Central Glass Company, Limited

Takako Yamazaki

Akihiro Ishii

Manabu Yasumoto

Takashi Masuda

Ryuichi Okamoto

Hideyuki Tsuruta

Kaori Mogi

Takashi Kashiwaba

Shunsuke Mimura

Masanori Fushimi

Haruki Kobayashi

Shoko Ishii

Mikihiro Takahashi

Satoru Miyazawa

Michitaka Ootani

Takashi Ootsuka

Kazunori Mori

Takehisa Ishimaru

Masataka Fujimoto

Akihiro Ishi

The present invention provides an industrially applicable method for production of a fluorine-containing cyclopropane carboxylic acid compound useful as an intermediate for pharmaceutical and agrichemical products. A fluorine-containing cyclopropane monoester is obtained by: forming a fluorine-containing cyclic sulfate with the use of a fluorine-containing diol compound and sulfuryl fluoride (as a cyclic sulfuric esterification step); reacting the fluorine-containing cyclic sulfate with a malonic diester, thereby forming a fluorine-containing cyclopropane diester (as a cyclopropanation step); and hydrolyzing the fluorine-containing cyclopropane diester (as a hydrolysis step). The fluorine-containing cyclopropane carboxylic acid compound, such as fluorine-containing cyclopropane monoester or its salt, can be obtained with high chemical and optical purity by mixing the fluorine-containing cyclopropane monoester with an amine and subjecting the resulting salt of the fluorine-containing cyclopropane monoester and amine to recrystallization purification.

Method for producing fluorine-containing cyclopropane carboxylic acid compound

The present invention provides an industrially applicable method for production of a fluorine-containing cyclopropane carboxylic acid compound useful as an intermediate for pharmaceutical and agrichemical products. A fluorine-containing cyclopropane monoester is obtained by: forming a fluorine-containing cyclic sulfate with the use of a fluorine-containing dial compound and sulfuryl fluoride (as a cyclic sulfuric esterification step); reacting the fluorine-containing cyclic sulfate with a malonic diester, thereby forming a fluorine-containing cyclopropane diester (as a cyclopropanation step); and hydrolyzing the fluorine-containing cyclopropane diester (as a hydrolysis step). The fluorine-containing cyclopropane carboxylic acid compound, such as fluorine-containing cyclopropane monoester or its salt, can be obtained with high chemical and optical purity by mixing the fluorine-containing cyclopropane monoester with an amine and subjecting the resulting salt of the fluorine-containing cyclopropane monoester and amine to recrystallization purification.

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 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

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

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

Disclosed is a process for producing a protected optically active fluoroamine, which comprises the step of reacting an imine-protected optically active hydroxyamine, an oxazolidine-protected optically active hydroxyamine, or a mixture of the imine-protected optically active hydroxyamine and the oxazolidine-protected optically active hydroxyamine, with sulfuryl fluoride (SOF) in the presence of a tertiary amine having a carbon number of 7 to 18 (produced by substituting all of three hydrogen atoms in ammonia by alkyl groups). The desired optically active fluoroamine can be produced by hydrolyzing the protected optically active fluoroamine under acidic conditions.

Process for production of optically active fluoroamine

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.

Growing community of inventors

Kawagoe, Japan

Takako Yamazaki