Aminocarbonylation route to tolvaptan.

Pd-catalyzed aminocarbonylation between aryl bromide and NH-benzazepinone was effectively carried out to furnish the key intermediate for tolvaptan (up to 85%) in one step.

Continuing efforts on the improvement of Beckmann rearrangement of indanone oxime.

Continuing search for beneficial additive toward the Beckmann rearrangement (BR) of indanone oxime has revealed that common Lewis acid catalyst in methanesulfonyl chloride (MsCl) showed increasing efficiency in this ionic rearrangement. The new protocol with MsCl is superior to the classical phosphorus-based methods such as PPA and Eaton reagent, especially in the reaction of indanone oximes.

Conversion of indanone oximes into isocarbostyrils.

New and effective method for the Beckmann rearrangement of indanone oxime mesylate is described, in which a selective and controlled production of the isomeric isocarbostyrils is achieved.

Glycosylation of sialyl acetates with a novel catalyst combination: bismuth triflate and BF3.OEt2 system.

A combined system of bismuth triflate [Bi(OTf)(3)] and boron trifluoride etherate (BF(3).OEt(2)) in dichloromethane is an efficient promoter for the glycosylation of N-acetylneuraminic acid derivatives. The co-existence of two acid catalysts such as Bi(OTf)(3)-BF(3).

Synthetic study on the unique dimeric arylpiperazine: access to the minor contaminant of aripiprazole.

The dimeric derivative of aripiprazole was synthesized via the two notable synthetic technologies as a key step: (1) efficient aldehyde bis-arylation by Bi(OTf)(3) and (2) facile Wynberg amination at room temperature. The synthesis has established the structural identity with the minor contaminant sometimes present in Aripiprazole.

The improved synthesis of OPC-29030, a platelet adhesion inhibitor via diastereoselective oxidation of chiral non-racemic sulfide.

An improved synthetic route of OPC-29030, the platelet adhesion inhibitor, was established via the diastereoselective oxidation of a chiral non-racemic sulfide (R)-5 to (S(S))-6 by the catalytic oxidation using VO(acac)(2) and cumene hydroperoxide (CHP) in the presence of MS4A. Under the current condition, the diastereoselectivity was not influenced by the presence of moisture, and moderate to high selectivity (72% de) was obtained at -30 degrees C. The obtained sulfoxide, which diastereomeric excess was easily raised by the recrystallization, could successfully lead to OPC-29030.

Progress in arylpiperazine synthesis by the catalytic amination reaction.

Careful base and solvent optimization for catalytic amination is described. A Pd-catalyzed amination between some arylbromide and unprotected piperazine (1equiv) was efficiently carried out with Pd/BINAP catalyst in a toluene-DBU solvent system, which is useful for the one-pot preparation of unsymmetrical piperazine through amination and in-situ N-protection. Reaction with N-BOC-piperazine was also successful in toluene-DBU or more polar NMP with Cs(2)CO(3) as a key base.

A practical synthesis of 3,4-diethoxybenzthioamide based on Friedel-Crafts reaction with potassium thiocyanate in methanesulfonic acid.

The synthesis of 3,4-diethoxybenzthioamide, the key intermediate for OPC-6535, is achieved by employing Friedel-Crafts reaction of 1,2-diethoxybenzene with potassium thiocyanate in methanesulfonic acid at ambient temperature.

Some aspects of NaBH(4) reduction in NMP.

In our solvent optimization study of NaBH(4) reduction, NMP was found to enhance the reactivity. A chemoselective debromination of the bromide and sulfonates can be attained in the new borohydride reagent system: NaBH(4)-LiOTf-NMP. This mixed system worked as an alternative to NaBH(3)CN and Bu(3)SnH for the S(N)2 type displacement of alkylbromide and sulfonate.

Interesting reaction of the indanone oximes under Beckmann rearrangement conditions.

Attempted Beckmann rearrangement of the 6-methoxyindanone oximes in conventional conditions resulted in the formation of the two kinds of unexpected products: 2-sulfonyloxyindanone and the dimeric product. Related rearrangement was also observed in the reaction with RhCl-trifluoromethansulfonic acid system.