Production process

Details Production process Production process

1999-12-20

2001-09-18

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06291680

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing a compound which is useful as a starting material for the manufacture of an excellent antifungal agent whereby it is useful in the field of pharmaceutical industry.
BACKGROUND ART
In the International Laid-Open Gazette WO 96/11210, there is a disclosure on a method wherein 1-(4-methoxycarbonyl-phenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione which is a starting material for the synthesis of antifungal agents of lipopeptide type is made to react with hydroxylamine hydrochloride to give methyl 4-[5-(4-pentyloxyphenyl)-isoxazol-3-yl]benzoate which is an aimed compound.
DISCLOSURE OF THE INVENTION
In the method mentioned in the above international patent application, 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione which is a starting material is made to react with hydroxylamine hydrochloride whereupon the aimed methyl 4-[5-(4-pentyloxyphenyl)-isoxazol-3-yl]benzoate is prepared. However, besides the aimed compound, its isomers are contaminated therein and, since separation of the aimed compound from the isomers is difficult, the yield of the aimed methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate is not fully satisfactory.
In view of the above, the present inventors have carried out an intensive investigation and, as a result, they have found a manufacturing method in which isomers of methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate are not produced whereby the above-mentioned problem in the conventional method has been solved. They have found a method for the manufacture of the related compounds as well.
The manufacturing method according to the present invention may be shown by the following reaction formulae.
[Wherein R
1
is carboxy or protected carboxy;
R
2
is lower alkoxy or higher alkoxy;
A
1
is divalent aromatic ring, divalent heterocyclic group or divalent cyclo(lower)alkane; and
A
2
is divalent aromatic ring, divalent heterocyclic group or divalent cyclo(lower)alkane.]
[Wherein R
1
is carboxy or protected carboxy;
R
2
is lower alkoxy or higher alkoxy;
A
1
is divalent aromatic ring, divalent heterocyclic group or divalent cyclo(lower)alkane; and
A
2
is divalent aromatic ring, divalent heterocyclic group or divalent cyclo(lower)alkane.]
The characteristic feature of this manufacturing method is to carry out the reaction through the compound (II) or a salt from the starting compound (III) or a salt, and the said compound (II) or a salt is novel.
An preferable salt of the compounds (I), (II) and (III) is a conventional nontoxic mono- or di-salt, and its examples are metal salt such as alkaline metal salt (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.); ammonium salt; salt with an organic base (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); addition salt with an organic acid (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); addition salt with an inorganic acid (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.); salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.); etc.
Suitable examples and explanations for various definitions included within the scope of the present invention mentioned in this specification both hereinabove and hereinafter will be mentioned in detail as follows.
Unless otherwise provided, “lower” is used to intend a group having 1 to 6 carbon atom(s).
Unless otherwise provided, “higher” is used to intend a group having 7 to 20 carbon atoms.
Suitable “lower alkoxy” may include straight or branched chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, and the like. More preferably, it is (C
3
-C
5
) alkoxy and, most preferably, it is pentyloxy.
Suitable “higher alkoxy” may include straight or branched chain such as heptyloxy, octyloxy, 5-dimethyloctyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, eicosyloxy, and the like.
Suitable “divalent aromatic ring” may include divalent group derived from benzene which may have lower alkyl (e.g., benzene, toluene, mesitylene, etc.), naphthalene, anthracene, etc., and more preferably, it is phenylene.
Suitable “divalent heterocyclic group” may include divalent group which is derived from:
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrroline, imidazole, pyrazole, pyridine, dihydropyridine, pyrimidine, pirazine, pyridazine, triazole (e.g., 4H-1,2,4-triazole, 1H-1,2,3-triazole, 2H-1,2,3-triazole, etc.), tetrazole (e.g., 1H-tetrazole, 2H-tetrazole, etc.), etc.;
saturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidine, piperidine, piperazine, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indole, isoindole, indolizine, benzoimidazole, quinoline, dihydroquinoline, isoquinoline, indazole, quinoxaline, dihydroquinoxaline, benzotriazole, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazole, isoxazole, oxadiazole (e.g., 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole, etc.),etc.;
saturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholine, sydnone, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazole, benzoxadiazole, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazole, isothiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, etc.), dihydrothiadiazole, etc.;
saturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidine, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thiophene, dihydrothiophene, dihydrodithiophene, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazole, benzothiadiazole, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing one oxygen atom, for example, furan, etc.;
unsaturated 3 to 8-membered (more preferably, 5 or 6-membered) heteromonocyclic group containing one oxygen atom and 1 or 2 sulfur atom(s), for example, dihydroxathiophene, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example, benzothiophene, benzodithiophene, etc.; and
unsaturated condensed heterocyclic group containing one oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiophene, etc.
Suitable “divalent cyclo(lower)alkane” may include divalent group derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.
Suitable “protected carboxy” may include a common one such as an esterified carboxy, and specific examples of the ester moiety in the said esterified carboxy are:
lower alkyl ester [e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.], suitably substituted lower alkyl ester, for example, lower alkanoyloxy lower alkyl ester [e.g., acetoxymethyl ester, p

Affiliated with

Also associated with

Rating

Production process does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Production process, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Production process will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2456461