Ajinomoto Co., Ltd.

Ajinomoto Co., Inc., Patent & Licensing Department

Hiroshi Shiragami

Kunisuke Izawa

Keizo Yamashita

Yumiko Uchida

Yasuo Irie

Kenzo Yokozeki

Naohiko Yasuda

Yutaka Honda

Yoshihito Koguchi

Hisao Iwagami

Hideyuki Shirae

Masayuki Arai

Yasuhiro Tanaka

Satoshi Katayama

Toshiya Tanabe

Masaru Otani

Satoshi Takamatsu

Toshihide Yukawa

Satoji Takahashi

Katsunori Kobayashi

A process for converting uridines to 2&prime;,3&prime;-dideoxy-2&prime;,3&prime;-didehydrouridines by reacting acetic anhydride with a 2&prime;,3&prime;-0-alkoxymethylideneuridine intermediate.

Process for producing and purifying 2&prime;,3&prime;-dideoxynucleosides, and process for producing 2&prime;,3&prime;-dideoxy-2&prime;,3&prime;-didehydronucleosides

A process for preparing 7-benzylpurine derivatives is provided. An acetylpurine nucleoside is reacted with a benzyl halide to benzylate the 7-position of the purine base, and an acid is then added to the reaction mixture to hydrolyze the glycoside bond. The 7-benzylpurines may be used to prepare 9-substituted purine derivatives. Specifically, a process for producing a 7-benzylpurine compound of Formula (5):

Process for producing purine derivatives

Purine derivatives in which a desired substituent is introduced into the 9-position only are synthesized by first introducing an easily-removable substituent in the 7-position of a purine base of natural purine nucleosides obtained through fermentation or derivatives thereof, then hydrolyzing the ribose moiety to form purine derivatives having the substituent in the 7-position, subsequently introducing the desired substituent in the 9-position, and then removing the substituent in the 7-position.

9-Substituted purine derivatives of formula (4) ##STR1## are prepared by debenzylating a compound of formula (3): ##STR2##

A process for preparing 7-benzylpurine derivatives is provided. An acetylpurine nucleoside is reacted with a benzyl halide to benzylate the 7-position of the purine base, and an acid is then added to the reaction mixture to hydrolyze the glycoside bond. The 7-benzylpurines may be used to prepare 9-substituted purine derivatives.

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

Nucleoside derivatives such as 2'-deoxy-2'-bromo-5'-O-acetyl-5-methyluridine, etc., are important intermediates which can be converted into nucleoside derivatives, such as 3'-azido-3'-deoxythymidine, etc., which are useful as medicines.

Pyrimidine nucleoside derivatives and methods for producing them

A process for preparing a 2', 3'-dideoxy-2',3'-didehydropyrimidine nucleoside comprising reacting the pyrimidine ribofuranoside with a trialkyl orthoester to yield the 2',3'-O-alkoxyethylidene derivative; which is reacted with hydrogen bromide in acetic acid or acetyl bromide to yield the 2-deoxy-2'-bromo-3'-acetyl-pyrimidine nucleoside; which is then reduced with zinc to yield the 2',3'-olefin of the pyrimidine nucleoside.

Process for preparing 2',3'-Dideoxy-2',3'-dehydronucleosides

A process for preparing 2',3'-dideoxyinosine comprising reducing a nucleoside of the formula IIIa or IIIb ##STR1## wherein R.sup.2 is hydrogen, C.sub.1-12 acyl, C.sub.1-12 alkyl, C.sub.7-8 aralkyl or a silyl protecting group; X is Cl, Br, or I; R.sub.5 is C.sub.1-12 acyl; H.sub.x is hypoxanthine; with hydrogen in the presence of a palladium catalyst; wherein said reduction is conducted in a solvent containing a base of pH 9-11 and wherein the solvent is acetonitrile, aqueous acetonitrile, aqueous ethyl acetate, or aqueous methanol.

Process for preparing 2', 3'- dideoxyinosine

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

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.

Transglycosilation process for producing acyclic nucleosides

A method for selective hydrolysis of nucleoside derivatives using cyclodextrin in basic solution is disclosed.

Method for production of nucleoside derivatives by selective hydrolysis

A process for preparing 2',3'-dideoxyadenosine of the formula ##STR1## wherein B is adenine, wherein R.sup.1 is hydrogen, C.sub.1-12 acyl, C.sub.1-12 alkyl, C.sub.7-8 aralkyl, or silyl, said process comprising:

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Kawasaki, Japan

Hiroshi Shiragami