Ajinomoto Co., Ltd.

Michito Sumikawa

Yoshihito Koguchi

Yasuo Irie

Takao Ohgane

Tomoko Nakao

Naohiko Yasuda

Satoji Takahashi

Fusayoshi Kakizaki

Chieko Ishijima

Yukiko Matsuzawa

Makoto Maruo

Kazuo Miyazaki

Shigehiro Nishina

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

There is provided a method for producing easily highly-purified acylphenylalanine that is useful as a raw material of pharmaceutical products and the like, which comprises the step of reacting an acid chloride with phenylalanine in a mixed solvent of an organic solvent and water, while keeping the solvent under the alkali condition by using potassium hydroxide.

Methods for producing acylphenylalanine

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.

A method for producing B-type crystals of nateglinide substantially free of H-type crystals is provided, which comprises drying solvated wet crystals of nateglinide at a low temperature until no solvent remains and making a crystal conversion thereof. According to this method, B-type crystals of nateglinide can be produced at an industrial scale without allowing other forms of the crystalline polymorphism to coexist.

Methods for producing nateglinide B-type 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.

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 compound which is: ##STR1## wherein R may be 1 to 5 H, Cl, Br, F, C.sub.1 -C.sub.4 straight chain or branched alkyl, OH, or CF.sub.3.

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Kawasaki, Japan

Michito Sumikawa