Phenylacetyl chloride → (3R,5S)-5-Phenylacetylamino-piperidine-3-carboxylic acid cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-amide

HRID 1698337Notes

Reaction equation

HRID 1698337 reaction equation
C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][C@@H:20]([C:34](=[O:57])[N:35]([CH:54]4[CH2:56][CH2:55]4)[C:36]4[CH:37]=[CH:38][C:39]5[O:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[N:41]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:40]=5[CH:53]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.CCOC(C)=O.C1(CC(Cl)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C1CCN2C(=NCCC2)CC1>>[CH:54]1([N:35]([C:36]2[CH:37]=[CH:38][C:39]3[O:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[N:41]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:40]=3[CH:53]=2)[C:34]([C@@H:20]2[CH2:21][C@H:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:23][NH:18][CH2:19]2)=[O:57])[CH2:56][CH2:55]1

Participants

6

Reactant 5

HCID 7679Phenylacetyl chlorideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 81531DiisopropylethylamineHCID 21866389Hydrogen chloride-ethyl acetateHCID 67272727(3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-[1,4]oxazin-6-yl]-carbamoyl}-5-phenylacetylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Product 1

HCID 57870277(3R,5S)-5-Phenylacetylamino-piperidine-3-carboxylic acid cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-amide

Procedure

(3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-[1,4]oxazin-6-yl]-carbamoyl}-5-phenylacetylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (90 mg, 0.12 mmol) is treated with 4N HCl/AcOEt (2 mL) at r.t. for 1 hr, then evaporated. The evaporated residue is dissolved in CH2Cl2 (1 mL). To the solution is added phenylacetyl chloride (20.4 mg, 0.132 mmol) and diisopropyl ethyl amine (32 mg, 0.264 mmol) at 0° C. and stirred for 40 min. After adding 1N HClaq, the mixture is extracted with CH2Cl2, washed with sat NaHCO3aq, brine and dried (MgSO4). Concentration under vacuum and the evaporated residue is dissolved in THF (1 mL). To the solution is added DBU (9 mg, 0.06 mmol) and N-(2-mercaptoethyl)aminoethyl polystyrene (2.1 mmol/g, 286 mg, 0.6 mmol) and stirred for 1 h at r.t. The reaction mixture is filtered via celite pad and washed with THF. Concentration under vacuum and purification with RP-HPLC gives the title compound. MS: 549 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.78 min.

Workup

  1. customevaporated
  2. dissolutionThe evaporated residue is dissolved in CH2Cl2 (1 mL)
  3. additionAfter adding 1N HClaq
  4. extractionthe mixture is extracted with CH2Cl2
  5. washwashed
  6. dry with materialdried (MgSO4)
  7. concentrationConcentration under vacuum
  8. dissolutionthe evaporated residue is dissolved in THF (1 mL)
  9. stirringstirred for 1 h at r.t
  10. filtrationThe reaction mixture is filtered via celite pad
  11. washwashed with THF
  12. concentrationConcentration
  13. customunder vacuum and purification with RP-HPLC

Sources & evidence

ORD record
ord-bfe0e64833f24e708e08500ce0c07fbe
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

Loading…