Dimethylformamide → N2-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine

HRID 2236191Notes

Reaction equation

HRID 2236191 reaction equation
[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>[Pd].CO>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 783082-Chloro-5-nitropyridineHCID 66877244cis-3-(Tert-butyl-dimethyl-silanyloxy)-cyclopentylamine

Product 1

HCID 67537770N2-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
75 °C

Procedure

To a 20 mL vial containing cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine, prepared according to literature reference (see Chen, et al US 2004/0204427 A1), (580 mg, 2.69 mmol) was added DMF (10 mL), 2-chloro-5-nitro-pyridine (428 mg, 2.69 mmol), and TEA (1.5 mL). The vessel was purged with Ar, sealed, heated to 75° C. for 4.5 hr, cooled to room temperature and allowed to stir over the weekend (60 hr). The reaction mixture was heated again at 75° C. for an additional 6 hr and then allowed to cool to RT overnight (18 hr). The reaction mixture was concentrated and redissolved in DMF (10 mL). 2 eq of K2CO3 was added (744 mg) and heated to 70° C. for 1 hr. The reaction mixture was concentrated, supported on silica gel, and purified by flash chromatography using an Analogix with a 80 g Redisep silica gel column at 60 mL/min with increasing concentrations of Et2O in hexane (0-5 min: 0%, 5-25 min: 0-20%, 25-40 min: 30%, 40-65 min: 30-100%). The appropriate fractions were collected and dried producing a clear oil, 490.8, 54.0% (LCMS 4.23 min, 338 (M+H), calcd. C16H27N3O3Si (m/e) 337, 50-100% ACN in H2O/HCOOH, C18, APCI). The nitropyridyl compound was transferred to a PARR vessel with MeOH (10 mL), Pd/C (10%) was added and the vessel was pressurized with H2 at 54 psi. After 3 hr the reaction mixture was filtered through a bed of celite and concentrated to dryness twice from DCM. The purple black material was used immediately for amide coupling (LCMS 2.94 min, 308 (M+H), calcd. C16H27N3O3Si (m/e) 307, 10-100% ACN in H2O/HCOOH 0.3%, C18, APCI).

Workup

  1. customprepared
  2. customThe vessel was purged with Ar
  3. customsealed
  4. temperaturecooled to room temperature
  5. temperatureThe reaction mixture was heated again at 75° C. for an additional 6 hr
  6. temperatureto cool to RT overnight (18 hr)
  7. concentrationThe reaction mixture was concentrated
  8. dissolutionredissolved in DMF (10 mL)
  9. temperatureheated to 70° C. for 1 hr
  10. concentrationThe reaction mixture was concentrated
  11. custompurified by flash chromatography
  12. temperaturewith increasing concentrations of Et2O in hexane (0-5 min: 0%, 5-25 min: 0-20%, 25-40 min: 30%, 40-65 min: 30-100%)
  13. customThe appropriate fractions were collected
  14. customdried
  15. customproducing a clear oil, 490.8, 54.0% (LCMS 4.23 min, 338 (M+H), calcd. C16H27N3O3Si (m/e) 337, 50-100% ACN in H2O/HCOOH, C18, APCI)
  16. additionwas added
  17. filtrationAfter 3 hr the reaction mixture was filtered through a bed of celite and
  18. concentrationconcentrated to dryness twice from DCM
  19. customwas used immediately for amide coupling (LCMS 2.94 min, 308 (M+H), calcd. C16H27N3O3Si (m/e) 307, 10-100% ACN in H2O/HCOOH 0.3%, C18, APCI)

Sources & evidence

ORD record
ord-704f26ab593e4e47a325970ee2307166
Source dataset
uspto-grants-2010_05
Patent number
US07714126B2

Reaction notes

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