Isopropanol → (4aR,11bR)-2-amino-10-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)-3,3,11b-trimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide

HRID 627743Notes

Reaction equation

HRID 627743 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13]C(=O)OC(C)(C)C)=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.Cl[C:31]1[C:32]2[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CC(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[NH2:13][C:11]1[C:10]([CH3:21])([CH3:22])[S:9](=[O:24])(=[O:23])[C@@H:8]2[CH2:25][CH2:26][O:27][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]4[C:32]5[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=5[N:34]=[CH:35][N:36]=4)=[CH:29][C:6]=3[C@@:7]2([CH3:28])[N:12]=1

Participants

6

Reactant 4

HCID 3776IsopropanolHCID 521998p-Toluenesulfonic acid monohydrateHCID 867159014-Chloro-7-methoxypyrido(3,2-d)pyrimidineHCID 90307362tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate

Product 1

HCID 90308657(4aR,11bR)-2-amino-10-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)-3,3,11b-trimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxideYield 61.4%

Reagents, catalysts & solvents 1

HCID 516892Sodium BicarbonateSolvent

Procedure

A disposable tube was charged with tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (60 mg, 0.142 mmol), 4-chloro-7-methoxypyrido[3,2-d]pyrimidine (30.5 mg, 0.156 mmol) and 2-propanol (708 μl, 0.142 mmol), followed by p-toluenesulfonic acid monohydrate (53.9 mg, 0.283 mmol). The resulting mixture was stirred from rt to 90° C. for 25 min. The reaction mixture was diluted with sat. NaHCO3 and extracted with EtOAc to yield the crude product as a yellow solid. The crude material was absorbed onto a plug of silica gel and purified by column chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 20% to 35% to 50% EtOAc/MeOH/NEt3 (80/20/2) in (40% EtOAc in Heptane), to provide (4aR,11bR)-2-amino-10-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)-3,3,11b-trimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide (42 mg, 0.087 mmol, 61.4% yield) as white solid. MS m/z=483.2 (M+H).

Workup

  1. extractionextracted with EtOAc
  2. customto yield the crude product as a yellow solid
  3. customThe crude material was absorbed onto a plug of silica gel
  4. custompurified by column chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  5. washeluting with a gradient of 20% to 35% to 50% EtOAc/MeOH/NEt3 (80/20/2) in (40% EtOAc in Heptane)

Sources & evidence

ORD record
ord-38529412ccc04b5ebcce4d1e47ea74b4
Source dataset
uspto-grants-2016_04
Patent number
US09309263B2

Reaction notes

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