Bromoacetate → Ethyl 3-amino-4-(3'-chloro-3-fluorobiphenyl-4-yl)butanoate

HRID 1945062Notes

Reaction equation

HRID 1945062 reaction equation
BrCCBr.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[C:14]([F:21])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.BrCC([O-])=O.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.BrCC(OCC)=O.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].[Zn].CC(O)=O>[NH2:20][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=2)=[CH:13][C:14]=1[F:21])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]

Participants

12

Reactant 5

HCID 6226BromoacetateHCID 7748Ethyl bromoacetateHCID 78391,2-DibromoethaneHCID 5049666Sodium triacetoxyborohydrideHCID 596077962-(3'-Chloro-3-fluorobiphenyl-4-yl)acetonitrile

Product 1

HCID 59607761Ethyl 3-amino-4-(3'-chloro-3-fluorobiphenyl-4-yl)butanoate

Reagents, catalysts & solvents 6

HCID 7748Ethyl bromoacetateCatalystHCID 23994ZincCatalystHCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
70 °C

Procedure

A suspension of zinc (479 mg, 7.33 mmol) and 1,2-dibromoethane (0.032 ml, 0.366 mmol) in THF (8 ml) is heated at 70° C. under nitrogen then a few drops of ethyl bromoacetate is added. After stirring for 20 min, a solution of 2-(3′-chloro-3-fluorobiphenyl-4-yl)acetonitrile (300 mg, 1.221 mmol) in THF (2 ml) is added in one portion. The remaining bromoacetate is added dropwise over 50 min (total amount of ethyl bromoacetate: 4.88 mmol). After stirring for 15 min at the same temperature, the reaction mixture is cooled to ambient temperature. To the reaction mixture, sodium triacetoxyborohydride (2588 mg, 12.22 mmol) and AcOH (8 ml) are added. The reaction mixture is allowed to stir for 13 hours, and concentrated to give crude. The crude is diluted with EtOAc, and 2M aqueous Na2CO3 is added to be pH of 10. The products are extracted with EtOAc. The organic layer is dried over K2CO3, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% NH4OH) to 100% MeCN to give ethyl 3-amino-4-(3′-chloro-3-fluorobiphenyl-4-yl)butanoate (148 mg) as orange oil; HPLC retention time=0.85 minutes (condition B); MS (m+1)=336.13; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.1 Hz, 3H) 2.36 (A of ABX, Jab=15.9 Hz, Jax=8.8 Hz, 1H) 2.52 (B of ABX, Jab=15.9 Hz, Jbx=4.0 Hz, 1H) 2.71-2.76 (m, 1H) 2.82-2.87 (m, 1H) 3.51-3.57 (m, 1H) 4.15 (d, J=7.1 Hz, 2H) 7.24-7.39 (m, 5H) 7.42-7.44 (m, 1H) 7.54-7.55 (m, 1H).

Workup

  1. stirringAfter stirring for 15 min at the same temperature
  2. temperaturethe reaction mixture is cooled to ambient temperature
  3. stirringto stir for 13 hours
  4. concentrationconcentrated
  5. customto give crude
  6. additionis added
  7. extractionThe products are extracted with EtOAc
  8. dry with materialThe organic layer is dried over K2CO3
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give crude
  12. customThe resulting residue is purified by preparative HPLC

Sources & evidence

ORD record
ord-1fdb2f364ddc48f9a23326cea40cbbb2
Source dataset
uspto-grants-2013_03
Patent number
US08394853B2

Reaction notes

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