Sodium Hydroxide → (4S)-6-chloro-1,1-dioxo-3,4-dihydro-2H-thieno(3,2-e)thiazin-4-ol

HRID 2259401Notes

Reaction equation

HRID 2259401 reaction equation
Br[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([Cl:10])[S:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].B(Cl)([C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1)[C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1.[K].[OH-].[Na+]>COC(C)(C)C.O1CCCC1.C(OCC)C>[Cl:10][C:8]1[S:7][C:6]2[S:11](=[O:13])(=[O:12])[NH:14][CH2:2][C@@H:3]([OH:4])[C:5]=2[CH:9]=1

Participants

8

Reactant 4

HCID 14798Sodium HydroxideHCID 5462222PotassiumHCID 98088223-(2-Bromoacetyl)-5-chloro-2-thiophenesulfonamideHCID 86810452(+)-B-Chlorodiisopinocampheylborane

Product 1

HCID 11746721(4S)-6-chloro-1,1-dioxo-3,4-dihydro-2H-thieno(3,2-e)thiazin-4-ol

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent2×

Procedure

In the fourth step of the process, 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4) is reduced with an appropriate reagent to provide initially an (S)-bromohydrin, which upon subsequent treatment with aqueous sodium hydroxide cyclizes to (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5). The preferred reducing agent is (+)-β-chlorodiisopinocampheylborane, which is well known to provide bromohydrins in high enantiomeric excess from prochiral α-bromo ketones [H. C. Brown, W. S. Park, B. T. Cho, and P. V. Ramachandran J. Org. Chem. 52, 5406 (1987) and H. C. Brown U.S. Pat. No. 4,918,246 (1990)]. Several different reaction solvents can be used for the reduction of (4), including diethyl ether, tetrahydrofuran, and t-butyl methyl ether. The reduction is typically carried out using 1.2 to 2.2 equivalents of (+)-β-chlorodiisopinocampheylborane at a temperature of -40° to 0° C. for 6 to 24 hours. A higher enantiomeric excess is obtained at the lower temperature; however, the reaction rate is slower. The preferred conditions utilize t-butyl methyl ether at a temperature of -25° to -15° C. After the reduction is complete, aqueous potassium or sodium hydroxide is added and the mixture is stirred at ambient temperature for a period of 1 to 5 hours to accomplish cyclization. The product is isolated by phase separation, acidification of the aqueous phase, extraction, solvent removal, and trituration. The enantiomeric excess of the (5) produced is typically greater than 96%.

Workup

  1. customat a temperature of -40° to 0° C.
  2. customfor 6 to 24 hours
  3. customA higher enantiomeric excess is obtained at the lower temperature
  4. customat a temperature of -25° to -15° C
  5. customThe product is isolated by phase separation, acidification of the aqueous phase, extraction, solvent removal, and trituration

Sources & evidence

ORD record
ord-f533a59d64c54d19b823d9186c3bc034
Source dataset
uspto-grants-1995_12
Patent number
US05473067

Reaction notes

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