1-Hydroxybenzotriazole → HCID 71493648, compound

HRID 1486968Notes

Reaction equation

HRID 1486968 reaction equation
[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:41]3[CH2:42][CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27583493,3-Difluoropiperidine hydrochlorideHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid

Product 1

HCID 71493648HCID 71493648, compoundYield 15.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1.0 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.656 g, 1.2 eq.), 3,3-difluoropiperidine hydrochloride (0.540 g, 1.2), DIPEA (435 mg, 1.2 eq) and HOBT (25.92 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry and extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.70 g of crude compound. No trans compound was formed as confirmed by LCMS and 1H NMR. Purification by column chromatography afforded 0.20 g of material that was further recrystallized/triturated using ether: petroleum ether to remove aliphatic impurity affording 0.180 g (14.1% yield) of desired pure compound.

Workup

  1. customthen quenched with 50 mL ice-water slurry
  2. extractionextracted with CH2Cl2 (2×25 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customto afford 0.70 g of crude compound
  7. customNo trans compound was formed
  8. customPurification by column chromatography

Sources & evidence

ORD record
ord-e1af5b4f587e47d29c0b5600ac45b477
Source dataset
uspto-grants-2016_08
Patent number
US09428490B2

Reaction notes

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