Sodium Hydroxide → 1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-ylmethyl}1H-indole-3-carboxylic acid

HRID 1757498Notes

Reaction equation

HRID 1757498 reaction equation
[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6]1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:37]=[N:38][N:39]([C:41]([CH3:49])([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:42])[N:40]=2)=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].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.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:37]=[N:38][N:39]([C:41]([CH3:49])([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:42])[N:40]=2)=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH3:4]

Participants

9

Reactant 4

HCID 14798Sodium HydroxideHCID 9980291HCID 9980291, compoundHCID 103762901-butylindole-3-carboxylic AcidHCID 178418339Butyllithium

Product 1

HCID 103707811-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-ylmethyl}1H-indole-3-carboxylic acid

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 1-butyl-3-indolecarboxylic acid (20.0 g, 0.092 mol), preparedas Example 13, in 450 mL of THF was cooled to -40° C. under argon. n-Butyllithium (2.5M in hexane, 73.7 mL, 0.184 mol) was added at a rate such that the reaction temperature remained below -25° C. and then the mixture was allowed to warm to 0° C. The mixture was let stand for 30 minutes, cooled to -40° C. and then zinc chloride (1M in diethyl ether, 220 mL, 0.219 mol), tetrakis(triphenylphosphine)palladium(0) (2.03 g, 0.0018 mol) and 4-bromomethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl (38.01 g, 0.0878 mol), prepared as in Example 12, were sequencially added.The mixture was allowed to warm to room temperature and then 200 mL of ethyl acetate and 200 mL of 1N sodium hydroxide were added. The aqueous layer was separated and extracted with 50 mL of ethyl acetate. The combined ethyl acetate layers were washed with 200 mL of 1M hydrochloric acid and then brine and dried (sodium sulfate). The mixture was filtered and the solvent was removed. The residue was redissolved in 200 mL of ethyl acetate and 200 mL of methanol was slowly added to the solution giving a crystalline product which was isolated by filtration. The filtrate was concentrated and the residue was dissolved in 50 mL of ethyl acetate and proceeding similarly additional crystalline product was obtained. Drying and combining the products from each crystallization gave1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-ylmethyl}-1H-indole-3-carboxylic acid (45.5 g, 0.08 mol), m.p. 146°-148° C.

Workup

  1. customremained below -25° C.
  2. customfor 30 minutes
  3. temperaturecooled to -40° C.
  4. temperatureto warm to room temperature
  5. customThe aqueous layer was separated
  6. extractionextracted with 50 mL of ethyl acetate
  7. washThe combined ethyl acetate layers were washed with 200 mL of 1M hydrochloric acid
  8. dry with materialbrine and dried (sodium sulfate)
  9. filtrationThe mixture was filtered
  10. customthe solvent was removed
  11. dissolutionThe residue was redissolved in 200 mL of ethyl acetate
  12. addition200 mL of methanol was slowly added to the solution
  13. customgiving a crystalline product which
  14. customwas isolated by filtration
  15. concentrationThe filtrate was concentrated
  16. dissolutionthe residue was dissolved in 50 mL of ethyl acetate
  17. customproceeding similarly additional crystalline product was obtained
  18. customDrying

Sources & evidence

ORD record
ord-804a20ef1f424d09b8ab76ba653e280c
Source dataset
uspto-grants-1995_08
Patent number
US05446121

Reaction notes

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