Ethyl Acetate → (S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 242329Notes

Reaction equation

HRID 242329 reaction equation
CC([O-])(C)C.[Na+].Br[C:8]1[CH:9]=[C:10]([Cl:16])[C:11]([O:14][CH3:15])=[N:12][CH:13]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([O:29][C:30]2[C:31]3[CH2:39][NH:38][CH2:37][CH2:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([O:29][C:30]2[C:31]3[CH2:39][N:38]([C:8]4[CH:13]=[N:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[CH:9]=4)[CH2:37][CH2:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 23676156Sodium t-butoxideHCID 404270045-Bromo-3-chloro-2-methoxypyridineHCID 57495303(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester2×

Product 1

HCID 57495339(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 60%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

X-Phos (0.073 g, 0.154 mmol), Pd2(dba)3 (0.100 g, 0.110 mmol), NaOtBu (0.395 g, 4.11 mmol) and 5-bromo-3-chloro-2-methoxy-pyridine (0.732 g, 3.29 mmol) were combined and flushed under a stream of argon for 10 min. To this mixture, a solution of (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 7) (2.15 g, 6.72 mmol) in THF (6 mL) was added at rt and the reaction mixture was stirred at 90° C. for 3 h. The reaction was cooled down to rt, EtOAc was added, the mixture filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 99/1 to 95/5) gave (S)-3-[6-(5-chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow foam (0.766 g, 60% yield). LCMS: [M+H]+=462.1, Rt(3)=1.84 min

Workup

  1. customflushed under a stream of argon for 10 min
  2. temperatureThe reaction was cooled down to rt
  3. filtrationthe mixture filtered through a celite pad
  4. concentrationconcentrated under vacuum
  5. customPurification by flash chromatography on silica gel (CH2Cl2/MeOH 99/1 to 95/5)

Sources & evidence

ORD record
ord-18d6da84b45448bfa784084fbe5cbfaa
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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