Ajinomoto Co., Ltd.

Masanobu Yatagai

Noriyasu Kataoka

Takayuki Hamada

Akinori Tatara

Toshihiro Matsuzawa

Junko Yamanaka

Takashi Yamamoto

Takashi Tsuji

Manabu Suzuki

Yoshiyuki Takahara

Hiroyuki Matsueda

Shigekatsu Tsuchiya

Masaki Naito

Chieko Ejima

Isao Arai

Katsutoshi Sakata

Seiichi Nishi

Takashi Ohnuki

Masayuki Oshita

Haruya Sato

Eiko Hayashi

Tomoyuki Tabata

Kenzo Tanaka

Tohru Nishiwaki

Masafumi Minomura

The present invention provides a method for producing a phenylalanine derivative(s) having a quinazolinedione ring of formula (5), including steps comprising of reacting an acylphenylalanine derivative(s) of formula (1) with a carbonyl group-introducing reagent(s) and a derivative(s) of anthranilic acid to form an asymmetric urea intermediate(s); making the asymmetric urea intermediate(s) into a quinazolinedione compound(s) of formula (4) in the presence of a base(s); and N-alkylating quinazolinedione ring amide of the obtained quinazolinedione compounds with N-alkylation agents. This production method is an industrially applicable method for producing phenylalanine derivatives having a quinazolinedione skeleton, which are compounds highly useful as drugs having &#x3b1; 4 integrin inhibiting activity. In the formulae (1) and (5), R1 represents a phenyl group having a substituent(s) and the like, R2 represents an alkyl group and the like, R3 represents a dialkylamino group and the like, and R4 represents an alkyl group and the like. 

Methods for producing phenylalanine derivatives having a quinazolinedione skeleton and intermediates for production thereof

The present invention provides a method for producing a phenylalanine derivative(s) having a quinazolinedione ring of formula (5), including steps comprising of 

The invention provides a process for producing optically active 2,2-dimethylcyclopropanecarboxylic acid by reacting an optical isomer mixture of 2,2-dimethylcyclopropanecarboxylic acid with an optically inactive amine to form (precipitate, crystallize or the like) an ammonium salt of optically active 2,2-dimethylcyclopropanecarboxylic acid, for example, optically active (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid. The production (optical resolution, separation of an optically active substance, purification of an optically active substance or the like) of optically active 2,2-dimethylcyclopropanecarboxylic acid which is important as an intermediate for production of agricultural chemicals, medications and the like can easily be conducted at low cost. Further, the invention provides an intermediate therefor (an ammonium salt of optically active 2,2-dimethylcyclopropanecarboxylic acid, especially preferably an ammonium salt of optically active (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid, or the like), and an optical resolution agent (optically inactive amine) for separation of optically active 2,2-dimethylcyclopropanecarboxylic acid.

Process for producing optically active carboxylic acid

The present invention provides a production method including reacting a diphenylmethylene halide compound represented by the following formula (1) with a malonic acid diester compound represented by the following formula (2) in an organic solvent selected from N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone and N,N-dimethylformamide, in the presence of a base selected from an alkali metal hydride and an alkali metal t-butoxide to give a diester compound represented by the following formula (3), and then subjecting the diester compound to hydrolysis and decarboxylation to give a diphenylalanine compound represented by the following formula (4). According to the present invention, diphenylalanine compound (4) can be obtained industrially advantageously in a high yield. wherein each symbol is as defined in the specification.

Production method of optically active diphenylalanine compounds

Optically active diphenylalanine compounds may be conveniently prepared in a good yield by reacting a diphenylalanine compound represented by formula (1) with an optically active amine compound represented by formula (2) in the presence of an organic solvent to give a diastereomeric salt represented by formula (5) and then treating the diastereomeric salt under acidic conditions to give an optically active diphenylalanine compound represented by formula (3): wherein each symbol is as defined in the specification.

Production method of optically active dephenylalanine compounds

The present invention relates to a method of producing a compound represented by the formula [I] or a salt thereof, which comprises reacting a compound represented by the formula [II] or a salt thereof with a compound represented by the formula [III] or a salt thereof, in the presence of a base, in alcohol, and provides a production method of an O-substituted tyrosine compound, which is superior in productivity, versatility and safety, and economically and industrially useful: wherein each symbol is as defined in the specification.

Production method of O-substituted tyrosine compound

The present invention relates to a novel process for preparing an aminostilbene derivative, which is important as an active component of anticancer drugs or an intermediate for preparation thereof, as well as methods of producing the same.

Process for preparing aminostilbene derivatives

The present invention relates to a modified physiologically active protein, modified physiologically active proteins produced by the process and pharmaceutical compositions containing the same.

Modified physiologically active proteins and medicinal compositions containing the same

An industrially suitable process for preparing V-28-3M useful as an antimycotic agent by conducting methyl esterification of V-28-3 efficiently. V-28-2 is efficiently converted into V-28-3M by protecting the amino group of the amino sugar of V-28-3 with an appropriate protecting group, subjecting the carboxyl group of V-28-3 to methyl esterification with methyl methanesulfonate or methyl p-toluenesulfonate in the presence of a base, and deprotecting the N-protected intermediate.

Process for preparing antifungal V-28-3M

A process for purifying 2-amino-6-chloro-9-&lsqb;(1&prime;S,2&prime;R)-1&prime;,2&prime;-bis(hydroxymethyl) cycdopropane-1&prime;-yl&rsqb;methylpurine represented by the following formula (5) comprises the step of selectively isolating 2-amino-6-chloro-9-&lsqb;(1&prime;S,2&prime;R)-1&prime;,2&prime;-bis(hydroxymethyl) cyclopropane-1&prime;-yl&rsqb;methylpurine from a mixture of 2-amino-6-chloro-9-&lsqb;(1&prime;S,2&prime;R)-1&prime;,2&prime;-bis(hydroxymethyl)cyclopropane-1&prime;-yl&rsqb;methylpurine and 2-amino-6-chloro-7-&lsqb;(1&prime;S,2&prime;R)-1&prime;,2&prime;-bis(hydroxymethyl)cyclopropane-1&prime;-yl&rsqb;methylpurine represented by the following formula (6) by the crystallization. This process has a satisfactory medicinal quality on an industrial scale without necessitating complicated operations such as chromatographic purification.

Process for isolating 2-amino-6-chloro-9-&lsqb;(1'S,2'R)-1'2'-bis(hydroxymethyl)-cyclopropane-1'-YL&rsqb;methylpurine and an optical isomer thereof

A pure (-)-9-[1'S, 2'R-bis(hydroxymethyl)cyclopropan-1'-yl]methylguanine is prepared by:

Method for purifying nucleic acid derivatives

A method for resolving optically impure 3-oxa-2-oxobicyclo�3.1.0!hexane-1-carboxylic acid esters. A method is provided for producing a 1-alkoxycarbonyl-2-hydroxymethylcyclopropane-1-carboxylic acid.N-benzyl-.alpha.-phenylethylamine diastereomer salt. An enantiomer of N-benzyl-.alpha.-phenylethylamine is reacted with a 1-alkoxycarbonyl-2-hydroxymethylcyclopropane-1-carboxylic acid to produce a precipitate that is enriched in one diastereomer of the salt. After isolating the optically active salt, the N-benzyl-.alpha.-phenylethylamine may be separated to produce the corresponding 1-alkoxycarbonyl-2-hydroxymethylcyclopropane-1-carboxylic acid. Under acidic conditions, the carboxylic acid and hydroxyl groups undergo ring closure to afford the optically active 3-oxa-2-oxobicyclo�3.1.0!hexane-1-carboxylic acid ester.

Method of producing optically active cyclopropane derivatives

There is disclosed a process for asymmetrically reducing a carbonyl compound, which comprises reducing the carbonyl compound by the use of a reducing agent comprising (i) an optically active tartaric acid or ester thereof and (ii) a metal borohydride, thereby producing an optically active hydroxyl compound. The process can be used for the production of optically active hydroxyesters and alcohols from ketoesters and ketones. These products are useful for the production of medicaments and liquid crystals.

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Kawasaki, Japan

Masanobu Yatagai