Maleic Anhydride → HCID 178498080, compound

HRID 255004Notes

Reaction equation

HRID 255004 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]1(=[O:24])O[C:21](=[O:22])[CH:20]=[CH:19]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:48][CH2:49][C:50]1[C:51](=[N:56][NH:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[CH:59]=2)[C:52]([NH2:55])=[N:53][N:54]=1>COCCOC.C(OCC)C.CN(C=O)C>[CH3:2][O:3][C:4]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:18](=[O:24])[CH:19]=[CH:20][C:21](=[O:22])[NH:48][CH2:49][C:50]1[C:51](=[N:56][NH:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[CH:59]=2)[C:52]([NH2:55])=[N:53][N:54]=1)=[O:10]

Participants

10

Reactant 6

HCID 7923Maleic AnhydrideHCID 8471Triethylamine2×HCID 10868DicyclohexylcarbodiimideHCID 80170N-HydroxysuccinimideHCID 2733200methyl L-prolinate hydrochlorideHCID 178510679HCID 178510679, compound

Product 1

HCID 178498080HCID 178498080, compoundYield 38%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 80711,2-DimethoxyethaneSolvent2×

Procedure

To a suspension of L-proline methyl ester hydrochloride (200 mg, 1.21 mmole) in 8 mL of ethylene glycol dimethyl ether was added triethylamine (244 mg, 2.4 mmole). The white cloudy mixture was stirred at ambient temperature for 20 min, and was then treated with maleic anhydride in 1 mL of diethyl ether. After 1 hour, the reaction mixture was filtered. The filtrate was mixed with a solution of N-hydroxysuccinimide (172 mg, 1.5 mmole) in ethylene glycol dimethyl ether, and then DCC (412 mg, 2 mmole) was added. The reaction mixture was stirred at ambient temperature overnight. After filtration, the solution of the NHS ester was added in 4 mL portions to a solution of 5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg, 0.25 mmole) and triethylamine (0.51 mmole, 52 mg) in 4 mL of DMF at 45° C. After stirring at ambient temperature for 45 minutes, the reaction was quenched by the addition of saline and ethyl acetate. The ethyl acetate extracts were concentrated and the resulting crude material was purified by preparative TLC (CH2Cl2:CH3OH=12:1) to yield 44 mg (38%) of the title compound as a yellow powder. MS (m/z, ES+): 444 (M+1, 56%), 445 (M+2, 13%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.92 (br s, 1H), 8.80 (br s, 1H), 7.35-7.62 (m, 3H), 7.10 (d, J=14.8 Hz, 1H), 7.09 (br s, NH2), 6.90 (d, J=14.8 Hz, 1H), 4.56 (dd, J=8.5 Hz, 1H), 4.36 (dd, J=8.5, 4.0 Hz, 1H), 3.66 (m, 1H), 3.60 (s, OCH3), 3.45 (m, 1H), 3.34 (m, 1H), 2.17 (m, 1H), 1.75-2.00 (m, 3H).

Workup

  1. waitAfter 1 hour
  2. filtrationthe reaction mixture was filtered
  3. stirringThe reaction mixture was stirred at ambient temperature overnight
  4. filtrationAfter filtration
  5. stirringAfter stirring at ambient temperature for 45 minutes
  6. customthe reaction was quenched by the addition of saline and ethyl acetate
  7. concentrationThe ethyl acetate extracts were concentrated
  8. customthe resulting crude material was purified by preparative TLC (CH2Cl2:CH3OH=12:1)

Sources & evidence

ORD record
ord-93d8536c914d439781c41f9f47ba8b86
Source dataset
uspto-grants-2011_01
Patent number
US07875728B2

Reaction notes

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