Merck + Co., Inc.

Cheng-Yi Chen

Robert D Larsen

Kevin Campos

Artis Klapars

Lisa F Frey

Robert Wenslow

Yaling Wang

J Christopher McWilliams

Alex Minhua Chen

Andrey V Peresypkin

C Scott Shultz

Debra J Wallace

The present invention is directed to a practical process for the preparation of an enamide (II) by palladium catalyzed coupling of a primary amide (IV) with a compound of structural formula (III), as shown below: As well as to crystalline forms of a compound produced by this process, in particular, an anhydrous crystal form, Form B, and crystalline solvates falling into three patterns, Type 1, Type 2, and Type 3, and crystalline intermediate compounds produced in the process. Still further, the present invention relates to the stereoselective reduction of the tetrasubstituted enamide (II) to the corresponding amide (I).

Formation of tetra-substituted enamides and stereoselective reduction thereof

Indoles of structural formula (III): ##STR1## are synthesized by the palladium-catalyzed coupling/ring closure of a 2-halo or 2-trifluoromethylsulfonyloxy aniline and an alkyl ketone derivative. The process is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a facile leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride.

Palladium catalyzed indolization

We have found that indoles of structural formula (III): ##STR1## can be cost-effectively synthesized in high yield by the palladium-catalyzed coupling/ring closure of a 2-halo- or 2-trifluoromethylsulfonyl-aniline and a cyclic ketone derivative. The process of the present invention is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a good leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride. By this invention, there is provided a process comprising the step of contacting a compound of Structure I with a compound of Structure II to form a compound of StructureIII: ##STR2##

We have found that 2-unsubstituted indoles of structural formula (IV) can be cost-effectively synthesized in high yield by the palladium-catalyzed coupling/ring closure of a 2-halo or 2-trifluoromethylsulfonyloxy aniline (I) and an acyl silane derivative (II), followed by deprotection of the silyl protecting groups. ##STR1## The process of the present invention is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a good leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride. When applied to 5-triazolyl substituted indoles, the present process also eliminates the tendency of triazolyl polymerization in the Fischer indole synthesis.

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Colonia, NJ, United States of America

Cheng-Yi Chen