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

To a solution of compound 13-1 (1 1 g. 44.84 mmol) in DCM (200 mL) at -78 °C was added EtTo a solution of compound 9-1 (11.0 g, 44.84 mmol) in DCM (200 mL) was added EtTo a solution of compound 9-1 (ll .0 g.44.84 mmol) in DCM (200 mL) was added HtA'SF-, (8.85 mL.67.3 . , at rt for another 19 hrs. After the reaction was completed, the reaction was quenched with NH11063] To a solution ofcompound 13-1 (11 g, 44.84 mmol) in DCM (200 mE) at —78° C. was added Et2NSF3 (8.85 mE, 67.3 mmol) dropwise. At the end of addition, the mixture was stirred at —78° C. for 2 hrs and then at it for another 19 hrs. After the reaction was completed, the reaction was quenched with NH4C1 aqueous solution (100 mE). The resulting mixture was extracted with DCM (100 mEx3), and the combined organic layers were dried over anhydrous Na2 SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as a pale yellow solid (5.0 g, 70percent). The compound was characterized by the following spectroscopic data:11064] MS (ESI, pos.ion) mlz: 248.26 [M+H]11065] ‘H NMR (400 MHz, CDC13) ö (ppm): 5.26 and 5.13 (ds, 1H), 4.55-4.41 (m, 1H), 3.88-3.74 (m, 1H), 3.73 (s, 3H), 3.64-3.58 (m, 1H), 2.52-2.44 (m, 1H), 2.40-2.32 (m, 1H), 1.42-1.47 (d, 9H, J=20 Hz).Compound 9-1 (11.0 g, 44.8 mmol) was dissolved in DCM (200 mL) and Et 2NSF 3(8.85mL, 67.3 mmol). After the addition was completed, the reaction was carried out at aconstant temperature for 2.0 hours and at room temperature for 19 hours. After thereaction was completed, the reaction was quenched by the addition of aqueous ammoniumchloride solution (100 mL). The aqueous layer was extracted with DCM (100 mL × 3). Theorganic phases were combined, washed with brine, dried over anhydrous Na 2SO 4Afterdrying and concentration, the residue was purified by column chromatography (eluent: PE/ EtOAc (v / v) = 20/1) to give 7.75 g of a pale yellow liquid. Yield: 70percent.To a stirred solution of compound obtained in step II (24.5 g, 0.1 mol) in 1, 2- dichloroethane (300 rnL) cooled to -10Methyl (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylate (4.91 g, 0.020 mol) and sodium fluoride (1.01 g, 0.024 mol) were suspended in dichloromethane (50 mL), followed by addition of Ishikawa reagent (4.35 mL, 0.024 mol) under ice cooling. Under the Nitrogen protected, a solution of compound 9 (2 g, 8.2 mmol) in dry CHUnder the Nitrogen protected, a solutionof compound 15 (2 g, 8.2 mmol) in dry CHUnder the nitrogen protected, a solution of compound 11 (2g, 8.2mmol) in dry CHTo a solution of compound 5-8 (11.0 g, 44.84 mmol) in DCM (200 mL) was added Et2NSF3 (8.85 mL, 67.3 mmol) dropwise at -78 °C. The mixture was stirred at this temperature for 2 hours and then stirred at rt for 19 hours. After the reaction was completed, the reaction was quenched with saturated aqueous NH4C1 and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were wash a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (7.75 g, 70percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 248.3 [M+H]+; and NMR (400 MHz, CDCI3): δ 5.26, 5.13 (ds, ds, 1H), 4.55-4.41 (m, 1H), 3.88-3.74 (m, 1H), 3.73 (s, 3H), 3.64-3.58 (m, 1H), 2.52-2.44 (m, 1H), 2.40-2.32 (m, 1H), 1.42-1.47 (d, 9H, J= 20 Hz) ppm.A stirred solution of l-tert-butyl-2-methyl (25, 4 ?)-4-hydroxy pyrrolidine- 1, 2-dicarboxy late (Ila) (10 g, 40.8 mmol) in dichloroethane (100 ml) was cooled to -78°C and diethylamino sulfur trifluoride (8.2 ml, 61.2 mmol) was added to the solution. The reaction contents were stirred at this temperature for 2 hours and later quenched by adding saturated aqueous solution of NaHC( (10ml). The organic layer was separated, washed with brine and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure to obtain the compound (Ilia) as thick oil (7 g, yield: 69percent). (0139) Analysis: (0140) Mass: 248.2 (M+H); (0141) 1H NMR (400 MHz, CDC1Methyl (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylate, a trans-4-hydroxy-L-proline derivative, was fluorinated at its 4-position using Ishikawa reagent alone or in combination with a hydrogen fluoride-scavenger. The results of the comparison between these two cases are shown below. The same procedure as used in was repeated except for the conditions indicated in the following table. For reference purposes, the fluorination yield of the same compound is 81percent when using diethylaminosulfur trifluoride (Tetrahedron Letters 39(10), 1169-1172 (1998)). [Table 1] Entry Ishikawa reagent (molar equivalents) Reaction temperature (°C) Reaction time (hrs) Hydrogen fluoride-scavenger (molar equivalents) Yield (percent) 1 1.9 12 20 None 14 2 1.9 12 20 NaF (1.9) 85 3 1.2 21 8 NaF (1.2) 85The present invention enables the production of a target cis-4-fluoro-L-proline derivative in good yield and under mild conditions while avoiding side reactions. The method of the present invention is therefore an excellent method which enables the provision of a cis-4-fluoro-L-proline derivative in high yield and on an industrial scale, as compared to conventional techniques.Examples 2-9Preparation of Optically Active Fluoropyrrolidine Derivatives (Ib); (If)Optically active fluoropyrrolidine derivatives (Ib)(If) were prepared by reaction of optically active hydroxypyrrolidine derivatives with an arylsulfur trifluoride in a similar manner as described in Example 1. The optically active hydroxypyrrolidine derivatives and the arylsulfur trifluorides employed in Examples 2-9 are shown in Table 2. The results and reaction conditions are also shown in Table 2 together with those of Example 1. In Examples 3, 6, and 9, the reactions were conducted in the presence of sodium fluoride as a HF-trapping agent (which is shown as an additive in Table 2).To a stirred solution of (2S, 4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2- dicarboxylate (1.0 g) in DOE (30 rnL) cooled to 100C was added DAST (0.6 mL) over a period of 30 mins. The mixture was stirred at this temperature for 1 hour, and then at RT for 16 hours. The mixture was quenched by addition of crushed ice (30 g) and solid NaHOO3 (5 g).The organic layer was separated. The aq. layer was extracted with DOM (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 The solvent was removed under reduced pressure. The residue was purified by column chromatography (eluting with PE:EA = 5:1) to give (2S, 4S)-1-tert-butyl 2-methyl 4- fluoropyrrolidine-1 , 2-dicarboxylate (526 mg) as a white solid. 1H-NMR (400 MHz, 0D013) 6ppm 5.20 (d, J = 52.8 Hz, 1 H), 4.49 (dd, J = 46.7, 9.4 Hz, 1 H), 3.98-3.49 (m, 5H), 2.60-2.22 (m, 2H), 1.45 (dd, J= 22.4, 10.7 Hz, 9H).To a solution of compound 13a (1.44 g, 5.8 mmol) in dry methylenechloride (100 mL) was added activated 4 Å molecular sieve powder.This solution was cooled to 0 °C, and dry pyridine (0.65 mL, 6.96.mmol)was added, followed by trifluoromethanesulfonic anhydride (1.0 mL, 6.38 mmol). The solution was allowed to stir for 1 h and then quenchedwith 1N HCl solution. The aqueous phase was extracted with methylenechloride (2×50 mL), and the combined organic extracts were driedover MgSO4(s) and then filtered (the work-up should be as fast aspossible to avoid the decomposition of the unstable intermediate). Tothis filtrate was added activated 4 Å molecular sieve powder andTBAF·3H2O (2.2 g, 1.2 equiv, in one portion) successively. The resultingmixture was stirred at room temperature overnight, and then concentratedunder reduced pressure. Chromatography (silica gel, 1:1 ethylacetate/petroleum ether) furnished 15a (1.1 g, 78percent) as colorless oil;mixture of rotamers. [α]D25 −58.7 (c=1 in CHCl3); 1H NMR(400 MHz, CDCl3): δ 5.20 (dm, JHF=53.3 Hz, 1H), 4.56 and 4.42 (total1H, each d, each J=9.4 Hz, amide isomers), 3.89–3.58 (m, 5H), 2.53–2.44 (m, 2H), 1.49 and 1.41 (total 9H, s, each amide isomers); 13CNMR (100 MHz, CDCl3): δ 172.2, 171.9, 153.9, 153.6, 92.2(d, 1JCF=177.8 Hz), 91.1, (d, 1JCF=177.8 Hz), 80.4, 80.3, 57.6, 57.2, 53.2 (d, 2JCF=24.5 Hz), 52.8 (d, 2JCF=24.2 Hz), 52.3, 52.2, 37.4 (d, 2JCF=22.0 Hz), 36.6 (d, 2JCF=22.0 Hz), 29.7, 28.3, 28.2. {NMR dataare consistent with those reported [29]}.