The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate (1) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the second stage that obviated the need for an extraction and solvent exchange, and significant optimization of the final reaction, including the beneficial effect of adding a quaternary ammonium salt to the alkylation reaction and development of a nonaqueous process for removal of NMP and triethylamine from the product mixture to decrease the level of decomposition of product during the isolation.

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Several 6-trichloromethyl dibenzo[di] [1.3.2] dioxaphosphepin 6-oxide (3a), 2-chloroethoxy dibenzo[di] [1.3.2] dioxaphosphepin 6-oxide (3b) and alkylcarbamato dibenzo [di] [1.3.2] dioxaphosphepin 6-oxides (6a-c) have been synthesized from reactions of equimolar quantities of 2.2'-dihydroxybiphenyi (1) with trichloromethylphosphonic dichloride (2a), O-2-chloroethyi phosphoryldichloride (2b) and dichlorophosphinyl carbamates (5a-c) at 45-50°C for (3a & 3b) and 40-45°C for (6a-c) in dry toluene in the presence of tnethylamme. Elemental. IR and NMR (*H & "P) data have been discussed and supported all structures. Brought to you by | University of California Authenticated Download Date | 6/7/15 5:03 AM Vol. 7, No. 3, 2001 Synthesis and characterization of 6-substituted dibenzo[d,J][1,3,2Jdioxa phosphepin 6-oxides Brought to you by | University of California Authenticated Download Date | 6/7/15 5:03 AM Vol. 7, No. 3, 2001 Synthesis and characterization of 6-substituted dibenzo [dJ] [1,3,2]dioxa phosphepin 6-oxides solution of 1 (1.86 g, 0.01 mol) and triethylamine (2.02 g, 0.02 mol) in dry toluene (50 mL). When the addition was complete, the mixture was stirred and allowed to warm slowly to 40-45°C and maintained at this temperature for 7 hours. The completion of the reaction was monitored by TLC analysis. The solid triethylamine hydrochloride was filtered off and the solvent was evaporated under reduced pressure. The gummy residue was washed with water, dried and treated with 2-propanol. A white solid obtained after recrystallization of the crude product from 2-propanol afforded 6b, yield 0.192 g (60%), mp 250-252°C. Physical and spectral data of 6a-c are given in tables 1-2.

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Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gpss20 Synthesis and Spectral Studies of 2,10-Dichloro-6-Bis(2-Chloroethyl)Amino-4,8-Dinitrodibenzo[ d , g ] [1,3,6,2]-Dioxathiaphosphocin, 2,10-Dichloro-6-Bis(2-Chloroethyl)Amino-4,8-Dinitrodibenzo[ d , g ][1,3,6,2]Dioxathiaphosphocin 6-Oxide, 2-Bis(2-Chloroethyl)Amino-2,3-Dihydro-5-Thiophenoxy-1 H -1,3,2-Benzodiazaphosphole 2-Oxide, 2-Bis(2-Chloroethyl)Amino-1,2,3,4-Tetrahydro-1,3,2-Benzodiazaphosphorinane 2-Oxide, 5-Bromo-5-Nitro-2-Bis(2-Chloroethyl)Amino-1,3,2-Dioxaphosphorinane 2-Oxide, and 8-Bis(2-Chloroethyl)Amino-16 HDinaphtho[2,1-d :1′,2′-g ]1,3,2-Dioxaphosphocin 8-SYNTHESIS AND SPECTRAL STUDIES OF 2,10-DICHLORO-6-BIS(2-CHLOROETHYL)AMINO-4,8-DINITRODIBENZO[d,g][1,3,6,2]-DIOXATHIAPHOSPHOCIN, 2,10-DICHLORO-6-BIS(2-CHLOROETHYL)AMINO-4,8-DINITRODIBENZO[d,g][1,3,6,2]-DIOXATHIAPHOSPHOCIN 6-OXIDE, 2-BIS(2-CHLOROETHYL)AMINO-2,3-DIHYDRO-5-THIOPHENOXY-1H-1,3,2-BENZODIAZAPHOSPHOLE 2-OXIDE, 2-BIS(2-CHLOROETHYL)AMINO-1,2,3,4-TETRAHYDRO-1,3,2-BENZODIAZAPHOSPHORINANE 2-OXIDE, 5-BROMO-5-NITRO-2-BIS(2-CHLOROETHYL)AMINO-1,3,2-DIOXAPHOSPHORINANE 2-OXIDE, AND 8-BIS(2-CHLOROETHYL)AMINO-16H-DINAPHTHO-[2,1-d:1 ,2 -g]1,3,2-DIOXAPHOSPHOCIN 8-OXIDE-POTENTIAL ANTICANCER AGENTS

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