Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-21
2002-09-10
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06448408
ABSTRACT:
The present invention relates to a process for the preparation of heteroaryl-phenylalanines and, more particularly, it relates to a cross-coupling process for the preparation of phenylalanine derivatives having the phenyl group substituted by a heteroaryl group.
Heteroaryl-phenylalanines are known compounds, well described in the literature. For example, heteroaryl-phenylalanines endowed with pharmacological activity as antihypertensive agents have been described in the British patent n° 1554667 (Merck & Co., Inc.).
Moreover, heteroaryl-phenylalanines can be used as synthetic intermediates for the preparation of compounds endowed with pharmacological activity.
In the International patent application no. WO 97/24342 in the name of the same applicant, heteroaryl-phenylalanines are used for the preparation of N-mercaptoacyl derivatives of phenylalanine of formula
wherein
R is a hydrogen atom, a straight or branched C
1
-C
4
alkyl group or a benzyl group;
R
1
is a 5 or 6 membered aromatic heterocyclic group, optionally substituted, having 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur;
R
2
is a C
2
-C
4
straight or branched alkyl group or an aryl or arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety in which the aryl group is phenyl or a 5 or 6 membered aromatic heterocyclic group having 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted by one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, alkylthio, alkylsulfonyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C
1
-C
3
alkyl groups comprising one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulfonyl groups, mono- or di-alkylamino or mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety;
R
3
is a mercapto group or a R
4
COS group convertible into a mercapto group in the body in which R
4
is a straight or branched C
1
-C
4
alkyl group or a phenyl group.
Such compounds are endowed with metallopeptidases inhibitory activity and are useful in therapy for the treatment of cardiovascular diseases.
Many processes for the preparation of heteroaryl-phenylalanines are described in the literature.
Within this field, the processes comprising cross-coupling reactions starting from heterocyclic compounds and phenylalanine derivatives are particularly attractive.
For example, 4-(2-furanyl)-phenylalanine is prepared following a cross-coupling process comprising the reaction between N-(tert-butoxycarbonyl)-tyrosine triflate methyl ester and 2-furanboronic acid in the presence of palladium(0)tetrakis(triphenylphosphine) as described by W. C. Shieh in J. Org. Chem. 1992, 57, 379-381.
Nevertheless, as reported by the same Author, for the preparation of such a compound with valuable yield, amounts of catalyst equal to 30% in moles compared to 2-furanboronic acid, significantly higher than the ones requested for the conversion of other arylboronics substrates, i.e. phenylboronics, are needed.
An alternative route to the above process for the preparation of thienyl-phenylalanine, essentially comprising a cross-coupling reaction between thienylboronic acids and bromo-phenylalanine in the presence of palladium acetate and tri(o-tolyl)phosphine, has been described by M. J. Burk et al. in J. Am. Chem. Soc. 1994, 116, 10847-10848.
The arylboronic derivatives used as synthetic intermediates in the above processes are in turn prepared from the corresponding aryl-magnesium or aryl-lithium derivatives, by reaction with trialkylborates.
Nevertheless, to avoid the formation of di- or tri-arylboron derivatives as by-products, the preparation of the arylboronic acids, for example 2- and 3-furanboronic acids, requires reaction temperatures particularly low equal to −70° C. (J. Org. Chem. 1984, 49, 5237-5243).
According to an alternative synthetic process, the heteroaryl-phenylalanines can be prepared by cross-coupling between halogenated heterocyclic derivatives and stannyl-phenylalanine derivatives (Bioconjugate Chem., 1993, 4, 574-580); nevertheless the alkylstannanes used for the preparation of stannyl-phenylalanines are highly toxic compounds.
Therefore, the high toxicity and the prolonged and difficult preparation of some intermediates make the cross-coupling processes for the synthesis of heteroaryl-phenylalanine, described in the literature, unsuitable for industrial application.
Now we have found a process for the preparation of heteroaryl-phenylalanines by cross-coupling reaction that uses organo-zinc compounds, easily practicable and particularly indicated for an industrial application.
Therefore, object of the present invention is a process for the preparation of heteroaryl-phenylalanines of formula
in which
R is a hydrogen atom, a straight or branched C
1
-C
4
alkyl groups or a benzyl group;
R
1
is an optionally substituted 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen and sulphur;
that comprises the reaction between a compound of formula
R
1
—Zn—Y (III)
in which
R
1
has the above reported meanings and Y is a chlorine, bromine or iodine atom; and a compound of formula
in which
R has the above reported meanings;
R′ is an optionally protected amino group;
X is an iodine or bromine atom or a methansulfonyloxy, fluoromethansulfonyloxy, p.toluensulfonyloxy or trifluoromethansulfonyloxy group;
in the presence of a transition-metal (0) based catalyst;
and, when R′ is a protected amino group, the deprotection reaction of the amino group.
The process object of the present invention is easily practicable and it enables to obtain the heteroaryl-phenylalanines of formula II with high yields, equal to or greater than 80% with respect to the starting compound of formula IV.
The cross-coupling reaction, according to the process object of the present invention, is carried out by reaction between an organo-zinc compound of formula III and a compound of formula IV.
Preferably, compound III and compound IV are used in a molar ratio III:IV from 1:1 to 3:1.
Still more preferably, the molar ratio of the compounds III:IV is from 1:1 to 2:1.
In the process object of the present invention the compounds of formula IV in which X is a iodine atom are preferably used.
The cross-coupling reaction is carried out in the presence of a transition-metal(0) based catalyst.
The amount of the catalyst is preferably from 0.05% to 5% in moles with respect to the organo-zinc compound of formula III.
Preferred examples of transition-metal(0) based catalysts are optionally supported palladium or nickel, in the presence of ligands such as, for example, triphenylphosphine.
The transition-metal(0) based catalysts can be optionally prepared in situ starting from the corresponding salts such as, for example, nickel chloride, cobalt chloride, nickel acetylacetonate, ferric chloride, palladium chloride, lithium tetrachlorocuprate, palladium acetate and palladium acetylacetonate.
Exclusively for practical reasons, palladium tetrakis(triphenylphosphine), nickel tetrakis(triphenylphosphine) or palladium on charcoal in the presence of triphenylphosphine, optionally prepared in situ as described, for example, in Org. Synth., 66, 67-74, 1988, are preferred.
The cross-coupling reaction is carried out in the presence of an organic solvent.
Suitable organic solvents are, for example, C
6
-C
12
aliphatic hydrocarbons, tetrahydrofuran, di-ethyl ether, methyl-tert-butyl ether, ethylene glycol di-methyl ether, dioxane, toluene, xylene or mixtures thereof.
Preferably tetrahydrofuran, toluene or mixtures thereof are used.
Usually the reaction temperature is between 20° C. and the reflux temperature of the reaction mixture.
Preferably, a temperature between 40° C. and 60° C. is used.
From a practical point of view, the use of a compound of formula IV in which R′ is a protected amino group is preferred for the preparation of the compounds of formula II.
Exampl
Arrighi Katiuscia
Paiocchi Maurizio
Villa Marco
Gerstl Robert
Zambon Group S.p.A.
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