Methanesulfonic Acid → 5-(Aminomethyl)-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one

HRID 1040163Notes

Reaction equation

HRID 1040163 reaction equation
[N-:1]=[N+]=[N-].[Na+].[NH2:5][CH2:6][C:7]1([C:17]2[S:18][C:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][N:21]=2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.CS(O)(=O)=O>C(Cl)(Cl)Cl>[NH2:5][CH2:6][C:7]1([C:17]2[S:18][C:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][N:31]=4)[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][N:21]=2)[CH2:8][CH2:9][NH:1][C:10](=[O:11])[CH2:15][CH2:16]1

Participants

5

Reactant 3

HCID 6395Methanesulfonic AcidHCID 33557Sodium AzideHCID 67429575N-(3-{2-[8-(aminomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-1,3-thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine

Product 1

HCID 584562885-(Aminomethyl)-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-oneYield 2.5%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Conditions

Temperature
65 °C

Procedure

Sodium azide (20.45 mg, 0.315 mmol, 3.0 equiv) was added to a stirring solution of the product of Step 1 (53 mg, 0.11 mmol) in chloroform (5 ml). Methanesulfonic Acid (0.082 ml, 1.258 mmol, 12 equiv) was added and the reaction was capped and stirred at 65° C. for 1 h. The yellow mixture was partitioned between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (90 ml), and the combined organic layers were dried over MgSO4 and concentrated. The residual colorless oil was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present). The desired fractions were partitioned between EtOAc (2×55 ml) and saturated aqueous NaHCO3 (65 ml). The combined organic layers were dried over Na2SO4 and concentrated, providing the desired title compound (1.3 mg, 2.5%) as a colorless solid-oil. MS ESI: [M+H]+ m/z 477.21. 1H NMR (500 MHz, CD3OD) δ 8.72 (d, 1H, J=4.6 Hz), 8.19 (bs, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.13 (d, 1H, J=4.6 Hz), 3.45 (s, 2H), 2.95 (m, 2H), 2.05 (s, 3H), 1.90-1.57 (m, 6H). rhSYK activity=+++

Workup

  1. customthe reaction was capped
  2. customThe yellow mixture was partitioned between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (90 ml)
  3. dry with materialthe combined organic layers were dried over MgSO4
  4. concentrationconcentrated
  5. customThe residual colorless oil was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present)
  6. customThe desired fractions were partitioned between EtOAc (2×55 ml) and saturated aqueous NaHCO3 (65 ml)
  7. dry with materialThe combined organic layers were dried over Na2SO4
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-544102bbf5a84accb5fcb5d8092f02ed
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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