1-HYDROXYMETHYL-CYCLOPROPANECARBOXYLICACIDETHYLESTER

A 1M solution of lithium aluminum tri-tert-butoxyhydride in tetrahydrofuran (70.90 mL, 70.90 mmol) was added to a stirred solution of diethyl cyclopropane-1, 1′-dicarboxylate (6 g, 32.20 mmol) in tetrahydrofuran (129 mL) at 23° C. The resulting solution was heated to 65° C. and stirred for 24 h. The cooled reaction mixture was diluted with a 10percent solution of sodium bisulfate (275 mL) and extracted with ethyl acetate. The combined organic layers were dried (MgSOExample 64 Example 64 Preparation of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate-A 1M solution of lithium aluminum tri-tert-butoxyhydride in tetrahydrofuran (12 mL, 12 mmol, 2.2 equiv) was added to a stirred solution of diethyl cyclopropane-1, 1'-dicarboxylate (1.0 mL, 5.7 mmol, 1.0 equiv) in tetrahydrofuran (19 mL) at 23° C. Synthesis of 1-Hydroxymethyl-cyclopropanecarboxylic acid ethyl ester To a stirred solution of diethyl cyclopropane-1, 1-dicarboxylate (2.13 g, 11.4 mmol) in THF (80 mL) at RT, lithium aluminum tri-tert-butoxyhydride (38.76 mL, 38.76 mmol, 1.0 M solution in THF) was added slowly. After the addition was completed, the reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with IN aq HCI (20 mL), water (20 mL), 5percent aq. NaHC0Preparation of intermediate 5A:1 -(hydro xymethyl)cyclopropanecarboxylic acid ethyl esterCyclopropane- 1, 1-dicarboxylic acid diethyl ester (0.88 mL, 5 mmol) was dissolved in 10 mL of THE Under nitrogen protection and at room temperature, THF solution of LiAl(0-t-Bu)3H (1.1 M, 10 mL, 11 mmol) was added dropwise. The reaction solution was heated to reflux for 2 hours and it was terminated by adding saturated aqueous solution of ammonium chloride. A great amount of precipitate was produced which was filtered. The organic phase was collected, dried, evaporated, and the resulting residue purified with a silica gel column (n-hexane: ethyl acetate = 10: 1) to give 400 mg of colorless liquid 5A. Yield: 55.5percent. MS (ESI, m/z): [M+H]Example 91 2'-amino-6'-(5-chloropyrid-3-yl)-l'-methyldispiro[cyclopropane-l, 3'-chroman-4', 4'- imidazol]-5'(l'H)-oneStep A: A mixture of diethyl cyclopropane-l, l-dicarboxylate (14.1 mL, 80.6 mmol) and lithium tri-tert- butoxyaluminohydride (201.4 mL, 201.4 mmol) was heated to reflux in THF for 3 hours. The mixture was cooled down and partitioned between water and EtOAc. The organics were washed with water, brine and dried with NaTo a stirring solution of compound 71 (1 .0 g, 6.32 mmol) and triethylamine (0.97 ml, 7.59 mmol) in THF (18 ml) at -10 °C, was added isobutyl chloroformate (0.90 ml, 6.96 mmol) dropwise. Then the reaction mixture was stirred 1 h at 0°C, the insoluble material was filtered off, and the filtrate was directly used later. To an ice-cooling solution of NaBH[0371] To a stirring solution of compound 71 (1.0 g, 6.32mmol) and triethylamine (0.97 ml, 7.59 mmol) in THF (18ml) at -10° C., was added isobutyl chloroformate (0.90 ml, 6.96 mmol) dropwise. Then the reaction mixture was stirred1 h at oo C., the insoluble material was filtered off, and thefiltrate was directly used later. To an ice-cooling solution ofNaBH4 (0.71 g, 18.97 mmol) in THF (10 ml) and water (2.5ml), was added the filtrate obtained above dropwise. After thereaction mixture was allowed to stirred at oo C. for 1 h, thenreaction mixture was poured into 10percent of aqueous solutionHOAc, the aqueous phase was extracted with EtOAc (30mlx3), and the combined organic phase was washed withbrine, dried over Na2S04 , filtered and concentrated to affordcrude product, which was purified by silica gel column chromatography(Petroleum ether: ethyl acetate=9: 1 to 2:1) to givecompound 72 (0.65 g, yield 61 percent) as a colorless oil.[0372] 1HNMR (CDCI3): ll 4.15 (2H, q, 1=7.0 Hz), 3.62(2H, s), 1.28-1.23 (5H, m), 0.86 (2H, q, 1=4.2 Hz)

Molecular Weight:144.17
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:144.078644241
Monoisotopic Mass:144.078644241
Topological Polar Surface Area:46.5
Heavy Atom Count:10
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes