Toluene → N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide

HRID 1062896Notes

Reaction equation

HRID 1062896 reaction equation
COC(=O)[C@H](C)N([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)C(OC(C)(C)C)=O.C(N(CCC)C(C1C=C(C=CC=1)[C:32]([NH:34][C@@H:35]([CH2:54]C1C=CC=CC=1)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])=[O:33])=O)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:69])C.[Na+].C1COCC1.[C:86]1([CH3:92])[CH:91]=CC=C[CH:87]=1>C(O)(=O)C.CO>[C:86]([O:69][C:32]([NH:34][C@@H:35]([CH2:54][C:13]1[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:52])[CH3:53])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH3:39])=[O:33])([CH3:92])([CH3:91])[CH3:87]

Participants

8

Reactant 5

HCID 1140Toluene2×HCID 8028TetrahydrofuranHCID 5049666Sodium triacetoxyborohydrideHCID 9938756N-[(2S)-2-({3-[(dipropylamino)carbonyl]-benzoyl}amino)-3-phenylpropyl]-L-alanyl-N1-isobutyl-L-valinamideHCID 69734307N-t-butoxycarbonyl(3,5-difluorophenyl)alanine methyl ester

Product 1

HCID 10152485N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamideYield 34%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent2×

Conditions

Temperature
-78 °C

Procedure

N-t-Butoxycarbonyl(3,5-difluorophenyl)alanine methyl ester (1.3 g, 4.1 mmol) in toluene (20 mL) is placed under nitrogen and cooled to −78° C. To the stirred solution is added, dropwise over 10 min, 12.0 mL of a 1 M solution of Dibal in toluene. After 1 h, 2 mL of methanol is added dropwise, and the solution is poured into an aqueous solution of Rochelle salts cooled in an ice bath. The mixture is stirred and the organic material is extracted into ethyl ether. The organic phase is washed with water and brine, dried over Na2SO4, and concentrated to N-t-butoxycarbonyl(3,5-difluorophenyl)alanal as a white solid, 1.2 g (quantitative). N-t-Butoxycarbonyl(3,5-difluorophenyl)alanal (700 mg, 2.45 mmol) and L-alanyl-N1-isobutyl-L-valinamide (EXAMPLE 1, 700 mg, 2.87 mmol) are combined with sodium triacetoxyborohydride (1.0 g, 4.7 mmol) in 14 mL of THF containing 0.30 mL (5.0 mmol) of acetic acid. The mixture is allowed to stir 18 h. The reaction is quenched with 1 N NaHCO3 and the product is taken up in 200 mL of ethyl acetate and several mL of methanol. The organic phase is washed with more bicarbonate, and then with brine, and dried over Na2SO4. It is concentrated to a solid, which is chromatographed over silica gel, eluting with 25% to 30% acetone in dichloromethane. The product-containing fractions are concentrated to afford 432 mg (0.84 mmol, 34%) of the title product as a white solid. HRMS (ESI) calcd for C26H42F2N4O4+H1 513.3252, found 513.3259.

Workup

  1. additionTo the stirred solution is added, dropwise over 10 min
  2. additionthe solution is poured into an aqueous solution of Rochelle salts
  3. temperaturecooled in an ice bath
  4. extractionthe organic material is extracted into ethyl ether
  5. washThe organic phase is washed with water and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to N-t-butoxycarbonyl(3,5-difluorophenyl)alanal as a white solid, 1.2 g (quantitative)
  8. stirringto stir 18 h
  9. customThe reaction is quenched with 1 N NaHCO3
  10. washThe organic phase is washed with more bicarbonate
  11. dry with materialwith brine, and dried over Na2SO4
  12. concentrationIt is concentrated to a solid, which
  13. customis chromatographed over silica gel
  14. washeluting with 25% to 30% acetone in dichloromethane
  15. concentrationThe product-containing fractions are concentrated

Sources & evidence

ORD record
ord-b885ff8204624ca59ac4ae2d1c99def8
Source dataset
uspto-grants-2005_11
Patent number
US06962934B2

Reaction notes

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