Diisopropylethylamine → HCID 67076385, compound

HRID 1676775Notes

Reaction equation

HRID 1676775 reaction equation
C1(N2CC(F)(F)C(=O)N(C)C3C=NC(NC4C=CC(C(O)=O)=C(F)C=4F)=NC2=3)CCCC1.[CH:33]1([N:38]2[CH2:44][C:43]([F:46])([F:45])[C:42](=[O:47])[NH:41][C:40]3[CH:48]=[N:49][C:50]([NH:52][C:53]4[CH:68]=[CH:67][C:56]([C:57]([NH:59][CH:60]5CCN(C)CC5)=[O:58])=[C:55]([F:69])[C:54]=4[F:70])=[N:51][C:39]2=3)[CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O.C(OCC)(=O)C.O>[CH:33]1([N:38]2[CH2:44][C:43]([F:46])([F:45])[C:42](=[O:47])[NH:41][C:40]3[CH:48]=[N:49][C:50]([NH:52][C:53]4[CH:68]=[CH:67][C:56]([C:57]([NH:59][CH3:60])=[O:58])=[C:55]([F:69])[C:54]=4[F:70])=[N:51][C:39]2=3)[CH2:34][CH2:35][CH2:36][CH2:37]1

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 6364545Methylamine hydrochlorideHCID 67075958HCID 67075958, compoundHCID 67076488HCID 67076488, compoundHCID 178484293HCID 178484293, compound

Product 1

HCID 67076385HCID 67076385, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 0.0804 g of the 2:1 mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-benzoic acid and 4-{4-[(2-carboxy-2,2-difluoro-ethyl)-cyclopentyl-amino]-5-methylamino-pyrimidin-2-ylamino}-2,3-difluoro-benzoic acid (from example 243) in 7 mL of dimethylformamide was treated with 0.1546 g (0.406 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.1558 g (1.206 mmole) of diisopropylethylamine. After 15 minutes, 0.0243 g (0.356 mmole) of methylamine hydrochloride in 1 mL of dimethylformamide was added. The reaction mixture stirred for 30 minutes and then diluted with 150 mL of ethyl acetate and 25 mL of water. The mixture was then washed successively with 20 mL of ammonium chloride, 20 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0411 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-N-methyl-benzamide (I-245) as a white solid.

Workup

  1. washThe mixture was then washed successively with 20 mL of ammonium chloride, 20 mL of saturated aqueous sodium bicarbonate
  2. dry with materialdried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customPurification by silica gel chromatography
  6. washeluting with dichloromethane-methanol (gradient, 95:5-80:20)

Sources & evidence

ORD record
ord-921578ecc92648a9895b2ba7d7670c82
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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