Sodium Bicarbonate → 5-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-1,1-dioxo-1,2,3,6-tetrahydro-1lambda6-[1,4]thiazin-3-yl)-4-fluoro-phenyl]-amide

HRID 920187Notes

Reaction equation

HRID 920187 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:48])=[C:36]([C@:38]2([CH3:47])[CH2:43][S:42](=[O:45])(=[O:44])[CH2:41][C:40]([NH2:46])=[N:39]2)[CH:37]=1.C([O-])(O)=O.[Na+]>CO>[NH2:46][C:40]1[CH2:41][S:42](=[O:44])(=[O:45])[CH2:43][C@:38]([C:36]2[CH:37]=[C:32]([NH:31][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:33]=[CH:34][C:35]=2[F:48])([CH3:47])[N:39]=1

Participants

6

Reactant 4

HCID 516892Sodium BicarbonateHCID 124007345-Cyanopyridine-2-carboxylic acidHCID 231494114-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrateHCID 90067101(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1lambda6-[1,4]thiazin-3-ylamine

Product 1

HCID 725481985-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-1,1-dioxo-1,2,3,6-tetrahydro-1lambda6-[1,4]thiazin-3-yl)-4-fluoro-phenyl]-amideYield 37%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
0 °C

Procedure

Method b): To a solution of 5-cyanopicolinic acid (69.1 mg, 466 μmol, Eq: 1.1) in Methanol (6 ml) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride hydrate (187 mg, 636 μmol, Eq: 1.5) and the mixture was stirred at 0° C. for 15 minutes. Added (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (115 mg, 424 μmol, Eq: 1.00) in Methanol (6 ml) and stirred at 23° C. overnight. Poured into sat NaHCO3-sol., extracted with ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a brown oil. The crude material was purified by silica gel flash chromatography (10 g): washed first with ethyl acetate, then added 5% of a 7 M solution of ammonia in methanol to give the 5-cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-1,1-dioxo-1,2,3,6-tetrahydro-1λ6-[1,4]thiazin-3-yl)-4-fluoro-phenyl]-amide (63 mg, 157 μmol, 37.0% yield) as a light yellow solid. MS (ISP): m/z=402.4 [(M+H)+].

Workup

  1. additionPoured
  2. extraction, extracted with ethyl acetate
  3. dry with materialthe organic layer was dried over Na2SO4
  4. customRemoval of the solvent in vacuum
  5. waitleft a brown oil
  6. customThe crude material was purified by silica gel flash chromatography (10 g)
  7. washwashed first with ethyl acetate
  8. additionadded 5% of a 7 M solution of ammonia in methanol

Sources & evidence

ORD record
ord-2425138bd4234e9483c1063f9cbac273
Source dataset
uspto-grants-2016_03
Patent number
US09273042B2

Reaction notes

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