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Cesium fluoride → tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate

HRID 1520440
Notes
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Reaction equation

HRID 1520440 reaction equation
Br[C:2]1[S:6][C:5]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][N:3]=1.[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19].[F-].[Cs+]>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@@H:22]([C:23]1[CH:24]=[CH:25][C:26]([C:2]2[S:6][C:5]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][N:3]=2)=[CH:27][CH:28]=1)[OH:33])=[O:19]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 25953Cesium fluorideHCID 73425299Tert-butyl ((5-bromo-1,3,4-thiadiazol-2-YL)methyl)carbamateHCID 866953832,2-Dichloro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamide

Product 1

HCID 86695389tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamateYield 7.5%

Reagents, catalysts & solvents

3
HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of tert-butyl ((5-bromo-1,3,4-thiadiazol-2-yl)methyl)-carbamate (0.878 g, 2.98 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (1.20 g, 2.71 mmol) in dimethylformamide (20 mL) is added CsF (0.818 g, 5.42 mmol) followed by CuI (0.051 g, 0.271 mmol). Resulting reaction mixture is degassed with nitrogen for 30 minutes and Pd(PPh3)4 (0.313 g, 0.271 mmol) added. The reaction mixture is heated to 90° C. for 5 hours. Reaction mixture is concentrated in vacuo to give the crude material, which is purified by column chromatography on silica gel eluting in 1% methanol in CH2Cl2 to give the title compound (100 mg): 1H-NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 4.24-4.26 (m, 1H), 4.29-4.33 (m, 0.5H), 4.41-4.45 (m, 0.5H), 4.52 (d, J=5.96 Hz, 2H), 4.57-4.61 (m, 0.5H), 4.69-4.72 (m, 0.5H), 4.93 (t, J=3.76 Hz 1H), 6.08 (d, J=4.28 Hz, 1H), 6.49 (s, 1H), 7.51 (d, J=8.24 Hz, 2H), 7.86-7.90 (m, 3H), 8.63 (d, J=8.96 Hz, 1H). LC-Ms (m/z): [M−H]=490.80.

Workup

  1. customResulting
  2. customreaction mixture
  3. customis degassed with nitrogen for 30 minutes
  4. customReaction mixture
  5. concentrationis concentrated in vacuo
  6. customto give the crude material, which
  7. customis purified by column chromatography on silica gel eluting in 1% methanol in CH2Cl2

Sources & evidence

ORD record
ord-5064f33b66594944a7aacf3b18dae2a6
Source dataset
uspto-grants-2015_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09073894B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes