1-(1,1-Dimethylethyl) (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate

White powder

To a solution of compound 13-2 (5.83 g, 23.58 mmol) in THF (30 mL) at 0 °C was added LiOH aqueous solution (1.98 g, 30 mL), and the mixture was stirred at rt for 2 hrs and adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo, and the aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over NaTo a solution of compound 9-2 (5.83 g, 23.58 mmol) in THF (30 mL) was added LiOH aqueous solution (1.98 g, 30 mL) at 0 °C. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M) and the THF solvent was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over NaTo a solution of compound 9-2 (5.83 g.23.58 mmol) in THF (30.0 mL) was added LiOH aqueous solution (1.98 g, 30.0 mL) at 0 °C. and the mi.xture was stirred at rt for 2.0 hrs and then adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over and concentrated in vacuo to give the title compound as a white solid (5.3 g.96percent). The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlz: 234.2 [M+H] : and NMR (400 MHz. CDCL) δ (ppm): 8.76 (brs.1H), 5.28-5.12 (m.1H), 4.56-4.44 (m.1H).3.86-3.58 (m. 2H), 2.77-2.01 (m.2H).1.48-1.44 (d.9H../= 16 Hz).To a solution of compound 11-1 (5.83 g, 23.58 mmol) in THF (30 mL) at 0 °C was added an aqueous solution of lithium hydroxide (1.98 g, 30 mL) dropwise. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (1M) till pH = 5, and then the THF was removed in vacuo. The aqueous layers were acidified with aqueous HC1 (1M) till pH = 2 and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a white solid (5.27 g, 96percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 234.3 [M+H]+; and lU NMR (400 MHz, CDC13): δ 8.76 (brs, 1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J= 16 Hz) ppm.11067] To a solution of compound 13-2 (5.83 g, 23.58 mmol) in THF (30 mE) at 0° C. was added EiOH aqueous solution (1.98 g, 30 mE), and the mixture was stirred at it for 2 hrs and adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo, and the aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mEx3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a white solid (5.3 g, 96percent). The compound was characterized by the following spectroscopic data:11068] MS (ESI, pos.ion) mlz: 234.24 [M+H]11069] ‘H NMR (400 MHz, CDC13) ö (ppm): 8.76 (brs, 1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J=16 Hz).Compound 9-2 (5.83 g, 23.6 mmol) was dissolved in THF (30 mL) and an aqueoussolution of lithium hydroxide (1.98 g, 30 mL) was slowly added dropwise thereto at 0 °C. After the addition was completed, the mixture was stirred at rt for 2.0 hours. Afterthe reaction was completed, the pH of the reaction mixture was adjusted to 5 with dilutehydrochloric acid (1M). After removing the THF, the aqueous layer was adjusted to pH 2with dilute hydrochloric acid (1 M), extracted with EtOAc (80 mL x 3) Wash withsaturated brine, anhydrous Na 2SO 4Drying and concentration gave 5.27 g of white solid, yield: 96percent.A solution of compound 10 (2.46 g, 9.96 mmol) in dioxane (20 mL), was added 10 mL of HA solution of compound 16 (2.46 g, 9.96mmol) in dioxane (20 mL), was added 10 mL of HA solution of compound 12 (2.46g, 9.96mmol) in dioxane (20mL), was added 10mL of HTo the stirred solution of l-tert-butyl-2-methyl (2[482] 500 mg (2.02 mmol) of 1-t-butyl 2-methyl(2S, 4S)-4-fluoropyrrolidine-l, 2-dicarboxylate obtained by referring to WO 03/002553 was dissolved in 16 mL of tetrahydrofuran and 4 mL of distilled water. Thereafter, 250 mg (6.06 mmol) of lithium hydroxide was added thereto, then stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and ethylacetoacetate was added thereto. The resulting solution was neutralized with IN hydrochloric acid, then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 330 mg of the title compound (yield: 70percent).[483] Mass (m/e) 234 (M+ 1)

Molecular Weight:233.24
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:233.10633615
Monoisotopic Mass:233.10633615
Topological Polar Surface Area:66.8
Heavy Atom Count:16
Complexity:300
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes