Central Glass Company, Limited

Tokyo Institute of Technology

Toyama Prefecture

Akihiro Ishii

Manabu Yasumoto

Takashi Ootsuka

Yokusu Kuriyama

Koji Ueda

Masatomi Kanai

Kenjin Inomiya

Hideyuki Tsuruta

Takako Yamazaki

Kaori Mogi

Mari Imamura

Takashi Masuda

Takashi Hayami

Koichi Mikami

Mikihiro Takahashi

Yoshiyuki Kikuchi

Yuzuru Morino

Shunsuke Mimura

Masaki Matsui

Kazumasa Funabiki

Katsuyoshi Shibata

Takayuki Nishimiya

Yasunobu Nishimura

Takehisa Ishimaru

Kohsuke Aikawa

Kazuto Kimura

Satoru Miyazawa

Michitaka Ootani

Yasuhisa Asano

Kazunori Mori

Mikio Ujiie

Masataka Fujimoto

Ryuichi Okamoto

Hirokatsu Nagura

Hiroshi Minesaki

Misugi Kato

Tetsuro Nishii

Katsuhide Suto

Kanjin Inomiya

Masato Kimura

Mitsuru Tanuma

Hirotsune Kondoh

Kenichi Fuhshuku

Junpei Aida

Ken-Ichi Fuhshuku

Disclosed is a practical method for production of 3,3-difluoro-2-hydroxypropionic acid, which is important as pharmaceutical and agrichemical intermediates. The method includes forming a 4,4-difluoro-2,2-dichloro-3-oxobutanoic acid ester by reaction of a 4,4-difluoro-3-oxobutanoic acid ester with chlorine (Cl), forming 3,3-difluoro-1,1-dichloro-2-propanone by reaction of the chlorination product with an acid, and then, reacting the degradation product with a basic aqueous solution.

Practical method for manufacturing 3,3-difluoro-2-hydroxypropionic acid

A production method of &#x3b1;,&#x3b1;-difluoroacetaldehyde according to the present invention includes reaction of an &#x3b1;,&#x3b1;-difluoroacetic acid ester with hydrogen gas (H) in the presence of a ruthenium catalyst. It is possible to selectively obtain &#x3b1;,&#x3b1;-difluoroacetaldehyde as a partially reduced product of the hydrogenation reaction by the adoption of specific reaction conditions (in particular, reaction solvent and reaction temperature). This hydrogenation process can be alternative to the industrially unpractical hydride reduction process.

&#x3b1;,&#x3b1;-Difluoroacetaldehyde production method

&#x3b1;,&#x3b1;-difluoroacetaldehyde production method

A production method of a 1,1,1,5,5,5-hexafluoroacetylacetone hydrate according to the present invention includes: step 1: step 1: obtaining a reaction mixture that contains at least 1,1,1,5,5,5-hexafluoro-3-pentyn-2-one or an equivalent thereof by reaction of a 3,3,3-trifluoropropynyl metal with a trifluoroacetate; and step 2: forming the 1,1,1,5,5,5-hexafluoroacetylacetone hydrate by contact of the reaction mixture obtained in the step 1 with water in the presence of an acid. It is possible to produce 1,1,1,5,5,5-hexafluoroacetylacetone by dehydration of the thus-formed hydrate. Thus, the production method according to the present invention is industrially applicable.

Method for producing 1,1,1,5,5,5-hexafluoroacetylacetone

A production process of an &#x3b1;-fluoroaldehyde according to the present invention includes reaction of an &#x3b1;-fluoroester with hydrogen gas (H) in the presence of a ruthenium complex. It is possible in the present invention to allow relatively easy industrial production of the &#x3b1;-fluoroaldehyde and to directly obtain, as stable synthetic equivalents of the &#x3b1;-fluoroaldehyde, not only a hydrate (as obtained by conventional techniques) but also a hemiacetal that is easy to purify and is of high value in synthetic applications. The present invention provides solutions to all problems in the conventional techniques and establishes the significantly useful process for production of the &#x3b1;-fluoroaldehyde.

Process for producing &#x3b1;-fluoroaldehydes

Disclosed is a method for producing (S)-1,1,1-trifluoro-2-propanol with high optical purity and high yield by having at least one kind of microorganism, which is selected from the group consisting ofand, act on 1,1,1-trifluoroacetone. Since microorganisms found in nature are made to act in a natural state, the problems to be raised when a transformant or the like is used can be avoided in this method. Consequently, the method can be easily put in industrial practice.

[object Object]

A production process of a fluorosulfuric acid aromatic-ring ester according to the present invention includes reaction of an aromatic-ring hydroxyl compound with sulfuryl fluoride (SOF) in the presence of a tertiary amine except pyridine and methylpyridine. The sulfuryl fluoride, used as the reactant in the production process according to the present invention, is widely adapted as a fumigant and is easily available on a large scale. Further, the target compound can be obtained rapidly with a high yield under moderate reaction conditions in the production process according to the present invention. In this way, all of the prior art problems can be solved in the production process according to the present invention. The production process according to the present invention is thus particularly useful for industrial production of the fluorosulfuric acid aromatic-ring ester.

Process for producing fluorosulfuric acid aromatic-ring esters

Fluorosulfuric acid esters can be produced by reacting alcohols with sulfuryl fluoride (SOF) in the presence of a base and water. As a substrate thereof, optically active secondary alcohols are preferable, and optically active &#x3b1;-hydroxyesters and optically active 4-hydroxyprolines are particularly preferable. By performing the reaction in a two-phase system in the presence of a reaction solvent immiscible with water, a desired reaction proceeds particularly well. The present invention is a production method solving all the problems involved in conventional techniques while being industrially practicable.

Method for producing fluorosulfuric acid ester

Disclosed is a method of producing an optically active fluorinated oxetane, which can be an important pharmaceutical or agricultural intermediate, by reaction of a fluorinated &#x3b1;-keto ester with an acyl alkenyl ether in the presence of a transition metal complex with an optically active ligand. This method utilizes a catalytic asymmetric synthesis process and does not require a stoichiometric amount of chiral source. It is thus possible to dramatically reduce the amount of use of the asymmetric catalyst especially when the reaction is performed at a high concentration of substrate (with the use of a small amount of reaction solvent) or in the absence of a reaction solvent (under neat conditions). Further, the target optically active fluorinated oxetane can be obtained with high yield and with very high optical purity. The product contains almost no difficult-to-separate impurity and shows high chemical purity.

Method for producing optically active fluorinated oxetane

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

A production method of a &#x3b2;-fluoroalcohol includes performing a reaction of an &#x3b1;-fluoroester with hydrogen gas (H) in the presence of a specific ruthenium complex (i.e. a ruthenium complex of the general formula [2], preferably a ruthenium complex of the general formula [4]). This production method can employ a suitable hydrogen pressure of 1 MPa or less by the use of such a specific ruthenium complex and does not require a high-pressure gas production facility when put in industrial practice. In addition, this production method can remarkably reduce the amount of catalyst used therein (to e.g. a substrate/catalyst ratio of 20,000) in comparison to the substrate/catalyst ratio conventional reduction of &#x3b1;-fluoroalcohol. It is possible by these reduction in hydrogen pressure and catalyst amount to largely reduce the production cost of the &#x3b2;-fluoroalcohol. 

Method for producing &#x3b2;-fluoroalcohol

An &#x3b1;-trifluoromethyl-&#x3b1;,&#x3b2;-unsaturated ester can be produced by reacting an &#x3b1;-trifluoromethyl-&#x3b1;-hydroxy ester with sulfuryl fluoride (SOF) in the presence of an organic base. It is preferable that the raw substrate has a hydrogen atom as one &#x3b2;-position substituent group and either an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group as the other &#x3b2;-position substituent group. It is more preferable that an ester moiety of the raw substrate is an alkyl ester. This raw substrate is readily available. Further, the desired reaction can proceed favorably with the use of this raw substrate. It is also preferable to use either 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the organic base. The desired reaction can proceed more favorably with the use of this organic base.

Process for producing &#x3b1;-trifluoromethyl-&#x3b1;,&#x3b2;-unsaturated ester

&#x3b1;-Trifluoromethyl-&#x3b2;-substituted-&#x3b2;-amino acids can be produced by allowing &#x3b1;-trifluoromethyl-&#x3b2;-substituted-&#x3b1;,&#x3b2;-unsaturated esters to react with hydroxylamine to convert &#x3b1;-trifluoromethyl-&#x3b2;-substituted-&#x3b1;,&#x3b2;-unsaturated esters into dehydrogenated closed-ring body of &#x3b1;-trifluoromethyl-&#x3b2;-substituted-&#x3b2;-amino acid, and by hydrogenolyzing the dehydrogenated closed-ring body. According to this production process, novel &#x3b1;-trifluoromethyl-&#x3b2;-substituted-&#x3b2;-amino acids which are free amino acids whose functional groups are not protected can be produced, in which &#x3b2;-position substituent is not limited to aromatic ring group or substituted aromatic ring group while the relative stereochemistry of &#x3b1;-position and &#x3b2;-position can be also controlled.

Process for production of &#x3b1;-trifluoromethyl-&#x3b2;-substituted-&#x3b2;-amino acid

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Kawagoe, Japan

Akihiro Ishii