Ammonium Hydroxide → HCID 69038495, compound

HRID 369002Notes

Reaction equation

HRID 369002 reaction equation
B(Br)(Br)[Br:2].[CH2:5]([N:8]1[CH2:27][CH2:26][C@:15]23[C:16]4[C:17]5[O:25][C@@:14]2([CH3:28])[C:13](=[O:29])[CH2:12][CH2:11][C@@:10]3([O:30][CH2:31][CH2:32][CH3:33])[C@H:9]1[CH2:22][C:21]=4[CH:20]=[CH:19][C:18]=5[O:23]C)[CH:6]=[CH2:7].[NH4+].[OH-]>C(Cl)Cl>[BrH:2].[CH2:5]([N:8]1[CH2:27][CH2:26][C@:15]23[C:16]4[C:17]5[O:25][C@@:14]2([CH3:28])[C:13](=[O:29])[CH2:12][CH2:11][C@@:10]3([O:30][CH2:31][CH2:32][CH3:33])[C@H:9]1[CH2:22][C:21]=4[CH:20]=[CH:19][C:18]=5[OH:23])[CH:6]=[CH2:7]

Participants

5

Reactant 3

HCID 14923Ammonium HydroxideHCID 25134Boron tribromideHCID 69036288HCID 69036288, compound

Product 1

HCID 69038495HCID 69038495, compoundYield 47%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
2.5 °C

Procedure

A mixture of 7,8-dihydro-5-methyl-14-n-propyloxycodeinone described in our copending application with priority from May 18, 1994) (9; 2.67 g, 7.19 mmol), KHCO3 (3.6 g, 35.93 mmol), 1-chloroethyl chloroformate (4.73 ml, 43.12 mmol), and 35 ml of 1,2-dichloroethane was stirred under reflux for 3.5 h. After cooling, the inorganic material was filtered off and the filtrate evaporated. The residue (4.67 g of a yellowish oil of 17-(1-chloroethoxy)-carbonyl-4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one (compound 11); pure by TLC) was not further purified and characterized. A solution of the compound 11 in MeOH was refluxed for 1 h and then evaporated. The residue (3.54 g slightly brown foam) was crystallized from 2.5 ml MeOH/2 ml diethyl ether to give 1.68 g (66%) of 4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxy-morphinan-6-one hydrochloride (compound 12). M.p. 186-188° C. IR (KBr): 3425 (+NH2), 1725 (CO)cm-1. EI-MS: m/z 357 (M+). 1H-NMR (DMSO-d6): σ 10.11 and 8.15 (2 broad s, +NH2), 6.83 (d, J=8.2 Hz, 1 arom. H), 6.74 (d, J=8.2 Hz, 1 arom. H), 3.78 (s, CH3O), 1.48 (s, CH3 --C(5)), 0.95 (t, J=7.4 Hz, CH3). Analysis calculated for C21H27NO4. HCl. 0.6 MeOH (413.14): C 62.80, H 7.42, N 3.39, Cl 8.58; found: C 62.66, H 7.34, N 3.40, Cl 8.98. A mixture of the compound 12 (1.45 g, 3.68 mmol), allyl bromide (0.36 ml, 4.06 mmol), potassium carbonate (2.9 g, 20.8 mmol), and 10 mnl of anhydrous N,N-dimethyl formamide was stirred at 80° C. (bath temperature) for 1.5 h. The inorganic solid was filtered off and the filtrate evaporated to give 1.7 g of a yellowish oily residue. This residue was partitioned between CH2Cl2 and H2O. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated. The residue (1.375 g of a slightly yellow oil) was crystallized from ethanol to yield 1.28 g (88%) of 17-allyl-4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one (compound 13) as slightly yellow crystals. M.p. 122-124° C. IR(KBr): 1720 (CO)cm-1. EI-MS: m/z 397 (M+). 1H-NMR (CDCl3): δ 6.63 (d, J=8.3 Hz, 1 arom. H), 6.55 (d, J=8.3 Hz, 1 arom. H), 5.79 (m, 1 olef. H), 5.13 (m, 2 olef. H), 3.84 (s, OCH3), 1.60 (s, CH3 --C(5)), 1.00 (t, J=7.4 Hz, CH3). Analysis calculated for C24H31NO4 (397.51): C 72.52, H 7.86, N 3.52; found: C 72.14, H 7.76, N 3.44. A 1 M solution of boron tribromide in CH2C12 (10.8 ml) was added to an ice-cooled solution of the compound 13 (577 mg, 1.45 mmol) in 75 ml of CH2Cl2 at once. After stirring at 0-5° C. for 2 h, a mixture of 20 g ice and 4 ml of conc. NH4OH was added. The resulting mixture was stirred at room temperature for 30 min and the extracted with CH2Cl2 (3×50 ml). The combined organic layers were washed with brine (70 ml), dried over Na2SO4 and evaporated. The residue (600 mg brownish foam) was converted into the hydrobromide salt in the usual way and crystallized from MeOH to afford 314 mg (47%) of 17-allyl-4,5α-epoxy-3-hydroxy-5-methyl-14-n-propyloxymorphinan-6one hydrobromide (compound 14). M.p. 244-247° C. (dec.). IR (KBr): 3441 and 3332 (+NH, OH), 6.68 (d, J=8.2 Hz, 1 arom. H), 6.62 (d, J=8.2 Hz, 1 arom. H), 5.92 (m, 1 olef. H), 5.67 (m,2 olef. H), 1.49 (s, CH3 --C(5)), 0.96 (t, J=7.2 Hz, CH3).

Workup

  1. customThis residue was partitioned between CH2Cl2 and H2O
  2. washThe organic layer was washed with H2O and brine
  3. dry with materialdried over Na2SO4
  4. customevaporated
  5. customThe residue (1.375 g of a slightly yellow oil) was crystallized from ethanol
  6. customto yield 1.28 g (88%) of 17-allyl-4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one (compound 13) as slightly yellow crystals
  7. additionwas added
  8. stirringThe resulting mixture was stirred at room temperature for 30 min
  9. extractionthe extracted with CH2Cl2 (3×50 ml)
  10. washThe combined organic layers were washed with brine (70 ml)
  11. dry with materialdried over Na2SO4
  12. customevaporated
  13. customcrystallized from MeOH

Sources & evidence

ORD record
ord-6012eed5092d40fd93cfab6d084bac7e
Source dataset
uspto-grants-2000_10
Patent number
US06136817

Reaction notes

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