1-(Ethoxycarbonyl)cyclopropanecarboxylic acid

Synthesis of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid Diethyl 1, 1-cyclopropane dicarboxylate (20g) was hydrolyzed in IN NaOH (107 m4) and ethanol (220D) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by IN HCI. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica gel column to give the title compound in a yield of 94percent. 1H NMR(CDCl3) No. 1.06 (t, 3H), 1.53 (m, 2H), 1.62 (m, 2H), 4.21 (q, 2H) ESI: 159 +1) +C7H1004Synthesis of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid Diethyl 1, 1-cyclopropane dicarboxylate (20g) was hydrolyzed in IN NaOH (107 m4) and ethanol (220D) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by IN HCI. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica gel column to give the title compound in a yield of 94percent. 1H NMR(CDCl3) No. 1.06 (t, 3H), 1.53 (m, 2H), 1.62 (m, 2H), 4.21 (q, 2H) ESI: 159 +1) +C7H1004In the 2L three-mouth reaction bottle, Add 255.3 g of diethyl 1, 1-cyclopropanedicarboxylate, 840mL EtOH, The ice water bath cools it to 0 °C.Slowly add 137.32g KHCO3The temperature control is added below 30 °C.Naturally rise to room temperature, Stir the reaction for 15 h, TLC monitors the reaction completely, Add 1L of water, Extracted with (PE: EA = 1:1) 300 mL × 2, Remove the organic phase, Concentrated HCl adjusts pH=2, Extracted with EA 370mL×2, Take the organic phase, Desolvent1, 1-cyclopropanedicarboxylic acid monoethyl ester 201.7 g, The yield was 93percent.Step 1: Step 2) 1-(Ethoxycarbonyl)cyclopropanecarboxylic acid To a solution of diethyl cyclopropane-1, 1-dicarboxylate (4.77 g, 25.6 mmol) in ethanol (40 mL) was added KOH (1.43 g, 25.6 mmol) in HTo a solution of diethyl cyclopropane- 1, 1 -dicarboxylate (4.77 g, 25.6 mmol) in ethanol (40 mL) was added KOH (1.43 g, 25.6 mmol) in HMonoethyl cyclopropane-1, 1-dicarboxylate STR19 KOH (2.8 g, 50 mmol), was added to a solution of IV-1 (9.3 g, 50 mmol) in 200 mL EtOH. The reaction mixture was stirred at rt overnight. After concentrated under reduced pressure, the residue was re-dissolved in 50 mL of NaHCO500ml three-necked flask to 200ml of ethanol and 1, 1-diethyl-cyclopropylamino burn 30g (161mmol), coldBut to l ° C, added dropwise with stirring a solution of sodium hydroxide (NaOH 6. 4g, 161mmol; water 32ml). Dropping was completed, the reaction at room temperature for 3 hours When the end of the reaction, the solvent was evaporated under reduced pressure to give a white solid. The solid was added water and ethyl acetate 200ml 100ml, stirring pointsLayer, the organic phase was discarded. Aqueous layer was washed with 2mol / L hydrochloric acid, adjusted to pH ρΗ3~4, ethyl acetate (100ml X 2) and extracted with ethyl acetateLayer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a colorless oil translucent 20. 0g (78. 5percent).To 500 ml of a three-necked flask was added 200 ml of methanol and 30 g of 1, 1-cyclopropanedicarboxylic acid diethyl ester, cooled to 10 ° C, stir A solution of sodium hydroxide (NaOH 6.4 g, water 32 ml) was added dropwise, The reaction was carried out at room temperature for 3 hours, the reaction was terminated, the solvent was distilled off under reduced pressure, A white solid. To the solid was added 200 ml of water and 150 ml of ethyl acetate, ] Stir and layer, discard the organic phase. The aqueous layer was adjusted to pH 3 to 4 with 2 mol / L hydrochloric acid, Ethyl acetate extraction (200 ml x 2), The organic phase was dried over anhydrous sodium sulfate, filtered, The solvent was distilled off under reduced pressure, To give a colorless translucent oilEthyl 1, 1-cyclopropyl dicarbonate (1.0 g, 5.37 mmol) was added to tetrahydrofuran (3 ml) at 25 °C under the protection of nitrogen, then a mixed solution of sodium hydroxide/methanol (1 mol/L, 5.37 ml) was added thereto, and the mixture was stirred under the protection of nitrogen for 16 hours at 25 °C. The solution was concentrated under reduced pressure at 30 °C and then added to water (20 ml). The aqueous phase was washed with ethyl acetate (20 ml * 2), the pH was adjusted to 2 with hydrochloric acid (2 mol/L) (20 ml * twice) and extracted with ethyl acetate (20 ml * 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 168A (creamy white solid, 500 mg, the yield was 64.6percent). A solution of 1, 1-diethyl cyclopropane-1, 1-dicarboxylate (10.00 g, 53.70 mmol, 1.00 equiv), sodium hydroxide (2.15 g, 53.75 mmol, 1.00 equiv) in ethanol (50 mL) was stirred for 12 h at 25 A solution of Synthesis of ethyl 1-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylate The carboxylic acid prepared in Preparation 14 (16g) was dissolved in dichloromethane, 10.8mNo. of oxalyl chloride was added dropwise, and 2 drops of dimethylformamide was added. The reaction mixture was stirred at room temperature for 3. hours and distilled under reduced pressure to give ethoxycarbonyl 1, 1-cyclopropane carbonylchloride. This compound, not purified, was dissolved in 30mNo. of dimethylformamide and the resulting solution was cooled with water-ice. 36g of NaN3 was added and the reaction was carried out at room temperature for 3 hours. The reaction solution was extracted with 100mNo. of water and 200mNo. of diethylether, and the diethylether extract was concentrated to give crude compound which was purified by silica gel column to give an azide compound. 1H NMR(CDCl3) No. 1.28 (t, 3H), 1.54 (m, 4H), 4. 19 (q, 2H) To the azide compound thus obtained (13g) was added dropwise I lmt of benzyl alcohol and the reaction mixture was heated to 100C, by which the reactants were vigorously reacted with each other with the generation of gas. The reaction mixture was heated at 100 C for further 1 hour, cooled to room temperature, and distilled under reduced pressure to remove benzyl alcohol. The residue was purified by silica gel column to give the title compound. 1H NMR(CDCl3) No. 1.19 (m, 5H), 1. 54 (m, 2H), 4.11 (m, 2H), 5.15 (br. s, 2EI), 7. 32 (m, 51-1)General procedure: Ethyl hydrogen malonate (0.70g, 5.25 mmol) was added dropwiseto a solution of 4-fluoro-N-hydroxybenzimidamide (17, 0.78g, 5.0 mmol), EDCI (1.5eq.) and triethylamine (1.01g, 10.0 mmol) in dichloromethane in an ice bath. Upon completion ofthe addition, the reaction mixture was removed from the ice bathand placed in room temperature for 8h and monitored by thin-layerchromatography (TLC). The mixture was washed with 10% K2CO3(150 mL3) followed by brine (150 mL1), and the organic phasewas separated, dried and evaporated to yield ethyl 3-((4-fluorobenzimidamido)oxy)-3-oxopropanoate as yellow solid.A flask was charged with l-(ethoxycarbonyl)cyclopropane-l-carboxylic acid (6.60 g, 40.0 mmol, 1.00 equiv), HATU (22.8 g, 60.0 mmol, 1.50 equiv), DIPEA (15.5 g, 120 mmol, 3.00 equiv), acetohydrazide (2.96 g, 40.0 mmol, 1.00 equiv) and DCM (100 mL). The resulting mixture was stirred overnight at room temperature and quenched with water (60 mL). The mixture was extracted with DCM (2 x 50mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by recrystallization to provide 4.77 g (crude) of ethyl l -(2- acetylhydrazine-l-carbonyl)cyclopropane-l-carboxylate. LCMS (ESI, m/z): 215 [M+H]+

Molecular Weight:158.15
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:158.05790880
Monoisotopic Mass:158.05790880
Topological Polar Surface Area:63.6
Heavy Atom Count:11
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes