Ethanol → Rac-n-{3-[1-cyclopentyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-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 421500Notes

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)[C:57]([CH2:64][NH:65][CH:66]1[CH2:70][CH2:69][CH2:68][CH2:67]1)([CH3:63])[CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:66]1([N:65]2[CH2:64][C:57]([CH3:63])([CH2:58][CH2:59][CH:60]([CH3:61])[CH3:62])[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])[CH2:67][CH2:68][CH2:69][CH2:70]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; 0.274 g, 0.775 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.324 g, 0.853 mmol) and 4-methylmorpholine (0.171 mL, 1.55 mmol) were added sequentially to a solution of rac-2-cyclopentylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (0.209 g, 0.776 mmol) in N,N-dimethylformamide (8 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 (15 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.51 mL, 4.66 mmol) was added and the reaction mixture was heated to 70° C. for 24 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 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; 40-100% ethyl acetate in hexanes) to afford rac-N-{3-[1-cyclopentyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-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 (0.032 g, 0.057 mmol, 7%) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ: 0.83-0.86 (6H, m), 0.88-0.91 (1H, m), 1.01 (3H, s), 1.08-1.17 (6H, m), 1.23-1.30 (2H, m), 1.41-1.51 (3H, m), 1.95-2.01 (1H, m), 2.95 (3H, s), 3.17-3.21 (1H, m), 3.46-3.51 (1H, m), 3.99-4.05 (1H, m), 4.23 (2H, d, J=5.4 Hz), 7.24 (1H, s), 7.64 (1H, bs). LC-MS (ESI) calculated for C23H34N4O6S3 558.16. found 559.1 [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 (15 mL) at 25° C
temperaturethe reaction mixture was heated to 70° C. for 24 h
temperatureAfter cooling to 25° C.
customthe reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 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; 40-100% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-2c2bf75c1c444230a6de84dcf4bdaff7
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08097613B2

Reaction notes

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