Central Glass Company, Limited

Hideyuki Tsuruta

Akihiro Ishii

Manabu Yasumoto

Takashi Ootsuka

Kenjin Inomiya

Koji Ueda

Mikihiro Takahashi

Kaori Mogi

Takako Yamazaki

Yuzuru Morino

Satoru Miyazawa

Michitaka Ootani

Yokusu Kuriyama

Takashi Masuda

Masataka Fujimoto

Hirokatsu Nagura

Disclosed is a purification method of reducing and removing fluoride ions contained in an optically active &#x3b1;-fluorocarboxylic acid ester represented by formula [1] [in the formula, Rrepresents a Calkyl group, Rrepresents a Calkyl group, and * represents an asymmetric carbon], the purification method of the optically active &#x3b1;-fluorocarboxylic acid ester being characterized by that a distillation is conducted in the presence of an organic base. By this method, it is possible to greatly reduce the concentration of fluoride ion traces contained in the optically active &#x3b1;-fluorocarboxylic acid ester by a relatively easy operation. Of the organic base, a tertiary amine is preferable, and above all tri-n-butylamine is particularly preferable.

Method for purification of optically active &#x3b1;-fluorocarboxylic acid esters

In the presence invention, a (2R)-2-fluoro-2-C-methyl-D-ribono-&#x3b3;-lactone precursor is produced in the form of a ring-opened fluorinated compound by reaction of a 1,2-diol with sulfuryl fluoride (SOF) in the presence of an organic base and, optionally, a fluoride ion source. The production method of the present invention secures less number of process steps as compared to the conventional production method (shortening of three steps: cyclic sulfurous esterification, oxidation and ring-opening fluorination to one step) and satisfies the requirements for industrial production (high yield and high reproductivity). The thus-obtained (2R)-2-fluoro-2-C-methyl-D-ribono-&#x3b3;-lactone precursor is useful as an important intermediate for the synthesis of 2'-deoxy-2&#x2032;-fluoro-2&#x2032;-C-methylcytidine with antivirus activity.

Method for producing (2R)-2-fluoro-2-C-methyl-D-ribono-&#x3b3;-lactone precursor

According to the present invention, there is provided a production process of a 2-fluoroacrylic ester including: a bromination step of converting a 2-fluoropropionic ester to a 2-bromo-2-fluoropropionic ester by reaction of the 2-fluoropropionic ester with a nitrogen-bromine bond-containing brominating agent in the presence of a radical initiator; and a dehydrobromination step of reacting the 2-bromo-2-fluoropropionic ester with a base. It is not necessary in this process to adopt very-low-temperature conditions and to use a stoichiometric amount of expensive reagent. The target 2-fluoroacrylic ester can be thus produced at low cost.

Process for preparation of 2-fluoroacrylic esters

An optically active &#x3b1;-fluorocarboxylate is produced by reacting an optically active &#x3b1;-hydroxycarboxylate with sulfuryl fluoride (SOF), trifluoromethanesulfonyl fluoride (CFSOF) or nonafluorobutanesulfonyl fluoride (CFSOF) in the presence of organic base and in the absence of reaction solvent. More preferably, a distillation purification is conducted after adding acid to the reaction-terminated liquid. With this, it is possible to produce an optically active &#x3b1;-fluorocarboxylate of a still higher purity. It is possible by this process to advantageously produce an optically active &#x3b1;-fluorocarboxylate on a large-amount scale.

Process for producing optically active &#x3b1;-fluorocarboxylate

By reacting a &#x3b2;-hydroxy-&#x3b1;-amino acid with sulfuryl fluoride (SOF) in the presence of an organic base, it is possible to produce an &#x3b1;-fluoro-&#x3b2;-amino acid of the formula [2]. By using a C8-12 tertiary amine having two or more alkyl groups of C3 or higher, and especially diisopropylethylamine, as the organic base, by-production of quantery ammonium salts is effectively suppressed. By applying the production process of the present invention, it is possible to very easily produce (2R)-3-(dibenzylamino)-2-fluoropropionic acid methyl ester, which is extremely important as a pharmaceutical intermediate, with high positional selectivity even on an industrial scale.

Process for producing &#x3b1;-fluoro-&#x3b2;-amino acids

There is disclosed a purification method of an optically active 1-(2-trifluoromethylphenyl)ethanol represented by the formula [1], which includes recrystallizing the optically active 1-(2-trifluoromethylphenyl)ethanol from an aliphatic hydrocarbon solvent where * denotes an asymmetric carbon. This method makes it possible to improve the optical purity of the ethanol significantly.

Method for purifying optically active 1-(2-trifluoromethylphenyl)ethanol

There is provided a novel, useful dehydroxyfluorination agent containing sulfuryl fluoride (SOF) and an organic base that is free from a free hydroxyl group in the molecule. According to the present dehydroxyfluorination agent, it is not necessary to use perfluoroalkanesulfonyl fluoride, which is not preferable in large-scale use, and it is possible to advantageously produce optically-active fluoro derivatives, which are important intermediates of medicines, agricultural chemicals and optical materials, for example, 4-fluoroproline derivatives, 2'-deoxy-2&#x2032;-fluorouridine derivatives, optically-active &#x3b1;-fluorocarboxylate derivatives, and monofluoromethyl derivatives, even in large scale.

Dehydroxyfluorination agent

There is provided a method for producing an optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl derivative, which includes the steps of conducting reductive alkylation of an optically active secondary amine and a formaldehyde (including an equivalent thereof) or lower aldehyde in the presence of a transition metal catalyst under a hydrogen gas atmosphere, thereby converting the secondary amine to an optically active tertiary amine of the formula, and subjecting the tertiary amine to hydrogenolysis. The target optically active compound can be produced efficiently by this production method.

Method for producing optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl) alkylamine N-monoalkyl derivative

It was found that a fluoro derivative can be produced by reacting a hydroxy derivative with sulfuryl fluoride (SOF) in the presence of an organic base or in the presence of an organic base and 'a salt or complex comprising an organic base and hydrogen fluoride'. According to the present production process, it is not necessary to use perfluoroalkanesulfonyl fluoride, which is not preferable in industrial use, and it is possible to advantageously produce optically-active fluoro derivatives, which are important intermediates of medicines, agricultural chemicals and optical materials, specifically 4-fluoroproline derivatives, 2'-deoxy-2&#x2032;-fluorouridine derivatives, optically-active &#x3b1;-fluorocarboxylate derivatives, and the like, even in a large scale.

Process for production of fluoro derivative

The present invention relates to a process for producing an optically active &#x3b1;-fluorocarboxylate derivative represented by the formula [2], by reacting an optically active &#x3b1;-hydroxycarboxylate derivative with trifluoromethanesulfonyl fluoride (CFSOF) in the presence of an organic base, in the formula [2], R represents a straight-chain or branched-chain alkyl group of a carbon number of 1 to 12; one of or two by any combination of aromatic hydrocarbon groups, unsaturated hydrocarbon groups, straight-chain or branched alkoxy groups of a carbon number of 1 to 6, aryloxy groups, halogen atoms (fluorine, chlorine, bromine and iodine), protected carboxyl groups, protected amino groups or protected hydroxyl group can be substituted on any carbon atoms of the alkyl group; Rrepresents a straight-chain or branched-chain alkyl group of a carbon number of 1 to 8; any carbon atoms of the alkyl groups of R and Rmay form a covalent bond; and * represents an asymmetric carbon.

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Fujimino, Japan

Hideyuki Tsuruta