Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Reexamination Certificate
2000-11-29
2001-11-13
Lankford, Jr., Leon B. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
C435S132000, C435S170000, C549S513000, C549S520000
Reexamination Certificate
active
06316233
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing a (S)-3-halogeno-1,2-propanediol (abbreviated as (S)-[1]) by reacting a racemic 3-halogeno-1,2-propanediol (abbreviated as racemate [1]) with a microorganism which has an ability to grow by assimilating a (R)-3-halogeno-1,2-propanediol (abbreviated as (R)-[1]) as a single carbon source and obtaining (S)-[1].
(S)-3-halogeno-1,2-propanediols are very important as intermediates in making optically active compounds, such as pharmaceuticals, agrochemicals or physiologically active compounds.
PRIOR ART
As to biological or enzymatic methods for preparing a (S)-3-halogeno-1,2-propanediol the following methods are known.
There are two known methods by Takahasi et al. (Japanese Patent Publication A 62-122596, Japanese Patent Publication A 63-36798) and Nikaido et al. (Japanese Patent Application A 6-209781), which comprise reacting racemate [1] with a microorganism to degrade (R)-[1] and recovering remained (S)-[1]. Although, each microorganism used in both methods has an ability to stereoselectively degrade and metabolize (R)-[1] in racemate [1], but the microorganism has not an ability to assimilate (R)-[1] as a single carbon source and therefore, the said microorganism can not grow and propagate in a completely synthetic medium containing racemate [1] as a single carbon source, and an inorganic nitrogen compound such as ammonium sulfate or ammonium nitrate as a nitrogen source. In these methods, in order to obtain (S)-[1] from racemate [1], after the microorganism was separately in a large amount cultivated in a culture medium in which the microorganism can grow, the cells are made to react with racemate [1], or otherwise racemate [1] must be added to a nutrient culture medium in which the microorganism can grow.
Especially, the method of Takahasi et al. belongs to the reaction utilizing the degradatively metabolizing reaction by oxidation, and in order to efficiently progress the reaction, it is necessary to add glutathione or a compound having a SH group such as sodium hydrosulfide or potassium hydrosulfide.
On the other hand, the method of Nikaido et al. is one utilizing a strain belonging to the same genus Pseudomonas as in the present invention, but the strain has not have an ability to assimilate (R)-[1] and therefore, the degradatively assimilating reaction of (R)-[1] with growth of the strain in a synthetic medium containing racemate [1] as a single carbon source does not occur and it is impossible to get (S)-[1].
These two known methods are not convenient and practical from the viewpoints of optical resolution of racemate [1], recovery and purification of (S)-[1] obtained, and are not economical from the viewpoint of the industrial production scale.
DETAILED DESCRIPTION OF INVENTION
The problem to be solved is to provide a method for preparing (S)-[1] from racemate [1] more economically, cheaper and more simply in technique.
The present inventors extensively engaged in seeking a microorganism which has an ability to preferentially assimilate (R)-[1] in racemate [1] and furthermore, can grow by assimilating (R)-[1] as a single carbon source, and have found such a microorganism to complete the present invention.
The present invention relates to a method for obtaining (S)-[1] which comprises cultivating a microorganism belonging to the genus Pseudomonas (abbreviated as the microorganism of the present invention) which has an ability to assimilate (R)-[1] and can grow by assimilating (R)-[1] as a single carbon source, in a culture medium containing racemate [1] as a substrate, and isolating (S)-[1] from the culture medium.
Halogen atoms of racemate [1] used as a substrate in the present invention are preferably chlorine atom and bromine atom.
The present invention is in more detail explained as follows.
The microorganism of the present invention is inoculated into a completely synthetic medium containing racemate [1] as a single carbon source and inorganic compounds such as many kinds of ammonium salts or nitrates as nitrogen sources, and a small amount of metalic salts or inorganic salts such as phosphoric acid salts, and cultivated or reacted to assimilate (R)-[1], and then (S)-[1] remaining in the culture broth is recovered, or the microorganism of the present invention may be cultivated in a nutrient culture medium usually used, such as a bouillon culture medium or a peptone culture medium containing organic carbon sources and nitrogen sources, if necessary inorganic salts, a small amount of metalic salts, or vitamines to assimilate (R)-[1], and then (S)-[1] remaining in the culture broth is recovered.
The present invention, namely relates to the method for recovering (S)-[1] remained in the culture broth or the reaction solution by preferentially degradative assimilating racemate [1] with the microorganism of the present invention.
The assimilating reaction is preferably carried out within optimum pH of the strain used herein and optimum temperature. When the microorganism of the present invention grows by assimilating (R)-[1] as a carbon source, hydrochloric acid in the same amount as (R)-[1] which is degraded with dehalogenation is generated.
When pH gradually becomes lower by hydrochloric acid released from (R)-[1] with progress of the assimilating reaction, it is necessary to adjust pH of the reaction solution to optimum pH by addition of a suitable alkali. For example, the solution is preferably controlled in the range of optimum pH by using a known acid-neutralizing agent, such as an aqueous alkali carbonate solution, e.g. an aqueous calcium carbonate solution, an aqueous sodium carbonate solution, an aqueous potassium carbonate solution or an aqueous ammonium carbonate solution, an aqueous alkali hydroxide solution, e.g. sodium hydroxide solution, an aqueous potassium hydroxide solution or an aqueous calcium hydroxide solution, or an aqueous ammonium solution.
The culture medium for cultivation of the microorganism of the present invention and for making assimilating reaction of (R)-[1] is preferably a completely synthetic medium containing racemate [1] as a single carbon source, inorganic compounds such as many kinds of ammonium salts or nitric acid salts as nitrogen sources, and a small amount of metalic salts, or inorganic salts such as a phosphoric acid salt in the economical viewpoint, but is not limited as long as the conventional culture medium containing racemate [1] as a substrate in which the microorganism of the present invention can grow. For example, carbohydrates such as glucose or fructose, alcohols such as glycerol, sorbitol, or mannitol, organic acids, such as acetic acid, citric acid, malic acid, maleic acid, fumaric acid or gluconic acid, or a salt thereof, or a mixture thereof, can be used as carbon source.
Inorganic nitrogen compounds such as ammonium sulfate, ammonium nitrate or ammonium phosphate, organic nitrogen compounds such as urea, peptone, casein, yeast extract, meat extract, corn steep liquor or a mixture thereof, can be used as nitrogen source. Furthermore, inorganic salts such as a phosphoric acid salt, metalic salts such as a magnesium salt, a potassium salt, a manganese salt, an iron salt, a zinc salt, or a copper salt, or if suitable, vitamins may be used.
The cultivation mentioned above is aerobically carried out in an usual manner, at pH 4-10, preferably 5-9, at 15-50° C., preferably 20-37° C. under stirring or agitating for 20-96 hours.
The microorganism of the present invention may be previously cultivated in a nutrient culture medium usually used, such as a bouillon culture medium or a peptone culture medium cont
Idogaki Hideaki
Kasai Naoya
Nakagawa Atsushi
Suzuki Toshio
Daiso Co. Ltd.
Lankford , Jr. Leon B.
Wenderoth , Lind & Ponack, L.L.P.
Winston Randall
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