Koji Tomimoto

Tributylmagnesium ate complex-mediated novel bromine-magnesium exchange reaction for selective monosubstitution of dibromoarenes

Abstract Lithium tributylmagnesate complex (n-Bu3MgLi), readily prepared from n-BuLi and n-BuMgCl (2:1), is a novel metallation agent. It is quite efficient for the selective mono-bromine–magnesium exchange of 2,6-dibromopyridine ( 1 ) under non-cryogenic conditions (at −10°C) to give a stable magnesate intermediate. Subsequent treatment with DMF gave 6-bromo-2-formylpyridine ( 3 ) in excellent yield. This method is also applicable for selective monosubstitution of several other kinds of dibromoarenes.

A facile bromination of hydroxyheteroarenes

Abstract Bromination of hydroxyheteroarenes using P 2 O 5 /Bu 4 NBr proceeds under mild conditions to afford high yields of various bromoheteroarenes. This procedure is successfully applied to large-scale syntheses of bromoheteroarenes.

J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors.

A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M3 receptors over M2 receptors. Subsequent synthetic derivatizations resulted in highly potent M3 receptor antagonists with selectivity greater than two orders of magnitude for M3 over M2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hyd roxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for M3 receptors (Ki = 4.2 nM) over M2 receptors (Ki = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K(B) value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease.

Non-cryogenic metalation of aryl bromides bearing proton donating groups: formation of a stable magnesio-intermediate

Abstract Bromine–metal exchange of o -bromobenzoic acid ( 1 ) with Bu 2 Mg followed by n -BuLi was successfully carried out at non-cryogenic temperature (>−20°C), and gave a stabilized metal species which smoothly reacted with several electrophiles. This methodology expanded to several other bromides bearing proton donating groups (PDGs).

Efficient synthesis of substituted 2-aminopyrazines: FeCl3-promoted condensation of hydroxyiminoketones with aminoacetonitriles

Abstract FeCl 3 -promoted condensation of hydroxyiminoketones with aminoacetonitriles followed by catalytic hydrogenation afforded the desired pyrazines in moderate–good yields. This protocol provides an efficient and practical synthesis of substituted 2-aminopyrazines.

Electrophilic synthesis of 6-[18F]fluoro-l-dopa: Use of 4-O-pivaloyl-l-dopa as a suitable precursor for routine production

Abstract A method of 6-[18F]fluoro- l -3,4-dihydroxyphenylalanine (6-[18F]FDOPA) synthesis suitable for the routine production in human PET studies is described. Direct fluorination of l -3-(3-hydroxy-4-pivaloyloxyphenyl)alanine with acetyl [18F]hypofluorite in acetic acid showed the preferable regioselectivity for 6-[18F]FDOPA to its 2- and 5-fluoro isomers. The HCl-hydrolysis of the reaction mixture followed by HPLC separation using the buffered physiological saline as an eluting solution, gave a sterile and apyrogenic 6-[18]FDOPA injection for clinical studies: decay-corrected radiochemical yields of 15–21% based on acetyl [18F]hypofluorite, radiochemical purity of >97% and preparation time of 60 min.

Synthesis and biological activity of J-104,118, a novel, potent inhibitor of squalene synthase

Abstract A new structural class of squalene synthase (SQS) inhibitor, J-104,118, was developed by chemical modification of L-592,901. The absolute configuration of J-104,118 was determined by X-ray crystal analysis. An oral dose of J-104,118 potently inhibited cholesterol synthesis in mice.

J-104,123, a novel and orally-active inhibitor of squalene synthase: Stereoselective synthesis and cholesterol lowering effects in dogs

Abstract J-104,123, a potent inhibitor of squalene synthase having monocarboxylic acid structure, was discovered by chemical modification of J-104,118. An oral dose of J-104,123 lowered serum cholesterol levels in dogs. J-104,123 was synthesized stereoselectively from methyl (R)-3-hydroxybutyrate.

STEREOSELECTIVE SYNTHESIS OF J-104,118 AND J-104,123, NOVEL, POTENT INHIBITORS OF SQUALENE SYNTHASE

Abstract A novel class of squalene synthase inhibitors (J-104,118 and J-104,123) were synthesized efficiently. An amine intermediate 1 was synthesized using two distinct methods. First, the racemic amine 1 was synthesized diastereoselectively using a key reaction consisting of the stereo-controlled reduction of the ketone 7 by L-Selectride®. Second, the optically active amine 1 was synthesized efficiently and enantioselectively using Sharpless dihydroxylation as a key reaction. A stereo-controlled method for synthesizing J-104,123 was developed starting from a commercially available methyl ( R )-3-hydroxybutyrate.

Efficient and stereoselective synthesis of J-104,118, a novel, potent inhibitor of squalene synthase

J-104,118, a novel and potent inhibitor of squalene synthase, was synthesized stereoselectively. The chiral amine 1 was efficiently synthesized by Sharpless asymmetric dihydroxylation as a key reaction.