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The mixture of 4-amino-2-fluoro-Nmethylbenzamide(22) (1.68 g, 10 mmol) [35], H2SO4 (0.68 mL) andwater (13 mL) was gently heated until all the components werecompletely dissolved. The mixture was cooled to 0e5 understirring, then the solution of NaNO2 (0.7 g,10 mmol) inwater (2 mL)was added dropwise. The resulting mixture was stirred at 0e5for 0.5 h and then slowly poured into the solution of KI (5 g) in coldwater (20 mL). The solutionwas then heated up to 80 and stirredfor 0.5 h. After cooling it was treated with 30 mL of chloroform andfiltered. The organic layer was washed with 5% Na2SO3 solution,dried over Na2SO4 and rotovapped. Column chromatography onsilica gel (hexane/EtOAc 6:1) afforded 2.33 g (83%) of 2-fluoro-4-iodo-N-methylbenzamide (37). MS (ESI) [MH] 280. 1H NMR(400 MHz, DMSO-d6) d 8.25 (m, 1H), 7.73 (d, J 10.0 Hz, 1H), 7.65 (d,J 7.8 Hz, 1H), 7.37 (t, J 7.8 Hz, 1H), 2.75 (d, J 4.4 Hz, 3H). Thesolution of compound 37 (9 g, 32 mmol) in DMF (25 mL) was addedto the ice cooled suspension of NaH (1.48 g, 36.8 mmol, 60% in oil,washed with hexane) in DMF (50 mL). The resulting mixture wasvigorously stirred for 0.5 h in an ice bath, then SEM-chloride (6.46 g,39 mmol) was added and the mixture was continuously stirredovernight at the ambient temperature. After the reaction wascompleted, the mixture was poured into water (400 mL) and theobtained product was extracted with benzene (2 200 mL),washed with water, dried over Na2SO4 and then filtered through3 cm layer of silica gel washing with 5:1 hexane/EtOAc. The solventwas evaporated in vacuo providing 11 g (84%) of 2-fluoro-4-iodo-Nmethyl-N-[2-(trimethylsilyl)ethoxymethyl]benzamide (40). MS(ESI) [MH] 520. 1H NMR (400 MHz, CDCl3) d 7.58 (m,1H), 7.52 (m,1H), 7.12 (m, 1H), 5.01 (s, 0.8H), 4.58 (s, 1.2H), 3.63 (t, J 8.2 Hz,0.8H), 3.31 (t, J 8.2 Hz, 1.2H), 3.14 (s, 1.8H), 2.92 (d, J 0.8 Hz,1.2H), 0.99 (t, J 8.2 Hz, 0.8H), 0.82 (t, J 8.2 Hz, 1.2H), 0.04 (s,3.6), 0.01 (s, 5.4). The mixture of 6.69 g (51 mmol) of aminoacid(R)-36a or 9.55 g of (R)-36b, 17.4 g (42.5 mmol) of 40, 1.62 g(8.5 mmol) of CuI, 23.5 g (0.17 mol) of K2CO3, 36mL of water,145mLof DMF and 3e5 drops of Et3N was stirred for 10 min, then 6.56 g (46.8 mmol) of 2-acetylcyclohexanone was added and stirringcontinued at 100 for 24 h. After cooling the mixture was rotovapped,the residue was treated with 200mL of water and acidifiedwith hydrochloric acid to 2e3 (~30 mL). Then 200 mL of etherwas added, the mixture was stirred for 0.5 h and the formed precipitatewas filtered off, washed with 50 mL of ether and dried invacuo to give 10.7 g (65%) of (R)-3-(3-fluoro-4-{methyl[2-(trimethylsilyl)ethoxymethyl]carbamoyl}phenylamino)-tetrahydrofuran-3-carboxylic acid ((R)-41) (55% from ester (R)-36b). MS (ESI)[MH] 413. 1H NMR (400 MHz, DMSO-d6) d 12.97 (brs, 1H), 7.07(m, 2H), 6.31 (brs, 1H), 6.17 (brs, 1H), 4.85 (brs, 0.67H), 4.60 (brs,1.33H), 4.10 (brs, 1H), 3.87 (brs, 3H), 3.51 (brs, 0.67H), 3.24 (brs,1.33H), 2.93 (s, 2H), 2.86 (brs, 1H), 2.56 (brs, 1H), 2.16 (brs, 1H), 0.89(brs, 0.67H), 0.73 (brs, 1.33H), 0.03 (m, 9H). The mixture of 10.7 g(26 mmol) of (R)-41 and 8.9 g (39 mmol) of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (42) [34] in pyridine (100 mL) wasstirred at 80 for 48 h. The residue formed after cooling androtovapping was then treated with ethyl acetate and filteredthrough 2 cm layer of silica gel. The solvent was removed underreduced pressure and the desired product was crystallized fromethanol to obtain 4.85 g (30%) of 4-{(R)-3-[4-cyano-3-(trifluoromethyl)phenyl]-4-oxo-2-thioxo-7-oxa-1,3-diazaspiro[4.4]non-1-yl}-2-fluoro-N-methyl-N-[2-(trimethylsilyl)ethoxymethyl]benzamide ((R)-43). MS (ESI) [MH] 623. 1H NMR (400 MHz,CDCl3) d 8.01 (d, J 8.0 Hz, 1), 7.98 (s, 1), 7.85 (d, J 8.0 Hz, 1),7.57 (m, 1), 7.28 (m, 1), 7.21 (m, 1), 5.06 (s, 0.8), 4.63 (s, 1.2),4.41 (d, J 10.4 Hz, 1), 4.16 (d, J 10.4 Hz, 1), 3.97 (q, J 7.6 Hz,1), 3.78 (m, 1), 3.66 (t, J 8.2 Hz, 0.8), 3.66 (t, J 8.2 Hz, 1.2),3.20 (s, 1.8), 2.99 (s, 0.8), 2.72 (m, 1), 2.47 (m, 1), 1.01 (t,J 8.2 Hz, 0.8), 0.83 (t, J 8.2 Hz, 1.2), 0.06 (s, 3.6), 0.01 (s,5.4). TFA (15 mL) was added to the solution of compound (R)-43(4.8 g, 7.7 mmol) in DCM (30 mL), then the resulting mixture wasstirred for 3 h. The solvent was removed under reduced pressureand the formed residue was subjected to column chromatographyon silica gel (CHCl3/MeOH 60:1) to give 2.96 g (78%) of desiredproduct (R)-6. |
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