Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-25
2001-07-24
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06265586
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing indolmycin which is useful as an antibacterial agent, especially as an anti-
Helicobacter pylori
agent.
BACKGROUND ART
Indolmycin can be produced by using producer strains
Streptomyces griseus
subsp. griseus ATCC12648 (American Type Culture Collection Catalogue of Bacteria & Bacteriophages], 18th edition, 1992), etc., in accordance with the method described, for example, in Antibiotics and Chemotherapy (Washington, D.C.), 10, 312 (1960) and in Antibiotics and Chemotherapy (Washington, D.C.), 10, 316(1960). However, there are problems in that, in the method using microorganisms, the yield of the desired product is low and in that purification process is complicated. Though Indolmycin can be produced by using microorganisms as shown above, it can also be produced by chemical production methods. The production is shown in, for example, 1) Tetrahedron, 24, 6131 (1968) and 2) Chemistry Letters, 163 (1980), etc. In the method shown in the above literature 1), Indolmycin is produced through (−)-&bgr;-indolmycenic acid which is obtained by optical resolution of racemic &bgr;-indolmycenic acid, which is produced by using indole as starting material, with (+)-&agr;-Phenylethylamine. However, in this method, the stereochemistry of the two asymmetric carbons contained in indolmycin is not controlled, and as a result, yield of the desired compound is low. The method shown in the above literature 2) involves many production steps and gives low yield of the desired product though stereochemistry is controlled in the method. As the production method of the racemate of indolmycin, there are known, for example, Journal of Organic Chemistry 51, 4920(1986), Tetrahedron Letters, 37, 6447(1996) ect,. Though there were fewer number of steps in this method, but optically active compounds were not obtained in this method.
DISCLOSURE OF INVENTION
After extensive investigation in view of the above problems, the present inventors found that indolmycin can be obtained as optically active compound in a high yield and that in the process stereochemistry of the two asymmetric carbons is controlled. The inventors conducted further investigation based on this finding, and developed the present invention. Thus the present invention is to provide a process for producing indolmycin, which has industrial advantages.
The present invention relates to:
(1) A process for producing a compound of the formula:
or a salt thereof, which comprises reacting a compound of the formula:
or a salt thereof with methylamine or a salt thereof.
(2) A process for producing a compound of the formula (II) or a salt thereof, which comprises reacting a compound of the formula:
wherein R
1
is a hydrocarbon group which may be substituted, or a salt thereof with guanidine or a salt thereof in a secondary or tertiary alcohol, and
(3) A process for producing a compound of the formula (I) or a salt thereof, which comprises reacting a compound of the formula (II) or a salt thereof, which is obtained by reacting a compound of the formula (III) or a salt thereof with guanidine or a salt thereof in a secondary or tertiary alcohol, with methylamine or a salt thereof.
In the above formula(III), as the “hydrocarbon group” in “hydrocarbon group which may be substituted” represented by R
1
, there may be mentioned a chain aliphatic hydrocarbon group, an alicyclic hydrocarbon group and an aryl group, etc. Among them, a chain aliphatic hydrocarbon group is preferable.
The chain aliphatic hydrocarbon groups in the definition of hydrocarbon group include a straight chain or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group, etc. Among them, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, etc. are preferable, and lower alkyl groups are the most preferable. The lower alkyl groups include, for example, C
1-6
alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, etc. Among them, C
1-3
alkyl groups such as methyl, ethyl, propyl, etc. are preferable, and C
1-2
alkyl groups such as methyl, ethyl are the most preferable. The lower alkenyl groups include C
2-6
alkenyl such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc. Among them, C
2-5
alkenyl such as vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2propenyl, 3-methyl-2-butenyl, etc., are preferable. The lower alkynyl groups include C
2-6
alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Among them, C
2-4
alkynyl such as ethynyl, 1-propynyl, 2-propynyl, etc. are preferable.
The alicyclic hydrocarbon groups in the definition of the hydrocarbon group may be saturated or unsaturated, and include cycloalkyl group, cycloalkenyl group, cycloalkadienyl group, etc. The cycloalkyl groups include ones having 3 to 9 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc. Among them, C
3-6
cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. are preferable. The cycloalkenyl groups include C
3-6
cycloalkenyl such as 2-cyclopentene-1-yl, 3-cyclopentene-1-yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl, 1-cyclobutene-1-yl, 1-cyclopentene-1-yl, etc. The cycloalkadienyl groups include C
4-6
cycloalkadienyl such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl, etc.
The aryl groups in the definition of the hydrocarbon groups may be monocyclic or condensed aromatic hydrocarbon groups, and include ones having 6 to 12 carbon atoms such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc. Among them, ones having 6 to 10 carbon atoms such as phenyl, 1-naphthyl, 2-naphthyl, etc. are preferable.
The substituents in the definition of hydrocarbon groups which may be substituted, shown by R
1
include aryl groups which may be substituted(e.g. aryl having 6 to 12 carbon atoms such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc.), cycloalkyl groups which may be substituted (e.g. cycloalkyl having 3 to 9 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), cycloalkenyl groups which may be substituted(e.g. C
3-6
cycloalkenyl such as 2-cyclopentene-1-yl, 3-cyclopentene-1-yl, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl, 1-cyclobutene-1-yl, 1-cyclopentene-1-yl, etc.), amino groups which may be substituted (e.g. alkylamino having 1 to 4 carbon atoms such as amino, methylamino, ethylamino, propylamino, etc., dialkylamino having 2 to 8 carbon atoms such as dimethylamino, methylethylamino, diethylamino, methylpropylamino, dipropylamino, etc.), hydroxyl group which may be substituted (e.g., hydroxyl group, alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, etc. ), thiol group which may be substituted (e.g. mercapto, alkylthio having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, etc. ), halogen (e.g., fluorine, chlorine, bromine, iodine), etc. The hydrocarbon group may be substituted with 1 or more, preferably one to three of these substituents at any position.
As the salts of the compounds of the formula (I), there may be mentioned acid addition salts. The acids which form the acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, phosphonic acid, sulfamic acid, etc. and organic acids such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic
Kamiyama Keiji
Nakayama Yutaka
Chao Mark
McKane Joseph K.
Murray Joseph
Riesen Philippe Y.
Takeda Chemical Industries Ltd.
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