Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

50 g of 1, 2-cyclopentanedioic acid and 15 g of formamide were mixed, and after nitrogen substitution, the temperature was raised to 170 ° C. to react with At the same time steamed low boilers, the reaction measured by HPLC method when the control material is less than 0.2percent, the reaction was terminated; Cooling to 80 ° C, adding 50g of purified water and 0.5g of activated carbon, stirring at 50 ° C for half an hour, filtering by hot filtration, cooling the filtrate to 20 ° C, extracting with dichloromethane, concentrating the organic phase to dry 90 ° C without fraction, adding 100g toluene, The mixture was cooled to 5 ° C and dried under reduced pressure at 40 ° C to obtain about 60.6 g of white crystals in a yield of 93.5percent and a purity of 99percent or more and a content of 98percent or more.Load 1 kg of diethyl 1, 2-cyclopentanedicarboxylate and 1.02 kg of 27percent ammonia into an autoclave. The reaction mixture is heated in the autoclave at a temperature of 130° C. for a minimum of 4 hours. After cooling to 60° C. and depressurisation, evaporation of the solvent is carried out. The residue is then subjected to pyrolysis at 280° C. for 1 hour. The imide is purified by distillation in vacuo (4-12 mbars) at a temperature of 200° C. After isolation, the title product is obtained in a yield of 96percent.Melting point: 89° CTo the solution of 1-bromo-2-cyclopropylbenzene (8.5 g, 0.043 mol) in THF (20 mL) was added n-BuLi (21 mL, 0.052 mol, 2.5M in hexane) at -78 C under N 2 atmosphere. Then the mixture was stirred at -78C for 1 hour. To the solution of tetrahydrocyclopenta [c] pyrrole-1, 3 (2H, 3aH) -dione (4 g, 0.029 mol) in THF (20 mL) was added n-BuLi (13 mL, 0.035 mol, 2.5M in hexane) at -78C under N 2 atmosphere. Then the mixture was stirred at 0C for 1 hour. The solution formed from 1-bromo-2-cyclopropylbenzene was added dropwise to the solution formed from tetrahydrocyclopenta [c] pyrrole-1, 3 (2H, 3aH) -dione at -78C. The resulting mixture was stirred at room temperature for 3 hours. TLC showed tetrahydrocyclopenta [c] pyrrole-1, 3 (2H, 3aH) -dione was consumed. NaBH 3CN (2.2 g, 0.035 mol) was added to the mixture and then followed by addition of 6N HCl acid (20 mL) at 0C, and further stirred at room temperature for 1 hour. Na 2CO 3 (50 mL) was added to the mixture to adjust the pH to 8-9. The mixture was then extracted with EA (50 mL 3), and the organic layer was washed with brine (50 mL 2). The combined organic layer was dried, filtered and concentrated. The residue was purified by column chromatograph on silica gel (eluent: PE/EA = 10/1) to obtain 3- (2-cyclopropylphenyl) hexahydrocyclopenta [c] pyrrol-1 (2H) -one (2.8 g). 1H NMR (400MHz, CDCl 3) delta ppm: 7.19-7.23 (m, 1H), 7.11-7.16 (m, 2H), 6.95-7.01 (m, 1H), 6.20 (s, 1H), 5.44 (d, J=7.7 Hz, 1H), 3.08-3.24 (m, 1H), 2.93-3.04 (m, 1H), 2.73-2.87 (m, 1H), 1.91-2.06 (m, 1H), 1.73-1.83 (m, 2H), 1.51-1.64 (m, 1H), 1.40-1.49 (m, 2H), 1.33 (s, 1H), 1.10-1.20 (m, 1H), 0.52-0.73 (m, 2H). MS (ESI, m/e) [M+1] + 242.3.tert-Butyl 4-(4-chloro-2-(2-((1, 3-dioxohexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)thieno[3, 2-b]pyridin-7-yl)-6-methylphenoxy)piperidine-1-carboxylate. To diisopropyl azodicarboxylate (99 mg, 0.49 mmol) and tert-butyl 4-[4-chloro-2-[2-(hydroxymethyl)thieno[3, 2-b]pyridin-7-yl]-6-methyl-phenoxy]piperidine-1-carboxylate (30 mg, 0.06 mmol) in THF (5 mL) was added triphenylphosphine polymer bound (0.55 mmol) and In a 500 ml four-necked flask, 50 g of urea, 110 ml of cyclohexanone was added, 15 g of toluene was added, 32 g of ammonium hydrogencarbonate was added, and the temperature was refluxed for 14 hours. The end of the water was added, 100 ml of water was added, and 15% of dilute sulfuric acid was added dropwise. The mixture was hydrolyzed at a temperature of 120 C for 4 hours, allowed to stand, layered, and the organic phase was added with 300 ml of methanol, and the crystals were purified, centrifuged and dried to obtain 83.03 g of 2-oxocyclohexanecarboxamide, the content was 97.56%, and the yield was 68.91%. ; 83.03g of 2-oxocyclohexanecarboxamide was placed in a 500ml four-necked flask, 300ml of dichloroethane was added, the temperature was lowered to -10-0 C, chlorine gas was started, chlorine was passed for 10 hours, and chlorine gas was introduced. g, the system was poured into 200 ml of ice water, hydrolyzed for 2 hours, layered, centrifuged, dried to obtain 12 chloride 96.88g, content of 97.83%, single step yield of 93.36%, two-step yield of 64.33%; 96.88g of chloride was put into a 1000ml four-necked flask, 500ml of ammonia water was added, the temperature was lowered to -10-0 C, ammonia gas was introduced, the ammonia was passed for 5 hours, 22.58 g of ammonia gas was introduced, and the mixture was centrifuged and washed with water. Drying, obtaining 1, 2-cyclopentane dimethylamide 73.65g, content of 95.26%, single step yield of 82.93%, three-step yield of 53.35%; 73.65g of 1, 2-cyclopentadiolamide was placed in a 250ml four-necked flask, 12g of cyclopentanedicarboxylic acid was added, the temperature was raised to 220 C, and the temperature was kept at 220-240 C for 2 hours. 0.25 g of ammonium metaphosphate was added, distilled, and added. The toluene was purified, cooled, crystallized, centrifuged, and dried to obtain 56.5 g, a content of 99.88%, a single step yield of 90.50%, and a four-step yield of 48.28%.50 g of 1, 2-cyclopentanedioic acid and 15 g of formamide were mixed, and after nitrogen substitution, the temperature was raised to 170 C. to react with At the same time steamed low boilers, the reaction measured by HPLC method when the control material is less than 0.2%, the reaction was terminated; Cooling to 80 C, adding 50g of purified water and 0.5g of activated carbon, stirring at 50 C for half an hour, filtering by hot filtration, cooling the filtrate to 20 C, extracting with dichloromethane, concentrating the organic phase to dry 90 C without fraction, adding 100g toluene, The mixture was cooled to 5 C and dried under reduced pressure at 40 C to obtain about 60.6 g of white crystals in a yield of 93.5% and a purity of 99% or more and a content of 98% or more.

Molecular Weight:139.15
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:139.063328530
Monoisotopic Mass:139.063328530
Topological Polar Surface Area:46.2
Heavy Atom Count:10
Complexity:180
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes