Ajinomoto Co., Ltd.

Satoji Takahashi

Tadashi Takemoto

Daisuke Takahashi

Michito Sumikawa

Yoshihito Koguchi

Yasuo Irie

Takao Ohgane

Seiichi Nishi

Kunisuke Izawa

Masao Nakamura

Yasuhiro Tanaka

Toyoto Hijiya

Toshihide Yukawa

Hiroshi Shiragami

Kazutaka Nagashima

Yutaka Honda

Katsumi Sugiyama

Shinji Fujita

Koji Toi

Masayuki Arai

Kunio Hisamitsu

Mitsuhiko Kojima

Tatsuya Ishikawa

Shouichi Kondou

Yoshinori Ogawa

The present invention relates to a method for producing a nucleoside derivative represented by formula (2), comprising the step of reducing a nucleoside of formula (1) in the presence of a noble metal catalyst comprising a carrier and a noble metal supported thereby, selected from the group consisting of (A) a homogeneously supported catalyst where the specific surface area of the noble metal is 95.0 m/g or more and the particle size of the noble metal is 4.3 nm or less, and (B) a surface-loaded catalyst where the specific surface area of the noble metal is 56.0 m/g or more and the particle size of the noble metal is 8.0 nm or less, wherein Ris hydrogen or a protective group, Ris NHor OH, Ris an acyl group, and X is a chlorine or bromine atom. According to the present invention, the yield can be made equal even when the amount of catalyst is smaller than that used for the conventional products.

Method for producing nucleoside derivatives

There is provided methods for producing nateglinide crystals, which comprises the steps of adding an acid(s) to a reaction mixture containing nateglinide to make it acidic, the reaction mixture being obtained by reacting trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent of ketone solvent and water in the presence of an alkali; and then adjusting the temperature of the mixture to 58&#xb0; C. to 72&#xb0; C. and the concentration of ketone solvent to more than 8 wt % and less than 22 wt % to conduct precipitation of nateglinide crystals. This producing method is the industrially beneficial methods for crystallization of nateglinide.

Methods for producing nateglinide crystals

Stable crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine may be produced by treating this compound with a solvent at a temperature of at least 10.degree. C. and forming crystals in the solvent at a temperature of at least 10.degree. C. For example, crystals may be formed by crystallization out of solution, or may be formed from solid particles of the compound suspended in a solvent. Crystals formed in this way have different melting point, infra red spectrum and X-ray diffraction patterns from previously known forms of the compound and have enhanced processability, eg. stability to grinding.

Crystals of N-(trans-4-isopropylcyclohexycarbonyl)-D-phenylalanine and

Stable crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine may be produced by treating this compound with a solvent at a temperature of at least 10.degree. C. and forming crystals in the solvent at a temperature of at least 10.degree. C. For example, crystals may be formed by crystallization out of solution, or may be formed from solid particles of the compound suspended in a solvent. Crystals formed in this way have different melting point, infra red spectrum and X-ray diffraction patterns from previously known forms of the compound and have enhanced processability, e.g., stability to grinding.

Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and

A crude 2',3'-dideoxynucleoside compound is purified by extracting with an organic solvent, or crystallizing, the 2',3'-dideoxynucleoside compound from a basic aqueous solution having a pH of not less than 12 containing the same. In another embodiment of purification a basic aqueous solution having a pH of not less than 11 of a crude 2',3'-dideoxynucleoside derivative is brought into contact with a nonpolar porous resin, whereby the derivative is adsorbed on the resin, and then the thus adsorbed derivative is desorbed with an aqueous alcoholic solution. 2',3'-Dideoxynucleoside compounds which have utility as anti-AIDS drugs or anti-virus drugs can be isolated and purified in high purity and in high yield from their crude products containing impurities.

Method of purifying 2',3'-dideoxynucleosides

The methyl ester of .alpha.-L-aspartyl-L-phenylalanine may be obtained in high yields directly from a reaction solution which contains N-protected- or unprotected-.alpha.-L-aspartyl-D-phenylalanine (or its methyl ester derivative), and .alpha.-L-aspartyl-L-phenylalanine methyl ester by selective crystallization of the .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride from an aqueous solution containing N-protected- or unprotected-L-aspartyl-L-phenylalanine and/or its methyl ester derivative and N-protected- or unprotected-L-aspartyl-D-phenylalanine and/or its methyl ester derivative, hydrochloric acid, and methanol, with or without stirring.

Method for production of .alpha.-L-aspartyl-L phenylalanine methyl ester

This invention is directed to provide a method for obtaining .alpha.-L-aspartyl-L-phenylalanine selectively in high yields. Diffusion dialysis with an ion exchange membrane is used to decrease hydrochloric acid concentration of a mixed solution containing hydrochloric acid and one or more of four .alpha.-L-aspartyl-L-phenylalanine derivatives, i.e., .alpha.-L-aspartyl-L-phenylalanine methyl ester, .alpha.-L-aspartyl-L-phenylalanine, .alpha.-L-aspartyl-L-phenylalanine-.beta.-methyl ester and .alpha.-L-aspartyl-L-phenylalanine dimethyl ester. The resultant solution is concentrated, to which a base is added for neutralization. Subsequently, .alpha.-L-aspartyl-L-phenylalanine is crystallized and isolated.

Method for preparing .alpha.-L-aspartyl-L-phenylalanine

A method for producing an .alpha.-aspartylphenylalanine derivative represented by formula (2), which comprises reacting a .beta.-aspartylphenylalanine derivative represented by formula (1): ##STR1## with a basic compound in an alcohol solvent in the presence of a hydroxide, sulfate, chloride, carbonate or acetate of an element selected from the group consisting of zinc, copper, nickel, magnesium, aluminum, iron, tin, silicon and titanium, wherein R.sub.1 and R.sub.2 represent hydrogen or an alkyl group having 1 to 4 carbon atoms.

Method for producing .alpha.-aspartylphenylalanine derivatives

A method for purifying aspartic acid comprising suspending aspartic acid crystals containing chloride ion impurities in an aqueous solution at a temperature of 50.degree. C. or higher, followed by separating the purified aspartic acid crystals, is disclosed.

Method for purifying aspartic acid

An imide of the formula: ##STR1## where R.sub.1 is hydrogen or C.sub.1-4 alkyl.

Imides

A method for producing .alpha.-L-aspartyl-L-phenylalanine dimethyl ester, which comprises reacting 3-benzyl-6-carboxymethyl-2,5-diketopiperazine or methyl ester thereof in a methanolic solvent substantially free from water in the presence of a strong acid.

Method for producing .alpha.-L-aspartyl-L-phenylalanine derivatives

A method for the production of N-carbobenzoxy-.alpha.-L-aspartyl-L-phenylalanine methyl ester characterized by the reaction of L-phenylalanine methyl ester with fine N-carbobenzoxy-L-aspartic anhydride crystals, is disclosed.

Method for production of N-protected-alpha-L-aspartyl-L-phenylalanine

The invention relates to a process for producing N-protected-.alpha.L-aspartyl-L-phenylalanine methyl ester, which comprises esterifying L-phenylalanine with methanol in the presence of a strong acid catalyst, adding, to the resulting solution, an aqueous alkaline solution to neutralize the acid catalyst and a water-immiscible organic solvent to extract the free L-phenylalanine methyl ester thus formed, collecting the organic layer, and reacting the L-phenylalanine methyl ester dissolved in said collected organic layer with N-protected-L-aspartic anhydride.

Process for producing N-protected-.alpha.-L-aspartyl-L-phenylalanine

A process for producing an .alpha.-L-aspartyl-L-phenylalanine lower alkyl ester or its hydrochloride which comprises (a) treating an L-N-(1-methyl-2-lower aliphatic acylvinyl or 1-methyl-2-lower alkoxycarbonylvinyl)-aspartic acid or an alkali metal salt thereof with a dehydrating agent in an organic solvent containing an acid, (b) reacting the solution resulting from such treatment with an L-phenylalanine lower alkyl ester and (c) treating the resulting reaction mixture with water or an aqueous acid solution to remove the 1-methyl-2-lower aliphatic acylvinyl or 1-methyl-2-lower alkoxycarbonylvinyl group from the L-N-(1-methyl-2-lower aliphatic acylvinyl or 1-methyl-2-lower alkoxycarbonylvinyl)-aspartyl-L-phenylalanine lower alkyl ester is disclosed, along with L-N-(1-methyl-2-acetylvinyl)-aspartic acid anhydride.

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Yokkaichi, Japan

Satoji Takahashi