Hydrochloric Acid → 2-[2-[(4aR,7aR)-2-Amino-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-6-yl]-5-fluoro-6-methyl-pyrimidin-4-yl]propan-2-ol hydrochloride

HRID 470295Notes

Reaction equation

HRID 470295 reaction equation
[F:1][C:2]1[C:3]([C:32]([OH:35])([CH3:34])[CH3:33])=[N:4][C:5]([N:9]2[CH2:17][C@@H:16]3[C@@:11]([C:27]4[S:31][N:30]=[CH:29][CH:28]=4)([N:12]=[C:13]([NH:18]C(=O)C4C=CC=CC=4)[S:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8].N1C=CC=CC=1.[ClH:42].CON.Cl.O1CCOCC1>C(O)C.C(Cl)Cl>[ClH:42].[NH2:18][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:17][N:9]([C:5]3[N:4]=[C:3]([C:32]([OH:35])([CH3:34])[CH3:33])[C:2]([F:1])=[C:7]([CH3:8])[N:6]=3)[CH2:10][C@:11]2([C:27]2[S:31][N:30]=[CH:29][CH:28]=2)[N:12]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 312751,4-DioxaneHCID 521874O-Methylhydroxylamine hydrochlorideHCID 86762241N-[(4aR,7aR)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 867622562-[2-[(4aR,7aR)-2-Amino-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-6-yl]-5-fluoro-6-methyl-pyrimidin-4-yl]propan-2-ol hydrochlorideYield 62.5%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

N-[(4aR,7aR)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (33 mg, 0.064 mmol) is dissolved in ethanol (2 mL). To this solution is added pyridine (0.052 mL, 0.6 mmol) and O-methylhydroxylamine hydrochloride (55 mg, 0.6 mmol). The reaction is warmed to 70° C. for 4 hours. The reaction is cooled to room temperature and stirred overnight (˜16 hrs). The mixture is concentrated to give the crude product which is purified via silica gel chromatography using a 0-10% (7 N NH3 in MeOH)/DCM to give the pure freebase. The freebase is dissolved in DCM (2 mL) and treated with 4 M HCl in dioxane (0.3 mL, 1.2 mmol). The mixture is concentrated to give the title compound as a white solid (18 mg, 0.04 mmol). ES/MS (m/z): 409 (M+H). [α]D20=−6.0° (C=1.0, MeOH).

Workup

  1. temperatureThe reaction is cooled to room temperature
  2. concentrationThe mixture is concentrated
  3. customto give the crude product which
  4. customis purified via silica gel chromatography
  5. customto give the pure freebase
  6. concentrationThe mixture is concentrated

Sources & evidence

ORD record
ord-cd89b06d82c6459b8be55e0293dd9e8e
Source dataset
uspto-grants-2014_01
Patent number
US08629270B2

Reaction notes

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