Ajinomoto Co., Ltd.

Biogen Ma Inc.

Ea Pharma Co., Ltd.

Taisuke Ichimaru

Daisuke Takahashi

Tamotsu Suzuki

Koji Ohsumi

Tadakiyo Nakagawa

Munetaka Tokumasu

Tatsuhiro Yamada

Takahiro Koshiba

Kunihiro Hirai

Kayo Matsumoto

Satoshi Katayama

Naoko Hirose

Ken Yamashita

William F Kiesman

Xianglin Shi

Robert S Gronke

Yannick Fillon

Xuan Zhou

Firoz Antia

Wuming Yan

Hong Jiang

Takuya Hamagaki

Hien Nguyen

The present disclosure describes a convergent liquid phase process for manufacturing oligonucleotides by coupling two or more oligonucleotide fragments, each of which have two or more nucleotides. Also provided by the present disclosure are reaction steps involved the convergent liquid phase process.

Convergent liquid phase syntheses of oligonucleotides

A method for producing an oligonucleotide, including a step of removing a temporary protecting group of a 5'-hydroxyl group by adding an acid to a protected oligonucleotide having a phosphorothioate (PS), phosphate (PO) or H-phosphonate moiety, and deacylating a by-product having an acylated 5′-hydroxyl group by solvolysis can complete a condensation reaction to improve a condensation yield, and can markedly reduce impurities such as single base deletion form (N-1mer) and the like.

Production method for oligonucleotides

Oligonucleotides may be produced by a process, including (1) condensing a nucleoside, nucleotide or oligonucleotide (b), and a nucleoside, nucleotide or oligonucleotide (a), or a substituted nucleotide or oligonucleotide (&#x3b1;) in a non-polar solvent to give a reaction solution containing a phosphite triester product (c); (3) oxidizing or sulfurizing the phosphite triester product (c) to give a reaction solution containing an oligonucleotide (d) wherein the 5'-hydroxy group is protected; (4) deprotecting the oligonucleotide (d) to give a reaction solution containing an oligonucleotide (e) wherein the 5&#x2032;-hydroxy group is not protected; and (6) adding a polar solvent to the reaction solution containing the oligonucleotide (e) and purifying the oligonucleotide (e) by solid-liquid separation, wherein said nucleoside, nucleotide or oligonucleotide (a) or said substituted nucleotide or oligonucleotide (&#x3b1;) is a compound represented by formula (a-i): wherein Base, R, R, m, L, Y, and Z are defined herein.

Oligonucleotide production method, and nucleoside, nucleotide, or oligonucleotide

Precipitation promoters, which are an organic compound having one or more linear aliphatic hydrocarbon groups having not less than 10 carbon atoms, wherein the aliphatic hydrocarbon group has not less than 20 carbon atoms in total are useful for precipitating an organic compound protected by an organic group having one or more aliphatic hydrocarbon groups having not less than 10 carbon atoms from a solvent.

Precipitation promoter and precipitation method in which same is used

Compounds represented by the following formula (I); wherein each symbol is as defined in the specification, are useful as hyperglycemic inhibitors having a serine protease inhibitory action and as prophylactic or therapeutic drugs for diabetes.

Heteroarylcarboxylic acid ester derivative

Compounds represented by the following formula (I); wherein each symbol is as defined in the specification,are useful as hyperglycemic inhibitors having a serine protease inhibitory action and as prophylactic or therapeutic drugs for diabetes.

Compounds represented by the following formula (I), are useful as hyperglycemic inhibitors having a serine protease inhibitory action and as prophylactic or therapeutic drugs for diabetes.

Growing community of inventors

Kawasaki, Japan

Taisuke Ichimaru