Glycine → (3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-propionylamino)-acetic acid

HRID 1877433Notes

Reaction equation

HRID 1877433 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:29][CH2:28]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:69][CH2:70][C:71]([OH:73])=[O:72]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:15]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH:27]4[CH2:28][CH2:29]4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([Cl:30])=[CH:4][C:3]=1[CH2:31][CH2:32][C:33]([NH:69][CH2:70][C:71]([OH:73])=[O:72])=[O:34]

Participants

6

Reactant 4

HCID 750GlycineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 592944963-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-propionic acid

Product 1

HCID 59294535(3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-propionylamino)-acetic acidYield 16.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-propionic acid (50 mg, 0.098 mmol, 1.0 equiv; Example 173) in anhydrous DMF (1 mL) was added HATU (44.5 mg, 0.12 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and N-ethyldiisopropylamine (25 mg, 33 μL, 0.20 mmol, 2.0 equiv; [CAS RN 7087-68-5]). After stirring the reaction mixture for 10 min, glycine (8.1 mg, 0.11 mmol, 1.1 equiv; [CAS RN 56-40-6]) was added and stirring continued at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9 mg (16%) of the title compound as a light yellow oil. MS (ISP): 569.2 [M+H]+.

Workup

  1. stirringstirring
  2. waitcontinued at rt over night
  3. customRemoval of the solvent mixture
  4. customunder reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  5. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  6. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-9ae67634f4174ac08e37212895edef7d
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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