BOC-4-OXO-PRO-OME

Yellow Solid

(a) Step 1. To a solution of compound 5-8 (6.86 g, 27.97 mmol) in DCM (70 mL) at 0 °C was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 7 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of sodium thiosulfate (100 mL) and filtered through a Celite Pad. The filtrate was extracted with DCM (100 mL x 3) and the organic layers were washed, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as pale yellow liquid (5.78 g, 85percent).The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre el al. .1. Org. ( Example 12. (S )- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 .2-dicarboxylate The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem. 1992, 57, 2060-2065. Alternatively Swern oxidation procedureis as following: A solution of (COC1)2 (13.0 ml, 74.38 mmol) in CH2C12 (350 ml) cooledto -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 mmand then (2S , 4R)- 1 -tert-butyl 2-methyl 4-hydroxypyrrolidine- 1 , 2-dicarboxylate (8.0 g, 32.63 mmoi) in CH2C12 (100 ml). After stirred at -78 °C for 2 h, triethylamine (50 ml, 180.3 mmol) was added dropwise, and the solution was warmed to room temperature. Themixture was diluted with NaH2PO4 (400 ml, 1.0 M) solution and separated. The aqueous layer was extracted with C[12C12 (2 x 60 ml). The organic layers were combined, dried over MgSO4, filtered, concentrated and purified by Si02 chromatography (7:3 hexanes/ EtOAc) to give the title compound (6.73 g, 85percent yield). ESI MS mlz+ 266.2 (M + Na).The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem.1992, 57, 2060-2065. Alternatively Swern oxidation procedure is as following: To a solution of (COCl)Intermediate 8: (S)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 , 2-dicarboxylate; Pyridinium chlorochromate (21 g, 98 mmol) was added portionwise to a stirred solution of (2S, 4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine- 1 , 2-dicarboxylate (intermediate 7) (12 g, 49 mmol) in DCM (200 mL) and the mixture was stirred at rt for 4 h. Next, the reaction was filtered through celite, filtrate concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 2/1) to give (S)-l-tert-butyl 2-methyl 4-oxopyrrolidine-l, 2-dicarboxylate (intermediate 8) (10 g, yield: 84percent) as a colorless oil. (S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1, 2-dicarboxylate Example 8 To a solution of compound 223-S2 (10 g, 41.2 mmol) in DCM (100 mL) was added TCCA (10.04 g, 43.2 mmol) followed by TEMPO (64.3 mg, 0.41 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was washed with saturated potassium carbonate solution and brine, dried over Na2SO4, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to afford compound 223-S3 (8 g, 80.7percent yield) as a white solid. LC/MS (ESI) m/z: 244 (M+H) .Step 1 To a stirred solution of (2S, 4R) -4-hydroxyproline (Aldrich) (25 g, [108] mmol) in methanol (50 mL) at [0 °C] was added [TRIMETHYLSILYLDIAZOMETHENE] (24.6 g, 216 mmol). The mixture was stirred at [0 °C FOR] 1 hour. The residue obtained on removal of solvent and purification by column chromatography using 50percent ethyl acetate in hexanes (27 g, 100percent) was used in the next step. To oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) [AT-78 °C, ] DMSO (18.6 mL, 236 mmol) was added slowly over 15 minutes. After the completion of addition, the above product (2S, [4R)-N-BOC-4-HYDROXYPROLINE] methylester (26.5 g, 108 mmol) in DCM (100 mL) was added at-78 °C for 20 minutes. Triethylamine (54.6 g, 540 mmol) was added followed by stirring at room temperature for 2 hours. The reaction mixture was then washed with 10percent aq [HC1] (200 mL) and the organic layer was separated and dried over sodium sulfate. The crude product obtained on removal of solvent was purified on silica gel column chromatography using 50percent EtoAc in hexanes to obtain (2S, 4R) -N-Boc-4-Ketoproline methylester (20 g, [78percent).] [[0477] 1H] NMR (300 MHz, [CDC13)] 8 4.80 (m, 1), 3.88 (d, [J=8.] 7, 2), 3.77 (s, 3), 2.98 (m, 1), 2.58 (m, 1), 1.45 (s, [9) ;] MS (ES+): [244] [(M+1).] [[0478]] To a stirred solution of [(2S, ] 4R) -N-Boc-4-Ketoproline methylester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to [0 °C] before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at [0 °C] for lh and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in [5ML] water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water [(LOOML)] and brine 100 mL), dried over [MGS04] and evaporated to dryness. T he residue obtained on removal of solvent was purified by silica gel column chromatography using 50percent EtOAc in hexanes to obtain 4-Hydroxy-4-allylproline methylester (0.94 g, 80percent). [[0479] 1H] NMR (300 MHz, [CDC13)] 8 5.87 (m, 1), 5.19 (m, 2), 4.34 (m, 1), 3.75 [(D, ] [J=4.] 8, 3), 3.50 (m, 3), 2.37 (m, 1), 2.21 (m, 1), 1.39 (d, [J=12.] 9, 9) ; MS (ES+): 308 [(M+23).] [[0480]] To a stirred solution of DAST (1.06 g, 6. [58] mmol) in DCM (10 mL) [AT-78 °C, ] [4-HYDROXY-4-ALLYLPROLINE] methylester (940 mg, 3.3 mmol) in dry DCM (10 mL) was added slowly. The mixture was then stirred at-78 °C for [LH, ] then at-10 °C for an additional [LH.] DCM (50 mL) was added, quenched with [NH4C1] [(10percent, ] 150 mL) and the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 5percent EtOAc in hexanes as eluent to obtain [4-FLUORO-4-ALLYLPROLINE] methylester (330 mg, 34percent). [[0481] IH] NMR (300 MHz, [CDC113)] [AMP;] 5.82 (m, 1), 5.12 (m, 2), 4.43 (m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1), 2.43 (m, 4), 1.37 (dd, [J=4.] 5, 13. 8, [9) ;] MS (ES+): [310 (M+23).] [[0482]] To a solution of 4-fluoro-4-allylproline methylester (0. [33] g, 1.15 mmol) in MeOH (15 mL) was added 10percent Pd/C (40 mg) and hydrogenated at 1 atmosphere. The catalyst was filtered through celite and washed with methanol. To the product obtained on removal of solvent (330 mg, 1.15 mmol) in THF (12 mL) was added aq lithium hydroxide monohydrate (60 mg, 1. [38] mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was taken up in ethyl acetate (50 mL), washed with 10percent citric acid (100 mL) and brine (20 mL). Removal of solvent resulted in 4-fluoro-4-propylproline (310 mg, 100percent). [[0483] 1H] NMR [(300] MHz, CD30D) 8 4.43 (m, 1), 3.71 (m, 6), 2.51 (m, 2), 1.98 (m, 3), 1.45 (m, 9), 0.96 (m, 3); MS (ES-): 274 (M-1). [[0484]] To a solution of 4-fluoro-4-propylproline (310 mg, 1.15 mmol) in DMF (3 mL) at [0 °C, ] 7-Methyl MTL 2b [(RL] =Me, R2=Me) (272 mg, 1.15 mmol), HBTU (469 [MG, L] 1.3 mmol) and DIEA (290 mg, 2.3 mmol) was added, left stirred at room temperature for 16 hours. DMF was removed and the residue obtained was purified by 3percent MeOH in DCM (40 mg, 93percent). The product from the column purification was taken in DCE (6 mL), to which triethylsilane (0.16 mL), TFA (2 mL) and water (0.16 mL) was added and stirred at room temperature for 1.5 hours. Removal of solvent followed by purification on silica gel column chromatography using 10percent MeOH in DCM resulted in the title compound as isomeric mixtures with lower RF fraction (160 mg, 50percent). [[0485] 1H] NMR (300 MHz, CD30D) 8 5.25 (d, [J=5.] 7, [1), ] 4.46 (m, 1), 4.24 (dd, [J=5.] 7, 10. 2, 1), 4.08 (m, 2), 3.81 [(D, ] [J=2.] 4, 1), 3.52 (m, 3), 2.73 (m, 1), 2.10 (m, 4), 1.88 (m, 2), 1.50 (m, 2), 0.99 [(T, ] [J=7.] 5, 3), 0.91 (dd, [J=3.] 0, 6. 9, 6) ; MS (ES+): 409 [(M+L) ;)] and higher Rf fraction (40 mg, [12percent). 1H] NMR (300 MHz, CD30D) [8] 5. [38 (D, J=5.] 4, 1), 4.46 (m, 1), 4.24 (dd, [J=2.] 7, 7. 2, 1), 4.08 (m, 2), 3.81 (d, [J=2.] 4, 1), 3.64 (m, 3), 2.73 (m, 1), 2.11 (m, 4), 1.84 (m, 2), 1.47 (m, 2), 0.98 (t, [J=7.] 5, 3), 0.91 (dd, [J=3.] 0, 6. 9, 6) ; MS (METHOD ES+): 409 [(M+1).]To a stirred solution of compound 3b (5.0 g, 20.4 mmol) in DCM (60 mL) was added Celite (8 g) then PCC (13.2 g, 61.2 mmol) and the mixture was stirred at RT overnight, TLC (PE:EA=2:1) showed the starting material was consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (PE:EA=1 :0 to 4: 1) to give 65a (3.6 g, 72percent) as a thick yellow oil. LC-MS (Agilent): Rt 3.17 min; m/z calculated for CMH, 7N05 [M+H-Boc]+ 144.1, [M+H-t-Buf 188.1 , found [M+H-Boc]+ 144.1 , [M+H-t-Bu]+ 188.1.PCC (52.9 g, 244.63 mmol) was added into a solution of (2S, 4R)-1-tert-butyl 2- methyl 4-hydroxypyrrolidine- 1 , 2-dicarboxylate (10 g, 81.54 mmol) in DCM (300 mE) under N2 and the mixture was stirred for 48 hours. After being filtered and concentrated, the residue was purified by column chromatography eluted with PE : EtOAc = 4: ito afford (S-1-tert-butyl 2-methyl 4- oxopyrrolidine-1, 2-dicarboxylate (ii g, yield: 55.5percent). ‘H-NMR (CDC13, 400 MHz) 4.674.79 (m, 1H), 3.86 (d, J= 12.0 Hz, 2H), 3.73 (s, 3H), 2.902.93 (m, 1H), 2.56 (d, J= 20.0 Hz, 1H), 1.45 (s, 9H). MS (M+H): 244.PCC (52.9 g, 244.63 mmol) was added into a solution of (25, 4R)-1-tert-butyl 2- methyl 4-hydroxypyrrolidine- 1 , 2-dicarboxylate (10 g, 81.54 mmol) in DCM (300 mL) under N2 and the mixture was stirred for 48 hours. After being filtered and concentrated, the residue waspurified by column chromatography eluted with PE: EtOAc = 4: 1 to afford (5)-i -tert-butyl 2-methyl 4-oxopyrrolidine-1, 2-dicarboxylate (11 g, yield: 55.5percent). ‘H-NMR (CDC13, 400 MHz)4.67—4.79 (m, 1H), 3.86 (d, J= 12.0 Hz, 2H), 3.73 (s, 3H), 2.90—2.93 (m, 1H), 2.56 (d, J= 20.0Hz, 1H), 1.45 (s, 9H). MS (M+H): 244.To a solution of DMSO ( 1.90 g, 24.3 mmoL 3.00 equiv) in diehlorornethane (20 mL) at -78 °C was added oxalyl chloride (1.54 g, 12.1 mmol, 1.50 equiv) and the mixture was stirred for 15 min. To this was added dropwise a solution of 1-tert-butyi 2-methyl (2S(c) To a solution of compound 14-1 (6.8 g, 27.97 mmol) in DCM (70 mL) at 0 °C was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of addition, the mixture was stirred at rt for 7 hrs. After the mixture was completed, the reaction was quenched with NaTo a solution of compound 9-1 (6.85 g, 27.97 mmol) in DCM (70 mL) was added Dess-Martin periodinane (23.7 g, 56 mmol) in a portionwise manner at 0 °C. At the end of the addition, the mixture was stirred at rt for 7.0 hrs. After the mixture was completed, the mixture was quenched with NaTo a solution of compound 12-5 (6.86 g. 27.97 mmol) in DCM (70.0 mL) was added Dess-Martin for 7.0 hrs. After the mixture was completed, the reaction was quenched with Na11119] To a solution ofcompound 14-1 (6.8 g, 27.97 mmol) in DCM (70 mE) at 00 C. was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of addition, the mixture was stirred at rt for 7 hrs. After the mixture was completed, the reaction was quenched with Na25203 aqueous solution, and the mixture was filtered through a celite pad. The filtrate was extracted with DCM (100 mLx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel colunm chromatography (PE/EtOAc (v/v)6/1) to give the title compound as pale yellow liquid (5.86 g, 85percent).The compound 9-1 (6.86 g, 27.97 mmol) was dissolved in DCM (70 mL) and Dess-Martin reagent (23.7 g, 56 mmol) was added portionwise to the reaction at 0 ° C. hour.After the reaction was completed, the reaction was quenched with aqueous sodiumthiosulfate (100 mL), filtered through celite and the filtrate was extracted with DCM(100 mL x 3). The combined organic phases were dried over anhydrous Na 2SO 4After dryingand concentrating, the residue was purified by column chromatography (eluent: PE / EtOAc(v / v) = 6/1) to give 5.78 g of a pale yellow liquid. Yield: 85percent.Compound BB-43-1 (9 g, 36.69 mmol) was dissolved in DCM (200 mL), Dess-Martin agent (31 g, 73.38 mmol) and NaHCO1, 3, 5-Trichloro-1, 3, 5-triazinane-2, 4, 6-trione (3.78 g, 16.27 mmol) was added to a cooled (0° C.) solution of (S)-i -tert-butyl 2-methyl 4-oxopyrrolidine- 1 , 2-dicarboxy- late (3.8 g, 15.49 mmol) in DCM (25 mE), followed by the addition of catalytic TEMPO (0.024 g, 0.155 mmol). Afier 5 mm the mixture was allowed to reach room temperature, stirred for another 30 minutes and filtrated over Celite. The organic layer was washed with 20 mE saturated potassium carbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The crude compound 1 was used without thrther purification.10283] Yield: 2.77 g, 74percent.10284] ‘H NMR (400 MHz, CDC13): ö 1.46 (s, 9H), 2.57(dd, J=18.8, 2.4, 1H), 2.90 (s, 1H), 3.75 (s, 3H), 3.88 (br s, 2H), 4.77 (dd, J=36.8, 8 Hz, 1H).j0285] MS (ESI) mlz 376.2 [M+MeOH+H].To a solution of (2R)-4-hydroxypyrrolidine-2-carboxylic acid (compound 15-1) (10.0 g, 76.2 mmol) in anhydrous MeOH (100 mL) under NTo a mixture of oxalyl chloride (9.0 mL), DCM (100 mL) and DMSO (9.5 mL) was added a solution of the abovecrude product in DCM (120 mL) dropwise at -78 °C. After the mixture was stirred at -78 °C for 2 hours, Et3N (28 mL)was added dropwise, and the mixture was allowed to warm to rt. Water (60 mL) was added to the mixture, and themixture was extracted with DCM (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 andconcentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give thetitle compound 15-2 as colorless slurry (11 g, 59percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): δ 4.83-4.70 (dd, J = 10 Hz, 10Hz, 1H), 3.91-3.88 (d, J = 8 Hz, 2H), 3.77 (s, 3H), 2.98-2.88(m, 1H), 2.62-2.55 (m, 1H), 1.48-1.47 (s, 9H).To a solution of 9.63 mL (7.2 mmol) of oxalyl chloride in 10.6 mL of CH

Molecular Weight:243.26
XLogP3:0.6
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:243.11067264
Monoisotopic Mass:243.11067264
Topological Polar Surface Area:72.9
Heavy Atom Count:17
Complexity:344
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes