Diethyl N-(4-aminobenzoyl)-L-glutamate → diethyl N-{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl}-L-glutamate

HRID 1289250

反応式

HRID 1289250 の反応式
[CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][C:21](=O)[C:7]=3[CH:8]=2)[N:3]=1.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.COCCOC>[CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:46][CH:47]=4)[C:7]=3[CH:8]=2)[N:3]=1

参加物

8

反応物 4

HCID 73002Diethyl N-(4-aminobenzoyl)-L-glutamateHCID 521998p-Toluenesulfonic acid monohydrateHCID 5003444Sodium cyanoborohydrideHCID 107113652-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]-quinazolin-4,6-dione

生成物 1

HCID 10532105diethyl N-{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl}-L-glutamate収率 44.2%

試薬・触媒・溶媒 3

HCID 176Acetic Acid溶媒HCID 887Methanol溶媒HCID 80711,2-Dimethoxyethane溶媒

実験手順

A reaction flask was charged with 2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (3.332 g, 10.15 mmol), diethyl p-aminobenzoyl-L-glutamate (6.54 g, 20.3 mmol), prepared as described in the Journal of Medicinal Chemistry, 1985, 28, 1428, p-toluenesulphonic acid monohydrate (0.12 g, 0.6 mmol), and dry 1,2-dimethoxyethane (100 ml), and fitted with a pressure equalising dropping funnel containing activated 3A molecular sieve beads (4-8 mesh; 41 g). A reflux condenser was fitted to the top of the dropping funnel and the mixture was stirred and heated under reflux under nitrogen for 4 hours. The apparatus enabled solvent vapour to pass up the side tube of the dropping funnel and condense in the reflux condenser, and the condensed solvent to percolate through the molecular sieves before returning to the reaction flask. The mixture was cooled to ambient temperature and a solution of sodium cyanoborohydride (1.0 g, 15.9 mmol) in methanol (18 ml) was added, followed immediately by acetic acid (1.0 ml). The mixture was stirred at ambient temperature for 18 hours and concentrated. The residue was partitioned between saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (3×25 ml) and the combined organic solution washed with brine (5×25 ml), dried (MgSO4) and concentrated to dryness. The residue was fractionated by chromatography with increasingly polar mixtures of dichloromethane and ethanol (ratio 100:0 to 100:4 v/v) as eluant. The appropriate fractions were combined and evaporated and the residue triturated with diethyl ether to give diethyl N-{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoyl}-L-glutamate (2.847 g, 44%), m.p. 171° C.

後処理

  1. customprepared
  2. customfitted with a pressure
  3. additioncontaining
  4. customA reflux condenser was fitted to the top of the dropping funnel
  5. temperatureheated
  6. temperatureunder reflux under nitrogen for 4 hours
  7. customthe side tube of the dropping funnel and condense in the reflux condenser
  8. stirringThe mixture was stirred at ambient temperature for 18 hours
  9. concentrationconcentrated
  10. customThe residue was partitioned between saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (150 ml)
  11. extractionThe aqueous layer was extracted with ethyl acetate (3×25 ml)
  12. washthe combined organic solution washed with brine (5×25 ml)
  13. dry with materialdried (MgSO4)
  14. concentrationconcentrated to dryness
  15. temperaturewith increasingly polar mixtures of dichloromethane and ethanol (ratio 100:0 to 100:4 v/v) as eluant
  16. customevaporated
  17. customthe residue triturated with diethyl ether

出典と根拠

ORDレコード
ord-868557dc3fdd40e5a0add2ca401bbe57
出典データセット
uspto-grants-1998_05
特許番号
US05747499

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