Diisopropylethylamine → (1-[4-(6-Chloro-1H-indol-2-yl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid

HRID 1500401Notes

Reaction equation

HRID 1500401 reaction equation
C([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:9]([CH3:23])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])(C)(C)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29](I)=[C:30]([NH2:32])[CH:31]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN1CCCC1=O>[Cl:25][C:26]1[CH:31]=[C:30]2[C:29]([CH:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[C:12]([CH3:13])=[C:8]([CH2:7][C:6]([OH:5])=[O:24])[C:9]([CH3:23])=[N:10]4)=[CH:20][CH:19]=3)[NH:32]2)=[CH:28][CH:27]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 6396975-Chloro-2-iodoanilineHCID 867165361-(4-ethynylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester

Product 1

HCID 66550737(1-[4-(6-Chloro-1H-indol-2-yl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acidYield 37.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred solution of 1-(4-ethynylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (4.4 g) and 5-chloro-2-iodophenylamine (3.4 g) in tetrahydrofuran (100 ml) at room temperature is added diisopropylethylamine (5.8 ml). The reaction is degassed and put under argon. Copper(I)iodide (260 mg) and bis(triphenylphosphine)palladiumdichloride (475 mg) are added. After 18 h, the reaction mixture is absorbed onto Extrelut and purified by flash chromatography (7:3 isocratic-cyclohexane:ethyl acetate) to yield a solid (4.3 g; HPLC retention time 1.66 min (Method J)). The solid (4.2 g) is dissolved in N-methyl-2-pyrrolidone (25 ml) and the solution degassed and put under argon. Potassium tert-butoxide (4.1 g) is added and the reaction is then heated to 50° C. After 15 h, further potassium tert-butoxide (1.0 g) is added. After 15 h the reaction temperature is increased to 75° C. After 3 h, the reaction mixture is allowed to cool to room temperature and a copious amount of water is added. The reaction mixture is extracted twice with ethyl acetate and the aqueous phase is acidified to pH 3 with 1M aqueous hydrochloric acid. The resultant precipitate is filtered off and triturated with hot acetonitrile to yield (1-[4-(6-Chloro-1H-indol-2-yl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid (2.0 g; [M+H]=394; HPLC retention time 1.51 min (Method E)).

Workup

  1. customThe reaction is degassed
  2. additionCopper(I)iodide (260 mg) and bis(triphenylphosphine)palladiumdichloride (475 mg) are added
  3. customthe reaction mixture is absorbed onto Extrelut
  4. custompurified by flash chromatography (7:3 isocratic-cyclohexane:ethyl acetate)
  5. customto yield a solid (4.3 g; HPLC retention time 1.66 min (Method J))
  6. customthe solution degassed
  7. additionPotassium tert-butoxide (4.1 g) is added
  8. waitAfter 15 h
  9. additionfurther potassium tert-butoxide (1.0 g) is added
  10. temperatureAfter 15 h the reaction temperature is increased to 75° C
  11. waitAfter 3 h
  12. temperatureto cool to room temperature
  13. additiona copious amount of water is added
  14. extractionThe reaction mixture is extracted twice with ethyl acetate
  15. filtrationThe resultant precipitate is filtered off
  16. customtriturated with hot acetonitrile

Sources & evidence

ORD record
ord-048d893319eb4c418806a936cbc089f4
Source dataset
uspto-grants-2015_12
Patent number
US09206164B2

Reaction notes

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