1-Hydroxybenzotriazole → HCID 68183264, compound

HRID 1615542Notes

Reaction equation

HRID 1615542 reaction equation
Cl.[NH2:2][CH2:3][CH2:4][CH:5]([C:13]1[N:14]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:16][C:17]=1[C:18]([OH:20])=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[CH2:4][CH2:3][NH:2][C:18](=[O:20])[C:17]3[S:16][C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][C:13]2=3)=[CH:11][CH:10]=1

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68183124HCID 68183124, compound

Product 1

HCID 68183264HCID 68183264, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 4-[3-amino-1-(4-chlorophenyl)propyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid hydrochloride (0.264 g, 0.631 mmol) in DCM (12.7 mL) was added 1-hydroxybenzotriazole (0.103 g, 0.763 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.239 g, 1.24 mmol) and N,N-diisopropylethylamine (0.320 mL, 1.84 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM, then the layers were separated and the organic layer was washed with water then brine and dried over anhydrous sodium sulfate then concentrated. The residue was purified using column chromatography on silica gel (12 gr Analogix column, gradient DCM to 10% MeOH in DCM over 15 minutes) to give the product. The racemic product was then separated into enantiomers on a Chiralpak IA 20×250 mm column using 70/10/20 hexane/IPA/EtOH mixture, with retention time 10.4 min for peak 1 (53 mg, 23%) and 14.5 min for peak 2 (53 mg, 23%). Absolute configuration for the enantiomers is unknown. LCMS: (AA) ES+ 364, 366. 1H NMR (400 MHz, d6-DMSO) δ: 7.95 (t, J=4.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 4.34 (dd, J=7.1, 5.3 Hz, 1H), 3.64-3.57 (m, 4H), 3.31-3.24 (m, 4H), 3.14-3.01 (m, 2H), 2.28-2.13 (m, 1H), 2.04-1.84 (m, 1H).

Workup

  1. customthe layers were separated
  2. washthe organic layer was washed with water
  3. dry with materialbrine and dried over anhydrous sodium sulfate
  4. concentrationthen concentrated
  5. customThe residue was purified
  6. customon silica gel (12 gr Analogix column, gradient DCM to 10% MeOH in DCM over 15 minutes)
  7. customto give the product
  8. customThe racemic product was then separated into enantiomers on a Chiralpak IA 20×250 mm column
  9. customfor peak 1 (53 mg, 23%) and 14.5 min

Sources & evidence

ORD record
ord-1e0dd924bb6f4343b32ab463ded85796
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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