Triethylamine → [(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate

HRID 1055170Notes

Reaction equation

HRID 1055170 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N:13]1[CH:14]=[CH:15][N:16]2[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][CH2:18][C:17]=12.O.Cl.Cl.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[NH:36][C:37]1[N:38]=[CH:39][C:40]2[CH2:45][NH:44][CH2:43][C:41]=2[N:42]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCCl.O1CCCC1.ClCCl>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH:28]1[NH:36][C:37]1[N:38]=[CH:39][C:40]2[CH2:45][N:44]([C:1]([O:23][CH2:22][C@@H:20]3[O:19][CH2:18][C:17]4=[N:13][CH:14]=[CH:15][N:16]4[CH2:21]3)=[O:2])[CH2:43][C:41]=2[N:42]=1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 86726534N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrateHCID 90423826(R)-(5,6-Dihydro-8H-imidazo[2,1-C][1,4]oxazin-6-YL)methanol

Product 1

HCID 90424066[(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylateYield 97%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Add 1,1′-carbonyldiimidazole (0.477 g; 1.1 equiv; 2.94 mmoles) to a solution of [(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methanol (0.412 g; 1.0 equiv; 2.67 mmoles) in 1,2-dichloroethane (15 mL) and tetrahydrofuran (5 mL). Heat the solution to 50° C. for 30 minutes, then add N-(2,3-dihydro-1h-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (1.01 g; 1.1 equiv; 2.94 mmoles) followed by triethylamine (1.30 mL; 3.5 equiv; 9.35 mmoles). Stir the resulting solution for 3 hours at 50° C. Pour the mixture into 50% saturated sodium bicarbonate and dichloromethane (50 mL each). Separate the layers and further extract the aqueous layer with dichloromethane (2×50 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to give a red oil. Purify the crude product by column chromatography (1 to 8% methanol in chloroform) to afford the desired [(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (1.12 g; 97%). Determine enantiomeric excess by chiral HPLC analysis (0.46×15 cm Chiralpak™ AS-H column, 100% methanol elution). Isolated product elutes at 13 minutes whereas the enantiomer elutes at 9.1 minutes, demonstrating the product to be 98.3% ee. MS (m/z): 433(M+1).

Workup

  1. customSeparate the layers
  2. extractionfurther extract the aqueous layer with dichloromethane (2×50 mL)
  3. dry with materialDry the combined organic extracts over magnesium sulfate
  4. filtrationfilter
  5. concentrationconcentrate
  6. customto give a red oil
  7. customPurify the crude product by column chromatography (1 to 8% methanol in chloroform)

Sources & evidence

ORD record
ord-9be48b000508413b9b3e8352a6c76eca
Source dataset
uspto-grants-2016_07
Patent number
US09394317B2

Reaction notes

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