Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Reexamination Certificate
2003-01-22
2004-12-28
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
C435S169000, C435S170000, C435S280000, C435S822000, C435S865000, C435S877000, C435S911000, C435S914000, C435S917000, C435S918000
Reexamination Certificate
active
06835559
ABSTRACT:
TECHNICAL FIELD
This invention relates to a process for producing optically active &bgr;-amino alcohols. More particularly, it relates to a process for producing optically active &bgr;-amino alcohols which are of value as drugs or their intermediates.
BACKGROUND ART
Ephedrines have been used for purposes of perspiration, antipyresis and cough soothing from the olden times, and particularly, d-pseudoephedrine is known to possess anti-inflammatory action. Pharmacological action such as vasoconstriction, blood pressure elevation, or perspiration is known for 1-ephedrine and it is used in therapy as a sympathomimetic agent. 1-Ephedrine is also used in the treatment of bronchial asthma. Specifically, processes for the production of optically active &bgr;-amino alcohols, including optically active ephedrines, are useful in the manufacture of drugs and their intermediates; thus, there is a need for efficient production processes.
In the conventional process for producing a &bgr;-amino alcohol with the desired optical activity, there was used a process by which a racemic &bgr;-amino alcohol is obtained and then a specific optically active form is produced by optical resolution or asymmetric synthesis among others.
However, since the racemic &bgr;-amino alcohol has two asymmetric carbons within its molecule, complicated steps had to be followed to obtain the specific optically active form. For example, according to Ger. (East) 13683 (Aug. 27, 1957), optically active phenylacetylcarbinol was produced from benzaldehyde by fermentation utilizing yeast and erythro-1-2-methylamino-1-phenyl-1-propanol (i.e., 1-ephedrine) could be produced by reductively condensing methylamine to the optically active phenylacetylcarbinol.
To obtain pseudoephedrine, the production is possible as described in U.S. Pat. No. 4,237,304: an oxazoline is formed from 1-ephedrine produced by the method described in Ger. (East) 13683 (Aug. 27, 1957), using acetic anhydride, and then the oxazoline is hydrolyzed through inversion to the threo form (i.e., d-pseudoephedrine).
As stated above, to produce pseudoephedrine with the desired optical activity from 2-methylamino-1-phenyl-1-propanone, steps are necessary such that ephedrine in the optical active erythro form is once produced and then it is inverted to the threo form. Hence, there arise problems that the number of steps grows and leads to complication and that the yields lower.
Furthermore, in the production of the pseudoephedrine while a substantial amount of diastereomers is produced as byproducts during the reduction of the starting ketone, the recovery of the diastereomers for their use as raw material is difficult, which is economically disadvantageous.
In addition, according to the method as described in the publication of JP, 8-98697, A, it is possible to produce an optically active 2-amino-1-phenylethanol derivative from a 2-amino-1-phenylethanol compound having one asymmetric carbon atom within its molecule through the use of a specific microorganism. The present state of art is, however, that there has been no efficient process for producing &bgr;-amino alcohol having two asymmetric carbon atoms.
DISCLOSURE OF THE INVENTION
This invention has been made in view of the above-indicated circumstances and it aims at producing a &bgr;-amino alcohol having the desired optical activity from an enantiomeric mixture of an &agr;-aminoketone compound or its salt in a high yield as well as in a highly selective manner with a simple process while sufficiently preventing the generation of diastereomeric byproducts.
The present inventors repeated studies diligently to solve the above-stated problems; consequently, it was discovered that by utilizing specific microorganisms only one enantiomer of the enantiomeric mixture of an &agr;-aminoketone compound or its salt could be reduced to produce the only desired kind among the corresponding four kinds of &bgr;-amino alcohols in a high yield as well as in a highly selective manner. This led to the completion of the present invention.
Specifically, the process for producing an optically active &bgr;-amino alcohol according to this invention comprises allowing at least one microorganism selected from the group consisting of microorganisms belonging to the genus
Morganella
, the genus
Microbacterium
, the genus
Sphingobacterium
, the genus
Nocardicides
, the genus
Mucor
, the genus
Absidia
, the genus
Aspergillus
, the genus
Penicillium
, the genus
Grifola
, the genus
Eurotium
, the genus
Ganoderma
, the genus
Hypocrea
, the genus
Helicostylum
, the genus
Verticillium
, the genus
Fusarium
, the genus
Tritirachium
, the genus
Mortierella
, the genus
Armillariella
, the genus
Cylindrocarpon
, the genus
Kiebsiella
, the genus
Aureobacterium
, the genus
Xanthomonas
, the genus
Pseudomonas
, the genus
Mycobacterium
, the genus
Sporobolomyces
, the genus
Sporidiobolus
, the genus
Amycolatopsis
, the genus
Coprinus
, the genus
Serratia
, the genus
Rhodococuss
and the genus
Rhodotorula
to act on an enantiomeric mixture of an &agr;-aminoketone or a salt thereof having the general formula (1):
wherein X may be the same or different and represents at least one member selected from the group consisting of a halogen atom, lower alkyl, hydroxyl optionally protected with a protecting group, nitro and sulfonyl; n represents an integer of from 0 to 3; R
1
represents lower alkyl; R
2
and R
3
may be the same or different and represent at least one member selected from the group consisting of a hydrogen atom and lower alkyl; and “*” represents an asymmetric carbon, to produce an optically active &bgr;-amino alcohol compound with the desired optical activity having the general formula (II):
wherein X, n, R
1
, R
2
, R
3
and “*” are as previously defined.
The microorganism according to this invention is preferably at least one microorganism selected from the group consisting of microorganisms belonging to
Morganella morganii, Microbacterium arborescens, Sphingobacterium multivorum, Nocardioides simplex, Mucor ambiguus, Mucor javanicus, Mucor fragilis, Absidia lichtheimi, Aspergillus awamori, Aspergillus niger, Aspergillus oryzae, Aspergillus candidus, Aspergillus oryzae
var.
oryzae, Aspergillus foetidus
var.
acidus, Penicillium oxalicum, Grifola frondosa, Eurotium repens, Ganoderma lucidum, Hypocrea gelatinosa, Helicostylum nigricans, Verticillium fungicola
var.
fungicola, Fusarium roseum, Tritirachium oryzae, Mortierella isabellina, Armillariella mellea, Cylindrocarpon sclerotigenum, Klebsiella pneumoniae, Aureobacterium esteraromaticum, Xanthomonas
sp.,
Pseudomonas putida, Mycobacterium smegmatis, Mycobacterium diernhoferi, Mycobacterium vaccae, Mycobacterium phlei, Mycobacterium fortuitum, Mycobacterium chlorophenolicum, Sporobolomyces salmonicolor, Sporobolomyces coralliformis, Sporidiobolus johnsonii, Amycolatopsis alba, Amycolatopsis azurea, Amycolatopsis coloradensis, Amycolatopsis orientalis lurida, Amycolatopsis orientalis orientalis, Coprinus rhizophorus, Serratia marcescens, Rhodococcus erythropolis, Rhodococcus rhodochrous
and
Rhodotorula aurantiaca.
In this invention the microorganism is preferably at least one microorganism selected from the group consisting of microorganisms belonging to the genus
Morganella
, the genus
Microbacterium
, the genus
Sphingobacterium
, the genus
Nocardioides
, the genus
Mucor
, the genus
Absidia
, the genus
Aspergillus
, the genus
Penicillium
, the genus
Grifola
, the genus
Eurotium
, the genus
Ganoderma
, the genus
Hypocrea
, the genus
Helicostylum
, the genus
Verticillium
, the genus
Fusarium
, the genus
Tritirachium
, the genus
Mortierella
, the genus
Armillariella
, the genus
Cylindrocarpon
, the genus
Klebsiella
, the genus
Aureobacterium
, the genus
Xanthomonas
, the genus
Pseudomonas
, the genus
Mycobacterium
, the genus
Sporobolomyces
, the genus
Sporidiobolus
and the genus
Rhodococuss
. More specifically, it is preferably a microorganism selected from the group consisting of microorganisms belonging to
Morganella morga
Kataoka Michihiko
Kita Shinji
Morikawa Tadanori
Sakamoto Keiji
Shimizu Sakayu
Daiichi Fine Chemical Co., Ltd.
Lilling Herbert J.
Osha & May L.L.P.
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