Hydrochloric Acid → rel-(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine, hydrochloride salt

HRID 1478737Notes

Reaction equation

HRID 1478737 reaction equation
[CH:1]1([C@@H:4]2[O:25][CH2:24][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:8]=[C:9]([NH:15]C(=O)C4C=CC=CC=4)[S:10][C@H:11]([CH2:12][O:13][CH3:14])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.FC1C=C(F)C=CC=1[C@]12CO[C@@H](C3CCO3)C[C@H]1CSC(N)=N2.[ClH:57]>ClCCl.C(OCC)C>[ClH:57].[CH:1]1([C@@H:4]2[O:25][CH2:24][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:8]=[C:9]([NH2:15])[S:10][C@H:11]([CH2:12][O:13][CH3:14])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 90253547(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amineHCID 90253558rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 131736523rel-(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine, hydrochloride salt

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

Conversion of rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C42) to the free base of the product was carried out via the method described for synthesis of (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (4) in Example 4. In this case, purification was effected using silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane), affording an oil. This was dissolved in dichloromethane and treated with a 1 M solution of hydrogen chloride in diethyl ether; removal of volatiles under reduced pressure provided the product as a solid. Yield: 8.6 mg, 21 μmol, 58%. LCMS m/z 369.2 [M+H+]. 1H NMR, free base of 5: (400 MHz, CDCl3) δ 7.33 (ddd, J=9.0, 9.0, 6.6 Hz, 1H), 6.74-6.87 (m, 2H), 4.03 (dd, J=10.9, 2.3 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.58-3.65 (m, 1H), 3.32-3.39 (m, 2H), 3.30 (s, 3H), 2.79-2.87 (m, 2H), 1.63-1.74 (m, 1H), 1.50-1.57 (m, 1H), 0.91-1.04 (m, 1H), 0.47-0.61 (m, 2H), 0.38-0.46 (m, 1H), 0.19-0.27 (m, 1H).

Workup

  1. customIn this case, purification
  2. customaffording an oil
  3. customremoval of volatiles under reduced pressure

Sources & evidence

ORD record
ord-96aa6d53f48a47159f689a6e7c169655
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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