Structure of 143062-84-4
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CAS No. : | 143062-84-4 |
Formula : | C10H14FNO3S |
M.W : | 247.29 |
SMILES Code : | N[C@H]1[C@@H](F)C1.O=S(C2=CC=C(C)C=C2)(O)=O |
MDL No. : | MFCD01861147 |
InChI Key : | XUWZMHVPMZXIRU-LMLSDSMGSA-N |
Pubchem ID : | 53350313 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 58.45 |
TPSA ? Topological Polar Surface Area: Calculated from |
88.77 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.18 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-1.35 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.8 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.3 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.64 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.73 |
Solubility | 45.6 mg/ml ; 0.184 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.01 |
Solubility | 239.0 mg/ml ; 0.967 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.13 |
Solubility | 1.83 mg/ml ; 0.00741 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-8.77 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.7 |
* 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 |
---|---|---|
With triethylamine; In toluene; at -10 - 20℃; for 1h; | 4-[(3S,4S)-3-tertiary butoxycarbonyl amino-4-fluoromethyl-1-pyrrolidinyl]-2,5-difluoro-3-methylbenzoyl acetate (334 mg, 0.729 mmol) and N,N-dimethylformamide dimethylacetal (0.194 ml, 1.46 mmol) were dissolved in benzene (6 ml), and the mixture was stirred 3 hours by heating in an oil bath at an external temperature of 80°C. The reaction solution was allowed to cool, and concentrated under reduced pressure to dryness. The resulting yellow oily product was dissolved in toluene (10 ml), and to this solution was added paratoluenesulfonate salt of (1R,2S)-2-fluorocyclopropylamine (270 mg, 1.09 mmol). The mixture was stirred at -10°C, and triethylamine (0.158 ml, 1.13 mmol) was added dropwise with stirring. The reaction solution was stirred at room temperature for 1 hour, and water (150 ml) and ethyl acetate (20 x 2 ml) were added to the solution. The solution was washed with saturated aqueous solution of sodium chloride (15 ml), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The yellow oily product was dissolved in dimethylformamide (5 ml), and potassium carbonate (202 mg, 1.46 mmol) was added in an ice bath, and the solution was stirred at room temperature for 4 days. To the reaction solution was added 10percent aqueous solution of citric acid (20 ml) in an ice bath, and the precipitated crystals were collected by filtration. The crystals were washed with an excess amount of purified water, and the resulting crude crystals were subjected to silica gel column chromatography to obtain 277 mg (73percent) of the title compound as pale yellow powder from the eluate of a mixed solution of chloroform and methanol (95 : 5). 1H-NMR (400 MHz, CDCl3) delta: 1.20-1.34 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 2.57 (3H, s), 2.88 (1H, s), 3.14-3.18 (1H, m), 3.44-3.60 (2H, m), 3.80-3.92 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 4.50-4.56 (1H, m), 4.65-4.70 (1H, m), 4.74-4.82 (1H, m), 4.94-4.90 (1H, m), 7.96 (1H, d, J = 13.2 Hz), 8.53 (1H, d, J = 2.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In toluene; at 25℃; for 0.166667h; | Example 3: Ethyl 3-[(1R,2S)-2-fluoro-1-cyclopropylamino]-2-[4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluorobenzoyl-3-methoxy]acrylate; A <strong>[143062-84-4](1R,2S)-2-fluorocyclopropylamine p-toluenesulfonic acid salt</strong> (359 mg, 1.0 eq.) was added to a solution containing ethyl 3-ethoxy-2-[4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluorobenzoyl-3-methoxy]acrylate (760 mg, 1.45 mmol), toluene (15.2 mL), and triethylamine (0.22 mL, 1.1 eq.), and the mixture was stirred for 10 minutes at 25°C. The formed organic layer was washed with water (10 mL .x. 2) and saturated saline (10 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure, to thereby yield 790 mg of the title compound as a yellow-orange (99percent).1H-NMR (270 MHz, CDCl3) delta: 0.61-1.31 (6H, m), 1.12 (3H, t, J = 7.0 Hz), 1.39 (9H, s), 3.18-4.13 (6H, m), 3.83 (3H, s), 4.10 (2H, q, J = 7.0 Hz, 10.3 Hz), 4.81 (1H, m), 7.25 (1H, m), 8.13 (1H, d, J = 13.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In toluene; at 25℃; for 0.5h; | Example 6: Ethyl 3-[(1R,2S)-2-fluoro-1-cyclopropylamino]-2-[4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluorobenzoyl]acrylate; Ethyl 4-[7-(S)-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-2,5-difluorobenzoylacetate (1.00 g, 2.29 mmol) was dissolved in acetic anhydride (2.16 mL, 10 eq.) and ethyl orthoformate (3.79 mL, 10 eq.), and the mixture was stirred for three hours at 130°C. After the reaction mixture was allowed to cool down, the solvent was removed under reduced pressure. Toluene (10 mL) was added to the residue, and the mixture was subjected to co-boiling twice. After completion of co-boiling, toluene (30 mL), triethylamine (0.38 mL, 1.2 eq.), and a <strong>[143062-84-4](1R,2S)-2-fluorocyclopropylamine p-toluenesulfonic acid salt</strong> (564 mg, 1.0 eq.) was added to the co-boiling residue, and the mixture was stirred for 30 minutes at 25°C. The formed organic layer was washed with water (20 mL) and an aqueous sodium bicarbonate solution (10 mL, NaHCO3, 1.0 g) and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1), and several fractions were combined. The solvent of the combined fraction was removed under reduced pressure, to thereby yield 870 mg of the title compound as a pale yellow solid (73percent).1H-NMR (270 MHz, CDCl3) delta: 0.69-1.50 (6H, m), 1.14 (3H, t, J = 7.0 Hz), 1.39 (9H, s), 3.16-4.00 (6H, m), 4.12 (2H, q, J = 7.0 Hz, 14.0 Hz), 4.82 (1H, m), 6.14 (1H, dd, J = 7.0 Hz, 14.0 Hz), 7.15 (1H, dd, J = 7.0 Hz, 14.0 Hz), 8.10 (1H, d, J = 13.5 Hz) MASS: m/e = 524 (FABMS) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ethyl {4-[(3R)-3-(1-tert-butoxycarbonylaminocyclopropyl)-pyrrolidin-1-yl]-2-fluoro-3-methoxybenzoyl}acetate (0.79 g) was dissolved in acetic anhydride (0.48 mL) and ethyl ortoformate (0.71 mL) at room temperature. The reaction liquid was heated (internal temperature: 120°C), stirred for 3 hours and then concentrated under reduced pressure. The concentrated residue was dissolved in toluene and toluene was distilled away under reduced pressure. The residue was added eith ethyl acetate (8.0 mL) and was dissolved therein, followed by addition of <strong>[143062-84-4](1R,2S)-2-fluorocyclopropylamine tosylate</strong> (0.46 g) and triethylamine (0.36 mL) in a water bath and stirring for two hours. An insoluble matter in the reaction mixture was distilled out, and the filtrate was washed with a saturated brine and water, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (1.11 g) of the title compound which is a mixture of E compound and Z compound as a red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethyl acetate; at 20℃; for 2h; | Example 2: Production of ethyl (E,Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-[(1R,2S)-fluorocy clopropylamine]acrylate To 22.3 g of ethyl 3-dimethylamino-2-(2,4-difluoro-3-methoxybenzoyl)acrylate was added 110 mL of ethyl acetate. While stirring the mixture at room temperature, 20.4 g of <strong>[143062-84-4](1R,2S)-2-fluorocyclopropylamine tosylate</strong> was added, and then 1.5 g of triethylamine was added dropwise to the mixture. After 2 hours, 30 mL of water was added to the reaction mixture, and the mixture was extracted with 25 mL of ethyl acetate and dried with anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 20.5 g of the title compound as a dark brown oily product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at -10 - 20℃; for 17h; | 3-Cyano-2,4,5-trifluorobenzoylethyl acetate (883 mg, 3.25 mmol) was dissolved in ethyl orthoformate (1.35 mL, 8.13 mmol). Acetic anhydride (1.07 mL, 11.4 mmol) was added thereto, and the resultant mixture was stirred at 100°C for 5 hours. The reaction mixture was concentrated under reduced pressure and co-boiled with toluene (5 mL .x. 3). The residue was dissolved in dichloromethane (20 mL). A <strong>[143062-84-4]2-(S)-fluoro-1-(R)-cyclopropylamine p-toluenesulfonic acid salt</strong> (964 mg, 3.90 mmol) was added thereto, triethylamine (679 muL, 4.88 mmol) was added dropwise to the resultant mixture under stirring at -10°C. After completion of dropwise addition, the reaction mixture was stirred at room temperature for 17 hours. Subsequently, water (150 mL) was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate (150 mL .x. 2). The organic layers were combined and washed with saturated brine (150 mL), followed by drying with sodium sulfate anhydrate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (8 mL). Potassium carbonate (898 mg, 6.50 mmol) was added thereto under stirring while cooling with ice, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled with ice, and 1N aqueous hydrochloric acid (15 mL) and water (30 mL) were added thereto, followed by stirring at room temperature for 2 hours. The solid matter that precipitated was collected through filtration and washed with water and a small amount of ethanol, to thereby yield the title compound as a pale yellow solid (890 mg, 82percent). 1H-NMR (CDCl3) delta ppm: 1.41(3H, t, J=7.1Hz), 1.74 (1H, d, J=25.4Hz), 1.86-1.97(1H,m), 3.95-4.00(1H,m), 4.41(2H,q,J=7.1Hz), 5.11(1H,d,J=62.3Hz), 8.55 (1H, dd, J=17.3, 8.5Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; | The reaction of the 5-bromo-2-([1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)isonicotinic acid takes place analogously to the reaction procedure in Example (Ik-127) using:100 mg (196 mumol) of 5-bromo-2-([1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)isonicotinic acid, 9.0 ml of dichloromethane, 48.3 mg (196 mumol) of (1R,2S)-2-fluorocyclopropanaminium 4-methylbenzenesulphonate, 96.6 mg (254 mumol) of HATU, 0.097 ml (587 mumol) of Huenig's base.The remaining residue is purified by means of column chromatography on silica gel using the eluent mixture cyclohexane:acetone (gradient).This gives 89.4 mg of 5-bromo-N-[(1R,2S)-2-fluorocyclopropyl]-2-([1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)isonicotinamide (80percent).1H-NMR (600 MHz, d3-acetonitrile): delta=9.65 (br. s, 1H), 8.52 (d, 1H), 8.22 (d, 1H), 4.75 (m, 1H), 3.97 (s, 3H), 2.88 (br. s, 1H), 1.01-1.22 (m, 2H) ppm.13C-NMR (600 MHz, d3-acetonitrile): delta=157.5; 151.8; 150.7; 148.3; 137.1; 114.2; 113.4; 111.2; 70.8; 39.6; 26.4; 12.2 ppm.HPLC-MSa): log P=3.19; mass (m/z)=568, 570 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | General procedure: A solution of keto esters 4a-d (1 mmol) and triethyl orthoformate (2.50 mL, 1.5 mmol) in acetic anhydride (5.5 mL, 6 mmol) was stirred for 8 h at reflux and concentrated under reduced pressure to give crude products 5a-d as yellow oils. To a solution of 5a-d and triethylamine (2.80 mL, 2 mmol) dissolved in dichloromethane (10 mL) was added (1R,2S)-fluorocyclopropanaminetosylate (3.71 g, 1.5 mmol) in portions and stirred for 2 h at room temperature, and then concentrated under reduced pressure togive crude products 6a-d as yellow oils. A mixture of 6a-d, DMF (10 mL) and K2CO3 (2.80 g, 2 mmol) was stirred for 1 h at 90 oC and then poured into water (100 mL). The precipitate was collected by filtration and purified by silica gel column chromatography to give the title compounds 7a-d (42.5-61.3percent, from 4a-d) as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | General procedure: A solution of keto esters 4a-d (1 mmol) and triethyl orthoformate (2.50 mL, 1.5 mmol) in acetic anhydride (5.5 mL, 6 mmol) was stirred for 8 h at reflux and concentrated under reduced pressure to give crude products 5a-d as yellow oils. To a solution of 5a-d and triethylamine (2.80 mL, 2 mmol) dissolved in dichloromethane (10 mL) was added (1R,2S)-fluorocyclopropanaminetosylate (3.71 g, 1.5 mmol) in portions and stirred for 2 h at room temperature, and then concentrated under reduced pressure togive crude products 6a-d as yellow oils. A mixture of 6a-d, DMF (10 mL) and K2CO3 (2.80 g, 2 mmol) was stirred for 1 h at 90 oC and then poured into water (100 mL). The precipitate was collected by filtration and purified by silica gel column chromatography to give the title compounds 7a-d (42.5-61.3percent, from 4a-d) as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | General procedure: A solution of keto esters 4a-d (1 mmol) and triethyl orthoformate (2.50 mL, 1.5 mmol) in acetic anhydride (5.5 mL, 6 mmol) was stirred for 8 h at reflux and concentrated under reduced pressure to give crude products 5a-d as yellow oils. To a solution of 5a-d and triethylamine (2.80 mL, 2 mmol) dissolved in dichloromethane (10 mL) was added (1R,2S)-fluorocyclopropanaminetosylate (3.71 g, 1.5 mmol) in portions and stirred for 2 h at room temperature, and then concentrated under reduced pressure togive crude products 6a-d as yellow oils. A mixture of 6a-d, DMF (10 mL) and K2CO3 (2.80 g, 2 mmol) was stirred for 1 h at 90 oC and then poured into water (100 mL). The precipitate was collected by filtration and purified by silica gel column chromatography to give the title compounds 7a-d (42.5-61.3percent, from 4a-d) as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 2h; | General procedure: A solution of keto esters 4a-d (1 mmol) and triethyl orthoformate (2.50 mL, 1.5 mmol) in acetic anhydride (5.5 mL, 6 mmol) was stirred for 8 h at reflux and concentrated under reduced pressure to give crude products 5a-d as yellow oils. To a solution of 5a-d and triethylamine (2.80 mL, 2 mmol) dissolved in dichloromethane (10 mL) was added (1R,2S)-fluorocyclopropanaminetosylate (3.71 g, 1.5 mmol) in portions and stirred for 2 h at room temperature, and then concentrated under reduced pressure togive crude products 6a-d as yellow oils. A mixture of 6a-d, DMF (10 mL) and K2CO3 (2.80 g, 2 mmol) was stirred for 1 h at 90 oC and then poured into water (100 mL). The precipitate was collected by filtration and purified by silica gel column chromatography to give the title compounds 7a-d (42.5-61.3percent, from 4a-d) as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
204 g | (1) Take 1.32 kg dimethyl malonate and 3.7 kg 1,1,2-tribromo-2-fluoroethane were added into a 50L in three-mouth flask. Dissolve in 15L anhydrous dimethylformamide. The three-mouth flask was placed in a 25 °C water bath. Under even stirring, add in batches 4.4 kg anhydrous potassium carbonate and react for 60 hours. the reaction end after adding ice water 30L, then ethyl acetate (8L × 5) extraction, the combined organic phase, the organic phase is washed to neutral saturated sodium chloride aqueous solution, then dried with anhydrous sodium sulfate, the solvent evaporation, then the residue by adding 3L ethyl ether, stirring in ice bath 4 hours, the final filtering to obtain 1.7 kg solid A.(2) The prepared solid A was added into a 10L hydrogenation autoclave. Add 6L methanol to dissolve. Then add 72g palladium-carbon as the catalyst. The hydrogen replaced the air in the autoclave 4 times. Under stirring conditions, continue to place hydrogen gas (5 atmospheric pressure) and react for 24 hours, filtering, solution concentrated to dry, the residue by adding 10L ethyl acetate, water washing (3L × 2), 2L saturated salt water washing, dried with anhydrous sodium sulfate, 78 °C to evaporate the solvent, get 898g B oily liquid.(3) The prepared oily liquid B was added into a 20L reactor. Add 5L dimethylformamide, 184 mL distilled water and 299g sodium chloride to prepare a mixed solution. Reflux reaction for 35 hours. Reaction liquid was added 12L distilled water, then ethyl acetate (2.5L × 6) extraction, the combined organic phase, the organic phase after the water washing (2L × 3), 2L saturated salt water washing, dried with anhydrous sodium sulfate, 114 °C atmospheric dryness to obtain 506g solid C.(4) The resulting solid C was added into a 10L reaction flask. Use 4L tetrahydrofuran and 2L distilled water to dissolve. Place in ice bath. Under stirring, add in batches 270g lithium hydroxide monohydrate. Maintan in ice water bath for 3 hours, then dropwise 4 mol/L hydrochloric acid to the reaction solution pH value is 2 - 3 the left and right, of the liquid, the resulting aqueous phase of ethyl acetate (1L × 3) extraction, the combined organic phase, 1L washing, 1L saturated salt water washing, dried with anhydrous sodium sulfate, concentrated, the residue dissolved in 0.5L ethyl acetate, stirring slowly dripping 4.5L petroleum ether, stirring at room temperature for 10 hours, filtering, washing the filter cake with petroleum ether, and a ground line to obtain 380g solid D.(5) The resulting solid D was added into 5L reaction flask. Use 3L ethanol to dissolve. Under stirring conditions, add dropwise 425g L-leucinamide in ethanol solution 0.5L. Heat to 50 °C and continue stirring for 3 hours. Then the solution cooled to room temperature and continue to stir 3 hours, filtering, the filter cake is washed with ethanol, and a ground line, the filter cake is dissolved into to the 2.5L acetonitrile and 0.5L in ethanol mixed solution, heating to 50 °C stirring 2 hours, then cooled to room temperature stirring 2 hours, filtering, filters the cake second gradethe nitrile washes, and a ground line to obtain 364g solid E.(6) The resulting solid E was disslved in 3L distilled water and placed in the ice bath. Under stirring condition slowly add dropwise 3 mol/L hydrochloric acid solution until the pH value is 2-3. Continue stirring for 1 hour. the solution after the reaction using methylene chloride (1L × 3) extraction, organic uses 0.5L saturated salt water washing, dried with anhydrous sodium sulfate, concentrated, the resulting residue is dissolved in the 0.25L ethyl acetate and 2.25L petroleum ether of the mixed solution, stirring at the room temperature 2 hours, filtering, by 149g solid F.(7) The resulting solid F, 393 ml diphenylphosphoryl azide and 315 ml triethylamine were added into 3L reaction flask.Use 2L tert-butanol to dissolve. Under stirring reflux for 12 hours. the reaction solution concentration, adding 3L ethyl acetate extraction, the organic phase for sequentially 400 ml saturated ammonium chloride solution washing, 400 ml saturated sodium bicarbonate solution washing, 300 ml saturated salt water washing, dried with anhydrous sodium sulfate, filtered, to evaporate the solvent, the resulting residue is dissolved in 800 ml of petroleum ether and ethyl acetate 10:1 in mixed solution stirring 3 hours, filtering pumping job 167g solid G.(8) The resulting solid G and 470g p-toluenesulfonic acid were dissolved in 3L acetonitrile. Stir at room temperature for 36 hours. concentrated, by adding 600 ml ethyl ether petroleum ether 1:1 mixed solution, stirring the reaction 3 hours, filtering pumping job 204g Sitafloxacin three membered ring intermediate (purity 99.2percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate (15 g, 56.3 mmol, compound 1) and triethylorthoformate (60 mL), anhydrous acetic anhydride (100 mL), after the mixture was stirred at 110-120 °C for 1.5 h and evaporated to dryness under reduced pressure to give concentrated product, it was dissolved in methylene dichloride (50 mL, A). Trifluoroacetic acid (70 mL) was cooled to 0-5 °C, added (1R, 2S)-(-)-cis-1,2-fluorine cyclopropane amino-p-toluenesulfonic acid salt. The reaction mixture was stirred at room temperature for 20 min and evaporated to concentrated in vacuo and methylene chloride (100 mL) and triethylamine (30 mL) under the ice bath were added, the mixture was stirred 20 min. At this time add the A, this mixture was stirred at room temperature for 1 h. The reacted mixture washed with the amount of water, saturated salt water. The solution was dried over MgSO4, filtration and evaporated to dryness under reduce pressure to give oily matter. The product was recrystallized from isopropyl ether to yield (Z)-ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-[{(1R,2S)-2-fluorocyclopropyl}amino]-acrylate (16.8 g, 82 percent, compound 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.86% | The compound 2-chloro-6-nitrobenzoic acid (806 mg, 4.0 mmol) was suspended in toluene (10 mL) and then suspended at room temperatureSOCl2 (952 mg, 8.0 mmol) was added in one portion to the reaction solution. The reaction solution was heated to 110 ° C and stirred for 9 hours. The solution was concentrated under reduced pressure. The resulting yellow oil was dissolved in 1,4-dioxane 10 mL) to give a yellow suspension.The compound(1R, 2S) -2-fluorocyclopropylamine tosylatesalt(1.0 g, 4.0 mmol) and NaHCO3 (1.34 g,16.0 mmol) was suspended in 1,4-dioxane (10 mL), and then the yellow suspension obtained above was added dropwise to the reaction solution at 5 ° C. The reaction solution was stirred at room temperature overnight and then diluted with 100 mL of water, The resulting mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compoundThe compound was a light yellow solid (940 mg, 90.86percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at -25 - 0℃; for 3.5h; | Ethyl 2-(4-bromo-2,5-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate(27, 11.4 g, 30.2 mmol) was dissolved in DCM(200 mL). (1R,2S)-2-Fluorocyclopropylamine tosylate (8.24 g,33.3 mmol) was added, and the mixture was cooled to -25C.Triethylamine (6.60 mL, 47.4 mmol) was added dropwise tothe reaction solution at -25C, and the mixture was stirredat -15C for 1 h and at 0C for 2.5 h. The solvent was evaporatedunder reduced pressure, and ethyl acetate and waterwere added to the residue to separate the layers. The organiclayer was washed with brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure togive an aminoacrylate as a yellow oil. The resulting aminoacrylatewas dissolved in DMF (350 mL). Cesium carbonate(19.8 g, 60.9 mmol) was added, and the mixture was stirred atroom temperature for 12 h. The solvent was evaporated under reduced pressure, and ethyl acetate and water were addedto the residue to separate the layers. The organic layer waswashed with brine and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. Theresidue was subjected to flash column chromatography (hexane-ethyl acetate = 9 : 1-1 : 1-1 : 2) to give the title compound(25, 2.98 g, 26%) as a colorless powder. mp: 191-195C (dec.).[alpha]D25 -166.5 (c = 0.159, CHCl3). 1H-NMR (CDCl3) delta: 8.56(1H, d, J = 3.2 Hz), 8.06 (1H, d, J = 8.1 Hz), 4.98-4.73 (1H,m), 4.40 (2H, q, J = 7.1 Hz), 3.91-3.82 (1H, m), 2.85 (3H, s),1.61-1.22 (2H, m), 1.41 (3H, t, J = 7.1 Hz). MS (ESI) m/z: 386(M + H)+. HR-MS (ESI) m/z: 386.0229 (M + H)+ (Calcd forC16H15BrF2NO3: 386.0203). IR (ATR) cm-1: 3083, 2976, 1724,1624, 1610, 1456, 1404, 1387, 1312, 1239, 1173, 1126, 1047,1031, 1022, 1006. |
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