1-Hydroxybenzotriazole → HCID 89734104, compound

HRID 926366Notes

Reaction equation

HRID 926366 reaction equation
[C:1]1([C:10]([OH:12])=O)[CH:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:35]1([C@H:41]([NH2:44])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([C@H:41]([NH:44][C:10]([C:1]2[CH:2]=[CH:3][N:4]3[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:12])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 5324978(R)-1-PhenylpropylamineHCID 123241775,6,7,8-Tetrahydroindolizine-1-carboxylic acid

Product 1

HCID 89734104HCID 89734104, compoundYield 88%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid (Comp. No. 8b) (6.22 g, 37.7 mmol) in dimethylformamide (125 ml) was added 1-hydroxybenzotriazole (5.60 g, 41.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.94 g, 41.4 mmol). The mixture was stirred for 30 min at 25° C., then (R)-1-phenyl-propylamine (6.11 g, 45.2 mmol) was added and the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h. The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added and the mixture was extracted 3 times with ethyl acetate, the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid, then 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness. The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 9.33 g (88%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 5): Rt=3.15 min; m/z=283.15 (M+H+).

Workup

  1. stirringthe mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h
  2. concentrationThe mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate
  3. additionwere added
  4. extractionthe mixture was extracted 3 times with ethyl acetate
  5. washthe combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid
  6. custom50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness
  7. customThe crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-08d47ea226024085b0f8018b0e04ac30
Source dataset
uspto-grants-2016_03
Patent number
US09284333B2

Reaction notes

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