Ethanol → Rac-n-{3-[6-cyclobutyl-1-(4-fluoro-benzyl)-4-hydroxy-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 421467Notes

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(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C[O:54][C:55](=O)[CH2:56][CH:57]([CH:67]1[CH2:70][CH2:69][CH2:68]1)[NH:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=1.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:67]1([CH:57]2[N:58]([CH2:59][C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[C:19](=[O: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:55]([OH:54])[CH2:56]2)[CH2:70][CH2:69][CH2:68]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; 0.119 g, 0.337 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.140 g, 0.368 mmol) and 4-methylmorpholine (0.074 mL, 0.673 mmol) were added sequentially to a solution of rac-3-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.089 g, 0.335 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 22 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 (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.46 mL, 1.42 mmol) was added and the reaction mixture was heated to 60° C. for 4 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; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[6-cyclobutyl-1-(4-fluoro-benzyl)-4-hydroxy-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 (0.063 g, 0.111 mmol, 31%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.64-1.94 (4H, m), 2.36 (1H, d, J=17.2 Hz), 2.64-2.71 (1H, m), 2.95 (3H, s), 3.03 (1H, dd, J1=6.5 Hz, J2=17.7 Hz), 3.53-3.57 (1H, m), 4.15 (1H, d, J=14.8 Hz), 4.24 (2H, d, J=6.2 Hz), 5.10 (1H, d, J=15.1 Hz), 7.12-7.16 (2H, m), 7.24 (1H, s), 7.34-7.38 (2H, m), 7.64 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C23H25FN4O6S3 568.09. found 569.2 [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 (5 mL) at 25° C
temperaturethe reaction mixture was heated to 60° C. for 4 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; 60-100% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-cde25aac055145a0b48282ac0aa2e314
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08097613B2

Reaction notes

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