Ethanol → N-{3-[5-(4-fluoro-benzyl)-8-hydroxy-6-oxo-5-aza-spiro[2.5]oct-7-en-7-yl]-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide

HRID 1515992Notes

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]([C:57]1([CH2:60][NH:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[CH2:59][CH2:58]1)=O.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][N:61]2[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])[C:57]3([CH2:58][CH2:59]3)[CH2:60]2)=[CH:68][CH:67]=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; 0.074 g, 0.209 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.088 g, 0.231 mmol) and 4-methylmorpholine (0.046 mL, 0.418 mmol) were added sequentially to a solution of 1-[(4-fluoro-benzylamino)-methyl]-cyclopropanecarboxylic acid methyl ester (0.050 g, 0.211 mmol) in N,N-dimethylformamide (3 mL) at 25° C. The reaction mixture was stirred at 25° C. for 17 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 (0.271 mL, 0.836 mmol) was added and the reaction mixture was heated to 60° C. for 24 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) N-{3-[5-(4-fluoro-benzyl)-8-hydroxy-6-oxo-5-aza-spiro[2.5]oct-7-en-7-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.015 g, 0.028 mmol, 13%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.80-0.90 (2H, m), 1.20-1.26 (2H, m), 2.95 (3H, s), 3.31 (2H, bs), 4.23 (2H, d, J=6.1 Hz), 4.61 (2H, s), 7.14-7.18 (3H, m), 7.32-7.36 (2H, m), 7.61 (1H, t, J=5.4 Hz). LC-MS (ESI) calculated for C21H21FN4O6S3 540.06. found 541.1 [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 (5 mL) at 25° C
temperaturethe reaction mixture was heated to 60° C. for 24 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-dfac934652f4420dadead08ff10dca2d
Source dataset: uspto-grants-2012_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08222404B2

Reaction notes

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