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CAS No. : | 125568-71-0 | MDL No. : | MFCD07779369 |
Formula : | C8H5F2NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KLMBOVOUTOBMLS-UHFFFAOYSA-N |
M.W : | 217.13 | Pubchem ID : | 11447263 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | 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 |
---|---|---|
96% | With iron; acetic acid In water at 40℃; for 1.5 h; | Iron powder (12 3 g, 0 22 mol, 4 equiv) was added to a solution of methyl 2,4-dιfluoro-5- nitrobenzoate intermediate 18 (12 0 g, 0 06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40 0C for 1 5 h The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate The organics were washed with satd aq NaCI, dried over Na2SO4, filtered and concentrated to give intermediate 19 (10 Og, 96percent yield) as a brown solid 1H NMR (400 MHz, DMSO-cfe) δ ppm 7 27 (dd, J=9 98, 742 Hz, 1 H), 7 14 (t, J=10 99 Hz, 1 H), 5 28 (s, 2 H), 3 77 (s, 3 H) ES-LCMS m/z 189 0 (M+H) |
96% | at 40℃; for 1.5 h; | Intermediate 5; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4- difluoro-5-nitrobeπzoate intermediate 17 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 400C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na- 2SO4, filtered and concentrated to give intermediate 5 (10.0g, 96percent yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H). |
96% | at 40℃; for 1.5 h; | Intermediate 3; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4-difluoro-5- nitrobenzoate intermediate 2 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 400C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na2SO4, filtered and concentrated to give intermediate 3 (10.Og, 96percent yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In 1,4-dioxane for 16 h; Heating / reflux | Step 1:To a solution of 2,4-difluoro-5-nitrobenzoic acid (4.96 g, 24.4 mmol, 1 eq) in MeOH (100 mL), was added a solution of 4N HCI in 1 ,4-dioxane (9 ml_). The reaction mixture was heated to reflux for 16 h, then cooled to RT and the MeOH was evaporated under vacuum. The residue was dissolved in EtOAc (50 mL) and the organic phase was washed with aqueous saturated NaHCO3 (25 mL) and brine (25 mL), then dried over MgSO4, filtered and concentrated. A quantitative yield of the ester 3a was obtained as a yellow solid (5.30 g, 24.4 mmol). |
93% | at 65℃; for 40 h; | 2,4-difluoro-5-nitrobenzoic acid (25.00 g, 123 mmol) was dissolved in MeOH (300 mL). Sulfuric acid (0.7 mL, 12.3 mmol, 0.1 eq) was added dropwise. The reaction was heated to 65 °C for 40 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was taken up into DCM (100 mL) and washed with water (50 mL), aqueous saturated NaHC03solution (50 mL) and brine (50 mL). The aqueous layer was back-extracted with DCM (2 x 50 mL). The combined organic phases were dried over Na2S04, filtered and concentrated under reduced pressure to afford 25.21g of the desired product as a light brown solid. Yield: 93percent in 99percent purity. |
92% | for 15 h; Heating / reflux | Preparation of methyl 2,4-difluoro-5-nitrobenzoate (Chem. Abstr. Reg. No. 125568-71-0); 2,4-Difluoro-5-nitrobenzoic acid (33.0 g, 162 mmol) was dissolved in 400 mL anhydrous methanol under an argon atmosphere, added 4 mL concentrated sulfuric acid, then heated to reflux for 15 hours. The solution was cooled and concentrated in vacuo. Redissolved in 400 mL diethyl ether, washed with sat. sodium bicarbonate (3 x 200 mL), brine, dried with magnesium sulfate, filtered and concentrated to yield title compound. (32.6 g, 92percent) APCI" 217.0; Anal. HPLC Retention time = 15.7 minutes (>99percent pure). |
85% | for 18 h; Heating / reflux | Sulfuric acid (3 mL) was added to a solution of 2,4-dιfluoro-5-nιtrobenzoιc acid intermediate 17(100 g, 049 mol, 1 equiv) in methanol (700 mL) and the reaction heated to reflux for 18 h The reaction mixture was concentrated and the residue taken up in water and brought to pH 8 by addition of 1N NaOH The product was extracted into ethyl acetate, dried over Na2SO4, filtered and concentrated The residue was purified by silica gel flash column chromatography (0 --> 25percent EtOAc Hexanes) to give intermediate 18 (90 g, 85percent yield) as a tan solid1H NMR (400 MHz, DMSO-cfe) δ ppm 8 56 - 8 64 (m, 1 H), 7 83 - 7 94 (m, 1 H), 3 85 - 3 92 (m, 3 H) |
85% | for 18 h; Heating / reflux | Intermediate 17; methyl 2,4-difluoro-5-nitrobenzoate; <n="24"/>Sulfuric acid (3 mL) was added to a solution of 2,4-difluoro-5-nitrobeπzoic acid intermediate 16 (100 g, 0.49 mol, 1 equiv) in methanol (700 mL) and the reaction heated to reflux for 18 h. The reaction mixture was concentrated and the residue taken up in water and brought to pH 8 by addition of 1 N NaOH. The product was extracted into ethyl acetate, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (0 --> 25percent EtOAc: Hexanes) to give intermediate. 7 (90 g, 85percent yield) as a tan solid. 1H NMR (400 MHz, DMSO-cfe) δ ppm 8.56 - 8.64 (m, 1 H), 7.83 - 7.94 (m, 1 H), 3.85 - 3.92 (m, 3 H). |
85% | for 18 h; Heating / reflux | Intermediate 2; methyl 2,4-difluoro-5-nitrobenzoate; <n="13"/>Sulfuric acid (3 mL) was added to a solution of 2,4-difluoro-5-nitrobenzoic acid intermediate 1 (100 g, 0.49 mol, 1 equiv) in methanol (700 mL) and the reaction heated to reflux for 18 h. The reaction mixture was concentrated and the residue taken up in water and brought to pH 8 by addition of 1N NaOH. The product was extracted into ethyl acetate, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (0 --> 25percent EtOAc: Hexanes) to give intermediate 2 (90 g, 85percent yield) as a tan solid.1H NMR (400 MHz, DMSO-Cf6) δ ppm 8.56 - 8.64 (m, 1 H), 7.83 - 7.94 (m, 1 H), 3.85 - 3.92 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 g | at 20℃; for 0.5 h; | 0.80mL fuming nitric acid was added dropwise 5mL concentrated sulfuric acid, stirred for 5min,Methyl 2,4-difluorobenzoate was added dropwise(1.50g, 8.71mmol, 1.0eq), and then reacted at room temperature for 30min, poured into ice water to precipitate a white solid, which was suction filtered to give a white solidProducts, dry, white solid product 1.8g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With iron; acetic acid; In water; at 40℃; for 1.5h; | Iron powder (12 3 g, 0 22 mol, 4 equiv) was added to a solution of methyl 2,4-diotafluoro-5- nitrobenzoate intermediate 18 (12 0 g, 0 06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40 0C for 1 5 h The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate The organics were washed with satd aq NaCI, dried over Na2SO4, filtered and concentrated to give intermediate 19 (10 Og, 96% yield) as a brown solid 1H NMR (400 MHz, DMSO-cfe) delta ppm 7 27 (dd, J=9 98, 742 Hz, 1 H), 7 14 (t, J=10 99 Hz, 1 H), 5 28 (s, 2 H), 3 77 (s, 3 H) ES-LCMS m/z 189 0 (M+H) |
96% | With water; iron; acetic acid; at 40℃; for 1.5h; | Intermediate 5; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4- difluoro-5-nitrobe?zoate intermediate 17 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 400C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na- 2SO4, filtered and concentrated to give intermediate 5 (10.0g, 96% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) delta ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H). |
96% | With water; iron; acetic acid; at 40℃; for 1.5h; | Intermediate 3; methyl 5-amino-2,4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2,4-difluoro-5- nitrobenzoate intermediate 2 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 400C for 1.5 h. The reaction mixture was filtered thru a pad of celite and the filtered solution extracted with ethyl acetate. The organics were washed with satd. aq. NaCI, dried over Na2SO4, filtered and concentrated to give intermediate 3 (10.Og, 96% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) delta ppm 7.27 (dd, J=9.98, 7.42 Hz, 1 H), 7.14 (t, J=10.99 Hz, 1 H), 5.28 (s, 2 H), 3.77 (s, 3 H). ES-LCMS: m/z 189.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In tetrahydrofuran; at 0℃; for 1h; | Step i:To a cooled solution (00C) of ester 3a (Example 3, step 1) (1.63 g ,7.52 mmol, 1 eq.) in THF (7 ml_), was added triethylamine (1.05 ml_,7.52 mmol, 1 eq.) and a solution of methylamine in THF (2N, 5.65 ml_,11.2 mmol, 1.5 eq.). The reaction mixture was allowed to stir for 1h at 00C, then was diluted with EtOAc (100 ml_), and washed withH2O (40 ml_) and brine. The organic phase was dried over MgSO4 and concentrated.The crude material 4a (1.70 g, 99% yield) was used in the next step without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 0℃; for 2h; | Step 2:A solution of ester 3a (3.0 g, 14 mmol) in THF (53 mL) was cooled in an ice bath, and triethylamine (3.85 mL, 27.6 mmol, 2 eq) and diallyl amine (2.4 mL, 19 mmol, 1.4 eq) were added. The reaction mixture was allowed to stir for 2 h, then was diluted with EtOAc (75 mL) and washed with HCI (0.1 N, 50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 3b (4.00 g) as a yellow EPO <DP n="47"/>oil, in a mixture with the bis allyl amine adduct (< 10 % of side product). The mixture was used in the subsequent reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; nitric acid; | Preparation of 2,4-Difluoro-5-nitrobenzoic acid methyl ester Fuming nitric acid 90% (8.5 mL, 0.19 mol) was added with gentle stirring to concentrated sulfuric acid 98% (125 mL) in a 1 L beaker. After stirring for 10 minutes at room temperature, 2,4-difluorobenzoic acid methyl ester (21.9 g, 0.127 mol) was added dropwise. After the addition, the reaction mixture was allowed to stir gently for 40 minutes at room temperature. The reaction mixture was then poured into ice-H2O (1 L) and stirred for 10 minutes. The mixture was extracted with EtOAc. The layers were separated, and the organic layer was washed sequentially with 1 NaCl, saturated NaHCO3, H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow residue. This residue was washed with 10% EtOAc/hexane, filtered, and dried to yield a pale yellow solid, 29.0 g (0.133 mol, 82%). mp 78-80 C. Analysis for C8H5F2NO4: Calcd: C, 44.25; H, 2.32; N, 6.45. Found: C, 44.18; H, 2.39; N, 6.14. | |
1.8 g | With sulfuric acid; nitric acid; at 20℃; for 0.5h; | 0.80mL fuming nitric acid was added dropwise 5mL concentrated sulfuric acid, stirred for 5min,Methyl 2,4-difluorobenzoate was added dropwise(1.50g, 8.71mmol, 1.0eq), and then reacted at room temperature for 30min, poured into ice water to precipitate a white solid, which was suction filtered to give a white solidProducts, dry, white solid product 1.8g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; | Preparation of tert-butyl 4-[5-fluoro-4-(methoxycarbonyl)-2- nitrophenyl]amino}piperidine-1-carboxylate; <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (32.6 g, 150 mmol) was dissolved in 100 mL N, N- dimethylformamide, added 4-amino-1-Boc-piperidine (30.7 g, 153 mmol), washed sides of flask with 100 mL N,N-dimethylformamide, added N,N-diisopropylethylamine and stirred reaction at ambient temperature for 3 days. The solution was diluted with 500 mL diethyl ether, washed with water (2 x 250 mL), 0.5M hydrogen chloride (2 x 250 mL), brine (250 mL), dried with magnesium sulfate, filtered and concentrated to yield title compound slightly wet with diethyl ether. (62.4 g, quant yield) APCI" 396.2; Anal. HPLC Retention time = 20.2 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 10h; | Preparation of methyl 4-[(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-2-fluoro-5- nitrobenzoate; A solution of 2,4-diflouro-5-nitro-benzoic acid methyl ester (7.5 g, 34.7 mmol) in DMF (20 mL) was cooled to O0C, DIEA (30 mL) was added followed by the addition of a solution of 8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-ylamine 2HCI (10 g, 34.7 mmol) in DMF (20 mL). The reaction mixture was cooled to rt and maintained for 10 h. The reaction mass was diluted with DCM (1 L), the organic layer was washed with water (250 mL), brine solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue; residue was washed with pet ether (250 mL), filtered and dried to obtain the crude product as yellow solid (7.7 g, 55%). 1HNMR(CDCI3): delta 8.9(d, 1 H), 8.26(d, 1H), 7.3-7.45(m, 4H), 6.5(d, 1H), 3.9(s, 3H), 3.64-3.84(m, 1 H), 3.58(s, 2H), 3.32(s, 2H), 2.1- 2.25(m, 2H), 1.92-2.02(m, 2H) and 1.7-1.82(m, 4H). LC-MS APCI (m/z) = 414 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | With sulfuric acid; for 12h;Reflux; | General procedure: To a solution of 2-((2-chloro-6-fluorophenyl)amino)-lH-imidazo[4,5-f]quinoline-5- carboxylic acid (0.050g, 0.014 mmol) in methanol (10 mL) was added cone. H2SO4 (1 mL). The reaction mass was refluxed for 12 h. After completion of reaction, methanol was removed under vacuum. Water was added to the obtained reaction mass, basified with NaHCC"3 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.030 g of the desired product. MS [M+H]+ : 371.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.84 g | With triethylamine; In acetonitrile; at 20℃; for 4h;Cooling with ice; | Preparation Example 26 [0129] To a mixture of 4.10 g of 156 <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> and 40 mL of 81 acetonitrile was added 4.76 mL of 82 triethylamine, and 2.60 g of 100 2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole was gradually added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction mixture were added 72 water and 83 ethyl acetate, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 3.84 g of 157 methyl 2-fluoro-5-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzoate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | Step 5: Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60 % in mineral oil, 1.1 eq.) was added in portions at - 10C to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3- oxopiperazine-l-carboxylate (26.66 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at - 10C for 30 min. Then the mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at - 20 C over 10 min. After addition, the resulting mixture was stirred between - 20 C and - 30 C for another 10 min. The reaction was quenched with sat. aq. NH4C1 (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3 X 1 L). The combined organic layers were washed with water (3 X 1 L) and brine, and dried over anhydrous Na2S04. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with petroleum ether : EtOAc 8:1-4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2- isopropyl-3-oxopiperazine-l-carboxylate (32 g, 66.3% yield) as a yellow solid.LC-MS MS (ESI) m/z 384.1 [M - 56 +H]+, 462.1 [M + Naf.1 NMR (CDC13 300MHz): delta 8.63 (d, / = 6.9 Hz, 1H), 7.16 (d, / = 10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, / = 6.9 Hz, 3H), 1.01 (d, / = 6.9 Hz, 3H). | |
66.3% | Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60 % in mineral oil, 1.1 eq.) was added in portions at - 10C to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3- oxopiperazine- 1 -carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at - 10C for 30 min. The mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at - 20 C over 10 min. After addition, the resulting mixture was stirred between - 20 C and - 30 C for another 10 min. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3 X 1 L). The combined organic layers were washed with water (3 X 1 L) and brine, and then dried over anhydrous Na2S04. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE : EtOAc 8: 1-4: 1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2- isopropyl-3-oxopiperazine-l-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M - 56 +H]+, 462.1 [M + Na]+. 1H NMR (CDC13 300MHz): delta 8.63 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H). | |
66.3% | Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60 % in mineral oil, 1.1 eq.) was added in portions at - 10C to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3- oxopiperazine- 1-carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at - 10C for 30 mm. The mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at -20 C over 10 mm. After addition, the resulting mixture was stirred between - 20 C and - 30 C for another 10 mm. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3 X 1 L). The combined organic layers were washed with water (3 X 1 L) and brine, and then dried over anhydrous Na2SO4. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8: 1--4: 1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2- isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) mlz 384.1 [M - 56 +H], 462.1 [M + Naf?. ?H NMR (CDC13 300MHz): 5 8.63 (d, J= 6.9 Hz, 1H), 7.16 (d, J= 10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J= 6.9 Hz, 3H), 1.01 (d, J= 6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Steps 2 an To a solution of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (986 mg, 3.42 mmol) in DMF (5 mL) was added a 2 M solution of KOtBu in THF (2.14 mL, 4.28 mmol) dropwise at 0 C. The reaction stirred for 1 h at 0 C and was then cooled to - 78C. In a separate flask, a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (928 mg, 4.28 mmol) in DMF (15 mL) was cooled to -78 C. To this solution was added a solution of the above anion via cannula at -78 C over a 5 min period. The reaction was allowed to warm to - 50 C and stirred at this temperature for 2 h. Sat. aq. NH4C1 (20 mL) was added to quench the reaction, followed by EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3 x 15 mL). The EtOAc layers were combined, dried and evaporated to give crude (R)-methyl-2-fluoro-4-(3-isopropyl-2-oxo-4-(4- (trifluoromethyl)pyrimidin-2-yl)piperazin-l-yl)-5-nitrobenzoate which was taken on directly for the next step without further purification. LC-MS m/z 486.20 [M + H]+. | ||
To a solution of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin- 2-one (986 mg, 3.42 mmol) in DMF (5 mL) was added a 2 M solution of KOtBu in THF (2.14 mL, 4.28 mmol) dropwise at 0 C. The reaction stuffed for 1 h at 0 C and was then cooled to -78C. In a separate flask, a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (928 mg, 4.28 mmol) in DMF (15 mL) was cooled to -78 C. To this solution was added a solution of the above anion via cannula at -78 C over a 5 mm period. The reaction was allowed to warm to -50 C and stuffed at this temperature for 2 h. Sat. aq. NH4C1 (20 mL) was added to quench the reaction, followed by EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3 x 15 mL). The EtOAc layers were combined, dried and evaporated to give crude (R)-methyl-2-fluoro-4-(3-isopropyl-2-oxo-4-(4- (trifluoromethyl)pyrimidin-2-yl)piperazin- 1 -yl)-5-nitrobenzoate which was taken on directly for the next step without further purification.LC-MS mlz 486.20 [M + H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.5 g | With triethylamine; In tetrahydrofuran; at 22 - 26℃; for 12h; | To a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (5.0 g, 0.0246 mol) in THF, TEA (10 mL) and methyl amine HC1 (4.15 g, 0.067 mol) were added. The reaction mass was stirred at RT for 12 h. After completion of reaction, THF was removed and the obtained mass was diluted with water and extracted with EtOAc. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of the desired product. 1H NMR (DMSO- 6): delta 2.93 (s, 6H), 3.79 (s, 3H), 5.61 (s, 1H), 8.19 (br s, 1H), 8.43 (br s, 1H), 8.67 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide; | Steps 2 and 3 To a solution of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (986 mg, 3.42 mmol) in DMF (5 mL) was added a 2 M solution of KOtBu in THF (2.14 mL, 4.28 mmol) dropwise at 0 C. The reaction stirred for 1 h at 0 C. and was then cooled to -78 C. In a separate flask, a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (928 mg, 4.28 mmol) in DMF (15 mL) was cooled to -78 C. To this solution was added a solution of the above anion via cannula at -78 C. over a 5 min period. The reaction was allowed to warm to -50 C. and stirred at this temperature for 2 h. Sat. aq. NH4Cl (20 mL) was added to quench the reaction, followed by EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3*15 mL). The EtOAc layers were combined, dried and evaporated to give crude (R)-methyl-2-fluoro-4-(3-isopropyl-2-oxo-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-5-nitrobenzoate which was taken on directly for the next step without further purification. LC-MS m/z 486.20 [M+H]+. | |
In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide; | Steps 2 and 3 To a solution of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (986 mg, 3.42 mmol) in DMF (5 mL) was added a 2 M solution of KOtBu in THF (2.14 mL, 4.28 mmol) dropwise at 0 C. The reaction stirred for 1 h at 0 C. and was then cooled to -78 C. In a separate flask, a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (928 mg, 4.28 mmol) in DMF (15 mL) was cooled to -78 C. To this solution was added a solution of the above anion via cannula at -78 C. over a 5 min period. The reaction was allowed to warm to -50 C. and stirred at this temperature for 2 h. Sat. aq. NH4Cl (20 mL) was added to quench the reaction, followed by EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3*15 mL). The EtOAc layers were combined, dried and evaporated to give crude (R)-methyl-2-fluoro-4-(3-isopropyl-2-oxo-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-5-nitrobenzoate which was taken on directly for the next step without further purification. LC-MS m/z 486.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | In water; N,N-dimethyl-formamide; mineral oil; | Step 5 Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at 10 C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.66 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at 10 C. for 30 min. Then the mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at 20 C. over 10 min. After addition, the resulting mixture was stirred between 20 C. and 30 C. for another 10 min. The reaction was quenched with sat. aq. NH4Cl (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3*1 L). The combined organic layers were washed with water (3*1 L) and brine, and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with petroleum ether: EtOAc 8:1-4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): delta 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H). |
66.3% | In water; N,N-dimethyl-formamide; mineral oil; | Step 5 Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at 10 C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at 10 C. for 30 min. The mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at 20 C. over 10 min. After addition, the resulting mixture was stirred between 20 C. and 30 C. for another 10 min. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3*1 L). The combined organic layers were washed with water (3*1 L) and brine, and then dried over anhydrous Na2SO4. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1-4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]', 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): delta 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H). |
66.3% | In water; N,N-dimethyl-formamide; mineral oil; | Step 5 Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at -10 C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at -10 C. for 30 min. The mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at -20 C. over 10 min. After addition, the resulting mixture was stirred between -20 C. and -30 C. for another 10 min. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3*1 L). The combined organic layers were washed with water (3*1 L) and brine, and then dried over anhydrous Na2SO4. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1?4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): delta 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H). |
66.3% | In water; N,N-dimethyl-formamide; mineral oil; | Step 5 Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at -10 C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.66 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at -10 C. for 30 min. Then the mixture was added dropwise to a 1 L three-neck flask containing <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at -20 C. over 10 min. After addition, the resulting mixture was stirred between -20 C. and -30 C. for another 10 min. The reaction was quenched with sat. aq. NH4Cl (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3*1 L). The combined organic layers were washed with water (3*1 L) and brine, and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with petroleum ether:EtOAc 8:1?4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): delta 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | A solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (CAS No. [125568-71 -0]; 15.7 g, 72.3 mmol) in acetonitrile (360 mL) was treated with triethylamine (1.30 eq., 13.1 mL, 94.0 mmol) and 3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commercially available; 1.40 eq., 14.3 g, 101 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (300 mL) and the pH of the mixture was adjusted to pH 3 by addition of aqueous HCl (2M). The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give a mixture of (±) methyl 2-fluoro-5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±) methyl 4-fluoro-5-nitro-2-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca 78:22, 33.5 g, quant.). The material (which contained minor amounts of the corresponding trans-products) was used in the next step without further purification. (0548) UPLC-MS (ESI+): [M + H]+ = 339; Rt = 1.72 / 1.76 min. Step 2: (±) methyl 2-methoxy-5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate In analogy to step 1 of intermediate 1 -28: An ice-cooled mixture of (±) methyl 2-fluoro- 5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±) methyl 4-fluoro-5- nitro-2-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca 78:22; 7.00 g, 16.5 mmol) from step 1 in methanol (15 mL) was slowly treated with a solution of sodium methanolate in methanol (CAS No. [124-41 -4]; 10 eq., 38 mL of a 30wt% solution) and stirred at 0 C for 1 hour. The suspension was taken up with ethyl acetate and washed with water. The phases were separated, the organic layer dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiO2-hexane/ ethyl acetate) to give the title compound (2.9 g, 50%) as racemic cis diastereomer. UPLC-MS (ESI+): [M + H]+ = 351 ; Rt = 1.57 min. | |
50% | A solution of methyl 2.4-difluoro-5-nitrobenzoate (CAS No. [125568-71 -0]; 15.7 g, 72.3 mmol) in acetonitrile (360 mL) was treated with triethylamine (1 .30 eq., 13.1 mL, 94.0 mmol) and (±) 3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commercially available; 1 .40 eq. , 14.3 g, 101 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (300 mL) and the pH of the mixture was adjusted to pH 3 by addition of aqueous hydrochloric acid (2M). The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give a mixture of (±) methyl 2-fluoro-5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±) methyl 4-fluoro-5-nitro-2-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca 78:22, 33.5 g, quant.). The material (which contained minor amounts of the corresponding trans-products) was used in the next step without further purification. UPLC-MS (ESI+): [M + H]+ = 339; Rt = 1 .72 / 1 .76 min. An ice-cooled mixture of (±) methyl 2-fluoro-5-nitro-4-[(cis)-3,3,5-trimethylcyclo- hexyl]amino}benzoate and (±) methyl 4-fluoro-5-nitro-2-[(cis)-3,3,5-trimethylcyclo- hexyl]amino}benzoate (ca 78:22; 7.00 g, 16.5 mmol) from step 1 in methanol (15 mL) was slowly treated with a solution of sodium methoxide in methanol (CAS No. [124-41 - 4]; 10 eq., 38 mL of a 30wt% solution) and stirred at 0 C for 1 hour. The suspension was taken up with ethyl acetate and washed with water. The phases were separated, the organic layer dried with sodium sulfate and concentrated in vacuo. The obtained material was purified by flash chromatography (SiC hexane/ ethyl acetate) to give the title compound (2.9 g, 50%) as racemic cis diastereomer. UPLC-MS (ESI+): [M + H]+ = 351 ; R, = 1 .57 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; at 20℃; | A solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (CAS No. [125568-71 -0]; 15.7 g, 72.3 mmol) in acetonitrile (360 mL) was treated with triethylamine (1.30 eq., 13.1 mL, 94.0 mmol) and 3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commercially available; 1.40 eq., 14.3 g, 101 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (300 mL) and the pH of the mixture was adjusted to pH 3 by addition of aqueous HCl (2M). The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give a mixture of (±) methyl 2-fluoro-5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±) methyl 4-fluoro-5-nitro-2-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca 78:22, 33.5 g, quant.). The material (which contained minor amounts of the corresponding trans-products) was used in the next step without further purification. (0548) UPLC-MS (ESI+): [M + H]+ = 339; Rt = 1.72 / 1.76 min. | |
With triethylamine; In acetonitrile; at 20℃; | A solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (CAS No. [125568-71-0]; 15.7 g, 72.3 mmol) in acetonitrile (360 mL) was treated with triethylamine (1.30 eq., 13.1 mL, 94.0 mmol) and 3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commercially available; 1.40 eq., 14.3 g, 101 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (300 ml.) and the pH of the mixture was adjusted to pH 3 by addition of aqueous hydrochloric acid (2M). The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give a mixture of (±) methyl 2-fluoro-5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±) methyl 4-fluoro-5-nitro-2-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca 78:22, 33.5 g, quant.). The material (which contained small amounts of the corresponding trans-products) was used in the next step without further purification. UPLC-MS (ESI+): [M + H]+ = 339; Rt = 1.72 / 1.76 min. | |
With triethylamine; In acetonitrile; at 20℃; | A solution of methyl 2.4-difluoro-5-nitrobenzoate (CAS No. [125568-71 -0]; 15.7 g, 72.3 mmol) in acetonitrile (360 mL) was treated with triethylamine (1 .30 eq., 13.1 mL, 94.0 mmol) and (±) 3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commercially available; 1 .40 eq. , 14.3 g, 101 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (300 mL) and the pH of the mixture was adjusted to pH 3 by addition of aqueous hydrochloric acid (2M). The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried with sodium sulfate and concentrated in vacuo to give a mixture of (±) methyl 2-fluoro-5-nitro-4-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±) methyl 4-fluoro-5-nitro-2-[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca 78:22, 33.5 g, quant.). The material (which contained minor amounts of the corresponding trans-products) was used in the next step without further purification. UPLC-MS (ESI+): [M + H]+ = 339; Rt = 1 .72 / 1 .76 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 10℃; for 2h;Inert atmosphere; | [000119] To a stirred solution of methyl 2, 4-difluoro-5-nitrobenzoate 51(9.0 g, 41.45 mmol) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1(6.97 g, 41.45 mmol), cesium carbonate (14.82 g, 45.60 mmol) at 0 C; warmed to 10 C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (800 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 52 (11 g, 73%) as an off-white solid. TLC: 10% EtOAc/ hexanes (R 0.4); 1H NMR (DMSO-d6,400 MHz): oe 8.69 (d, J= 6.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.81-7.69 (m, 3H), 6.60 (d,J= 11.5 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonia; In tetrahydrofuran; water; for 0.5h; | To a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (6.00 g, 27.6 mmol) in THF (25 mL) in an ice bath was added concentrated aqueous ammonia (5.20 mL, 78.0 mmol). After stirring for 30 min, THF (25 ml) was added to thin the very thick mixture, which was then allowed to warm to rt overnight. Solvent was removed and the residue was suspended in water (100 mL). The mixture was stirred for 30 min. The solids were filtered and washed with water to give methyl 4-amino-2-fluoro-5-nitrobenzoate (4.85 g, 82%). LCMS (ESI+): m/z = 215.0 (M+H). 1H NMR (400 MHz, DMSO-d6) delta 8.60 (d, J = 7.6 Hz, 1 H), 8.07 (bs, 2 H), 6.80 (d, J = 13.2 Hz, 1 H), 3.81 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
731 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | tert-Butylamine (420 mu, 2.00 mmol) in THF (5 ml) was added dropwise to a solution of <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (826 mg, 2.80 mmol) and DIEPA (1.29 ml, 7.6 mmol) in THF (10 ml) at 0 C and the mixture slowly reached room temperature overnight. One more portion of tert-butylamine (420 mu, 2.00 mmol) was added and the mixture stirred at room temperature for 2 h. EtOAc and water were added. The organic layer was washed with sat. NaHC03 and evaporated. The residue was purified by flash chromatography using toluene as eluent. Yield: 731 mg; yellow solid, methyl 4-(tert-butylamino)-2-fluoro-5- nitrobenzoate.MS(ESI+) m/z 111 [M+H]+. HPLC purity: 100%. 1H NMR (600 MHz, DMSO- d6) delta ppm 8.68 (d, J=7.9 Hz, 1 H), 8.53 (s, 1 H), 7.02 (d, J=14.0 Hz, 1 H), 3.82 (s, 3 H), 1.47 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 5.08333h;Inert atmosphere; | To a 0 C solution of methyl 2,4-difluoro-5nitrobenzoate (2406 mg, 11.08 mmol, Ace Synthesis, LLC) and (R)(6chioro4 (dirnethox methyl) 1,2,3,4- tetrahydronaphthalen-1-yi)methanoi (Intermediate AA1 1, Step 7; 2000 mg, 7.39mmol) in TFIF (37 mL) under N2 atmosphere was added LiH]?iDS (8.86 mL, 8.86 mrnol, 1.0 M solution in THF) dropwise over 5 mm. The resulting solution was allowed to warm to ambient temperature and stirred for 5.0 hr. The reaction mixture was slowly poured into a saturated aqueous NH4CI solution (30 mL) and diluted with water (20 mL). The organic layer was separated and the aqueouslayer was back extracted with EtOAc (2 >< 50 inL). The organic layers were combined, washed with water (15 mL) and brine (10 rnL), and dried over Mg504. After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on 40 g ISCO Gold silica gel column with 0-50% EtOAc/Hexanes to provide the title compound as a 1:1 mixture (2.78 g, 5.94mmol. 80% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 0 C solution of methyl 2,4-difluoro-5nitrobenzoate (2406 mg, 11.08 mmol, Ace Synthesis, LLC) and (R)(6chioro4 (dirnethox methyl) 1,2,3,4- tetrahydronaphthalen-1-yi)methanoi (Intermediate AA1 1, Step 7; 2000 mg, 7.39mmol) in TFIF (37 mL) under N2 atmosphere was added LiH]?iDS (8.86 mL, 8.86 mrnol, 1.0 M solution in THF) dropwise over 5 mm. The resulting solution was allowed to warm to ambient temperature and stirred for 5.0 hr. The reaction mixture was slowly poured into a saturated aqueous NH4CI solution (30 mL) and diluted with water (20 mL). The organic layer was separated and the aqueouslayer was back extracted with EtOAc (2 >< 50 inL). The organic layers were combined, washed with water (15 mL) and brine (10 rnL), and dried over Mg504. After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on 40 g ISCO Gold silica gel column with 0-50% EtOAc/Hexanes to provide the title compound as a 1:1 mixture (2.78 g, 5.94mmol. 80% yield); A mixture of (R)-methyl 4-((6-chioro- 1 -(dirnethoxymethyl)- 1,2,3,4- tetrahvdronaphthaien- I -yi)methoxy)-2-fluoro-5-nitrohenzoate and (R)-methyl 2-((6-chl oro- I -(dirnethox methyl)- I ,2,3,4-tetrahy dronaphthalen- I -yl)methoxy)-4- fluoro-5-nitrobenzoate (1:1 mixture, 198 g), and Pt02(98 mg, Sigma-Aldrich) in EtOAc (15 rnL) was left stirring under H2 atmosphere at ii for 30 h. The resulting reaction flask was purged with N2 for 5 mm, and the solid was removed byfiltration and washed with EtOAc After removal of organic solvents under reduced pressure, the crude material was taken on to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 0 C solution of methyl 2,4-difluoro-5nitrobenzoate (2406 mg, 11.08 mmol, Ace Synthesis, LLC) and (R)(6chioro4 (dirnethox methyl) 1,2,3,4- tetrahydronaphthalen-1-yi)methanoi (Intermediate AA1 1, Step 7; 2000 mg, 7.39mmol) in TFIF (37 mL) under N2 atmosphere was added LiH]?iDS (8.86 mL, 8.86 mrnol, 1.0 M solution in THF) dropwise over 5 mm. The resulting solution was allowed to warm to ambient temperature and stirred for 5.0 hr. The reaction mixture was slowly poured into a saturated aqueous NH4CI solution (30 mL) and diluted with water (20 mL). The organic layer was separated and the aqueouslayer was back extracted with EtOAc (2 >< 50 inL). The organic layers were combined, washed with water (15 mL) and brine (10 rnL), and dried over Mg504. After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on 40 g ISCO Gold silica gel column with 0-50% EtOAc/Hexanes to provide the title compound as a 1:1 mixture (2.78 g, 5.94mmol. 80% yield); A mixture of (R)-methyl 4-((6-chioro- 1 -(dirnethoxymethyl)- 1,2,3,4- tetrahvdronaphthaien- I -yi)methoxy)-2-fluoro-5-nitrohenzoate and (R)-methyl 2-((6-chl oro- I -(dirnethox methyl)- I ,2,3,4-tetrahy dronaphthalen- I -yl)methoxy)-4- fluoro-5-nitrobenzoate (1:1 mixture, 198 g), and Pt02(98 mg, Sigma-Aldrich) in EtOAc (15 rnL) was left stirring under H2 atmosphere at ii for 30 h. The resulting reaction flask was purged with N2 for 5 mm, and the solid was removed byfiltration and washed with EtOAc After removal of organic solvents under reduced pressure, the crude material was taken on to the next step without further purification; A mixture of (R}-methyi 5-arnino-4-((6-chloro- 1 -(dimethoxymethvi)I .2,3,4-tetrahy dronaphthalen- I -vl)methoxy)-2-fluorobenzoate and ((R)-methyl 5- arnino-2-((6-chloro- I -( imethoxymethyl>-1 ,2,3,4-tetrahydronaphthalen- 1-yl)methoxy)-4-fluorobenzoate (1:1 mixture) and HCi (4.0 N in 1 ,4-dioxane, Sigma Aldrich. 10,0 mL) was stirred at ambient temperature for 1.5 hr. The mixture was then slowly poured into saturated aq. NaHCO3 (10 mL), diluted with water (10 mL), and extracted with DCM (2 > 20 mL). After removal of organic solvents under reduced pressure, the crude material was taken on to the next stepwithout further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 mg | With triethylamine; In 1,4-dioxane; at 80℃; for 16h; | Methyl 2,4-difluoro-5-nitrobenzoate (0.80 g, 3.7 mmol, 1.0 eq) and 7-benzyl- 4,7-diazaspiro[2.5] octane (0.75 g, 3.7 mmol, 1.0 eq) was added to 20 mL 1,4-dioxane and 4 mL triethylamine at 80 C.16h. The reaction mixture was cooled, poured into water, extracted with DCM, dried over and passed through a column of PE / EA (v / v) = 20/1 to give a yellow oil400 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 80℃; for 3h;pH 1.0; | To a stirred solution of intermediate 11-01' (99%, 24 g, 110 mmol, 1.01 eq) and A/-(tert-butoxycarbonylH-cysteine (95%, 5.500 g, 24 mmol, leq) in DCE (700 mL) was added DIPEA (30.55mL, 219 mmol, 2 eq). The reaction was heated to 80 C and stirred for 3 h. The reaction mixture was added to water (400 mL) and DCM (200 mL) and acidified to pH 1 with IN HCI. The organic layer was separated and washed with brine (200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to afford the crude product as a yellow foam, which was used in the next step without further purification. Yield 45.90 g, 81% in 81% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate A-03 (466 mg, 1.78 mmol) was dissolved in 1,2-dichloroethane (30 mL). Then, DIPEA (0.50 mL, 3.57 mmol) was added. The resulting mixture was stirred at RT for 5 min before adding <strong>[125568-71-0]methyl 2,4-difluoro-5-nitrobenzoate</strong> (387 mg, 1.78 mmol). The resulting mixture was stirred for 22 h, before it was partitioned between DCM (40 mL) and water (40 mL). The pH was adjusted to pH=l by addition of 1M aqueous HCI. The organic phase was separated and dried over MgS04, filtered and the filtrate was concentrated under reduced pressure to afford 767 mg of a yellow oil in 55% UV purity and 55% yield. |
Tags: 125568-71-0 synthesis path| 125568-71-0 SDS| 125568-71-0 COA| 125568-71-0 purity| 125568-71-0 application| 125568-71-0 NMR| 125568-71-0 COA| 125568-71-0 structure
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Code | Phrase |
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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 |
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