tert-butyl 4-bromobutanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-mercapto-5-trifluoromethyl-benzoic acid methyl ester (990 mg, 4.19 mmol) in acetonitrile (25 mL) were added N,N-diisopropylethylamine (1.08 g, 1.46 mL, 8.38 mmol) and tert-butyl 4-bromobutanoate (935 mg, 4.19 mmol, CAS RN 110611-91-1). The clear yellow solution was stirred at room temperature for 2.5 hours and then poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow liquid (1.27 g, 80%). MS (ESI+): m/z=379 ([M+]). the layers were separated The aqueous layer was extracted twice with ethyl acetate The organic layers were washed with brine dried over magnesium sulfate filtered treated with silica gel evaporated The compound was purified by silica gel chromatography on a 50 g column eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of the indoquinone-Naloxone linker involves multiple steps. Starting from 2-methyl-5-methoxyindole, alkylation on nitrogen with sodium hydride and t-butyl 4-bromobutanoate, followed by formylation provides the 3-formyl indole. After the nitration reaction, the 4-NO2 group is reduced to the amino group. Treatment with Fremy's salt produces the indoquinone structure. The 3-formyl group is reduced and converted to 4-NO2-phenyl carbonate compound A. Morphine is converted to the carbamate compound B through an activated carbonate intermediate. Compounds A and B are combined in the presence of an amine in DMF to provide the completed drug-linker unit after an acid catalyzed t-butyl ester hydrolysis (Scheme 9).

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-CBz-L-valine (16.25 g, 65 mmole) was dissolved in DMF (40 ml). To the solution was added potassium t-butoxide (7.24 g, 65 mmole). After 10 min, 4-bromobutyric acid t-butyl ester (12 g, 53 mmole) was added. The reaction mixture was kept at 65° C. for 2.5 hr and then poured into sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic phase was dried and the product was isolated with silica gel column chromatography. 20.1 g. The reaction mixture was kept at 65° C. for 2.5 hr extracted with dichloromethane The organic phase was dried the product was isolated with silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Octyloxy-phenyl)-morpholine (1.50 g; 5.2 mmol), 4-bromo-butyric acid tert-butyl ester (1.38 g; 6.2 mmol) (prepared according to C. Morin, M. Vidal Tetrahedron, 1992, 48(42), 9277), potassium iodide (1.03 g; 6.2 mmol), K2CO3 (1.42 g; 10.29 mmol), and CH3CN (15 mL) were mixed and heated under reflux for 2 hours. After cooling to RT the reaction mixture was concentrated in vacuo, dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (1.90 g), TLC (SiO2Rf. 0.20 EtOAc:hexanes 1:1) heated under reflux for 2 hours was concentrated in vacuo dissolved in EtOAc washed with 5% aqueous NaHCO3 solution dried (Na2SO4) concentrated in vacuo purified by column chromatography (SiO2, Et2O:hexanes 1:1)