Chlorotrimethylsilane → (S)-2-Chloro-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[(2-tetrahydropyranyl)oxy]pyridinepropanoic Acid Methyl Ester

HRID 2119290Notes

Reaction equation

HRID 2119290 reaction equation
BrCCBr.C[Si]([Cl:9])(C)C.[CH3:10][O:11][C:12](=[O:24])[C@H:13]([CH2:22]I)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[CH2:32]1C[O:35][CH2:34][CH2:33]1.[CH3:37][C:38](N(C)C)=[O:39]>C1COCC1.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:24])[CH:13]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:22][C@:26]1([Cl:9])[C:31]([O:35][CH:34]2[CH2:33][CH2:32][CH2:37][CH2:38][O:39]2)=[CH:30][CH:29]=[CH:28][NH:27]1

Participants

9

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 2211262-IodopyridineHCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 69293768tetrahydrofuran N,N-dimethylacetamide2×

Product 1

HCID 86759327(S)-2-Chloro-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[(2-tetrahydropyranyl)oxy]pyridinepropanoic Acid Methyl EsterYield 60%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
30 °C

Procedure

To an amberized flask containing activated Zn dust (0.349 g, 5.51 mmol) under Ar is added THF (2 mL) and 1,2-dibromoethane (0.018 mL, 0.21 mmol). The suspension is brought to reflux for several minutes, cooled to approximately 30° C., and TMSCl (0.17 mL of a 1 M solution in THF) is added. The reaction mixture is stirred at 40±5° C. for 30 min and then is cooled to below rt. A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-iodo-L-alanine methyl ester [93267-04-0] (1.81 g, 5.50 mmol) in 11:7 dimethylacetamide/THF (9.0 mL) is added, and the resulting reaction mixture is stirred at 45° C. for 5 h. The reaction mixture is cooled to below rt, and solid PdCl2(PPh3)2 (0.192 g) is added, followed immediately by addition of a degassed solution of the iodopyridine (0.936 g, 2.76 mmol) in 1:1 THF/dimethylacetamide (5.6 mL). This reaction mixture is stirred for 4 h at 45° C. It is cooled to 0° C., quenched with sat'd aq NH4Cl, and extracted with EtOAc. The combined EtOAc portions are washed with sat'd aq NH4Cl and brine. The EtOAc solution is dried, filtered and concentrated to give a green-yellow colored foam, that upon purification by silica flash chromatography (7:3 hexanes/EtOAc) gives 0.879 g (1.85 mmol, 60%) of the title product: TLC (7:3 hexanes/EtOAc) Rf 0.21; 1H NMR (CDCl3, 300 MHz) d 7.39 (1H), 7.00 (1H), 5.46 (1H), 4.61 (1H), 4.13 (1H), 3.80 (3H), 3.62 (1H), 3.20 (1H), 2.13-1.53 (6H), 1.42 (9H).

Workup

  1. temperatureto reflux for several minutes
  2. temperatureis cooled to below rt
  3. customthe resulting reaction mixture
  4. stirringis stirred at 45° C. for 5 h
  5. temperatureThe reaction mixture is cooled to below rt
  6. stirringThis reaction mixture is stirred for 4 h at 45° C
  7. temperatureIt is cooled to 0° C.
  8. customquenched with sat'd aq NH4Cl
  9. extractionextracted with EtOAc
  10. washThe combined EtOAc portions are washed with sat'd aq NH4Cl and brine
  11. dry with materialThe EtOAc solution is dried
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customto give a green-yellow colored foam, that
  15. customupon purification by silica flash chromatography (7:3 hexanes/EtOAc)

Sources & evidence

ORD record
ord-e4ae1396d2ee4936a64710fca94ea73c
Source dataset
uspto-grants-2004_02
Patent number
US06685617B1

Reaction notes

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