Sodium ethoxide → N-[3-[(4aR,7aS)-1-[(3-chloro-4-fluoro-phenyl)methyl]-4-hydroxy-2-oxo-5,6,7,7a-tetrahydro-4aH-cyclopenta[b]pyridin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

HRID 731263Notes

Reaction equation

HRID 731263 reaction equation
C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=1)[C:11](=[O:30])[CH2:12][C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=2[S:15](=[O:29])(=[O:28])[N:14]=1)=O.[O-]CC.[Na+]>C(O)C>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[CH2:31][N:10]1[C@@H:6]2[C@@H:5]([CH2:9][CH2:8][CH2:7]2)[C:3]([OH:2])=[C:12]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][C:16]=3[S:15](=[O:29])(=[O:28])[N:14]=2)[C:11]1=[O:30]

Participants

4

Reactant 2

HCID 2723922Sodium ethoxideHCID 57832621(1R,2S)-2-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester

Product 1

HCID 135955913N-[3-[(4aR,7aS)-1-[(3-chloro-4-fluoro-phenyl)methyl]-4-hydroxy-2-oxo-5,6,7,7a-tetrahydro-4aH-cyclopenta[b]pyridin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamideYield 61.7%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
60 °C

Procedure

(1R,2S)-2-{(3-Chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (crude from Example 11b, 0.252 g, 0.42 mmol) was dissolved in ethanol (8.4 mL), followed by addition of a 21% w/w solution of sodium ethoxide in ethanol (0.545 mL, 1.68 mmol), and heated to 60° C. for 1 h. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (2 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and dried in vacuo. Recrystallization from 10-20% ethyl acetate in hexanes afforded the desired product, (4aR,7aS)-N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.147 g, 0.259 mmol, 61%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.51-1.58 (m, 3H), 1.99-2.00 (m, 3H), 3.06 (s, 3H), 3.30 (bs, 1H), 3.88 (bs, 1H), 4.47 (d, 1H, J=15.0 Hz), 4.89 (d, 1H, J=15.4 Hz), 7.36 (d, 2H, J=7.3 Hz), 7.50 (dd, 1H, J1=8.6 Hz, J2=2.4 Hz), 7.57-7.59 (m, 3H), 10.17 (bs, 1H). LC-MS (ESI) calcd for C23H22ClFN4O6S2 568.07, found 569.03 [M+H+].

Workup

  1. temperatureUpon cooling
  2. customthe reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (2 mL)
  3. extractionextracted with ethyl acetate (2×50 mL)
  4. dry with materialThe combined organic layers were dried over magnesium sulfate
  5. filtrationfiltered
  6. customdried in vacuo
  7. customRecrystallization from 10-20% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-f8ecd39c3e0b4d6faefa29cb3f044d5e
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

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