Ajinomoto Co., Ltd.

Yoshihito Koguchi

Michito Sumikawa

Kunisuke Izawa

Tomoko Nakao

Hiroshi Shiragami

Satoji Takahashi

Yasuo Irie

Takao Ohgane

Takayoshi Torii

Yumiko Uchida

Satoshi Takamatsu

Nateglinide M-type crystals (main peaks in powder X-ray diffraction: 6.0&#xb0;, 14.2&#xb0;, 15.2&#xb0;, 18.8&#xb0; (2&#x3b8;)) can be produced by dissolving nateglinide in a solvent in which nateglinide is highly soluble and then adding a solvent in which nateglinide is difficultly soluble.

Nateglinide crystals

New nateglinide crystals, i. e. nateglinide A-type crystals (main peaks in powder X-ray diffraction: 4.4&#xb0;, 5.2&#xb0;, 15.7&#xb0;, 18.5&#xb0; (2&#x3b8;)), M-type crystals (main peaks in powder X-ray diffraction: 6.0&#xb0;, 14.2&#xb0;, 15.2&#xb0;, 18.8&#xb0; (2&#x3b8;)) and P-type crystals (main peaks in powder X-ray diffraction: 4.8&#xb0;, 5.3&#xb0;, 14.3&#xb0;, 15.2&#xb0; (2&#x3b8;)), can be produced by dissolving nateglinide in a solvent in which nateglinide is highly soluble and then adding a solvent in which nateglinide is difficultly soluble or, alternatively, by dissolving nateglinide in a mixed solvent composed of a solvent in which nateglinide is highly soluble and another solvent in which it is difficultly soluble, cooling the nateglinide solution to form crystals, filtering the mixture and drying the crystals at a specified temperature.

New nateglinide crystals, i.e. nateglinide A-type crystals (main peaks in powder X-ray diffraction: 4.4&#xb0;, 5.2&#xb0;, 15.7&#xb0;, 18.5&#xb0;(2&#x3b8;)), M-type crystals (main peaks in powder X-ray diffraction: 6.0&#xb0;, 14.2&#xb0;, 15.2&#xb0;, 18.8&#xb0;(2&#x3b8;)) and P-type crystals (main peaks in powder X-ray diffraction: 4.8&#xb0;, 5.3&#xb0;, 14.3&#xb0;, 15.2&#xb0;(2&#x3b8;)), can be produced by dissolving nateglinide in a solvent in which nateglinide is highly soluble and then adding a solvent in which nateglinide is difficultly soluble or, alternatively, by dissolving nateglinide in a mixed solvent composed of a solvent in which nateglinide is highly soluble and another solvent in which it is difficultly soluble, cooling the nateglinide solution to form crystals, filtering the mixture and drying the crystals at a specified temperature.

The present invention provides a method for efficiently producing &bgr;-D-ribofuranose derivatives or optical isomers thereof, useful as synthetic intermediates of pharmaceutical nucleic acid-series products. The method comprises a step of producing 1-O-benzyl-&bgr;-D-ribofuranose-2,3,5-triacetate or an optical isomer thereof by allowing &bgr;-D-ribofuranose-1,2,3,5-tetraacetate or an optical isomer thereof to react with a benzyl alcohol in the presence of acid catalysts and a step of hydrolyzing the resulting 1-O-benzyl-&bgr;-D-ribofuranose-2,3,5-triacetate in the presence of a base to produce 1-O-benzyl-&bgr;-D-ribofuranose or an optical isomer thereof.

Method for producing &bgr;-D-ribofuranose derivatives or optical isomers thereof

Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar. Herein is also disclosed an industrially favorable method for the separation of 9-substituted purine nucleosides which are important intermediates for the synthesis of acyclic nucleosides such as acyclovir, ganciclovir, and the like from ribonucleosides, which method comprises crystallizing only the 9-isomer from a solution or suspension containing both a 9-substituted purine nucleoside and a 7-substituted purine nucleoside by cooling the solution or/and by adding a crystallizing solvent thereto.

Process for producing acyclic nucleosides and process for separating

Process for isomerizing acyclic nucleosides and process for separating

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

Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar.

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Kawasaki, Japan

Yoshihito Koguchi