Acetic Acid → 6-(Hydroxymethyl)-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

HRID 905558Notes

Reaction equation

HRID 905558 reaction equation
C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:9][CH2:10][C:11](=[O:15])[NH:12][C:13]=2[N:14]=1)=O.C([BH-](CC)CC)C.[Li+].C(O)(=O)C.OO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CO>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2[S:9][CH2:10][C:11](=[O:15])[NH:12][C:13]=2[N:14]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 784Hydrogen Peroxide2×HCID 656671Sodium PyrosulfiteHCID 21873660Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylateHCID 23664628Lithiumtriethylborohydride

Product 1

HCID 116080936-(Hydroxymethyl)-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneYield 73%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid methyl ester (WO 02/056882; 36.0 g, 161 mmol) in THF (240 mL) was added a solution of lithium triethylborohydride in THF (1M, 430 g, 3 eq.) at 5-10° C. over 70 min. Acetic acid (87 g, 9 eq.) was added dropwise at 10-25° C. to the brown solution. MeOH (180 mL) was added to the suspension at 20° C. The reaction vessel was then constantly cooled externally at 21-37° C. while a 5% w/w hydrogen peroxide solution (300 mL, 3 eq.) was added over 35 min, and a 10% w/w hydrogen peroxide solution (300 mL, 6 eq.) was added over further 35 min. A sat. aq sodium metabisulfite solution (147 g) was added at 24-36° C. The reaction mixture was concentrated under reduced pressure at 50° C. whereupon the product started to crystallize. MeOH was added to the suspension in three portions (3×180 mL) followed by removal of ca. 180 mL of solvent under reduced pressure after each addition. The solid was filtered, washed with water (2×150 mL) and tert-butyl methyl ether (150 ml). To the wet cake was added toluene in two portions (2×50 mL) followed by the removal of 50 mL solvent under reduced pressure at 50° C. The title compound was obtained as a light yellow solid (22.86 g, 73% yield; m.p. 120-135° C.).

Workup

  1. additionwas added over 35 min
  2. concentrationThe reaction mixture was concentrated under reduced pressure at 50° C. whereupon the product
  3. customto crystallize
  4. additionMeOH was added to the suspension in three portions (3×180 mL)
  5. customfollowed by removal of ca. 180 mL of solvent under reduced pressure
  6. additionafter each addition
  7. filtrationThe solid was filtered
  8. washwashed with water (2×150 mL) and tert-butyl methyl ether (150 ml)
  9. additionTo the wet cake was added toluene in two portions (2×50 mL)
  10. customfollowed by the removal of 50 mL solvent under reduced pressure at 50° C

Sources & evidence

ORD record
ord-01865bbc84da4e1e90d1e5ac9bbc8026
Source dataset
uspto-grants-2011_09
Patent number
US08012961B2

Reaction notes

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