Triethylamine → (5-Chloro-2,4-dihydroxy-phenyl)[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone

HRID 1625392Notes

Reaction equation

HRID 1625392 reaction equation
[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[CH2:49][NH:48][CH2:47]3)[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:48]2[CH2:47][C:46]3[C:50](=[CH:51][CH:52]=[C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]4)[CH:45]=3)[CH2:49]2)=[O:9])[CH:10]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 105728Benzoic acid, 5-chloro-2,4-dihydroxy-HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 666722875-(4-Methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole dihydrochloride

Product 1

HCID 11955816(5-Chloro-2,4-dihydroxy-phenyl)[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 5-chloro-2,4-dihydroxy-benzoic acid (176 mg, 0.93 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (179 mg, 0.93 mmol) then HOBt (126 mg, 0.93 mmol). After 45 min, the solution of the activated acid was added to a mixture 5-(4-methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole dihydrochloride (290 mg, 0.78 mmol) and triethylamine (0.28 mL, 2 mmol) then the mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo then the residue was partitioned between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and brine then dried (MgSO4), combined and concentrated. Some insoluble material remained and this was dissolved in 1N hydrochloric acid and methanol then combined with the organic extracts. The pH was adjusted to 14 with solid sodium hydroxide and the mixture allowed to stand overnight. The pH was adjusted to 7 with 1N hydrochloric acid and the resulting precipitate was filtered off then subjected to purification by preparative HPLC to afford the title compound as a red solid. This was converted to its hydrochloride salt by treatment with 4M HCl in dioxane, concentration in vacuo and trituration with ether which gave a brown solid (91 mg, 27%). 1H NMR (DMSO-d6) 11.10 (1H, br. s), 10.50 (1H, br. s), 7.26-7.15 (2H, m), 7.02-6.93 (2H, m), 6.69 (1H, s), 4.72-4.61 (4H, m), 3.78-3.72 (2H, m), 3.45 (2H, br. s), 3.12 (4H, br. s), 2.78 (3H, s). MS: [M+H]+ 386/388.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe residue was partitioned between ethyl acetate and water (×3)
  3. washEach extract was washed with saturated sodium bicarbonate solution and brine
  4. dry with materialthen dried (MgSO4)
  5. concentrationconcentrated
  6. dissolutionthis was dissolved in 1N hydrochloric acid
  7. waitto stand overnight
  8. filtrationthe resulting precipitate was filtered off
  9. customthen subjected to purification by preparative HPLC

Sources & evidence

ORD record
ord-b95d6d4d080947b09a6a1c1d49b85bce
Source dataset
uspto-grants-2014_07
Patent number
US08779132B2

Reaction notes

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