL). Then, dried K2CO3 (31.6 g, 229 mmol) and N-BOC-piperazine (21.2 g, 114 mmol) were added. The reaction mixture was heated to 40 C and stirred for 2.5h at this temperature. The reaction was poured into water (400 mL) and diluted with DCM (500 mL). Phases were separated and the organic phase was washed with water (2 x 150 mL), brine (100 mL), dried under MgSO4 and the solvent was removed in vacuo. The solid residue was dissolved in MeOH (120 mL) then water (15 mL) was added dropwise and the whole mixture was cooled to 5 C, and stored at this temperature for 2h. After this time, solid product A-2A (21.9 g) was filtered and washed with the mixture of MeOH:water (10:1, 20 mL). The filtrate was reduced to the half of its volume and stored at 5 C for 16h. Additional portion of compound A-2A (6.3 g) was filtered and combined with previously obtained solid. As a result, product A-2A was obtained as the yellow solid (28.2 g, 83% yield) with 95 % of purity, according to UPLCMS analysis (Method A). |
68% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 18h; | Example 10 4-(3-Fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester: To a solution of 1,3-difluoro-2-nitro-benzene (10 g, 62.9 mmol), ethyldiisopropylamine (27 mL, 157 mmol), in anhydrous DMSO (40 mL) was added piperazine-1-carboxylic acid tert-butyl ester (13.3 g, 69.1 mmol) and the solution stirred at room temperature, under nitrogen, for 18 h. The reaction was transferred to a separatory funnel with ethyl acetate (100 mL) and washed with distilled water (100 mL*3). The aqueous washings were combined and extracted with ethyl acetate (100 mL*2). The organic extracts were combined, washed with 1M aqueous citric acid solution (150 mL*2), saturated aqueous sodium bicarbonate solution (150 mL), brine (150 mL), decolorizing carbon and filtered. The filtrate was dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give a black liquid which solidified upon standing to give a dark yellow tinted crystalline solid (18.5 g). This material was adsorbed onto silica and purified by column chromatography, eluding with a solution of 33% ethyl acetate in hexane to afford an orange crystalline solid (13.9 g, 68%). Mass Spectrum (+ESI): 226 [M+H-Boc]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide; for 3h;Heating / reflux; | To a solution of 2,6-difluoronitrobenzene (5 g, 32 mmol) in methanol (50 mL) was added potassium hydroxide (1.8 g, 32.5 mmol), and the mixture was heated to reflux for 3 hr. Water was added, and the mixture was extracted with dichloromethane. The organic layer was separated, dried, filtered, and evaporated to yield 5.1 g (95%) of 1-fluoro-3-methoxy-2-nitrobenzene, 1e. MS m/z (MH+) 172. |
EXAMPLE 18; (2R,3R,4S,5R,6E)-3,4,5-trihydroxy-2-methoxy-N-[(3R)-6-methoxy-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-8,8-dimethylnon-6-enamide; Step 1: Preparation of 1-fluoro-3-methoxy-2-nitrobenzene (52); 252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 100 mL three-necked flask containing 10 mL of THF and 0.255 mL of MeOH. The mixture is stirred at room temperature for 1 hour, and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of THF is added. The reaction medium is left at room temperature for 16 hours. 10 mL of EtOAc are added and the resulting mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. 0.93 g of product 52 is obtained (cream-coloured solid).1H NMR (400 MHz, DMSO-d6), delta (ppm): 3.95 (s, 3H); 7.15 (broad t, J=8.0 Hz, 1H); 7.21 (broad d, J=8.0 Hz, 1H); 7.65 (dt, J=6.0 and 8.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 92 - Preparation of 2-(2-chloro-4-trifluoromethylphenoxy)-6-fluoro nitrobenzene This material was prepared in 47percent yield from 2,6-difluoronitrobenzene and <strong>[35852-58-5]2-chloro-4-trifluoromethylphenol</strong> following the general procedure outlined in Example 88. The product was isolated as an oil which was characterized by IR and 1H NMR spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a suspension of sodium hydride (1.522 g, 38.06 mmol) in anhydrous DMF (150 mL) at room temperature was added benzyl alcohol (3.44 mL, 33.3 mmol) dropwise over 10 minutes, and stirring was continued for another 10 minutes. 2,6-Difluoronitrobenzene (5.046 g, 31.72 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred for an hour, and 100 mL water and 100 mL ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with 75 mL ethyl acetate. The combined organic layers werre washed with 100 mL water and 100 mL brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (6% to 35% ethyl acetate in hexanes) to give 6.818 g (27.6 mmol, 87%) of 1-benzyloxy-3-fluoro-2-nitro-benzene as a yellow oil. MS: 248 (M+H)+. Also prepared in a similar manner using (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester in place of benzyl alcohol was [2-(3-Fluoro-2-nitro-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: 215 (M-BOC+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96 - 100% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Product distribution / selectivity; | Preparation of Intermediate 2-5; Step 1; [0056] Following the general procedure described for step 1 in example 1, 4- hydroxy-3,5-dimethyl-benzoic acid methyl ester (1.0 g, 5.55 mmol) was reacted with 2,6-difluronitrobenzene giving 1.70 g (96%) of crude 2-1 which was used in the next step without purification.; Example 14; Step 1; [00137] Following the procedure described for step 3 in example 8, 4-hydroxy- 3,5-dimethylbenzoic acid methyl ester (708 mg; 3.93 mmol) was reacted with 2,6- EPO <DP n="67"/>difluoronitrobenzene giving, after purification by FCC (silica gel; elution with 1 : 1 hexanes:EtOac), 1.3 g (100%) of 14-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | Step 3; [0089] To a solution of 8-2 (123 mg; 0.522 mmol) in DMF (5 mL) were added 2,6-difluoroitrobenzene (55 μL; 0.522 mmol) and Cs2CO3 (170 mg; 0.522 mmol). The reaction mixture was heated to 80 0C for 16 h. The mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The organic phases were combined and washed with water (IX) and brine (IX). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, elution with 3 : 1 EtOAc-hexanes) giving 91 mg (47% for 2 steps) of 8-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h; | To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry dimethylformamide (DMF -50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with dilute aqueous HCl and extracted with diethyl ether, dried (MgSO4), and concentrated in vacuo. Crystallization from hexane/ethylacetate (95/5), gave 2-(3-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (4.6 g, 54%). |
54% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h; | Step 1 To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) of dimethyl (3-fluoro-2-nitrophenyl)malonate. MS (ESI) m/z 272 [M+H]+). Step 1:; To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) of 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+). |
52% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h; | dimethyl 2-(3-fluoro-2-nitrophenyl)malonate; 1,3-Difluoro-2-nitrobenzene (2.83 g, 17.79 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (2.49 g, 18.02 mmol) was added to the mixture followed by dimethyl malonate (2.033 ml, 17.79 mmol). Mixture was warmed to 65 C. and held for 24 hours. Mixture was cooled to room temperature. Reaction was quenched with 1N hydrochloric acid. Material was extracted three times with diethyl ether and the aqueous phase was discarded. Material was washed twice with water and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Residue was crystallized with hexanes. Solids were filtered off and washed with hexanes. Title compound was obtained as yellow crystals in 52% yield. MS (M-H)-=270.1. |
21% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; | Step 1: dimethyl 2-(3-fluoro-2-nitro-phenyl)-malonate 5.40 g (38.3 mmol) potassium carbonate and 4.50 mL (38.0 mmol) dimethylmalonate were added successively to 6.00 g (37.7 mmol) <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> in 60 mL DMF and the mixture was stirred overnight at 65 C. Then the reaction mixture was cooled to RT and slowly poured onto 75 mL of 1N aqueous hydrochloric acid solution. The aqueous phase was extracted several times with EtOAc. The combined organic phases were washed with water and saturated sodium chloride solution, dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was stirred with n-hexane, suction filtered and dried. Yield: 2.18 g (21% of theoretical) ESI-MS: m/z=272 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 16h; | Step 1 To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.0 g, 6.28 mmol) and aniline (d 1.022, 1.15 mL, 12.6 mmol) in dry N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (1.40 g, 12.5 mmol) in portions. After 16 hours at room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane (2*50 mL). The combined organic layers were washed with water (1*50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford crude 3-fluoro-2-nitro-N-phenylaniline (1.15 g, 78%), which was used in the next step without further purification. |
73% | Step 1: (3-Fluoro-2-nitrophenyl)phenylamine Sodium tertbutoxide (1.2 g, 12.58 mmol) was added portionwise to a stirred solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (1 g, 6.29 mmol) and phenylamine (1.15 mL, 12.58 mmol) in a hydrous DMF (5 mL) under a nitrogen atmosphere at RT and stirring was continued for 20 h. The mixture was poured into an aqueous solution of NH4Cl and extracted with EtOAc (150 mL). The organic layer was washed with brine, then dried and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-15% EtOAc in cyclohexane) affording (3-Fluoro-2-nitrophenyl)phenylamine as a red solid (1.06 g, 73%). LCMS: RT 3.80 min. | |
With potassium fluoride; In dimethyl sulfoxide; at 95℃; for 15h; | (1) Add aniline (3.3mL, 36.2mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (3mL, 30mmol) and anhydrous potassium fluoride (1.8g, 30mmol) to 9mL of dimethyl sulfoxide and stir After the dissolution is complete, react at 95C for 15 hours; after the reaction is complete, cool the system to room temperature, then add 30mL of distilled water to the reaction system, stir until a large amount of red precipitate appears, filter the precipitate and wash with 30ml (10ml×3 times) distilled water 3 times The filtered solid is dried in a drying box to obtain intermediate product A; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; | Example 121 4-fluoro-1-(3-fluorophenyl)-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5 g, 31.4 mmol), potassium tert-butoxide (3.5 g, 31.3 mmol), and 3-fluoroaniline (3.47 g, 31.3 mmol) in anhydrous dimethylsulfoxide (20 mL) was stirred at room temperature. Upon completion, the reaction was partitioned between saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified on silica gel to give (3-fluoro-2-nitro-phenyl)-(3-fluoro-phenyl)-amine that was directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - 10℃; for 3h; | A mixture of potassium ferf-butoxide (12.3 g, 111.0 mmol) in NMP (100 ml) was cooled to -20 0C under N2. A mixture of 2, 6-difluoronitrobenzene (5.0 g, 31.43 mmol) and te/t-butylchloroacetate (7.6 ml, 53.11 mmol) in NMP (100 ml) was added slowly at -10 0C to -20 0C over 1.5 hrs. After 1.5 hrs the reaction was quenched by pouring into 2M HCI (120 ml) and ice, then heptane (300 ml) was added. The mixture was stirred for 10 minutes, separated and the aqueous extracted with heptane (2 x 400 ml). The organic layer was washed with brine twice, dried (MgSO4), filtered and washed with heptane. The solution was concentrated in vacuo and the residue purified by column chromatography (3-4% EtOAc/Heptane) to provide the title compound as an orange oil (4.34 g, 53 % yield). <n="22"/>1H NMR (300 MHz, CDCI3) δ: 7.06 (2H, d, J=8.7Hz), 3.59 (2H, s), 1.48 (9H, s). |
53% | With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - 20℃; for 1.5h;Inert atmosphere; | A mixture of potassium fe/t-butoxide (12.3 g, 111.0 mmol) in NMP (100 ml) was cooled to -20 0C under N2. A mixture of 2, 6-difluoronitrobenzene (5.0 g, 31.43 mmol) and tert- butylchloroacetate (7.6 ml, 53.11 mmol) in NMP (100 ml) was added slowly at -10 0C to - 20 0C over 1.5 hours. After 1.5 hours the reaction was quenched by pouring into 2M HCI (120 ml) and ice, then heptane (300 ml) was added. The mixture was stirred for 10 minutes, separated and the aqueous extracted with heptane (2 x 400 ml). The organic layer was washed with brine (x2), dried (MgSO4), filtered and washed with heptane. The solution was concentrated in vacuo and the residue purified by column chromatography (3-4% EtOAc/Heptane) to provide the title compound as an orange oil (4.34 g, 53 % yield). 1H NMR (300 MHz, CDCI3) δ: 7.06 (2H, d, J=8.7Hz), 3.59 (2H, s), 1.48 (9H, s). |
A mixture of potassium terf-butoxide (248g) in NMP (2000ml) was cooled under nitrogen to -200C. A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (100g) and tert- butylchloroacetate (16Og) in NMP (2000ml) was added slowly at -100C to -20C EPO <DP n="62"/>over 1.5 hours. After 30 minutes, a further portion of potassium ferf-butoxide (88g) was added. The reaction mass was quenched into 1600ml of 2M HCI and 1kg crushed ice, then 2000ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500ml). The combined hexane layers were washed with saturated brine (2 x 1000ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152g). |
With potassium tert-butylate; In N,N-dimethyl-formamide; at -35℃; for 2.5h;Inert atmosphere; | Stage 1 - tert-Butyl (3,5-difluoro-4-nitrophenyl)acetate A solution of difluoronitrobenzene (24.96 g, 157 mmol) and ter t-butyl chloroacetate (38.0 mL, 267 mmol) in anhydrous DMF (200 mL) was added dropwise over one hour to a cold (-35 C) suspension of potassium ert-butoxide (61.61 g, 549 mmol) in anhydrous DMF (200 mL) under nitrogen. The reaction mixture was stirred at -35 C for 1.5 hours, quenched with 2N HC1 (240 mL) and extracted with heptanes (4x200 mL). The combined organic extracts were washed with water (3x200 mL), brine (200 mL), dried (MgSC ), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (10 % EtOAc in heptanes) afforded a yellow oil (37.64 g). Another two batches (10.00 g and 23.54 g of difluoronitrobenzene) afforded 14.30 g and 31.39 g of product respectively. XH NMR's of all three batches showed a mixture of desired compound and small amounts of unidentified impurities. The 3 batches were combined and used in the next stage without further purification. NMR (300 MHz, CDC13) 7.05 (2H, d, J=8.5 Hz), 3.56 (2H, s), 1.46 (9H, s). | |
37.64 g | With potassium tert-butylate; In N,N-dimethyl-formamide; at -35℃; for 2.5h;Inert atmosphere; | A solution of difluoronitrobenzene (24.96 g, 157 mmol) and tert-butyl chloroacetate (38.0 mL, 267 mmol) in anhydrous DMF (200 mL) was added dropwise over one hour to a cold (- 35 C) suspension of potassium tert-butoxide (61.61 g, 549 mmol) in anhydrous DMF (200 mL) under nitrogen. The reaction mixture was stirred at -35 C for 1.5 hours, quenched with 2N HC1 (240 mL) and extracted with heptanes (4x200 mL). The combined organic extracts were washed with water (3x200 mL), brine (200 mL), dried (MgS04), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (10 % EtOAc in heptanes) afforded a yellow oil (37.64 g). Another two batches (10.00 g and 23.54 g of difluoronitrobenzene) afforded 14.30 g and 31.39 g of product respectively. 1H MR's of all three batches showed a mixture of desired compound and small amounts of unidentified impurities. The 3 batches were combined and used in the next stage without further purification.1H NMR (300 MHz, CDC13) 7.05 (2H, d, J=8.5 Hz), 3.56 (2H, s), 1.46 (9H, s). |
A mixture of potassium te/f-butoxide (248g) in NMP (2000ml) was cooled under nitrogen to -200C. A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (100g) and te/f-butylchloroacetate (16Og) in NMP (2000ml) was added slowly at -100C to -20C over 1.5 hours. After 30 minutes, a further portion of potassium te/f-butoxide (88g) was added. The reaction mass was quenched into 1600ml of 2M HCI and 1 kg crushed ice, then 2000ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500ml). The combined hexane layers were washed with saturated brine (2 x 1000ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152g). | ||
With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - -10℃; for 2h; | A mixture of potassium te/f-butoxide (248g) in N-methyl-2-pyrrolidinone (2000ml) was cooled under nitrogen to -200C. A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (10Og) and tert- butylchloroacetate (16Og) in N-methyl-2-pyrrolidinone (2000ml) was added slowly at -100C to -20C over 1.5 hours. After 30 minutes, a further portion of potassium te/f-butoxide (88g) was added. The reaction mass was quenched into 1600ml of 2M HCI and 1 kg crushed ice, then 2000ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500ml). The combined hexane layers were washed with saturated brine (2 x 1000ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152g). | |
With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - -10℃; for 0.833333h; | Description 1. t-Butyl 3,5-difluoro-4-nitrophenylacetate (D1); A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.5g), t-butyl chloroacetate (3.8ml) and N-methyl pyrrolidone (50ml) was added over 20min at -100C to -200C to a solution of potassium t- butoxide (4.2g) in N-methyl pyrrolidone (50ml). After 30min more at the same temperature the reaction was poured onto a mixture of ice and 2M hydrochloric acid and then extracted twice with hexane. Drying, evaporation and chromatography (2Og silica, 1 :1 hexane:dichloromethane) gave the title compound as a yellow oil, 1.3g. | |
37.64 g | With potassium tert-butylate; In N,N-dimethyl-formamide; at -35℃; for 2.5h;Inert atmosphere; | A solution of difluoronitrobenzene (24.96 g, 157 mmol) and tert-butyl chloroacetate (38.0 mL, 267 mmol) in anhydrous DMF (200 mL) was added dropwise over one hour to a cold (-35 C) suspension of potassium ferZ-butoxide (61.61 g, 549 mmol) in anhydrous DMF (200 mL) under nitrogen. The reaction mixture was stirred at -35 C for 1.5 hours, quenched with 2N HC1 (240 mL) and extracted with heptanes (4x200 mL). The combined organic extracts were washed with water (3x200 mL), brine (200 mL), dried (MgSC^), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (10 % EtOAc in heptanes) afforded a yellow oil (37.64 g). Another two batches (10.00 g and 23.54 g of difluoronitrobenzene) afforded 14.30 g and 31.39 g of product respectively. H NMR's of all three batches showed a mixture of desired compound and small amounts of unidentified impurities. The 3 batches were combined and used in the next stage without further purification. (0142) NMR (300 MHz, CDCb) 7.05 (2H, d, J=8.5 Hz), 3.56 (2H, s), 1.46 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With sodium hydride; In N,N-dimethyl-formamide; for 0.166667h; | To 2-fluoroaniline (1.55 g, 13.9 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (0.56 g, 13.9 mmol) and the reaction stirred for 10 minutes prior to the addition of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2 g, 15.5 mmol) dissolved in anhydrous dimethylformamide (2 mL). Upon disappearance of 2-fluoroaniline the reaction was partitioned between saturated ammonium chloride (50 mL) and ethyl acetate (50 mL) and the organics were dried over sodium sulfate. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine as a slightly impure off-white solid (1.5 g, 43%). (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine (1.5 g, 6 mmol) and a spatula tip of 5% Pd/C in methanol (100 mL) were reduced in the parr shaker. Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give 3-fluoro-N1-(2-fluoro[henyl)benzene-1,2-diamine as a brown oil (0.5 g, 38%). MS (ES) m/z 221.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h; | To a solution of compound A28f (318 mg, 2 mmol) in DMF (10 mL), were added K2C03 (552 mg, 4 mmol) and benzyl alcohol (226 L, 2.2 mmol). The reaction mixture was stirred for 12 h at 60 C. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na2S04, concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (10% EtOAc/hexanes) to obtain the compound A32 as yellow oil (400 mg, 81%). Rf = 0.2 (10% EtO Ac/hexanes) . |
74% | With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 90h; | Step A: To a stirred, cooled (0 C.) solution of DMF (75 mL) was added sodium hydride (0.45 g, 18.9 mmol). The ice-bath was removed from the resulting white slurry and benzyl alcohol (1.70 mL, 16.5 mmol) was added dropwise. The mixture was stirred 15 min, then the <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (1.66 mL, 15.71 mmol) was added in one portion. The reaction was stirred about 90 min. The reaction was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc (2*). The combined organic layers were washed with water (3*), brine (2*), dried over Na2SO4, concentrated and the residue was chromatographed on silica gel (120 g) eluting with a 0-to-20% EtOAc/hexane gradient, to give 1-(benzyloxy)-3-fluoro-2-nitrobenzene as a yellow oil, 2.87 g (74%). 1H NMR (400 MHz, DMSO-d6): δ 7.58 (m, 1H), 7.32 (m, 5H), 7.28 (d, J=8.7, Hz, 1H), 7.11 (m, 1H), 5.32 (s, 2H). |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;Enzymatic reaction; | Step 1: 1-(benzyloxy)-3-fluoro-2-nitrobenzene A mixture of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (1 g, 6 mmol), benzyl alcohol (0.81 mL, 7.8 mmol), potassium carbonate (1.79 g, 13.0 mmol) in N,N-dimethylformamide (5 mL) was heated at 60 C. for 18 h. The reaction mixture was cooled to room temperature then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in Hexanes to give the desired product. |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h; | A mixture of 1 ,3-difluoro-2-nitrobenzene (1.0 g, 6.29 mmol), benzyl alcohol (0.81 mL, 7.86 mmol) and potassium carbonate (1.74 g, 12.6 mmol) in DMF (5 mL) is heated at 60 0C for 18 h. The reaction mixture is poured into EtOAc, and washed with water and brine. The organic phase is concentrated and purified to give the title compound: 1H NMR (CDCI3) δ 7.36 (m, 6H), 6.83 (m, 2H), 5.20 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 200℃; for 0.333333h;Microwave irradiation; | Description 60. λ/-(3-Fluoro-2-nitrophenyl)-1-[frans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine (D60)(D60); A microwave vessel was charged with 2, 6-difluoro-1 -nitrobenzene (0.318g), 1-[frans-1- methyl-4-(methoxy)cyclohexyl]-4-piperidinamine dihydrochloride (diHCI salt of D57, 0.318g), dimethylformamide (3ml) and diisopropylethylamine (1.0ml) and heated at 2000C for 20 minutes in a microwave reactor. The cooled reaction was evaporated, dissolved in methanol and loaded onto a SCX cartridge which was eluted with methanol then 2M methanolic ammonia. The methanolic ammonia fraction was evaporated and the residue was chromatographed on silica gel eluted with dichloromethane - methanolic ammonia 0-5% to give the title compound as a yellow glass (0.249g). MH+ = 366. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 200℃; for 0.333333h;Microwave irradiation; | Description 58. 1 -[frans-4-(Ethyloxy)-1 -methylcyclohexyl]-λ/-(3-fluoro-2-nitrophenyl)- 4-piperidinamine (D58); (D58)A microwave vessel was charged with 2, 6-difluoro-1 -nitrobenzene (0.318g), 1-[frans-1- methyl-4-(ethoxy)cyclohexyl]-4-piperidinamine dihydrochloride (D47, 0.318g), dimethylformamide (3ml) and diisopropylethylamine (1.0ml) and heated at 2000C for 20 minutes in a microwave reactor. The cooled reaction was evaporated, dissolved in methanol and loaded onto a SCX cartridge which was eluted with methanol, then with 2M methanolic ammonia. The methanolic ammonia fraction was evaporated and the residue was chromatographed on silica gel eluted with 0-5% dichloromethane - methanolic ammonia to give the title compound as a yellow glass (0.1 14g). MH+ = 380. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | With potassium carbonate; In N,N-dimethyl acetamide; toluene; at 125℃; for 17h;Dean-Stark; | General procedure: The preparation of compound A7 is provided as a representative synthesis procedure of these compounds. (0012) Heptylamine (1.3186 g, 0.0114 mol) and 2,4-DFNB, (0.9262 g, 0.0058 mol) were weighed into separate vials. Potassium carbonate (3.03 g, 0.022 mol, 50% excess) was transferred to a 100 mL three-necked round-bottomed flask fitted with a magnetic stir bar, nitrogen inlet, thermometer, and a Dean-Stark trap fitted with a condenser. Each glass vial used for weighing starting materials was rinsed with DMAC (5 mL) and the washings were transferred to the reaction vessel to ensure full transfer of any residual reagents. Next, an additional 4 mL of DMAC was added to the reaction vessel, followed by 15 mL of toluene. An initial exotherm of 5 C was observed upon the dissolution of the starting materials, rendering the reaction mixture bright yellow in color. The reaction vessel was heated by an external temperature-controlled oil bath (with mild stirring) for 17 h at 125 C. At the completion of the reaction, the vessel was cooled, the reaction mixture was diluted with dichloromethane, and then filtered through celite to remove all salts. The filtrate was evaporated at reduced pressure to yield a crude product that was subsequently dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at reduced pressure, and the resulting solid was further purified via recrystallization in absolute ethanol to yield yellow needles. Spectroscopic data for the secondary amines are supplied as Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Step 1: To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (6.37 g, 40.0 mmol) in triethylamine (70 mL) under nitrogen was added dropwise isopropylamine (4.3 mL, 50 mmol, 12.5 equiv.) via an addition funnel. The reaction mixture was stirred at room temperature overnight. All volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (50 mL). Palladium on carbon powder (10 wt %, 0.4 g) was added, and the mixture was stirred under hydrogen atmosphere (20 psi) for 30 min. The reaction mixture was filtered through Celite and concentrated to dryness. The crude black liquid residue was purified by Isco CombiFlash Companion column chromatography (silica gel, 120-g column, 0-15% ethyl acetate/hexane) and the resulting purple solid was recrystallized (warm hexane/-25 C.) to give pure 3-fluoro-N-isopropylbenzene-1,2-diamine as light purple crystals. Yield: 4.21 g (63%). MS (ES) m/z 168.7 ([M+H]+); HRMS: calcd for C9H13FN2+H+, 169.1136; found (ESI, [M+H]+), 169.1139. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Synthesis of 2-(4-amino-3,5-difluorophenyl)propanoic Acid (cf. Example 26); KOtBu (3.57 g, 31.85 mmol) was dissolved in DMF (30 mL) and cooled to -45 C. To this solution a mixture of ethyl 2-chloropropionate (2 mL, 15.9 mmol) and <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.5 g, 15.7 mmol) was added slowly dropwise at -40 C. The resulting solution was stirred for 1 h. The reaction mixture was then acidified with HCl (16%) up to pH 4 and diluted with water (150 mL) afterwards. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with water (50 mL) and a saturated aqueous solution of NaCl (2×50 mL) and dried over MgSO4. The organic solvents were removed in vacuo and the product could be obtained as an oil (4.12 g, 99%) (a). | |
99% | With potassium tert-butylate; In N,N-dimethyl-formamide; at -45 - -40℃; | KOtBu (31.85 mmol, 3.57 g) was dissolved in DMF (30 ml) and cooled to -45 0C. A mix of ethyl-2-chloropropionate (15.9 mmol, 2 ml) and 1 ,3-difluoro-2-nitrobenzene (15.7 mmol, 2.5 g) was slowly added dropwise to the solution, which was kept at -40 0C, and after addition the mixture was stirred for a further 1 h. For working up, the reaction mix was set to pH 4 using 16 % HCI and diluted with water (150 ml). The mix was extracted with EE (3 x 50 ml), the combined organic phases were washed with water (50 ml) and sat. NaCI solution (2 x 50 ml) and dried over magnesium sulphate. After removal of the solvent under vacuum, the product was obtained as an oil (4.12 g, 99 % yield). |
56% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 0℃; for 0.166667h; | General procedure: To a stirred solution of potassium t-butoxide (20 mmol) in DMF (20 mL) was added a mixture of nitrobenzene 4 (10 mmol) and ethyl 2-chloropropionate (10 mmol) at 0 C dropwise. After being stirred for 10 min at 0 C, the mixture was quenched with 1 N HCl solution, diluted with water and extracted with diethyl ether several times. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 19; (2R,3R,4S,5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3R)-4-oxo-6-phenoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]non-6-enamide; Step 1: Preparation of 1-fluoro-2-nitro-3-phenoxybenzene (57); 252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 50 mL three-necked flask containing 10 mL of DMF and 0.592 g of phenol. The mixture is stirred at room temperature for 1 hour and a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> 47 (1.0 g, 6.29 mmol) in 10 mL of DMF is added. The reaction medium is left at room temperature for 24 hours. 50 mL of EtOAc are added and the mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. The crude product is chromatographed on a silica cartridge (120 g) eluting with heptane/EtOAc (as an EtOAc gradient: 0 to 50%). 1.07 g of expected product 57 are obtained (yellow oil).1H NMR (400 MHz, DMSO-d6), δ (ppm): 6.92 (broad d, J=8.0 Hz, 1H); 7.17 (broad d, J=7.5 Hz, 2H); 7.29 (t, J=7.5 Hz, 1H); 7.36 (broad t, J=8.0 Hz, 1H); 7.48 (t, J=7.5 Hz, 2H); 7.65 (dt, J=6.0 and 8.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 17; (2R,3R,4S,5R,6E)-N-[(3R)-6-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide; Step 1: Preparation N-[(2,2-dimethylpropanoyl)oxy]-S-(3-fluoro-2-nitrophenyl)-L-cysteine (48); A solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> 47 (2.0 g, 12.57 mmol) in 26 mL of ethanol is introduced into a 50 mL three-necked flask containing 2.78 g of L-Boc-Cys-OH (12.57 mmol), 22 mL of water and 3.05 g of NaHCO3 (36.33 mmol). The reaction medium is left at room temperature overnight and the medium is then maintained at 75 C. for 1 hour. The ethanol is evaporated off, the aqueous phase is then washed with 20 mL of ether, and once the ether phase has been separated out by settling, the aqueous phase is brought to pH 2-3 with HCl (1N) and extracted twice with 25 mL of EtOAc. The organic phases are combined, dried over MgSO4, filtered and finally evaporated to dryness. 1.29 g of crude product 48 are obtained (yellow oil), which product is used directly in the following step.1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.36 (s, 9H); 3.24 (dd, J=10.0 and 13.5 Hz, 1H); 3.53 (dd, J=5.0 and 13.5 Hz, 1H); 4.08 (m, 1H); 7.20 (d, J=8.0 Hz, 1H); 7.44 (t, J=8.0 Hz, 1H); 7.57 (t, J=8.0 Hz, 1H); 7.69 (dt, J=6.0 and 8.0 Hz, 1H); 12.8 (broad m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran; at 20℃; for 3h; | l,3-difluoro-2-nitrobenzene (1.0 equiv, 6.29 mmol, 1.0 g) was combined with ethyl amine solution (2.0 M in THF, 12 mL) and the resulting mixture was stirred at rt for 3 hrs, then concentrated and dried under vacuum to afford 1.0 g (86 %) of the desired product as an orange solid. MS (M+H)+= 185.2 |
69.1% | In ethanol; at 0 - 25℃; for 4.5h; | To a solution of 1 ,3-difluoro-2-nitrobenzene (10 g, 62.9 mmol) in ethanol (300 mL) was added ethanamine (47.2 g, 314 mmol) slowly at 0 C. The reaction mixture was stirred at0 C for 0.5 h and then warmed to 25 C for another 4 h. After removing the solvent, the residue was purified via silica gel chromatography (80 g, PEIEA= 5%) to give the title compound (8.0 g, 43.4 mmol, 69.1 % yield) as a solid. LC/MS: m/z 185 (M+H), 1.70 mm (ret. time). |
69.1% | In ethanol; at 0 - 25℃; for 4.5h; | To a solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (10 g, 62.9 mmol) in ethanol (300 mL) was added ethanamine (47.2 g, 314 mmol) slowly at 0 C. The reaction mixture was stirred at 0 C for 0.5 h and then warmed to 25 C for another 4 h. After removing the solvent, the residue was purified via silica gel chromatography (80 g, PE/EA= 5%) to give the title compound (8.0 g, 43.4 mmol, 69.1 % yield) as a solid. LC/MS: m/z 185 (M+H)+, 1.70 min (ret. time) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20 - 70℃; for 5h; | To a solution of 1 ,3-difluoro-2-nitrobenzene (5g, 31.4mmol) in THF (75ml) was added DIPEA (13.72ml, 7mmol) followed by (phenylmethyl) amine (3.78ml, 34.6mmol) at room temperature. The mixture was warmed to 700C for 5 hours. The solvent was removed on a rotary evaporator, the residue was taken up into DCM(150ml) and washed with water (100ml). The DCM layer was dried (MgSO4) and evaporated. The residue was not purified.Yield:6.8g (88%). LCMS: Rt = 3.81 min, No MH+ seen. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; for 18h;Reflux; | <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (3.000 g, 18.857 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (3.777 g, 18.857 mmol), potassium carbonate (3.127 g, 22.629 mmol) and potassium iodide (0.031 g, 0.189 mmol) were dissolved in N,N-dimethylformamide (150 mL) at room temperature, after which the resulting solution was heated under reflux for 18 hours, and then a reaction was finished bylowering a temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which water was poured into the resulting concentrate, and then an extraction was performed with ethyl acetate. An organic layer was washed with saturated sodium chloride aqueous solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 40 g cartridge; ethyl acetate/hexane = 0 to 40%) and concentrated to obtain a title compound (4.300 g, 67.2%) in a red solid form. |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 6h; | 5: 4-(3-Fluoro-2-nitro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester l,3-Difluoro-2-nitro-benzene (31 mmol) and 4-amino-l-Boc piperidine (31 mmol) were dissolved in DMF (50 rnL) and K2CO3 (50 mmol) was added. The mixture was stirred at 70 C for 6h, then it was cooled and poured into brine and extracted x3 with ethyl acetate. The combined organic phases were washed x3 with brine, dried on MgSO4, filtered and evaporated. The crude product was used without further purification. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 6h; | 5: 4-(3-Fluoro-2-nitro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester l,3-Difluoro-2-nitro-benzene (31 mmol) and 4-amino-l-Boc piperidine (31 mmol) were dissolved in DMF (50 rnL) and K2CO3 (50 mmol) was added. The mixture was stirred at 70 C for 6h, then it was cooled and poured into brine and extracted x3 with ethyl acetate. The combined organic phases were washed x3 with brine, dried on MgSO4, filtered and evaporated. The crude product was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (1.0 g, 6.3 mMol) in dimethylsulfoxide (7 mL) was added sodium azide (0.45 g, 6.9 mMol). After stirring for 2 h at 20 C. diisopropylethylamine (0.81 g, 6.3 mMol, 1.1 mL) was added to the reaction mixture followed by S-2-methylpiperazine (0.95 g, 9.5 mMol). The reaction mixture stirred at 60 C. for 10 h then 20 C. for an additional 12 h at which point it was diluted with ethyl acetate (50 mL), washed with 1N sodium hydroxide solution (20 mL) and water (2×20 mL). The organic layer was dried (MgSO4), evaporated and the residue dissolved in dichloromethane (25 mL) and treated with di-t-butyldicarbonate (1.5 g, 7.1 mMol). After stirring for 16 h at 20 C. the solvent was evaporated and the residue was chromatographed on silica gel eluted with 75% hexanes in ethyl acetate to provide the product as a yellow gum (2.2 g, 96%). 1H-NMR (CDCl3), δ=7.42 (dd, 1H, J=8.2 Hz, J=8.2 Hz), 7.0 (d, 1H, J=8.2 Hz), 6.95 (d, 1H, J=8.2 Hz), 4.28 (bm, 1H), 3.88 (bd, 1H, J=13.3 Hz), 3.00 (m, 5H), 1.48 (s, 9H), 1.22 (d, 3H, J=6.8 Hz). LC/MS (Method A), rt=2.05 mins., purity=89.8%, calculated mass=362, [M+H-C5H9O2]+=263. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 44A methy 4-fluoro-2-(3-fluoro-2-nitrophenoxy)benzoate To a solution of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (3.0 g) in tetrahydrofuran (65 ml) was added potassium t-butoxide (1.979 g) portionwise. The resulting solution was stirred at ambient temperature for 30 minutes and a solution of 1,3-difluoro-2-nitrobenzene (2.338 g) in tetrahydrofuran (15 ml) was added dropwise. After 1 hour the reaction was heated at reflux for 18 hours. The reaction was quenched with water (10 ml), diluted with brine (75 ml) and extracted with twice methylene chloride (75 ml). The crude product was isolated by concentration and purified on silica gel, and eluted with a 10, 20, 50% ethyl acetate in hexane step gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With ammonia; In methanol; at 20℃; for 120h;sealed tube; | Intermediate 15A; 3-fluoro-2-nitroaniline; To a pressure tube was added 1, 3 -difluoro-2 -nitrobenzene (2.8 mL, 26.4 mmol) and 7 TV NH3 in CH3OH (10 mL, 70 mmol). The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H20, extracted with CH2CI2, and the combined extracts were washed with brine, dried over Na2S04, filtered and concentrated to give an oil. The oil was triturated with hexane and the resulting orange solid was collected by filtration to give the title compound (2.1 g, 51%). |
With ammonia; In methanol; at 20℃; for 48h; | A solution of 7.0 M NH3 in MeOH (200 mL) containing <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (8.01 g, 50.3 mmol) was stirred at room temperature for 2 days in a sealed pressure vessel. The solution was then poured into H2O and the organics were extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residual solid was triterated with hexanes and collected via vacuum filtration yielding 6.20 g (39.7 mmol) of 3-fluoro-2-nitroaniline. 1H NMR (400 MHz, CDCl3) δ 7.21 (m, 1H), 6.54 (d, 1H, J=8.6 Hz), 6.45 (m, 1H), 5.61 (s(br), 2H) ppm. | |
With ammonium hydroxide; In ethanol; at 75℃; for 16h; | Example 15 N4 -(5-Cyclopropyl-lH-pyrazol-3-yl)- N2 -[(4-fluoro-lH-benzimidazol-5-yl)methyl]pyrimidine-2,4- diamine (1-29) step 1 : To a solution of l,3-difluoro-2-nitro-benzene (30 g, 0.188 moles) in EtOH (300 mL) was added 25% aq. ammonia solution (300 mL) and the resulting mixture was heated to 75 C for 16 h then cooled and concentrated in vacuo. The residue was dissolved in EtOAc, washed with water and brine solution, dried (Na2S04), filtered and concentrated to afford 25 g (85%) of 3-fluoro-2-nitro-phenylamine (138) as a brown solid which was used without any further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (200 mg, 1.26 mmol) in DMSO (2 mL) was added 3-amino-3-phenylpropionic acid (228 mg, 1.39 mmol) and potassium carbonate (347 mg, 2.52 mmol). The suspension was heated to 100 C. for 0.5 hour, and 4-methoxybenzylamine (180 μL, 1.39 mmol) was added, and heating continued for a further 3 hours. The suspension was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid (pH<4), and then extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluding with a mixture of dichloromethane and methanol (19:1) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.75 min, MH+ 422]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (500 mg, 3.14 mmol) in DMSO (3 mL) was added 3-amino-3-phenylpropionic acid (623 mg, 3.77 mmol) and potassium carbonate (529 mg, 3.83 mmol). The suspension was heated to 100 C. for 0.5 hour, then benzylamine (410 μL, 3.75 mmol) was added, and heating continued for a further 3 hours. The suspension was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was separated and acidified with dilute hydrochloric acid (pH<4), and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluding with a mixture of dichloromethane and methanol (97:3) to afford the title compound, 1H NMR: (CD3OD) 7.45-7.21 (m, 10H), 6.98 (dd, J=8.42, 8.42, 1H), 5.97 (d, J=8.42, 1H), 5.87 (d, J=8.79, 1H), 5.07-5.01 (m, 1H), 4.40-4.43 (m, 2H), 2.95-2.81 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (272 mg, 1.71 mmol) in DMSO (2 mL) was added methyl-3-amino-3-phenylpropanoate (553 mg, 2.57 mmol) and potassium carbonate (709 mg, 5.13 mmol), and the suspension stirred at room temperature for 24 hours. 4-Piperidinecarboxylic acid (335 mg, 2.59 mmol) was added, and the resulting suspension stirred at room temperature for 24 hours, and then heated at 100 C. for 3 hours. The suspension was cooled to room temperature, and diluted with water. The aqueous solution was extracted with ethyl acetate, and the separated aqueous layer acidified with dilute hydrochloric acid (pH<4), and re-extracted with ethyl acetate. The second organic extracts were evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluding with a mixture of dichloromethane and methanol (96:4) to afford the title compound, 1H NMR: (CDCl3) 7.36-7.22 (m, 5H), 7.02 (t, J=8.06, 1H), 6.34 (dd, J=8.06, 1.10, 1H), 6.19 (d, J=8.06, 1H), 4.89-4.85 (m, 1H), 3.66 (s, 3H), 3.25-3.21 (m, 2H), 2.87-2.77 (m, 4H), 2.48-2.41 (m, 1H), 2.02-1.82 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Step 3; [00156] 17-2 (187 mg; 0.407 mmol) was debenzylated by hydrogenation in MeOH in the presence of a catalytic amount of 10% Pd/C (1 small scoop) under 1 atm ofH2 (g) (balloon) for 3 d. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude phenol was taken up in DMF (4 mL) and 2,6 difluoronitrobenzene (43 μL; 0.407 mmol) and Cs2CO3 (133 mg; 0.407 mmol) were added. The mixture was heated to 80 C for 16 h. After cooling to room temperature the mixture was filtered through a pad of Celite, concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 3 : 1 hexanes:EtOAc) to afford 139 mg (67% for 2 steps) of 17-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00116] To a solution of 3-nitro-ρhenylamine (1.82 g, 0.013 mol) in DMF (8 ml) atO0C is added NaH (60% dispersion in mineral oil, 0.53 g, 0.013 mol). The reaction is stirred at this temperature for 15 min. Subsequently, a solution of l,3-difluoro-2-nitro- benzene (0.70 g, 4.4 mmol) in DMF (2 ml) is added slowly. After stirring for additional 30 min, it is poured into a saturated aqueous solution OfNH4Cl. The precipitate therefore formed is collected by vacuum filtration. The desired compound is obtained after flash EPO <DP n="42"/>column chromatography purification of the precipitate (silica gel, eluted by hexanes-ethyl acetate). 1H NMR (CDCl3) δ 6.77 (dd, IH, J1 = 10 Hz, J2 = 10.6 Hz), 7.11 (d, IH, J = 8.8 Hz), 7.35-7.41 (m, IH), 7.49-7.59 (m, 2H), 7.99 (dt, IH, J1 = 8.0 Hz, J2 = 2.0 Hz), 8.09 (t, IH, J = 2.0 Hz), 8.35 (bs, IH); LC-MS: 278.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | In tetrahydrofuran; at 20℃; for 9.33333h; | EXAMPLE 715-(4-{4-f|UOro-1 -[2-(methyloxy)ethyl]-1 H-benzimidazol-2-yl}-1 H-imidazol-2-yl)-1 ,3- benzothiazole trifluoroacetateStep 1 . (3-fluoro-2-nitrophenyl)[2-(methyloxy)ethyl]amine: To a solution of 2,6- difluorodinitrobenzene (4 g, 24.64 mmol) in Tetrahydrofuran (THF) (80 ml) at rt was added 2-methoxyethlyamine (2.164 ml, 24.64 mmol). This was stirred at rt for 80 min, at which time, LCMS showed nearly half complete. Allowed to stir for 8 hr. LCMS showed 12%sm, 85% product, and 3% double addition product. Diluted with Et20 and water, separated layers and back-extracted with Et20 twice. Washed with Brine and dried on MgS04. Filtered and concentrated. Purified via Biotage FCC (40 g SNAP column, 0-10%EtOAC/hex); baseline separation was acheived. Combined an concentrated product fractions to provide (3-fluoro-2-nitrophenyl)[2-(methyloxy)ethyl]amine (3.76 g, 17.55 mmol, 71 .2 % yield) as a bright orange oil. MS (m/z) 215.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 110℃; for 16h; | Example 20a; ethyl 2-(3-fluoro-2- nitrophenylamino)propanoate; To a solution of l,3-difluoro-2-nitrobenzene (4.7 g, 29.5 mmol) in DMA (98 ml) was added ethyl 2-aminopropanoate (3.46 g, 29.5 mmol) and diisopropylethylamine (25.8 ml, 148 mmol). The reaction was heated at 110 C 16 h, cooled to rt, diluted with 2N HC1 and extracted with isopropyl acetate two times. The organic layers were combined and washed with water 3 times and brine once, dried (anh. Na2S04) and concentrated. The residue was purified by chromatography on silica gel (100 g) eluting ethyl acetate in hexane in a gradient of 0-30% to give the title compound 20a (5.8 g, 77% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In methanol; at 20℃; for 3.5h;Cooling with ice; | A methanol solution of 40% methyl amine (12.2 mL, 119 mmol) was added dropwise to a methanol solution (39.5 mL) of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (7.90 g, 49.7 mmol) under ice cooling, and the mixture was stirred at the same temperature for 0.5 hours, and then stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and precipitated crystals were collected by filtration and washed with water. The resulting crystals were dried at 50 C., thereby obtaining 7.84 g of a red, powdery target compound (yield: 93%).1H-NMR (CDCl3) δ ppm: 2.98 (3H, d, J=5.1 Hz), 6.43 (1H, dd, J=11.6 Hz, 8.9 Hz), 6.57 (1H, d, 8.9 Hz), 7.2-7.4 (2H, m) |
75% | In methanol; at 0 - 20℃; for 3.5h; | To a solution of lnt-36 (1.0 g, 6.3 mmol) in MeOH (5 mL) was added 33% methyl amine (1.3 g, 13.8 mmol) in MeOH at 0 C, and the mixture was stirred at the same temperature for 0.5 h, then at room temperature for 3 h. After completion of the reaction indicated by LCMS, the reaction solution was poured into ice water, and precipitated crystals were collected by filtration and washed with water. The residue was dissolved in DCM, dried over Na2S04 and filtered. The filtrate was concentrated in vacuum to give lnt-37 (800 mg, 75%). LCMS (Agilent LCMS 1200-6120, Column: Halo C18 (30 mm *4.6 mm*2.7 pm); Column Temperature: 40 C; Flow Rate: 3.0 ml/min; Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CCN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CCN + 0.05% TFA] in 0.8 min, then under this condition for 0.4 min, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.01 min and under this condition for 0.2 min). Purity: 100%; Rt = 0.74 min; MS Calcd. : 171.1; MS Found: 170.1 [M+H]+. |
In dichloromethane; at 0℃; for 3h; | To a stirred solution of l,3-difluoro-2-nitrobenzene 1 (14.0 g, 88.1 mmol) in DCM (1568) (150 mL) at 0 C, was added methyl amine (7.00 g, 228 mmol) and the mixture was stirred for 3h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice water (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the cnide title compound (9.00 g). 1H-NMR (400 MHz, DMSO-d) d 8.29 (s, IH), 7.41 (dd, J= 4.24, 8.73 Hz, I H), 7.01 (dd, J= 8.73, 10.22 Hz, IH), 4.09 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In tetrahydrofuran; at 100℃; | Ethyl 3-(3-fluoro-2-nitrophenylamino)propionate (Step 1). A round bottomed flask was charged with <strong>[4244-84-2]ethyl 3-aminopropanoate hydrochloride</strong> (1 g, 6.51 mmol), l,3-difluoro-2- nitrobenzene (1.036 g, 6.51 mmol), potassium carbonate (2.70 g, 19.53 mmol), and a stirbar. THF (35 mL, 0.2 M) was added, and the mixture was stirred at 100 °C overnight. The mixture was concentrated with celite and purified by silica gel chromatography (eluting withhexanes/ethyl acetate) to yield ethyl 3-(3-fluoro-2-nitrophenylamino)propionate as a yellow amorphous solid (1.473g, 5.75 mmol, 88percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.7% | With potassium carbonate; In N,N-dimethyl acetamide; toluene; at 125℃; for 17h;Dean-Stark; | General procedure: The preparation of compound A7 is provided as a representative synthesis procedure of these compounds. (0012) Heptylamine (1.3186 g, 0.0114 mol) and 2,4-DFNB, (0.9262 g, 0.0058 mol) were weighed into separate vials. Potassium carbonate (3.03 g, 0.022 mol, 50% excess) was transferred to a 100 mL three-necked round-bottomed flask fitted with a magnetic stir bar, nitrogen inlet, thermometer, and a Dean-Stark trap fitted with a condenser. Each glass vial used for weighing starting materials was rinsed with DMAC (5 mL) and the washings were transferred to the reaction vessel to ensure full transfer of any residual reagents. Next, an additional 4 mL of DMAC was added to the reaction vessel, followed by 15 mL of toluene. An initial exotherm of 5 C was observed upon the dissolution of the starting materials, rendering the reaction mixture bright yellow in color. The reaction vessel was heated by an external temperature-controlled oil bath (with mild stirring) for 17 h at 125 C. At the completion of the reaction, the vessel was cooled, the reaction mixture was diluted with dichloromethane, and then filtered through celite to remove all salts. The filtrate was evaporated at reduced pressure to yield a crude product that was subsequently dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at reduced pressure, and the resulting solid was further purified via recrystallization in absolute ethanol to yield yellow needles. Spectroscopic data for the secondary amines are supplied as Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With potassium carbonate; In N,N-dimethyl acetamide; toluene; at 125℃; for 17h;Dean-Stark; | General procedure: The preparation of compound A7 is provided as a representative synthesis procedure of these compounds. (0012) Heptylamine (1.3186 g, 0.0114 mol) and 2,4-DFNB, (0.9262 g, 0.0058 mol) were weighed into separate vials. Potassium carbonate (3.03 g, 0.022 mol, 50% excess) was transferred to a 100 mL three-necked round-bottomed flask fitted with a magnetic stir bar, nitrogen inlet, thermometer, and a Dean-Stark trap fitted with a condenser. Each glass vial used for weighing starting materials was rinsed with DMAC (5 mL) and the washings were transferred to the reaction vessel to ensure full transfer of any residual reagents. Next, an additional 4 mL of DMAC was added to the reaction vessel, followed by 15 mL of toluene. An initial exotherm of 5 C was observed upon the dissolution of the starting materials, rendering the reaction mixture bright yellow in color. The reaction vessel was heated by an external temperature-controlled oil bath (with mild stirring) for 17 h at 125 C. At the completion of the reaction, the vessel was cooled, the reaction mixture was diluted with dichloromethane, and then filtered through celite to remove all salts. The filtrate was evaporated at reduced pressure to yield a crude product that was subsequently dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at reduced pressure, and the resulting solid was further purified via recrystallization in absolute ethanol to yield yellow needles. Spectroscopic data for the secondary amines are supplied as Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | With potassium carbonate; In N,N-dimethyl acetamide; toluene; at 125℃; for 17h;Dean-Stark; | General procedure: The preparation of compound A7 is provided as a representative synthesis procedure of these compounds. (0012) Heptylamine (1.3186 g, 0.0114 mol) and 2,4-DFNB, (0.9262 g, 0.0058 mol) were weighed into separate vials. Potassium carbonate (3.03 g, 0.022 mol, 50% excess) was transferred to a 100 mL three-necked round-bottomed flask fitted with a magnetic stir bar, nitrogen inlet, thermometer, and a Dean-Stark trap fitted with a condenser. Each glass vial used for weighing starting materials was rinsed with DMAC (5 mL) and the washings were transferred to the reaction vessel to ensure full transfer of any residual reagents. Next, an additional 4 mL of DMAC was added to the reaction vessel, followed by 15 mL of toluene. An initial exotherm of 5 C was observed upon the dissolution of the starting materials, rendering the reaction mixture bright yellow in color. The reaction vessel was heated by an external temperature-controlled oil bath (with mild stirring) for 17 h at 125 C. At the completion of the reaction, the vessel was cooled, the reaction mixture was diluted with dichloromethane, and then filtered through celite to remove all salts. The filtrate was evaporated at reduced pressure to yield a crude product that was subsequently dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at reduced pressure, and the resulting solid was further purified via recrystallization in absolute ethanol to yield yellow needles. Spectroscopic data for the secondary amines are supplied as Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | With potassium carbonate; In N,N-dimethyl acetamide; toluene; at 125℃; for 17h;Dean-Stark; | General procedure: The preparation of compound A7 is provided as a representative synthesis procedure of these compounds. (0012) Heptylamine (1.3186 g, 0.0114 mol) and 2,4-DFNB, (0.9262 g, 0.0058 mol) were weighed into separate vials. Potassium carbonate (3.03 g, 0.022 mol, 50% excess) was transferred to a 100 mL three-necked round-bottomed flask fitted with a magnetic stir bar, nitrogen inlet, thermometer, and a Dean-Stark trap fitted with a condenser. Each glass vial used for weighing starting materials was rinsed with DMAC (5 mL) and the washings were transferred to the reaction vessel to ensure full transfer of any residual reagents. Next, an additional 4 mL of DMAC was added to the reaction vessel, followed by 15 mL of toluene. An initial exotherm of 5 C was observed upon the dissolution of the starting materials, rendering the reaction mixture bright yellow in color. The reaction vessel was heated by an external temperature-controlled oil bath (with mild stirring) for 17 h at 125 C. At the completion of the reaction, the vessel was cooled, the reaction mixture was diluted with dichloromethane, and then filtered through celite to remove all salts. The filtrate was evaporated at reduced pressure to yield a crude product that was subsequently dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at reduced pressure, and the resulting solid was further purified via recrystallization in absolute ethanol to yield yellow needles. Spectroscopic data for the secondary amines are supplied as Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100 - 125℃; | 3 -Fluoro-N,N-diisobutyl-2-nitroaniline To a stirred solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (0.95 5 g, 6 mmol) in NMP (2mL) was added Hunig’s Base (1.153 mL, 6.60 mmol) followed by diisobutylamine (0.775g, 6.00 mmol). The solution was stirred 30 mm. at 100 C, after which time it was stillpale yellow with TLC showing a tiny new spot. The temperature was raised to 125 C,stirring was continued 2h longer, and overnight at 110 C. LCMS shows 1O% SM and essentially none of the bis-adduct; 0.1 mL more diisobutylamine was added, and the reaction was stirred lh longer at 125 C. The reaction was cooled and poured into aq. HOAc. This mixture was extracted with 1:1 ether-heptane, and the organic extract was washed with sat’d aq. sodium bicarbonate, dried, and stripped to afford 3-fluoro-N,N-diisobutyl-2-nitroaniline (1.5 g, 89% yield) as a dark oil. MS(ES): m/z = 269 [M+H].HPLC Tr: 4.83’. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.35 g | With potassium carbonate; In tetrahydrofuran; at 50℃; | 10 g (62.86 mmol) 2,6-Difluoronitrobenzene (commercially available) and 8.87 g (62.86 mmol) 3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commercially available) were given in 178 mL tetrahydrofurane. After addition of 9.56 g (69.14 mmol) potassium carbonate the reaction mixture was heated at 50 C overnight. The reaction mixture was evaporated to dryness yielding a red oily residue which was diluted with ethyl acetate (400 mL). The organic phase was extracted with water (100 mL) and brine (100 mL). After drying (sodium sulfate) the solvent was evaporated yielding 18.6 g (> 100%) of a darkred oil. 1.5 g of this crude material was purified for analytical reasons by column chromatography (Biotage, eluents: hexane/ ethylacetate) yielding 1.35 g of the desired product (mixture of stereoisomers) which was however still slightly contaminated. (0463) UPLC-MS (Method B): Rt = 1.65 min; m/z = 281 (ES+, M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; | Step 1 : 1 -(cyclopentoxy)-3-fluoro-2-nitro-benzene A suspension of cyclopentanol (1 .62 g, 18.8 mmol), 1 ,3-difluoro-2-nitro-benzene (1 .5 g, 9.42 mmol) and Cs2C03 (6.14 g, 18.8 mmol) in DMF (30 ml.) was heated at 100 C over night. The resulting mixture was diluted with water and EtOAc and afterwards the phases were separated. The water phase was further extracted with EtOAc (2x) and the organic phases were combined, dried over anhydrous Na2S04 and the solvent was removed. Purification by column chromatography (gradient: 100% CH to 4:1 CH: EtOAc) afforded the desired compound (900 mg, 4 mmol, 42%). 1H NMR (CDCIs, 400 MHz): δ = 7.32 (m, 1 H), 6.79 (d, 1 H, J = 8.7 Hz), 6.74 (dt, 1 H, J = 8.7, 0.9 Hz), 4.85 (q, 1 H, J = 4.0 Hz), 1.85 (m, 4H), 1 .75 (m, 2H), 1 .59 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 6h; | 1 .1 : 1 -fluoro-3-[3-fluoro-5-(trifluoromethyl)phenoxy]-2-nitro-benzene A suspension of 3-fluoro-5-(trifluoromethyl)phenol (1 g, 5.55 mmol), 1 ,3-difluoro-2-nitro- benzene (0.88 g, 5.55 mmol) and K2C03 (1 .53 g, 1 1.1 mmol) in DMF is heated to 100 C for 6 h. Water and ethyl acetate are added and the phases separated. The organic phase is washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure. Column chromatography (ISCO-Combi Flash Rf, cyclohexane/ethyl acetate) of the crude product yields the desired product in 85% (1.50 g). HPLC: 12 = 1 .433 min;MS (ESI) m/z = 320 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
NaH (0.50 mg, 12.6 mmol) was added in portions to propan-2-ol (20.0 mL, 57.6 mmol) and the mixture was stirred for 15 min at room temperature. Then 1 ,3-difluoro-2-nitro- benzene (2 g, 12.6 mmol) were added and the resulting solution stirred at 90 C for 1 h. After cooling to room temperature the solvent was removed under vacuum and the resulting solid resolved in water and ethyl acetate. The phases separated, the organic phase washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ = 7.32 (m, 1 H), 6.82 (d, 1 H, J = 8.7 Hz), 6.74 (dt, 1 H, J = 8.7, 0.9 Hz), 4.65 (q, 1 H, J = 4.0 Hz), 1 .34 (s, 3H), 1.33 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-Bromosuccinimide; sulfuric acid; at 80℃; | Intermediate 35:1-bromo-2,4-difluoro-3-nitro-benzene A mixture of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (intermediate 34) (19.5 g, 122.57 mmol) and NBS (26.2 g, 147.08 mmol) in sulfuric acid (150 mL) was stirred at 80 C. for overnight. LCMS indicated full conversion. The mixture was cooled to rt and slowly poured onto ice. This mixture was extracted with ethyl acetate (200 ml), the organic layer was washed with water (50 ml*2), sat. NaHCO3 solution (50 ml*2), brine, dried (anhydrous Na2SO4), filtered and concentrated. The residue was purified on silica gel column (eluted with 0 to 20% ethyl acetate in hexanes) to yield 1-bromo-2,4-difluoro-3-nitro-benzene (intermediate 35) (26.8 g, 92%) as a light-yellow oil. 1H NMR (500 MHz, DMSO-d6) 7.42-7.73 (1H, m), 8.06-8.26 (1H, m); m/z (ES+) [M+H]+=238. |
90% | With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 18h;Cooling with ice; | A mixed solution of sulfuric acid (10 mL) and trifluoroacetic acid (50 mL) was prepared under ice bath conditions.Add <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.4 mmol),N-bromosuccinimide (6.15 g, 34.5 mmol) was added slowly in portions.The reaction solution was stirred at room temperature for 18 h, and then poured into ice water (100 mL).Ethyl acetate (3 x 50 mL) was extracted and the organic layer was washed with 2M sodium hydroxide.Dry over anhydrous sodium sulfate, filter, spin dry,Made a red oil (6.6g),Yield 90.0% |
83% | With N-Bromosuccinimide; sulfuric acid; at 80℃; for 3h;Inert atmosphere; | Weigh 2,6-difluoro-nitrobenzene (2g, 12.57mmol) and dissolve it in 16mL sulfuric acid,Then add N-bromosuccinimide (3.41g, 15.09mmol),React at 80C for 3 hours under nitrogen protection. The reaction solution was cooled to 0C, poured into ice water, extracted with ethyl acetate (60mL) 3 times, and the combined organic phase was used with sodium bicarbonate solution (30mL)Washed 3 times, saturated saline (30 mL) washed 2 times, and dried with anhydrous sodium sulfate. filter,Concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain 2.5 g of product.Yellow oil, yield: 83%. |
79% | With N-Bromosuccinimide; sulfuric acid; at 80℃; for 16h; | To a solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (10.0 g, 62.8 mmol) in H2S04 (80 mL) was added NBS (13.4 g, 75.4 mmol). The reaction mixture was heated at 80C for16 h, then cooled to 0C, poured into ice cold H20 (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 2% EtOAc in hexanes) to afford the title compound (11.8 g, 79%)as a yellow liquid. oH (400 MHz, DMSO-d6) 7.53 (t, J 10.0 Hz, 1H), 8.13-8.19 (m, 1H). |
67% | With N-Bromosuccinimide; sulfuric acid; at 80℃; for 16h; | To a stirred solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (1 eq., 50.0 g, 314.29 mmol) in H2SO4 (400 ml_), NBS (1.20 eq., 67.12 g, 377.14 mmol) was added and the reaction mixture was heated to 80C for 16 h. The reaction was monitored by TLC (100% hexane) and after completion, the reaction mixture was poured into ice cold water and extracted with EtOAc (2L). The organic layer was separated and washed with saturated NaHCCh solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by FCC (gradient 1-5% EtOAc in n- hexane) to afford 1-bromo-2,4-difluoro-3-nitrobenzene (50 g, 67%) as yellow liquid. Analytical Data: 1H NMR (400 MHz, CDC ) d 7.78-7.71 (m, 1H), 7.09-7.03 (m, 1H). |
6.7 g | With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 70℃; for 1h; | A solution of 1 ,3-difluoro-2-nitrobenzene (6.77 g, 42.6 mmol) and N-bromosuccinimide (7.57 g, 42.6 mmol) in trifluoroacetic acid (TFA) (24 mL) and concentrated sulfuric acid (12.00 mL) was stirred at 70 C for 1 hour. The reaction was quenched on ice and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water (20 mL), saturated aqueous NaHC03, dried over Na2S04, filtered, and concentrated. The remaining oil was purified on silica (0-10%, CH2CI2/hexanes) to afford the desired product (6.7 g) as a clear colorless oil. GC-MS (ES) m/z = 238, 240 [M+H]+. NMR (400 MHz, DMSO-d6): δ 8.18 (ddd, J = 5.4, 7.6, 9.3 Hz, 1 H), 7.55 (dt, J = 1 .9, 9.6 Hz, 1 H). |
With N-Bromosuccinimide; | Intermediate 35:1-bromo-2,4-difluoro-3-nitro-benzene A mixture of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (intermediate 34) (19.5 g, 122.57 mmol) and NBS (26.2 g, 147.08 mmol) in sulfuric acid (150 mL) was stirred at 80 C. for overnight. LCMS indicated full conversion. The mixture was cooled to rt and slowly poured onto ice. This mixture was extracted with ethyl acetate (200 ml), the organic layer was washed with water (50 ml*2), sat. NaHCO3 solution (50 ml*2), brine, dried (anhydrous Na2SO4), filtered and concentrated. The residue was purified on silica gel column (eluted with 0 to 20% ethyl acetate in hexanes) to yield 1-bromo-2,4-difluoro-3-nitro-benzene (intermediate 35) (26.8 g, 92%) as a light-yellow oil. 1H NMR (500 MHz, DMSO-d6) 7.42-7.73 (1H, m), 8.06-8.26 (1H, m); m/z (ES+) [M+H]+=238. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium carbonate; In acetonitrile; at 60℃; for 12h; | <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (222.8 mg, 1.4 mmol, 3.0 eq.) and potassium carbonate (96.8 mg, 0.7 mmol, 1.5 eq.) were added to a solution of tert-butyl 3-(4-amino-3-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (200 mg, 0.467 mmol, 1.0 eq.) in acetonitrile (5 mL). The reaction mixture was stirred at 60 C. for 12 hours. After cooling to room temperature, the mixture was poured into water (10 mL), and then extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by thin layer chromatography (developer: ethyl acetate) to give the title compound (90 mg, yield: 34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | To a stirring solution of 2,6-difluoro nitrobenzene (3.83 g, 24 mmol) in acetonitrile (50 mL), 2-chlorobenzylamine (2.9 mL, 24 mmol) and DIPEA (5.1 mL, 28.9 mmol) were added. The solution was stirred at room temperature overnight. Water (100 mL) was added and the solution was extracted with ethyl acetate (3 X 50 mL). The combined organic solution was extracted with water (50 mL), brine (50 mL) and dried over sodium sulfate. The solution was filtered and concentrated. The residue was purified by ISCO, eluting with ethyl acetate/hexane (0-20%) to give the title compound as a purple solid (2.87 g, 43% yield). MS (ES+) m/z 281.0 [M+H]+.1H MR (400 MHz, chloroform-i ) δ ppm 4.56 - 4.65 (m, 2 H) 6.44 - 6.55 (m, 2 H) 7.22 - 7.37 (m, 3 H) 7.40 - 7.52 (m, 1 H) 7.62 (br. s., 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In chloroform; at 20 - 50℃;Inert atmosphere; | A solution of l-<strong>[702-24-9](4-methoxyphenyl)-N-methylmethanamine</strong> ( 5.23 g, 34.6 mmol ) in CHCb (20 ml) was added to a stirring solution of l,3-difluoro-2-nitrobenzene (5.5 g, 34.6 mmol) and TEA (5.78 mL, 41.5 mmol) in CHCb (250 mL) at RT under lh . The mixture was stirred at RT for 30 min and then heated to 50C overnight. Saturated NaHC03 was added, the organic layer was separated, the aqueous layer was as extracted with DCM, and the combined extracts were washed with brine, dried over Na2S0 filtered and concentrated. The residue was purified by silica column chromatography (0-12 % EtOAc in hexanes) to afford the title compound (8.5 g, 29.3 mmol, 85 % yield) as an orange oil. *H NMR (400 MHz, (2175) CHLOROFORM-d) delta ppm 7.29 - 7.34 (m, 1H) 7.20 (d, J = 8.28 Hz, 2H) 6.86 - 6.93 (m, 3H) 6.78 (t, J = 8.78 Hz, 1H) 4.29 (s, 2H) 3.82 (s, 3H) 2.80 (s, 3H); LCMS (LCMS Method D): Rt = 1.28, [M+H]+ = 120.5 |
85% | With triethylamine; In chloroform; at 20 - 50℃;Inert atmosphere; | A solution of <strong>[702-24-9]1-<strong>[702-24-9](4-methoxyphenyl)-N-methylmethanamine</strong></strong> C 5.23 g, 34.6 mmol) in CHCI3 (20 ml) was added to a stirring solution of 1,3-difluoro-2-nitrobenzene (5.5 g, 34.6mmol) and TEA (5.78 mL, 41.5 mmol) in CHCI3 (250 mL) at RT under N2 . The mixture was stirred at RT for 30 mm and then heated to 50°C overnight. Saturated NaHCO3 was added, the organic layer was separated, the aqueous layer was as extracted with DCM, and the combined extracts were washed with brine, dried over Na2504 filtered and concentrated. The residue was purified by silica column chromatography (0-12 percent EtOAc in hexanes) to afford thetitle compound (8.5 g, 29.3 mmol, 85 percent yield) as an orange oil. 1H NMR (400 MHz,CHLOROFORM-d) 3 ppm 7.29 - 7.34 (m, 1H) 7.20 (d, J = 8.28 Hz, 2H) 6.86 - 6.93 (m, 3H)6.78 (t, J = 8.78 Hz, 1H) 4.29 (s, 2H) 3.82 (s, 3H) 2.80 (s, 3H); LCMS (LCMS Method D): Rt =1.28, [M+H] = 120.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.2 g | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5h; | A mixture of (5)-i -(((S)-2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperidin-3 -amine(0.20 g, 0.81 mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.85 ml, 0.81 mmol) and K2C03 (0.17 g,1.21 mmol) in DMF (2.5 ml) was heated at 70C. After 5 hours water (10 nil) was added andthe mixture was extracted with CH2C12. Combined organic layers were washed with water, dried (Na2SO4) and concentrated to dryness. The residue (0.20 g) containing (S)-i-(((S)-2,3- dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)-N-(3 -fluoro-2-nitrophenyl)piperidin-3 -amine was used as such in the next step.(ES+) [M+i]: 388.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; | General procedure: A mixture of the corresponding nitrobenzene compound (1.0 equiv.), a suitable amine (1.1 equiv.), and /V,/V-diisopropylethylamine (1.2 equiv.) was stirred in 2-propanol at 120 C for 12 - 72 h. Thereafter, the mixture was poured into NaHC03 and extracted with DCMx3. The combined organics were dried (using MgS04), filtered, concentrated, and purified by silica gel chromatography |
Tags: 19064-24-5 synthesis path| 19064-24-5 SDS| 19064-24-5 COA| 19064-24-5 purity| 19064-24-5 application| 19064-24-5 NMR| 19064-24-5 COA| 19064-24-5 structure
[ 932373-92-7 ]
1,3-Difluoro-5-methyl-2-nitrobenzene
Similarity: 0.91
[ 314-41-0 ]
1,2,3,5-Tetrafluoro-4-nitrobenzene
Similarity: 0.91
[ 932373-92-7 ]
1,3-Difluoro-5-methyl-2-nitrobenzene
Similarity: 0.91
[ 314-41-0 ]
1,2,3,5-Tetrafluoro-4-nitrobenzene
Similarity: 0.91
[ 932373-92-7 ]
1,3-Difluoro-5-methyl-2-nitrobenzene
Similarity: 0.91
[ 314-41-0 ]
1,2,3,5-Tetrafluoro-4-nitrobenzene
Similarity: 0.91
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :