Dichloromethane → tert-Butyl 2-(5-(2,3-difluoro-4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 579357Notes

Reaction equation

HRID 579357 reaction equation
C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([N:20]3[CH2:23][C:22]4([CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[CH2:21]3)=[N:17][N:16]=2)=[C:11]([F:36])[C:10]=1[F:37])C1C=CC=CC=1.CCOC(C)=O.C(Cl)Cl>CO.C(Cl)Cl.CO.[Pd]>[F:36][C:11]1[C:10]([F:37])=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[S:19][C:18]([N:20]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH2:21]2)=[N:17][N:16]=1

Participants

7

Reactant 3

HCID 6344DichloromethaneHCID 8857Ethyl AcetateHCID 86727179tert-Butyl 2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Product 1

HCID 136341346tert-Butyl 2-(5-(2,3-difluoro-4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 34%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalyst3×HCID 887MethanolSolvent2×HCID 21226129Dichloromethane methanolSolvent2×

Procedure

A suspension of tert-butyl 2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (169 mg, 0.32 mmol) in a 1:3 mixture of MeOH:EtOAc (12 mL) was added to a nitrogen flushed flask containing 10% Pd/C (17 mg). The reaction mixture was placed under hydrogen atmosphere (50 psi) on a Parr shaker for 18 hours. Additional 10% Pd/C (169 mg) was added and the reaction was re-subjected to hydrogenation at 50 psi using a Parr shaker for a further 5 days. The reaction mixture was placed under an inert atmosphere (nitrogen), diluted with 10% MeOH/DCM (50 mL), filtered through celite, and rinsed with DCM. The filtrate was concentrated in vacuo to afford a pale brown solid which was re-dissolved in a 1:1 mixture MeOH:DCM (8 mL) and re-subjected to hydrogenation for 4 days at 50 psi using a Parr shaker and 10% Pd/C (169 mg) as the catalyst. The reaction mixture was diluted with 10% MeOH/DCM (50 mL), filtered through celite, and rinsed with DCM. The filtrate was concentrated in vacuo to afford the crude product as a slightly off-white solid. The crude material was purified by flash chromatography using a 12 g silica cartridge running a MeOH/DCM gradient to afford the title compound as an off-white solid (47 mg, 34% yield). LC-MS: Rt 1.27 min; MS m/z 439.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.65 (td, J=8.5, 2.2 Hz, 1H), 6.92 (td, J=8.5, 1.9 Hz, 1H), 3.87 (s, 4H), 3.20-3.31 (m, 4H), 1.67-1.78 (m, 4H), 1.40 (s, 9H).

Workup

  1. customfor 18 hours
  2. customfor a further 5 days
  3. filtrationfiltered through celite
  4. washrinsed with DCM
  5. concentrationThe filtrate was concentrated in vacuo
  6. customto afford a pale brown solid which
  7. filtrationfiltered through celite
  8. washrinsed with DCM
  9. concentrationThe filtrate was concentrated in vacuo
  10. customto afford the crude product as a slightly off-white solid
  11. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-056fcfa7354a40c4918988c9333709ba
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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