Ethanol → Rac-n-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide

HRID 421481Notes

Reaction equation

[CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH:57]([CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH:58]([CH3:60])[CH3:59])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:62]2[CH2:61][CH:57]([CH:58]([CH3:59])[CH3:60])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:69][CH:68]=1

Participants

Conditions

Temperature: 25 °C

Procedure

[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.174 g, 0.492 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.206 g, 0.542 mmol) and 4-methylmorpholine (0.109 mL, 0.990 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (0.132 g, 0.494 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.28 mL, 3.96 mmol) was added and the reaction mixture was heated to 70° C. for 38 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.100 g, 0.180 mmol, 36%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.73 (3H, d, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 1.86-1.94 (1H, m), 2.35 (1H, bs), 2.96 (3H, s), 3.33 (1H, dd, J1=3.5 Hz, J2=13.0 Hz), 3.55 (1H, dd, J1=5.6 Hz, J2=13.3 Hz), 4.24 (2H, d, J=6.3 Hz), 4.52 (1H, d, J=14.8 Hz), 4.68 (1H, d, J=14.6 Hz), 7.14-7.19 (2H, m), 7.25 (1H, s), 7.37-7.41 (2H, m), 7.64 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C22H25FN4O6S3 556.09. found 557.1 [M+H+].

Workup

concentrationwas concentrated in vacuo
customThe residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
dry with materialThe organic layers were dried over sodium sulfate
concentrationwere concentrated in vacuo
dissolutionThe residue was dissolved in ethanol (10 mL) at 25° C
temperaturethe reaction mixture was heated to 70° C. for 38 h
temperatureAfter cooling to 25° C.
customthe reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
dry with materialThe organic layers were dried over sodium sulfate
concentrationwere concentrated in vacuo
customThe residue was purified by flash chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-5046b7bc8646447c9224cb09e677fce5
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08097613B2

Reaction notes

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