Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Reexamination Certificate
2000-02-25
2003-05-27
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
C435S280000, C435S156000
Reexamination Certificate
active
06569652
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing optically active 1,2-diols.
The optically active 1,2-diols are useful as various pharmaceutical preparations and optically active, biologically active substances, as well as intermediates of their derivatives.
For example, cis-(1S,2R)-dihydroxyindane or trans-(1R,2R)-dihydroxyindane can be an important starting material of Crixivan used as an anti-AIDS drug because of its inhibitor activity on proteolytic enzymes for AIDS virus (J. Med. Chem., 34, 1228 (1991)).
BACKGROUND ART
Known methods of microbially producing optically active 1,2-diols include, for example, a method of reacting indene along with a cultured microorganism of the genus Pseudomonas (J. Chem. Soc., Chem. Commun., 339 (1989); J. Chem. Soc., Chem. Commun., 117 (1995)), a method of adding a derivative such as indene, 1,2-dihydronaphthalene or the like to a culture of
Mortierella isabellina
to convert it into a hydroxide (Bioorg. Med. Chem., 2, 439 (1994)), a method of using as a starting material optically active 2-bromo-1-hydroxyindane generated upon asymmetrical reduction of 2-bromoindane-1-one with
Cryptococcus macerans
(J. Org. Chem., 43, 4540 (1978)), and a method of stereoselectively hydrolyzing 1-methoxy-2-acetoxyindane in a culture of
Rhizopus nigricans
(J. Org. Chem., 49, 675 (1984)).
Further, known methods of synthesizing optically active 1,2-dihydroxyindane derivatives by chemical synthesis include a method of reacting 2-bromo-1-hydroxyindane in the presence of acetic acid or acetic acid and water (J. Chem. Soc. Perkin Trans. I., 2767 (1982)) and a method of oxidatively hydrating indene (Synthesis, 1142 (1985)).
However, these conventional methods, particularly chemical synthetic methods, have the problems that the starting materials are expensive, the operation is cumbersome and the yield is low because of the multiple-step reaction, or the optical purity of the resulting 1,2-dihydroxyindane is low, while the microbial methods also have the problem that the range of utilizable microorganisms is limited.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a process for producing optically active 1,2-diols efficiently by microorganisms not used in the conventional microbial methods.
That is, the present invention encompasses:
1. A process for producing optically active diols represented by the general formula (II):
wherein R
1
represents (CH
2
)
n
, CH═CH, O, S or NH whereupon n is an integer of 1 to 4, and R
2
represents hydrogen, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxy-carbonyl, hydroxy, carboxy, halogen, nitro or amino, which comprises treating compounds represented by the general formula (I):
wherein R
1
and R
2
have the same meanings as defined above, with a culture of a microorganism belonging to the genus Rhodococcus, Bacillus, Brevibacterium or Gordona and being capable of stereoselectively diolating a double bond in ring A, or with said microorganism itself, or with a treated material from said microorganism.
2. The process according to item 1 above wherein the microorganism capable of stereoselectively diolating a double bond in ring A is a microorganism belonging to the genus Rhodococcus.
3. The process according to item 2 above wherein the microorganism belonging to the genus Rhodococcus is
Rhodococcus rhodochrous
ATCC 21199.
4. The process according to item 2 above wherein the microorganism belonging to the genus Rhodococcus is
Rhodococcus rhodochrous
ATCC 21198.
5. The process according to item 1 above wherein the microorganism capable of stereoselectively diolating a double bond in ring A is a microorganism belonging to the genus Bacillus.
6. The process according to item 1 above wherein the microorganism capable of stereoselectively diolating a double bond in ring A is a microorganism belonging to the genus Brevibacterium.
7. The process according to item 1 above wherein the microorganism capable of stereoselectively diolating a double bond in ring A is a microorganism belonging to the genus Gordona.
8. The process according to item 1 above wherein substrate-adsorptive carriers are added to the reaction solution.
9. A process for producing optically active diols represented by the general formula (II):
wherein R
1
represents (CH
2
)
n
, CH═CH, O, S or NH whereupon n is an integer of 1 to 4, and R
2
represents hydrogen, C
1-6
alkyl, C
1-6
alkoxy, (C
1-6
alkoxy)-carbonyl, hydroxy, carboxy, halogen, nitro or amino, which comprises treating compounds represented by the general formula (I):
wherein R
1
and R
2
have the same meanings as defined above, with a culture of
Mortierella vinacea
, or with said microorganism itself, or with a treated material from said microorganism.
10. The process according to item 9 above wherein substrate-adsorptive carriers are added to the reaction solution.
In the definition of each group in the compounds shown in the general formula (I) or (II), the alkyl moiety in C
1-6
alkyl, C
1-6
alkoxy and (C
1-6
alkoxy)-carbonyl may be straight-chain or branched insofar as it is alkyl containing 1 to 6 carbon atoms, and examples of such alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. The halogen refers to each atom of fluorine, chlorine, bromine or iodine.
The purity of the compounds represented by the general formula (I), which are used in the present invention, is not particularly limited, and those of high purity or low purity may be used. Impurities are preferably compounds not adversely affecting the growth and existence of the microorganism and the enzyme activity, but there is no particular limit insofar as their influence is negligible.
The compounds represented by the general formula (I) are preferably those wherein R
1
is (CH
2
)
n
, more preferably those wherein R
1
is CH
2
or (CH
2
)
2
.
The microorganisms used in the present invention may be any microorganisms belonging to the genus Rhodococcus, Bacillus, Brevibacterium or Gordona, or
Mortierella vinacea.
The microorganisms belonging to the genus Rhodococcus include e.g.
Rhodococcus rhodochrous
ATCC 21198
, Rhodococcus rhodochrous
ATCC 21199
, Rhodococcus ruber
JCM 3205, Rhodococcus sp. IFM 18 and
Rhodococcus globerulus
ATCC 25714.
The microorganisms belonging to the genus Bacillus include e.g.
Bacillus megaterium
IAM 1032 and
Bacillus pasteurii
ATCC 11859.
The microorganisms belonging to the genus Brevibacterium include e.g.
Brevibacterium acetylicum
ATCC 953.
The microorganisms belonging to the genus Gordana include e.g.,
Gordana rubropertinctus
ATCC 27863 (equivalent to
Rhodococcus ruber
JCM 3205).
Mortierella vinacea
includes e.g.
Mortierella vinacea
TKBC 1102.
Rhodococcus rhodochrous
ATCC 21198
, Rhodococcus rhodochrous
ATCC 21199
, Rodococcus globerulus
ATCC 25714
, Bacillus pasteurii
ATCC 11859
, Brevibacterium acetylicum
ATCC 953 and
Gordona rubropertinctus
ATCC 27863 are stored in American Type Culture Collection (ATCC) in 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A. and also appear in a catalogue.
Rhodococcus ruber
JCM 3205 is stored in Japan Collection of Microorganisms (JCM) in the Institute of Physical and Chemical Research (RIKEN) in Hirosawa 2-1, Wako-shi, Saitama, JP and also appears in a catalogue.
Rhodococcus sp. IFM 18 is stored in Research Center for Pathogenic Fungi & Microbiol Toxicosis, Chiba University (formerly Institute of Food Microbiology) in Inohana 1-8-1, Chuo-ku, Chiba-shi, Chiba, JP and also appears in a catalogue.
Bacillus megaterium
IAM 1032 is stored in IAM Culture Collection (IAM), Center for Cellular and Molecular Research, Institute of Molecular and Cellular Biosciences, the University of Tokyo in Yayoi 1-1-1, Bunkyo-ku, Tokyo, JP and also appears in a catalogue.
Mortierella vinacea
TKBC 1102 is stored in TKBC Culture Collection (TKBC), Institute of Biological Science, University of Tsukuba in Tennodai 1-1-1, Tsukuba-shi, Ibaraki, JP and also appears in a catalogue.
Among the microorganisms described above, preferable microorganisms include microorg
Eguchi Tamotsu
Kumazawa Hideyo
Mochida Kenichi
Marx Irene
Merck & Co. , Inc.
Walton Kenneth R.
Winokur Melvin
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