JPH0520073B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing (R)-3-halogeno-1,2-propanediol. (R)-3-halogeno-1,2-propanediol is a substance useful as a raw material for the synthesis of various pharmaceuticals and optically active physiologically active substances. For example, (R)-3-chloro-1,2-propanediol is used in the synthesis of L-carnitine (Japanese Patent Application Laid-Open No. 165352/1983). (Prior art and problems) Regarding the production method of (R)-3-halogeno-1,2-propanediol, Hayden F. Jones describes methyl-5-chloro-5-deoxy-α-L-arabinofuranoside. How to get more, [Chemistry and Industry]
Industry), P.533, 15July, 1978], and H.
A method of obtaining it from 1,2,5,6-diacetonyl-D-mannitol by Jackson et al. [Chemistry and Biological Interactions (Chem.Biol.Interactions) 13 , 193]
(1976)], similarly the method of Y. Kawakami et al. [Journal of Organic Chemistry]
(Journal of Organic Chemistry) 47 , 3581
(1982)] are known. However, these methods cannot be called industrial production methods because the raw materials are difficult to obtain and the steps are complicated.
A method for producing halogeno 1,2-propanediol has been desired. (Means and effects for solving the problems) The present inventors discovered that (R)-3-halogeno-1,2-
As a result of intensive research aimed at industrial production of propanediol, we discovered that cheap (R-S)-3-halogen-
By treating 1,2-propanediol with a microorganism that has the ability to selectively metabolize (S)-3-halogeno-1,2-propanediol, (S)
- Discovered that it is possible to selectively inject 3-halogeno-1,2-propanediol and leave (R)-3-halogeno-1,2-propanediol,
The present invention has now been completed. Microorganisms that can be used in the present invention include the genus Absidia, the genus Amauroascus, the genus Anixiopsis, the genus Ascosphaera, the genus Aspergillus, the genus Acremoniella, and the genus Acrodontei. Acrodontium genus, Arxiella
Genus, Cladosporium, Beauveria, Calonectria, Coniochaetidium, Backusella, Beltraniella, Cladobotryum, Clideium Genus Chloridium, Corticium
Genus, Cunninghamella, Circinella, Botryoconis, Emericella
Genus, Gliocladium, Gliocephalotrichum
Genus, Helicosporium, Melanospora, Micronectriella, Echinopodospora, Gliomastix, Gelasinospora, Deightoniella Genus, Dendryphiella, Dichotomyces, Mortierella, Pycnoporus
Genus, Sporormiella, Syncephalastrum, Talaromyces, Pellicularia, Neosartorya, Penicillium, Thamnostylum, Chigorhynchus ( Genus Zygorhynchus, Monascus
Mention may be made of microorganisms belonging to the genus Periconia. For more information: Absidia corymbifera
IFO4009, Amauroascas. Amauroascus reticulatus IFO9196, Anixiopsis
fluvescens) IFO30411, Ascosp-haera apis (Ascosp-haera apis) IFO9831, Aspergillus ficuum
IFO4034, Acremoniella atra IFO5937, Acrodontium crateliforme
crateriforme) IFO30442, Arxiella terrestris IFO30203, Cladosporium resinae
IFO6367, Beauveria bassiana
bassiana) IFO8554, Calonectria hederae IFO30427, Coniochaetidium
savoryi) IFO30424, Backusella circina IFO9231, Beltraniella japonica
IFO30443, Cladobotulium. Cladobotryum apicu−latum IFO7795, Chloridium chlamydospolis
chlamydosporis) IFO7070, Cortesium
Corticium rolfsii IFO30071, Cunninghamella echinulata IFO4441, Circinella simplex
IFO6412, Botryochonis japonica (Botr−
yoconis japonica) IFO4862, Enericella nidulans (Enericella nidulans) IFO4340, Gliocladium delicensans (Gliocladium
deliquescens) IFO6790, Gliocephalotrichum
cylindosporum) IFO9326, Helicosporium
Helicosporium linderi IFO9207,
Melanospora ornata
ornata) IFO8354, Micronectriella cucumeris (M-icronectriella cucumeris) IFO3005,
Echinopodospora jamaicensis IFO30406, Gliomastix
murorum) IFO8269, Gelasi-nospora cerealis IFO6759, Deightoniella
torulosa) IFO7658, Dendryphiella salina IFO8281, Dichotomyces cejpii
IFO8396, Mortierella humicola IFO8188, Pycnoporus coccineus
IFO9768, Sporormiella isomera IFO8538, Synthephalastrum nigricans (S-
yncephalastrum nigricans) HUT1299, Talaromyces flavus
IFO7231, Pellicularia filamentosa IFO6254, Neosartorya aurata
IFO8783, Penicillium janthinellum IFO4651, Thamnostylum pyriforme
piriforme) IFO6117, Zygorhynchus molleri HUT1305, Monascus anka IFO5965, Periconia byssoides
There are IFO9444 etc. As the medium composition for culturing the above-mentioned microorganisms, any medium in which these microorganisms can grow can be used. For example, sugars such as glucose, sucrose, and maltose as carbon sources;
Alcohols such as ethanol, glycerol, and 1,2-propanediol; organic acids such as acetic acid and lactic acid, or mixtures thereof; nitrogen sources such as ammonium sulfate, ammonium phosphate, urea, yeast extract, meat extract, peptone, and other inorganic salts. ,
Nutrient sources used in normal culture, such as trace metal salts and vitamins, can be appropriately mixed and used. The above microorganisms may be cultured by conventional methods, for example, the culture medium pH should be in the range of 4.0 to 9.5, and the culture temperature should be in the range of 20 to 45.
It is preferable to culture aerobically at a temperature in the range of 10 to 96 hours. As a method for obtaining (R)-3-halogeno-1,2-propanediol by allowing microorganisms to act on (R,S)-3-halogeno-1,2-propanediol, the culture solution cultured as described above or this culture A method in which a substrate is added to a suspension of microbial cells obtained by centrifugation from a liquid, a method in which a substrate is added to a medium and culture and reaction are performed simultaneously, a method in which microorganisms immobilized by a conventional method are added to an appropriate buffer There is a method of adding a substrate to a suspension in a liquid. The reaction temperature is preferably 15 to 50°C and the reaction pH is preferably 4.0 to 10.0, and a buffer or the like can be used as appropriate to maintain the pH. The substrate concentration in the reaction solution is preferably 0.1 to 10 (W/V)%, and the substrate may be added all at once at the beginning of the reaction or may be added in portions. The reaction is usually carried out with shaking or stirring,
Although the reaction time varies depending on the substrate concentration, oxygen amount, and other reaction conditions, it is preferable to select conditions so that the reaction completes in 24 to 120 hours. To stop the reaction, analyze the remaining substrate using gas chromatography, etc.
From the viewpoint of yield, it is preferable to stop the process when the remaining substrate reaches approximately 50% of the added substrate. To collect the (R)-3-halogeno-1,2-propanediol thus obtained from the reaction solution, a general (R,S)-3-halogeno-1,
A method for collecting 2-propanediol can be used. For example, after removing bacterial cells from the reaction solution by centrifugation or the like, the supernatant is appropriately concentrated and extracted with a solvent such as ethyl acetate. After dehydrating the extract over anhydrous sodium sulfate or the like, the solvent is removed under reduced pressure to obtain a syrup of (R)-3-halogeno-1,2-propanediol. It may also be further purified by distillation. (Example) The present invention will be specifically described below with reference to Examples. Examples 1-44 Glucose 2%, Peptone 1%, Meat Extract 1
%, yeast extract 0.5%, and NaCl 0.1% (PH6.5), and put 500ml into two Sakaguchi flasks.
The mixture was divided into portions and sterilized at 120°C for 20 minutes. Inoculate each of the bacterial strains shown in Table 1 into the above medium and hold at 30°C.
Culture solution 1 was obtained by culturing with shaking for 48 hours. This culture solution was centrifuged to collect the bacterial cells, and after washing with water, the bacterial cells were suspended in 500 ml of 0.3M phosphate buffer (PH7.0) and added to (R,S)-3-chloro-1,2 −
1.5g of propanediol was added and reacted at 30°C for 96 hours with shaking. 500 ml of the reaction solution was sterilized by centrifugation, the supernatant was concentrated to about 50 ml, and extracted three times (450 ml in total) with 150 ml of ethyl acetate. The extract was dehydrated with anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a syrup. When the specific optical rotation of this product was measured, the values shown in Table 1 were obtained. [Literature value of (R)-3-chloro-1,2-propanediol [α] ²² _D -6.9 (c = 2, H ₂ O)] In addition, after tosylating each syrup by a conventional method, optical HPLC analysis (retention) using an isomer separation column [Chiralcel OC column (0.46 cm x 25 cm)] (manufactured by JASCO) using a solvent of hexane-isopropyl alcohol (95:5) at a flow rate of 2.0 ml/min and a wavelength of 235 nm. (35 minutes for the (S) form and 38.5 minutes for the (R) form), it was confirmed that the corresponding (R) forms were contained.

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[Table] Examples 45-88 Using the strains shown in Table 1, the substrate was (R,S)-
The same operations as in Examples 1 to 44 were performed except that 3-bromo-1,2-propanediol was used, and the results shown in Table 2 were obtained. [Literature value of (R)-3-bromo-1,2-propanediol [α] ²⁵ _D −3.94 (c=5.07CHCl ₃ )

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Claims (1)

[Scope of Claims] 1 Absidia genus, Amauroascus genus, Anixiopsis genus, which have the ability to selectively metabolize (S)-3-halogeno-1,2-propanediol; Ascosphaera, Aspergillus, Acremoniella, Acrodontium, Arxiella
Genus, Cladosporium, Beauveria, Calonectria, Coniochaetidium, Backusella, Beltraniella, Cladobotryum, Chloridium Genus Chloridium, Corticium
Genus, Cunninghamella, Circinella, Botryoconis, Emericella
Genus, Gliocladium, Gliocephalotrichum
Genus, Helicosporium, Melanospora, Micronectriella, Echinopodospora, Gliomastix, Gelasinospora, Deightoniella, Genus Dendryphiella, Genus Dichotomyces, Genus Mortierella, Genus Pycnoporus.
Genus, Sporormiella, Syncephalastrum, Talaromyces, Pellicularia, Neosartorya, Penicillium, Thamnostylum, Zygorhynchus ) genus, Monascus
Microorganisms belonging to the genus Periconia are allowed to act on (R,S)-3-halogeno-1,2-propanediol, and the remaining (R)-3-halogeno-1,2-propanediol is collected. A method for producing optically active (R)-3-halogeno-1,2-propanediol, characterized by: 2 The microorganism is Absidia. Absidia corymbifera, Amauroascus reticulatus,
Anixiopsis falbesans
Ascosphaera apis, Aspergillus ficuum, Acremoniella atra, Acrodontium
crateriforme), Arxiella terrestris, Cladosporium resinae, Beauveria bassiana, Calonectria hederae, Coniochaetidium savoryi,
Backusella circina,
Beltraniella japonica (Beltraniella)
japonica), Cladobotryum apiculatum, Chloridium chlamydospolis
chlamydosporis), Corticium rolfsii, Cunninghamella echinulata, Circinella simplex,
Botryoconis japonica
Japonica), Emericella nidulans, Gliocladium
Gliocladium deliquescens, Gliocephalotrichum cylindrosporum, Helicosporium
linderi), Melanospora ornata, Micronectriella
Micronectriella cucumeris, Echinopodospora Jamaicensis, Gliomastix murorum,
Gelasinospora cerealis (Gelasinospora
cerealis), Deightoniella torulosa, Dendriphyella
Dendryphiella salina, Dichotomyces cejpii, Mortierella
humicola), Pycnoporus coccineus, Sporormiella isomera, Syncephalastrum nigricans
nigricans), Talaromyces flavus, Pellicularia filamentosa, Neosartorya aurata
aurata), Penicillium janthinellum, Thamnostylum piriforme,
Zygorhynchus moereri
moelleri), Monascus anca (Monascus
anka), Periconia bisoides (Periconia
byssoides) according to claim 1. 3 (R,S)-3-halogeno-1,2-propanediol is (R,S)-3-chloro-1,2-
The manufacturing method according to claim 1 or 2, which is propanediol. 4 (R,S)-3-halogeno-1,2-propanediol is (R,S)-3-bromo-1,2-
The manufacturing method according to claim 1 or 2, which is propanediol.