Hydrochloric Acid → 5'-[(R)-2-Carboxy-1-(2-trifluoromethyl-benzyl)-ethylcarbamoyl]-2'-methyl-biphenyl-2-carboxylic Acid

HRID 2361134Notes

Reaction equation

HRID 2361134 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1C)[C:5]([OH:7])=[O:6].CCN([CH:18]([CH3:20])[CH3:19])C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:46][C@H:47]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([F:62])([F:61])[F:60])[CH2:48][C:49]([OH:51])=[O:50].C([O:67][C:68]([C:70]1[CH:75]=CC=[CH:72][C:71]=1B1OC(C)(C)C(C)(C)O1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.CCO.C1(C)C=CC=CC=1>[C:49]([CH2:48][C@H:47]([NH:46][C:68]([C:70]1[CH:71]=[CH:72][C:18]([CH3:19])=[C:20]([C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:75]=1)=[O:67])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([F:60])([F:61])[F:62])([OH:51])=[O:50]

Participants

15

Reactant 8

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 81531Diisopropylethylamine2×HCID 821303-Bromo-4-methylbenzoic acidHCID 4376764Tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 24820267(R)-3-Amino-4-(2-(trifluoromethyl)phenyl)butanoic acid hydrochloride

Product 1

HCID 710738395'-[(R)-2-Carboxy-1-(2-trifluoromethyl-benzyl)-ethylcarbamoyl]-2'-methyl-biphenyl-2-carboxylic AcidYield 95%

Reagents, catalysts & solvents 6

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent3×HCID 8857Ethyl AcetateSolvent

Procedure

3-Bromo-4-methylbenzoic acid (100 mg, 465 μmol, 1.0 eq.), DIPEA (434 μL), HATU (177 mg, 465 μmol, 1.0 eq.), and DCM (4 mL) were combined and stirred for 5 minutes at room temperature. Predissolved (R)-3-amino-4-(2-trifluoromethylphenyl)butanoic acid hydrochloride (132 mg, 465 μmol, 1.0 eq.) and DIPEA (0.2 mL) in DCM (10 mL) was then added and the resulting mixture was stirred for 2 hours. The reaction was quenched with saturated NH4Cl and the mixture was extracted with DCM, dried and evaporated to yield a crude material. 2-t-Butoxycarbonylphenylboronic acid pinacol ester (140 mg, 460 μmol, 1.0 eq.) and toluene (540 μL) were added to the crude material, followed by EtOH (0.3 mL) then K2CO3 (128 mg, 930 μmol, 2.0 eq.) predissolved in water (0.1 mL). The mixture was stirred to aid in dissolution. The reaction vessel was purged with nitrogen then Pd(PPh3)4 (53.7 mg, 46.5 μmol) was added quickly. The reaction vessel was capped and heated to 100° C. for 30 minutes. Upon completion of the reaction, the mixture was acidified to pH ˜5 with 1N HCl. EtOAc was added, with stirring. The organic layers were removed and evaporated under vacuum to yield a crude material. The crude material was then dissolved in DCM and TFA (0.3 mL each) and stirred for 2 hours. The solvents were removed by evaporation and the resulting product was purified by preparative HPLC (using AcOH as solvent) to yield the title compound (57 mg, 95% purity). MS m/z [M+H]+ calc'd for C26H22F3NO5, 486.15. found 486.4.

Workup

  1. stirringthe resulting mixture was stirred for 2 hours
  2. customThe reaction was quenched with saturated NH4Cl
  3. extractionthe mixture was extracted with DCM
  4. customdried
  5. customevaporated
  6. customto yield a crude material
  7. stirringThe mixture was stirred
  8. dissolutionto aid in dissolution
  9. customThe reaction vessel was purged with nitrogen
  10. customThe reaction vessel was capped
  11. temperatureheated to 100° C. for 30 minutes
  12. customUpon completion of the reaction
  13. stirringwith stirring
  14. customThe organic layers were removed
  15. customevaporated under vacuum
  16. customto yield a crude material
  17. customThe solvents were removed by evaporation
  18. customthe resulting product was purified by preparative HPLC (using AcOH as solvent)

Sources & evidence

ORD record
ord-e8279476860d410597d72dd46e751d80
Source dataset
uspto-grants-2014_04
Patent number
US08686184B2

Reaction notes

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