Diisopropylethylamine → (r)-3-Cyclohexyl-2,3-dihydro-6-[(cis)-4-benzyl-2,6-dimethylpiperazin-1-yl-carbonyl]pyrrolo[1,2,3-de]-1,4-benzoxazine hydrochloride salt

HRID 500448Notes

Reaction equation

HRID 500448 reaction equation
[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([Cl:21])=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:31]([N:38]1[CH2:43][C@H:42]([CH3:44])[NH:41][C@H:40]([CH3:45])[CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[ClH:21].[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([N:41]4[C@H:42]([CH3:44])[CH2:43][N:38]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][C@@H:40]4[CH3:45])=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 12197174(3r,5s)-1-Benzyl-3,5-dimethylpiperazineHCID 87537363(R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid chloride

Product 1

HCID 68674127(r)-3-Cyclohexyl-2,3-dihydro-6-[(cis)-4-benzyl-2,6-dimethylpiperazin-1-yl-carbonyl]pyrrolo[1,2,3-de]-1,4-benzoxazine hydrochloride saltYield 42.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid chloride (380 mg, 1.23 mmol) and N,N diisopropyl ethylamine (0.2 ml, 1.3 mmol) in dichloromethane (20 ml) was added 1-N-benzyl-(cis)3,5-dimethylpiperazine (250 mg, 1.2 mmol) in dichloromethane (5 ml) and the mixture was stirred for 16 h at room temperature. The mixture was partitioned between sodium bicarbonate solution and dichloromethane. The organic layer was separated and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 0-5% (v/v) methanol in dichloromethane. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (2 M solution in diethyl ether; 2 ml) to the free base in dichloromethane (1 ml). The precipitate was filtered and dried to afford (R)-3-cyclohexyl-2,3-dihydro-6-[(cis)-4-benzyl-2,6-dimethylpiperazin-1-yl-carbonyl]pyrrolo[1,2,3-de]-1,4-benzoxazine hydrochloride salt as a light blue powder (240 mg, 0.51 mmol).

Workup

  1. customThe mixture was partitioned between sodium bicarbonate solution and dichloromethane
  2. customThe organic layer was separated
  3. customthe solvent removed in vacuo
  4. customThe residue was purified by flash chromatography
  5. washeluting with 0-5% (v/v) methanol in dichloromethane. Hydrochloride salt formation
  6. additionwas achieved by the addition of hydrogen chloride (2 M solution in diethyl ether; 2 ml) to the free base in dichloromethane (1 ml)
  7. filtrationThe precipitate was filtered
  8. customdried

Sources & evidence

ORD record
ord-db3cb2b4656b403f9ff5bd255e5742a1
Source dataset
uspto-grants-2010_08
Patent number
US07772227B2

Reaction notes

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