Cyclopropanamine, 2-fluoro-, (1R,2S)-, 4-methylbenzenesulfonate (1:1)

(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.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.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).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).(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).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.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.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.

Molecular Weight:247.29
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:247.06784264
Monoisotopic Mass:247.06784264
Topological Polar Surface Area:88.8
Heavy Atom Count:16
Complexity:253
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes