Diisopropylethylamine → Rac-(3r,4r)-4-[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)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid benzyl ester

HRID 1676600

Reaktionsgleichung

Reaktionsgleichung von HRID 1676600
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([O:18][CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([N:25]2[CH2:31][C:30]([F:33])([F:32])[C:29](=[O:34])[N:28]([CH3:35])[C:27]3[CH:36]=[N:37][C:38]([NH:40][C:41]4[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=4[O:50][CH3:51])=[N:39][C:26]2=3)[CH2:24][CH2:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([NH:40][C:38]3[N:37]=[CH:36][C:27]4[N:28]([CH3:35])[C:29](=[O:34])[C:30]([F:32])([F:33])[CH2:31][N:25]([CH:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[C:26]=4[N:39]=3)=[C:42]([O:50][CH3:51])[CH:43]=2)[CH:13]([O:18][CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Komponenten

7

Edukt 4

HCID 81531DiisopropylethylamineHCID 252529054-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acidHCID 67354303benzyl (3R,4R)-4-amino-3-methoxypiperidine-1-carboxylateHCID 178484289HCID 178484289, Verbindung

Produkt 1

HCID 67354650Rac-(3r,4r)-4-[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)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid benzyl esterAusbeute 58,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

A mixture of 0.058 g (0.22 mmole) of (rac)-(3R,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid benzyl ester, 0.089 g (0.20 mmole) 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)-3-methoxy-benzoic acid (I-22), 0.083 g (0.22 mmole) 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate, 0.057 g (0.44 mmole) of diisopropylethylamine and 2 mL of dimethylformamide was stirred at room temperature for 1 hour. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated aqueous ammonium chloride solution, once with 25 mL of saturated aqueous sodium bicarbonate solution, once with 25 mL of brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2) to give 0.081 g of rac-(3R,4R)-4-[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)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid benzyl ester (I-55) as a foam. Tritruration of the foam with diethyl ether gave a white solid.

Aufarbeitung

  1. extractionextracted three times with 25 mL of ethyl acetate
  2. washThe combined organic extracts were washed three times with 25 mL of water
  3. dry with materialonce with 25 mL of saturated aqueous ammonium chloride solution, once with 25 mL of saturated aqueous sodium bicarbonate solution, once with 25 mL of brine and dried over anhydrous magnesium sulfate
  4. filtrationThe mixture was filtered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel chromatography
  7. washeluting with dichloromethane-methanol (98:2)

Quellen und Nachweise

ORD-Eintrag
ord-d42e31f5c4de43678a056264b8cb36c3
Quelldatensatz
uspto-grants-2011_08
Patentnummer
US08003785B2

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