3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile → 3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]benzonitrile

HRID 2168277Notes

Reaction equation

HRID 2168277 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C@:9]23[CH2:18][O:17][C@@H:16]([CH3:19])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:20]C(=O)C2C=CC=CC=2)=[N:10]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].NC1SC[C@@H]2C[C@H](C)OC[C@]2(C2C=C(C=CC=2Cl)C#N)N=1>>[NH2:20][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([CH3:19])[O:17][CH2:18][C@:9]2([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[N:10]=1

Participants

3

Reactant 2

HCID 762818493-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrileHCID 86762643N-[(4aR,6S,8aS)-8a-(3-cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 762818503-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]benzonitrile

Procedure

N-[(4aR,6S,8aS)-8a-(3-Cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C24) was converted to the product using the method described for the synthesis of 3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile (6) in Example 6. Purification by reverse phase HPLC (Column: Waters Sunfire C18, 19×100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 20.0% to 60% B, linear over 8.5 minutes). QC conditions: (Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute). Yield 22.5 mg, 0.08 mmol, 50%. LC/MS m/z 288.2 [M+H+]. Retention time: 1.62 minutes.

Workup

  1. customPurification by reverse phase HPLC (Column: Waters Sunfire C18, 19×100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 20.0% to 60% B, linear over 8.5 minutes)
  2. custom(Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute)

Sources & evidence

ORD record
ord-482ccf6c5aa74afbbf2d94361c624c0e
Source dataset
uspto-grants-2015_06
Patent number
US09045498B2

Reaction notes

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