Process for producing depsipeptide derivatives and novel...

Details Process for producing depsipeptide derivatives and novel... Process for producing depsipeptide derivatives and novel...

1999-04-06

2001-05-22

Raymond, Richard L. (Department: 1624)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

C514S018700, C514S016700, C530S317000, C530S328000

Reexamination Certificate

active

06235875

ABSTRACT:

TECHNICAL FIELD
This invention relates to an alternative process for producing a cyclodepsipeptide derivative having vermicidal activity and to novel intermediates for synthesis of said depsipeptide derivative.
BACKGROUND ART
The cyclodepsipeptide derivative of this invention, represented by the following general formula (I), is known to be a compound having high vermicidal activity and finds application as an anthelmintic in animals and man. In the conventional synthesis of such cyclodepsipeptides, the cyclization reaction involved is invariably carried out in the manner of amide bond formation to construct a cyclic structure (WO 93/19053, Kokai Tokkyo Koho H5-320148, EP-626375, EP-626376).
For example, a cyclization process using the following route is known (WO 93/19053).
Conventional Route:
DISCLOSURE OF INVENTION
The inventors of this invention studied the possible cyclization reaction by ester bond formation in the production process for such cyclodepsipeptides and have developed this instant invention.
The depsipeptide of this invention can be represented by the following general formula (I).
In accordance with this invention, the objective compound (I) or its salt can be produced by a process involving the following series of steps.
[In the respective formulas, R
1
represents hydrogen or a hydroxyl-protecting group; R
2
represents a carboxyl group or a protected carboxyl group; R
3
, R
4
, R
7
and R
9
each represents a lower alkyl group, an aryl group, or a substituted or unsubstituted aralkyl group; R
5
, R
6
, R
9
and R
10
each represents a lower alkyl group; R
11
represents hydrogen or an amino-protecting group]
Compound (II) in the above process includes known compounds and novel compounds, and compounds (IV), (VII) and (VIII), inclusive of their reactive derivatives, as well as salts thereof are novel compounds.
Throughout this specification, amino acids, peptides, protective groups, condensing agents, etc. are indicated by using the abbreviations recommended by IUPAC-IUB (a committee on biochemical nomenclature) which are in common use.
Moreover, the amino acids and their residues as indicated by such abbreviations mean the L-configured compounds and residues unless otherwise specified, and D-configured compounds and residues are indicated by the symbol D-.
The abbreviations used in the invention are as follows.
MeLeu: methylleucine
p-MorPhLac: 2-hydroxy-3-(4-morpholinophenyl)-propionic acid [&bgr;-(p-morpholinophenyl)lactic acid]
Lac: 2-hydroxypropionic acid [lactic acid]
MOM: methoxymethyl
Boc: t-butoxycarbonyl
Bzl: benzyl
The preferred salts of Compounds (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) include conventional nontoxic salts, which are salts with various bases and acid addition salts. More particularly, there can be mentioned salts with inorganic bases, such as alkali metals (e.g. sodium salt, potassium salt, cesium salt, etc.) and alkaline earth metals (e.g. calcium salt, magnesium salt, etc.), and ammonium salts; salts with organic bases, such as organic amine salts (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclo-hexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); inorganic acid addition salts (e.g. hydro-chloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic acid addition salts or organic sulfonic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); and salts with basic or acidic amino acids (e.g. arginine salt, aspartate, glutamate, etc.).
The preferred examples and the explanations of the various definitions made in the foregoing as well as the following disclosure and falling under the scope of the invention are now given in detail.
The preferred “hydroxyl-protecting group” includes but is not limited to acyl, substituted or unsubstituted aralkyl, which will be described in detail hereinafter, lower alkoxy(lower)alkyl, carbamoyl and silyl.
The preferred examples of the “acyl” mentioned just above are aliphatic acyl groups and acyl groups having an aromatic ring or heterocycle. The preferred examples of such acyl include but are not limited to:
lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.;
lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.;
lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.;
aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.;
ar(lower)alkanoyl groups such as phenylacetyl, phenylpropionyl, etc.; and
ar(lower)alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.
The above-mentioned acyl groups may each have one or more suitable substituent groups such as chlorine, bromine, fluorine and iodine.
The preferred examples of said lower alkoxy(lower)alkyl are 1-methyl-1-methoxyethyl, methoxy-methyl and methoxypropyl, among others.
The preferred “protected carboxyl” includes esterified carboxyl such as the following “esterified carboxyl” groups. The preferred ester moiety of such esterified carboxyl includes lower alkyl esters optionally containing one or more suitable substituent groups. For example, there can be mentioned lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc.; lower alkanoyloxy(lower)alkyl esters such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, etc.; mono(or di- or tri-)halo(lower)alkyl esters such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.; lower alkenyl esters such as vinyl ester, allyl ester, etc.; ar(lower)alkyl esters optionally having one or more substituent groups, such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxy-phenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.
The protective group for said “protected carboxyl” includes those protective groups which are conventionally used for temporary protection of carboxyl groups in the field of amino acid or peptide chemistry.
The “lower” means the range of 1~6 carbon atoms, preferably 1~4 carbon atoms, unless otherwise specified.
The preferred “lower alkyll” includes straight-chain or branched-chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl and hexyl.
The preferred “aryl” includes but is not limited to phenyl, naphthyl, and lower alkyl-substituted phenyl (e.g. tolyl, mesityl, cumenyl, xylyl, diethylphenyl, diisopropylphenyl, di-tert-butylphenyl, etc.).
The “substituted or unsubstituted aralkyl” means said lower alkyl group having an aryl group in an arbitrary position and includes benzyl, phenethyl, 3-phenylpropyl, benzhydryl, and trityl, to mention a few preferred examples.
The “aralkyl” for R
3
, R
7
may have 1 or more substituent groups.
The preferred substituent groups for “substituted benzyl”, among said “substituted or unsubstituted aralkyl”, includes but is not limited to hydroxyl, lower alkoxy, lower alkoxy(lower)alkoxy, lower alkoxy-(lower)alkoxy(lower)alkoxy, heterocyclic(lower)-alkoxy, lower alkyl, amino, mono- or di-substituted lower alkylamino, cyclic amino, nitro, and halogen such as fluorine, chlorine, bromine or iodine. One or more of such substituent groups may be present.
The above preferred “lower alkoxy” includes but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, and hexyloxy.
The above preferred “lower alkoxy(lower)alkoxy” includes but is not limited to methoxymethoxy, methoxyethoxy, methoxypropo

Affiliated with

Also associated with

Rating

Process for producing depsipeptide derivatives and novel... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for producing depsipeptide derivatives and novel..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing depsipeptide derivatives and novel... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2549263