EP1240239A1

EP1240239A1 - Coloured polyphenoxydendrimers, novel soluble supports, method for preparing same an use in organic synthesis

Info

Publication number: EP1240239A1
Application number: EP00988867A
Authority: EP
Inventors: Jidong Zhang
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 1999-11-25
Filing date: 2000-11-22
Publication date: 2002-09-18
Also published as: CA2392390A1; AU2522101A; FR2801594A1; JP2003514970A; FR2801594B1; WO2001038424A1

Abstract

The invention concerns products of formula (P-Y) wherein P represents a coloured part, Y represents a dendrimer radical of formula (I) wherein: R1, R2 and R3 represent hydrogen and X1, X2, X3 and X4 such that X1 represents (X1) wherein Z represents -((CH2)n1-W)n2, W represents -O- or -NH-CO-, n1 represents 2 to 6, n2 represents 0 to 3, Y1, Y2, Y3 and Y4 represent -OH, -NH2 or radicals obtained after reacting a linker L such as for example: -4-hydroxymethyl-phenoxyacetic acid, (L1), -p-hydroxymethylphenol linker, (L2); the salts of said products of formula (P-Y).

Description

Colored polyphenoxydendrimers, new soluble supports, their preparation process and their use in organic synthesis.

The present invention relates to colored polyphenoxydendrimers, new soluble supports, their preparation process and their use in organic synthesis.

The present invention more specifically relates to the use of colored dendrimers as soluble supports in organic synthesis, these colored dendrimers and their process of preparation.

Combinatorial chemistry is increasingly used by chemists as a new technology allowing the synthesis of a very large number of products. This technique, the advantage of which is that it allows rapid synthesis of a very large number of products, however, does not make it possible to synthesize a large quantity of each of these products: combinatorial chemistry is therefore a very useful technique for example in screening of a large number of products for which it is desired to seek a particular activity such as for example an affinity of these products for a particular receptor.

On the other hand in medicinal chemistry where one studies in depth products which have already been the subject of a selection for example for a particular activity highlighted in particular after a screening, large quantities of products are necessary because such selected products will be subjected to a considerable number of tests. The synthesis of significant quantities of products will be done in solution according to conventional organic chemistry techniques. One of the techniques used in combinatorial chemistry is organic synthesis supported by polymers. However, the adaptation of the chemistry in solution to the solid supports requires considerable time. Documents GB 2 316 941 and GB 2 317 173 describe the use in solution of large molecules called dendrimers, the advantage of which is that they can be attached to small molecules which can then be transformed chemically, which makes it possible to synthesize and isolate more easily the small molecules of sought-after products.

Dendrimers are fractal molecules also called molecular trees or cascading molecules. These names evoke the structure of these compounds made up of trees diverging from a central core, and built step by step, generation after generation. The dendrimers are therefore, tree-like monodispersed polymers, at the interface of classical chemistry and polymer chemistry, used in many fields: as catalysts in organometallic chemistry, to study the interactions between carbohydrates and proteins in glycobiology, as vectors of biomolecules for example in agrochemicals or in pharmacies. From 1941, PJ Flory (book ^Λ the dendrimers' Club CRIN ECRIN 1998) had imagined and prepared a new type of macromolecule resembling linear polymers due to the infinite formation of branches, but different from the latter, because obtained without any inter or intramolecular reaction during the tree structure process. This new concept took shape in 1978 with the first synthesis of dendrimers by F. Vôgtle (Buhleier, EW, ehner, W.; Vôgtle, F., Synthesis 1978, 155-158) and especially developed with Tomalia (Tomalia , DA; Baker, H.; Dewald, JR; Hall, M.; Kallos, G.; Matin, S.: Roeck, J.; Ryder, J.; Smith, P. 1) Polym. J. (Tokyo) 1985, 17, 117-132; 2) Macromolecules 1986, 19, 2466-2468).

One can emphasize the interest of dendrimers as new supports in parallel synthesis. By parallel synthesis is meant, according to a term commonly used in chemistry, reactions carried out in parallel at the same time in different reactors. It can be noted that the idea of using dendrimers as soluble supports arose from the problems encountered in the use of solid supports in synthesis. This parallel synthesis method has certain drawbacks:

- the adaptation of the chemistry in solution on solid supports requires too much time, - the resins present problems of accessibility as well as solvation, the loading rates are then generally very low and the quantities of product obtained are consequently insufficient for pharmacological tests, - the solid supports do not allow monitoring of the reaction on CCM, which considerably handicaps the chemist.

The dendrimers can solve some of these problems: - the dendrimers have a large number of functions at the periphery and therefore a high charge rate,

- they also have the advantage of being soluble unlike solid supports and can therefore be considered as protective groups, - this method does not, in principle, require adaptation of the chemistry in solution,

- each synthesis intermediate can be characterized by conventional techniques (IR, SM, NMR) and rapidly purify the reaction by steric exclusion chromatography (or ultrafiltration).

We had the idea and it is the object of the present invention to prepare new dendrimers by attributing to these dendrimers their own characteristics. Thus the dendrimers according to the present invention will be colored. This coloring of the dendrimers according to the present invention makes it possible in particular to facilitate the monitoring of the reactions in which such dendrimers are involved in particular in the purification steps. The dendrimers according to the present invention especially comprise amide or ether bonds. The coloring of such dendrimers according to the present invention will be yellow, blue or in particular red.

Such dendrimers of the present invention thus provide an additional solution compared to the techniques already existing in combinatorial chemistry and / or in parallel synthesis and thus in particular makes it possible to increase the productivity in organic synthesis.

The present invention thus relates to new dendrimers whose particularity is in particular to possess in their structure a colored fragment: by this coloring, one can thus follow with the naked eye the various stages of synthesis and in particular of purification of the dendrimers to which are therefore attached the small molecules of sought-after products.

It therefore results from the use of such colored dendrimers in solution of a considerable saving of precious time in a research activity.

The present invention therefore relates to dendrimers characterized in that they contain in their structure a colored part.

The present invention thus relates to the products of formula (P-Y) characterized in that Y represents a residue of dendrimer and P represents a colored part. In the products of formula (PY) as defined above, Y therefore represents a dendrimer residue which can be chosen from known dendrimers which can be found in the literature or the trade such as for example Starburst ™ polyamidoamine (PAMAM) (Tomalia et al, Polymer Journal, 17, (1), 117-132 (1985) to which a colored part P as defined in the present invention is added: such colored dendrimers thus obtained form part of the present invention The rest of dendrimer Y can also be chosen from the products of formula (I) as defined below.

A more specific subject of the present invention is the products of formula (P-Y) as defined above, characterized in that Y represents a residue of dendrimer and the colored part P represents: either:

such that R4 represents a phenyl, naphthyl or benzothienyl radical optionally substituted by one or more substituents chosen from the values of R6 and R7 n represents the whole 1 or 2

R5, R6, R7, R8, R9, RIO and R11, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl or alkoxy radical containing at most 4 carbon atoms, a hydroxyl radical , phenoxy, nitro or amino optionally substituted by an acyl radical or by one or two linear or branched alkyl radicals containing at most 4 carbon atoms, this or these alkyl radicals themselves being optionally substituted by a hydroxyl, cyano, acyl radical, acyloxy or phenyl itself optionally substituted by a linear or branched alkyl radical containing at most 4 carbon atoms, the naphthyl radical which R4 can represent is also optionally substituted by the radical

wherein R6 has the meaning indicated above, and the salts of said products of formula (P-Y).

For the definition of the substituents indicated above and in what follows, the definitions used can have the following values: The term alkyl designates a linear or branched radical having at most 12 carbon atoms such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyle, octyl, decyl, undecyl, dodecyl.

Preferred are alkyl radicals having at most 4 carbon atoms and in particular methyl, ethyl, propyl, isopropyl and n-butyl radicals.

The term alkoxy designates a linear or branched radical containing at most 12 carbon atoms such as preferably the methoxy, ethoxy, propoxy or isopropoxy radicals, but also linear, secondary or tertiary butoxy. By halogen is understood, of course, the atoms of fluorine, chlorine, bromine or iodine.

Fluorine, chlorine or bromine atoms are preferred. As specific examples of alkyl radicals substituted by one or more halogens, mention may be made of the monofluoro, chloro, bromo or iodomethyl, difluoro, dichloro or dibromomethyl and trifluoromethyl radicals.

The term “acyl radical” preferably means a radical having at most 7 carbon atoms such as the acetyl, propionyl, butyryl or benzoyl radical, but may also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical: it is also possible cite the formyl radical.

By acyloxy radical is meant the radicals in which the acyl radicals have the meaning indicated above and for example the acetoxy or propionyloxy radicals. By esterified carboxy is meant for example the radicals such as the alkyloxycarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl.

Mention may also be made of radicals formed with easily cleavable ester residues such as the methoxymethyl and ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkylalkylcarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.

A list of such ester radicals can be found, for example, in European patent EP 0 034 536. By salified carboxy is meant the salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of the salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine. The sodium salt is preferred.

The amino radical may be substituted by one or two alkyl radicals chosen from alkyl radicals as defined above to form an alkylamino or dialkylamino radical as defined above.

By alkylamino radical is preferably meant the radicals in which the alkyl comprises at most 4 carbon atoms. Mention may be made of the methylamino, ethylamino, propylamino or butyl (linear or branched) amino radicals.

Likewise, by dialkylamino radical is preferably meant the radicals in which the alkyl contains at most 4 carbon atoms. Mention may be made, for example, of the dimethylamino, diethylamino and methylethylamino radicals. The expression “esterified, etherified or protected hydroxyl radical” means the -0-CO-aι, a ₂ -0-a ₃ or -O-gp radicals respectively, formed from a hydroxyl radical, according to the usual methods known from l 'skilled in the art and in which gp represents a protective group and a _i; a ₂ and a ₃ represent in particular an alkyl, akenyl, alkynyl, aryl or arylalkyl radical, having at most 12 carbon atoms and optionally substituted as defined above in particular for R ₃ .

Examples of protective group gp, as well as the formation of the protected hydroxyl radical, are given in particular in the usual book of a person skilled in the art: Protective Groups in Organic Synthesis, Theodoa W. Greene, Harvard University; printed in 1981 by Wiley-Interscience Publishers, John iley & Sons. The hydroxyl radical protection group which gp can represent can be chosen from the list below: For example formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, metho-xyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Mention may also be made of the ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, βββ-trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclo propylethoxycarbonyl, tetrahydropyrannyl, tetrahydrothiopyrannyl, methoxyethyl, trichloroethyl, trichloroethyl, methoxyethyl, trichloroethyl, methoxyethyl, trichloroethyl, methoxyethyl, trichloroethanol, trichloroethyl, methoxyethyl, trichloroethyl, methoxyethyl, trichloroethyl, methoxyethyl, trichloroethanyl, methoxyethyl, trichloroethanyl, methoxyethyl, trichloroethanyl, methoxyethylenetroxyethyl, methoxyethylenetroxyethyl, methoxyethylenetroxyethyl, methoxyethylenetroxyethyl, methoxyethylenetroxyethylenetroxyethylenetylbenzol, 1-methoxyethyl, phthaloyl, propionyl, butyryl, isobuty-ryle, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, capryamyl, phenylcarbyl naphthylcarbamoyl. The protective group gp may especially represent the 2-hexahydropyrannyl radical or else a silicon derivative such as trimethylsilyl.

The addition salts with mineral or organic acids of the products of formula (PY) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxyl, aspartic, ascorbic, alkylmonosulfonic acids such as for example methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkoyldisulfonic acids such as for example methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzene sulfonic acid and aryldisulfonic acids.

When the products of formula (P-Y) as defined above comprise an amino radical salifiable by an acid, it is understood that these acid salts are also part of the invention. Mention may more particularly be made of the salts formed with hydrochloric or methanesulfonic acids for example.

The present invention particularly relates to the products of formula (PY) as defined above characterized in that Y represents a dendrimer residue and the colored part P is such that: R4 represents: either a naphthyl radical substituted by the radical:

either a benzothienyl radical substituted by a linear or branched nitro or alkoxy radical containing at most 4 carbon atoms or a phenyl radical substituted by one or more radicals chosen from halogen atoms, linear or branched hydroxyl, alkyl and alkoxy radicals containing at most 4 carbon atoms and the nitro radical, R5 represents a hydrogen atom, a hydroxyl radical or an amino radical optionally substituted by an acyl radical or by one or two linear or branched alkyl radicals containing at most 4 carbon atoms, this or these alkyl radicals being themselves optionally substituted by a hydroxyl, cyano or acyloxy radical,

R6 and R7, identical or different, represent a hydrogen atom, a halogen atom or a linear or branched alkyl or alkoxy radical containing at most 4 carbon atoms,

R8 represents a hydrogen atom,

R9, RIO and R11, identical or different, represent a hydrogen atom; a hydroxyl radical; phenoxy; amino optionally substituted by a phenyl radical itself optionally substituted by a linear or branched alkyl radical containing at most 4 carbon atoms or amino optionally substituted by a linear or branched alkyl radical containing at most 4 carbon atoms itself optionally substituted by a hydroxyl radical, and the salts of said products of formula (PY).

The present invention more particularly relates to the products of formula (PY) as defined above characterized in that Y represents a dendrimer residue and the colored part P is chosen from the fragments represented in FIG. 12, and the salts of said products of formula (PY).

A more particular subject of the present invention is also the products of formula (P-Y) as defined above, characterized in that Y represents a dendrimer residue and the colored part P represents the following fragment:

and the salts of said products of formula (P-Y). A subject of the present invention is also the products of formula (PY) as defined above, characterized in that the colored part P has the meaning indicated above and Y represents a residue of dendrimer chosen from the products of formula (I ):

in which :

RI, R2 and R3 identical or different are such that: R2 represents a hydrogen atom or is chosen from the values of RI and R3, RI and R3 are chosen from XI, X2, X3 and X4 defined as follows:

-O — z — ChL 2 C ° H ^π ——Y ^Y 1 (X ₄ )

Z represents - ((CH2) nl-W) n2,

W represents the divalent oxygen atom -O- or the amide bond -NH-CO-, ni represents an integer from 2 to 6, n2 represents an integer from O to 3,

Yi Y _{2 /} Y ₃ and Y _4, identical or different, either represent the functions: -OH, -Br, -Cl, -I, -SH, -C0 ₂ H, -C0 ₂ C1, -C0 ₂ Br,

-S0 ₃ H, -S0 ₂ C1, -NH ₂ , and -CH = CH ₂ , or represent residues obtained after reaction on these functions of a Linker L chosen from the following values:

-2, 4-dimethoxy-4 '-hydroxy-benzophenone,

-4- (4-hydroxymethyl-3-methoxyphenoxy) -butyric acid,

-4-hydroxymethylbenzoic acid, -4-hydroxymethyl-phenoxyacetic acid, (L _x )

-3- (4-hydroxymethylphenoxy) -propionic acid,

-p- t (R, S) -α- [1- (9H-fluoren-9-yl) methoxyformamido] -2,4- dimethoxy-benzyl] -phenoxyacetic acid,

-p-hydroxymethylphenol linker, (L ₂ ) -MBHA linker,

-Rink amide linker,

-Sieber linker,

-and trityl linker, and the salts of said products of formula (PY). Yl, Y2, Y3 and Y4 can therefore represent residues obtained after reaction with a Linker L as defined above on the functions: -OH, -Br, -Cl, -I, -SH, -C0 ₂ H, - C0 ₂ C1, -C0 ₂ Br, -S0 ₃ H, -S0 ₂ C1, -NH ₂ or -CH = CH ₂ as defined above: among these functions, the functions -NH2 and -OH are preferred. When Yl, Y2, Y3 and Y4 represent -NH2, the reaction can in particular be carried out with the acid function of a linker chosen from the list above such as for example the linker L1. When Yl, Y2, Y3 and Y4 represent -OH, we can first transform -OH into mesylate or equivalent which is then reacted with a linker chosen from the list above such as for example L2.

The present invention thus also relates to the products of formula (PY) as defined above in which the end of the dendrimer residue, opposite the end linked to the colored part P, is linked by a covalent bond to a fragment which are called Linkers: such Linkers make it possible to facilitate the use of the dendrimers of the present invention when they are used as soluble supports in organic synthesis as defined below.

The present invention particularly relates to the products of formula (PY) as defined above, characterized in that the colored part P has the meaning indicated above and Y represents a residue of dendrimer chosen from the products of formula (I ) as defined above in which Z, W, ni, n2, Y _1f Y ₂ , Y ₃ and Y have the meanings indicated above, and RI, R2 and R3 are such that: either R2 represents hydrogen and RI and R3 are chosen from the values of XI either RI, R2 and R3 represent X2 or X3 and the salts of said products of formula (PY). A more particular subject of the present invention is the products of formula (PY) as defined above, characterized in that the colored part P has the meaning indicated above and Y represents a residue of dendrimer chosen from the products of formula (I) as defined above in which RI, R2, R3, n2, Yi, Y ₂ , Y ₃ and Y ₄ have the meanings indicated in any one of Claims 6 and 7, and Z represents - ((CH2) 3-NH-CO-) n2 or - ((CH2) 2-0-) n2, and the salts of said products of formula (PY).

A more particular subject of the present invention is also the products of formula (PY) as defined above, characterized in that the colored part P has the meaning indicated above and Y represents a residue of dendrimer chosen from the products of formula (I) as defined above in which RI, R2, R3, ni, n2, Y _{1 #} Y ₂ , Y ₃ and Y ₄ have the meanings indicated above and Z represents - (CH2) 3-NH- CO- or - (CH2) 2-0- and the salts of said products of formula (PY).

A very particular subject of the present invention is the products of formula (PY) as defined above in which the colored part P has the meaning indicated above and Y represents a residue of dendrimer chosen from the products of formula (I) as defined above in which RI, R2, R3, ni, n2, Z, W, Y _{1 #} Y ₂ , Y ₃ and Y have the meanings indicated above characterized in that when Yi, Y ₂ , Y ₃ and Y ₄ represent a residue obtained after reaction with a Linker L, the Linker L is chosen from the following values:

4-hydroxymethyl-phenoxyacetic acid, (Li) p-hydroxymethylphenol linker, (L ₂ ) Rink amide linker.

The subject of the present invention is in particular the products of formula ((P-Y)) as defined above, characterized in that the Linker L represents: the Linker (L1) either:

or the Linker (L2) either and the salts of said products of formula (PY). The present invention particularly relates to the products of formula (PY) as defined above corresponding to the formulas of dendrimers a, b, c and d as defined respectively in FIGS. 1, 2, 3 and 4.

The present invention also very particularly relates to the products of formula (PY) as defined above corresponding to the formulas of the dendrimers a, b, c, d and dl as defined respectively by FIGS. 1, 2, 3, 4 and 4.1, the dendrimer dl corresponding to a dendrimer d in which n represents the value 0. Such dendrimers and products of formula (PY) according to the present invention can be synthesized in two different ways according to the so-called convergent and diverging pathways.

- in the divergent method, the synthesis of the dendrimer proceeds by reiteration of a reaction sequence from the heart to the surface. The number of terminal functions at the periphery can thus grow very rapidly over the course of generations.

- in the convergent method, we build the dendrimer from the periphery to the heart. This synthesis mode only involves a limited number of reaction sites for each generation.

The present invention thus also relates to a process for the preparation of products of formula P-Y as defined above, characterized in that a product of formula Dl is reacted:

in which R4 represents hydrogen or hydroxyl and alk represents an alkyl radical containing at most 4 carbon atoms, with a product of formula D2:

Br - G - NH-COOtBu (D ₂ )

in which Br represents a bromine atom, G represents the divalent radical - (CH ₂ ) nι- or - ((CH ₂ ) ₂ -0- (CH ₂ ) ₂ ) - and n _x represents an integer from 2 to 6, to obtain a product of formula (D3):

ι Λ OG-NH-COOtBu alkOOC— <—R5 (D ₃ )

-O-G-NH-COOtBu

in which G and alk have the meanings indicated above and R5 represents a hydrogen atom or the radical

- O - G - NH-COOtBu

in which G has the meaning indicated above, product of formula (D3) which is saponified to obtain the product of formula (D4):

in which G and R5 have the meanings indicated above, or product of formula (D3) in which the amino functions of the BOC are deprotected to obtain the product of formula (D5):

in which G and alk have the meanings indicated above, and R6 represents H or -0-G-NH ₂ , CIH then we proceed according to any one of the following routes: 1) According to the so-called convergent route: a) the product of formula (D4) as defined above is reacted with the product of formula (D5) as defined above above to obtain the product of formula (D6):

in which G and alk have the meanings indicated above,

Ra ₂ represents H or the value of Rai or Ra ₃ and Rai and Ra ₃ represent the radical:

in which R5 has the meaning indicated above, product of formula (D6) which is saponified to obtain the product of formula (D7):

in which Rai, Ra ₂ and Ra ₃ have the meanings indicated above, b) the product of formula (D4) is reacted with the product of formula (D8):

NH ₂ (D ₈ ) in which P has the meaning indicated in any one of claims 1 to 5, to obtain the product of formula (D9):

in which G, P and R ₅ have the meanings indicated above, and in which the amino functions of BOC are deprotected to obtain the product of formula (D10):

in which G, P and R ₆ have the meanings indicated above, which are reacted with the product of formula (D7) to obtain the product of formula (DU):

in which Rb ₂ represents H or the value of Rbi or Rb ₃ and Rbi and Rb ₃ represent the radical

in which G has the meaning indicated above, product of formula (DU) in which the amino functions of BOC are deprotected to obtain the product of formula (D12):

in which Rc ₂ represents H or the value of Rci or Rc ₃ and Rci and Rc ₃ represent the radical

in which R7 represents H or the radical

with G as defined above 2) According to the divergent route, the product of formula (D4) as defined above is reacted with the product of formula (D10) as defined above to obtain the product of formula (D13):

in which P, Rai, Ra ₂ and Ra ₃ have the meanings indicated above, product of formula (D13) in which the amine functions of BOC are deprotected to obtain the product of formula (D14):

in which P has the meaning indicated above, R ₈ represents H or Rd _x or Rd ₃ and Rdi and Rd ₃ represent the radical

in which G and R6 have the meanings indicated above, product of formula (D14) which is reacted, if necessary or if desired, with the product of formula (D4) as defined above to obtain the product of formula (DU) as defined above, product of formula (D14) which, if necessary or if desired, is subjected to a reaction of transformation of the amine NH2 functions into OH hydroxyl function to obtain the product of formula ( D15):

in which P has the meaning indicated above, Rf ₂ represents H or represents Rfi or Rf ₃ and Rfi and Rf ₃ represent the radical

in which R9 represents H or OG-OH with G having the meaning indicated above, products of formulas (D12), (D14) or (D15) as defined above, which can be products of formula (PY) and that, in order to obtain or other products of formula (PY), it is possible, if desired and if necessary, to undergo one or more of the following transformation reactions, in any order: a) a reaction of transformation of alkoxy function into hydroxyl function, or of hydroxyl function into alkoxy function, b) an oxidation reaction of alcohol function into aldehyde, acid or ketone function, c) a reaction of transformation of a halogenated function into formyl function or esterified carboxy, d) a reaction with the linker L as defined above, e) a reaction for eliminating the protective groups which the protected reactive functions can carry, f) a salification reaction with a mineral or organic acid or with u no basis for obtaining the corresponding salt. The reactions defined above from a) to f) which can be subjected, if desired and if necessary, the products of formulas (D12), (D14) or (D15) as defined above, are usual reactions known to a person skilled in the art and which are therefore, if necessary, carried out under the usual conditions known to a person skilled in the art.

Thus, the synthesis of the products of formula (P-Y) according to the present invention as defined above can consist in assembling units having several branches at a central part (heart), either in a convergent manner, or in a divergent manner.

Among the dendrimers of formula PY according to the present invention, it can be noted that the dendrimer a has eight final functions, the dendrimers b and d have nine final functions and the dendrimer c has six final functions, these final functions therefore being at the ends of the branches of the dendrimers and representing the anchor points on the dendrimers of the molecules to be synthesized for which the dendrimers are used as soluble supports.

The synthesis of the heart of the dendrimers is common to all the dendrimers. In particular concerning the dendrimers a, b, c and d according to the present invention, the synthesis of the heart of these dendrimers breaks down into three stages starting from Disperse Red 1 according to the diagram indicated in FIG. 5.

Regarding the dendrimer a, the following reaction is also carried out:

To synthesize molecule 5, the procedure is carried out in DMF in the presence of K ₂ CO ₃ at 80 ° C. according to conventional alkylation conditions or preferably using the PTBD resin in acetonitrile at room temperature. To construct the dendrimer a, the ester function of the product 5 is then saponified under conventional conditions.

We can therefore synthesize the dendrimer a by two different routes called the convergent route and the diverging route as indicated in the diagrams of FIGS. 6 and 7.

The convergent pathway for the synthesis of the dendrimer indicated in FIG. 6 is the quickest method. It can be noted that the synthesis of the dendrimer a by divergent route according to the diagram indicated in FIG. 7 and described in the experimental part in example 2 comprises an additional step compared to the synthesis of the dendrimer a by convergent route according to the diagram indicated in Figure 6 and described in Example 1.

To obtain the product of formula 12, it is possible to use dichloromethane or preferably acetonitrile (solvent used in the couplings for the synthesis of dendrimer b) it may be noted that in this latter solvent, the products precipitate during their formation. and are easily isolated by filtration.

The molecule 13 is then coupled with the linker 14. The dendrimers b and c can likewise be synthesized according to convergent and diverging pathways as indicated below.

The convergent pathway for synthesis of dendrimer b comprises one less step than dendrimer a. Dendrimer b can be synthesized under the same conditions as dendrimer a. All the couplings are carried out thanks to BOP / DIEA and all deprotections of the Boc groups are done in HCl-AcOEt.

The divergent pathway for the synthesis of dendrimer b is indicated on the diagram in FIG. 8. The dendrimer c as defined above is a "mixed" dendrimer, composed first of all of a fragment of 3 branches, then of 2 branches, which brings about a compromise between the number of final chains and molecular weight. The divergent pathway for the synthesis of dendrimer c is carried out according to the diagram indicated in FIG. 9.

In the experimental part of the present application indicated below, the synthesis of dendrimer a by convergent and divergent route and the syntheses of dendrimers b and c by divergent route are described precisely in examples 1 to 4. The colored dendrimers according to the present invention and in particular the three different types of dendrimers a, b and c as defined above can therefore be synthesized according to two synthetic routes. It may be noted that the so-called divergent dendrimer synthesis method as defined above is preferred.

The present invention also relates to the use of the dendrimers according to the present invention as soluble supports in organic synthesis. The use of the dendrimers of the present invention as soluble supports in organic synthesis is exemplified in the diagram indicated in FIG. 10.

To study the use of dendrimers as soluble supports according to the present invention, a model reaction was chosen which is the reaction of the Suzuki (Miyaura, N.; Yanagi, Y.; Suzuki, A. Synth. Commun., 1981 , 11, 513) (Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett, 1992, 207) (Martin, AR; Yang, Y. Acta Chem. Scand. 1993, 47, 221) (Suzuki, A Pure § Appl. Chem., 1994, 66, 213) (Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457).

In the experimental part of the present application indicated below, examples 5 to 6 describe examples of the use of the dendrimers according to the present invention as soluble supports in organic synthesis. Examples 5 and 6 relate in particular to the use of dendrimers b or c as soluble supports in organic synthesis according to the diagram in FIG. 10.

The reaction conditions of the scheme indicated in Figure 10 is summarized below.

By ester bond formation, the dendrimers, having six or nine terminal functions, are linked to ortho or para-iodobenzoic acids, with an excess of reagents (Acids, DCC). At the end of the reaction, we simply concentrate the

DMF, it is resolubilized in the minimum amount of dichloromethane and the solution is passed through Sephadex LH-20 cartridges, itself swollen in dichloromethane. The bright red color of the dendrimer makes it possible to follow the purification through the cartridge, thus limiting the use of the solvent. This purification lasts only about twenty minutes, once the cartridge is conditioned.

The synthesis can then be continued with the purified dendrimers. According to the Suzuki model reaction, two boronic acids are used, under the conventional conditions of this reaction, but also with an excess of reactants. After reaction, an extraction step makes it possible to remove the catalyst and the salts. The procedure is then carried out in the same way for the purification by passing a solution in CH ₂ Cl ₂ / MeOH over the cartridges where the gel is swollen in the same solvent.

After the cleavage of the dendrimer and the final acid, the dendrimer is separated from the acid formed according to various reaction conditions, for example using basic resins such as PTBD and Amberlyst A-26. It can be noted that the dendrimer with 9 terminal alcohol functions being sparingly soluble in CH ₂ C1 ₂ (the dendrimer with 6 terminal functions is soluble therein), it is also possible simply to salify the acid in basic medium, then to extraction with CH ₂ C1 ₂ . The dendrimer, located at the interface or in organic solution is easily removed by filtration. The aqueous phase is then acidified and the acid is extracted with ethyl acetate ^1.

The present invention also relates to the use of the products of formula (PY) as defined above as colored dendrimers as soluble supports in organic synthesis. Thus it can be noted that during such use of the products of formula (PY) as defined above as soluble supports in organic synthesis, the products of formula (PY) of the present invention are preferred in which Yl, Y2, Y3 and Y4 represent a residue obtained after reaction with a Linker as defined above.

Indeed, such a Linker is on the one hand linked to the dendrimer and on the other hand serves as an anchor to the molecule synthesized during the organic synthesis for which the dendrimer serves as a soluble support. From this structure, it follows that the cut-off allowing the molecule synthesized during organic synthesis to be released from the dendrimer is more easily achieved when the linker is more firmly linked to the rest of the dendrimer and thus in particular when the linker is firmly linked to the rest of the dendrimer. by a covalent bond: in particular in the products of the present invention, the Linker is linked to the dendrimer by an amidation reaction or by an etherification reaction. By way of example, two diagrams are indicated below according to which respectively the Linker L1 as defined above and L2 ′, which corresponds to L2 in which the hydroxyl function -OH is protected in -OAc, cling to a Dendrimer D of formula (PY) as defined above in which Yl, Y2, Y3 and Y4 respectively represent NH2 or OH to give another dendrimer of formula (PY) according to the present invention in which Yl, Y2, Y3 and Y4 represent a residue obtained after reaction with a linker L1 or L2 'as defined above. D-NH2 + HO-CO-CH2-0-phenyl-CH20H (L1) - ^

D-NH-CO-CH2-phenyl-CH20H D-OH + HO-phenyl-CH20Ac (L2) ---> D-0-phenyl-CH20Ac

The present invention particularly relates to the use of dendrimers a, b, c and d as defined above as colored dendrimers as soluble supports in organic synthesis.

The present invention also particularly relates to the use of dendrimers a, b, c, d and dl as defined above as colored dendrimers as soluble supports in organic synthesis.

When using a dendrimer for the synthesis of molecules, one can particularly note the efficiency of purification of the reactions by steric exclusion chromatography. This purification method is effective in particular in that it makes it possible to dispense with extractions in many reactions, the purification time is very short (about 20 min), the quantities of solvent are low and the automation by UV detector. is useless.

The synthesis of molecules in solution carried out by the use of dendrimers as soluble supports is therefore a technique supplementing all those already used in combinatorial chemistry. In the context of the present invention, it has been found that by increasing the length of the chain and by inserting ether functions, which are less reactive, rather than amide functions, the dendrimer can be used in wider conditions and be soluble in ordinary solvents. The size is then less important, which makes it possible to obtain more complete reactions at the level of the attachment of the linker 14. It may also be noted that it is advisable to avoid using the dendrimers under conditions which could alter these dendrimers such as certain reagents attacking the nitro group or too strong basic conditions.

The present invention therefore relates very particularly to dendrimers of formula PY as defined above in which the chains which constitute the dendrimer are of a length such that ni represents in particular 2 or 3 but also 3 or 4 or even 5 or 6 and n2 represents in particular 0 or 1 but also 2 or 3.

The present invention also relates very particularly to dendrimers of formula PY as defined above in which the chains which constitute the dendrimers comprise amide functions but also those which comprise ether functions rather than amide functions and in particular the products of formula ( PY) such that W represents a greater number of ether functions

-O- that of amide functions -CO-NH.

The present invention therefore relates to the use of dendrimers as defined above as soluble supports in organic synthesis and such use is followed by the purification of these dendrimers by steric exclusion chromatography or optionally by ultrafiltration.

By way of examples of the use of dendrimers as soluble supports, mention may be made of chemical synthesis by progressive attachment to the dendrimer but also chemical transformations on molecules attached to the dendrimer.

In particular, molecules having an acid function can be attached to the dendrimer by the formation of an ester bond and subsequently subjected to chemical transformations. The large molecular weight of the dendrimer allows it to be purified by simple steric exclusion chromatography. The reagents used in excess and of low molecular weight must be retained in the pores of the gel while the dendrimer is eluted.

Then by simply detaching the dendrimer, the purified molecule is obtained as shown in the reaction diagram of FIG. 11. The diagram in FIG. 11 describes the use of the dendrimers according to the present invention as soluble supports in organic synthesis.

The diagram in FIG. 11 represents a dendrimer of formula

(P-Y) as defined above and in particular the dendrimers a, b, c or d as defined above and shown respectively in Figures 1 to 4.

The present invention thus relates to the use of colored dendrimers as defined above as soluble supports in organic synthesis characterized in that one can follow with the naked eye the reactions of the desired organic synthesis thanks to the coloring dendrimers. To carry out such an organic synthesis of sought molecules, a dendrimer colored according to the present invention, proceeds to organic synthesis using the colored dendrimer as a support on which the desired molecule is gradually synthesized, then purifies the dendrimer on which the synthesized molecule is attached and finally detaches the synthesized molecule, all of these reactions from the sought organic synthesis can be followed with the naked eye on TLC thanks to the coloring of the dendrimers.

The present invention particularly relates to the use of colored dendrimers as defined above as soluble supports in organic synthesis as defined above, characterized in that these dendrimers are purified by steric exclusion chromatography in approximately 20 minutes, the quantities of solvents are small on the order of a few tens of ml and the detection of the synthesized molecules attached to the dendrimers is visible to the naked eye.

The examples described below illustrate the present invention without however limiting it. In these examples, the products indicated by a number is chronologically the product 1, product 2, up to product 33 correspond to the products of the diagrams indicated above or below or to the products of the diagrams of the figures of the present invention. The figures described below Figures 1 to 12 (a, b, c, d, e, f, g, h) are part of the present invention. Experimental part

For the analytical results (IR, NMR, MS) given below in the preparation of Examples 1 to 6, the TLCs are carried out on silicagel Merck 60 F ₂₅₄ plates and the reagents are revealed at UN = 254 nm, by the phosphomolybdic or iodine reagent, depending on the molecules. Abbreviations used below: APTS: ParaToluene Sulfonic Acid Boc: ter-ButOxyCarbonyl

BOP: Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate

DCC: DiCyclohexylCarbodiimide DIC: DilsopropylCarbodiimide

DIEA: DilsopropylEthylAmine

DMAP: DiMethylAminoPyridine

HOBT: 1-HydroxyBenzoTriazola hydrates MsCl: Mesyl Chloride

Pd (PPh ₃ ) ₄ . Tetrakis (TriPhenylPhosphine) Paladium (0)

PPh _3: TriPhenylPhosphine

PPTS: Pyridinium ParaToluene Sulfonate

PTBD: 1, 5, 7-Triazabicyclo [4,4, 0] -dec-5-ene linked to cross-linked polystyrene with 2% DVB

TEA: TriEthylAmine

TFA: TriFluoroAcetic acid

Preparation of the colored part of the dendrimer: product 3 The synthesis of the heart of the dendrimer is carried out below by the synthesis of the colored part (product 3) according to the diagram indicated in FIG. 5.

Stage 1: product 1

Disperse Red 1

In a 250 ml three-necked flask, Disperse Red 1 (5.10 g, 16.23 mmol) is dissolved in 100 ml of anhydrous CH ₂ C1 ₂ . TEA (6.77 ml, 48.70 mmol, 3 eq) is added using a syringe, then MsCl (1.89 ml, 24.35 mmol, 1.5 eq) at 0 ° C. After one hour of reaction, the reaction medium is taken up in CH ₂ C1 ₂ , then washed with HCl-1N, with water and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated on a rotary evaporator. (Yield = Q)

The expected product 1 is thus obtained in the form of red crystals. Analyzes :

CCM: Rf = 0, 80 in CH ₂ Cl ₂ / MeOH = 9: 1

Stage 2: product 2

In a 500 ml flask, product 1 (6.36 g, 16.22 mmol) obtained in stage 1 above is dissolved in 200 ml of DMSO. NaN ₃ (1.58 g, 24.33 mmol, 1.5 eq) is added. The reaction medium is stirred under a nitrogen atmosphere and at 40 ° C for 48 hours, then taken up in AcOEt, and finally washed with water and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated on a rotary evaporator (Yield = 5%). The expected product 2 is thus obtained in the form of red crystals. Analysis: TLC: Rf = 0.48 in Cyclo / AcOEt = 5: 5 Stage 3: product 3

O

Prod | NH ₂

In a 250 ml flask, the product 2 obtained in stage 2 above (5.35 g, 13.41 mmol) is dissolved in 100 ml of THF. PPh ₃ (4.57 g, 17.43 mmol, 1.3 eq) and 410 μl of water (22.79 mmol, 1.7 eq) are added. The mixture is heated to 40 ° C., under a nitrogen atmosphere, overnight. The solvent is evaporated off and the product is purified by chromatography on silica (eluent: CH ₂ Cl ₂ / MeOH ≈ 9: 1). (Yield = Q)

The expected product is thus obtained in the form of red crystals. Analyzes :

TLC: Rf = 0.17 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

3384 cm ^"1 Absorption NH ₂

1601, 1589, 1558 and 1517 cm ^"1 Absorption of the aromatic nucleus + Conjugated system

+ Absorption of N0 ₂ NMR: in CDC1 ₃

SM: in ElecroSpray 70eV, in MeOH 314 ⁺ = [M + H] ⁺ 297 ⁺ = [MH ⁺ -NH ₃ ] ^{+ +} 271 ⁺ = [314 ⁺ - (CH ₂ ) ₂ -NH ₂ ] ⁺ EXAMPLE 1: convergent synthesis of the dendrimer a as indicated in the diagram of FIG. 6. Stage 1: product 4

Product 4

In a 250 ml flask, the hydrobrominated 3-bromopropylamine (24.08 g, 110 mmol, 1.1 eq) is dissolved in 100 ml of anhydrous CH ₂ C1 ₂ , to which the TEA are added (16.68 ml, 120 mmol, 1.2 eq) then di-terbutyl-dicarbonate (21.82 g, 100 mmol). The mixture is stirred under a nitrogen atmosphere and at ambient temperature overnight. The reaction medium is taken up in CHC1 ₂ , then washed with water, with HCl-1N and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated on a rotary evaporator. (Yield = 96%) The expected product is thus obtained in the form of white crystals. Analyzes :

TLC: Rf = 0.76 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

3459 cm ^"1 Absorption NH 1710 cm ^{" 1} Absorption C = 0 1507 cm ^"1 Amide II Band NMR: in CDC1 ₃

SM: in El 70eV and direct introduction, in MeOH

237 ⁺ = M ⁺ (in isotopic massif characteristic of the presence of bromine)

180 ⁺ = M ⁺ - tBu (tBu ⁺ = 57 ⁺ )

181 ⁺ = M ⁺ -tBu + H Stage 2: product 5

PTBD resin, CH ₃ CN, TA

To synthesize product 5, the procedure is carried out in DMF in the presence of K ₂ C0 ₃ at 80 ° C. according to conventional alkylation conditions or preferably using the PTBD resin in acetonitrile at room temperature as follows:

In a 50 ml flask, the PTBD resin (1.81 g, 4 mmol, 4 eq) is dissolved in 10 ml of acetonitrile. Methyl 3,5-dihydroxybenzoate (0.168 g, 1 mmol) and product 4 obtained in stage 1 above (0.476 g, 2 mmol, 2 eq) are added. The mixture is stirred under a nitrogen atmosphere at ambient temperature for 48 hours. The resin is filtered on jena. The filtrate is concentrated. The expected product is thus obtained in the form of white crystals (yield = 80%). Analyzes :

CCM: Rf = 0.45 in CH ₂ Cl ₂ / AcOEt = 7: 3 IR: in CHC1 ₃ 3458 cm ^"1 Absorption NH 1711cm ^{" 1} Absorption C = 0

1598, 1507 and 1479 cm ^"1 Band Amide II + Absorption of the aromatic nucleus NMR: in CDC1 ₃

4.73ppm (2H, broad singlet)

SM: in El 70eV and direct introduction, in MeOH 482 ⁺ = M ⁺ 426 ⁺ = M ⁺ -tBu + H (57 ⁺ = tBu ⁺ )

408 ⁺ = M ⁺ -OtBu-H 382 ⁺ = M ⁺ -COOtBu + H 309 ⁺ = M ⁺ -COOtBu-OtBu + H Stage 3: product 6

Product 5 Product 6

The ester function of the product 5 obtained in stage 2 above is saponified to obtain the product 6 under standard conditions or as follows:

In a 100 ml flask, the product 5 obtained in stage 2 above (2.26 g, 4.68 mmol) is dissolved in 24 ml of EtOH.NaOH-2N (4.68 ml, 9.36 mmol , 2 eq) is added. Heated to 40 ° C overnight. The ethanol is evaporated. The medium is acidified with 4.68 ml of 2N HCl, then extracted with AcOEt, and finally washed with water and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated. The expected product is thus obtained in the form of crystals white. (Yield = 98%). Analyzes :

TLC: Rf = 0.20 in CH ₂ C1 ₂ / MeOH = 9: 1 IR: in CHC1 ₃ 3458 cm ^"1 Absorption NH / OH 1702 cm ^{" 1} Absorption C = 0

1597 and 1507 cm ^"1 Band Amide II + Absorption of the aromatic nucleus SM: in ElecroSpray 70eV, in MeOH 469 ⁺ = [M + H] ⁺

413 ⁺ = [M-tBu + H] ⁺ 357 ⁺ = [M-2tBu + 2H] ⁺ 313 ⁺ = [357 ⁺ -C0 ₂ ] ⁺ Stage 4: product 7

HCl -AcOEt AcOEt

Product 5 ^{Product 7}

In a 30 ml flask, the product 5 obtained in stage 2 above (0.501 g, 1.04 mmol) is dissolved in 5 ml of AcOEt. A HCl-AcOEt solution (6M, 3.47 ml, 20.81 mmol, 20 eq) is introduced dropwise and at 0 ° C. The mixture is left to stir under nitrogen. After 3 hours of reaction, the solvent is evaporated (Yield = Q). The expected product is thus obtained in the form of white crystals. Analyzes :

TLC: Rf = 0.24 in CH ₂ C1 ₂ / MeOH = 8: 2 IR: in nujol

3458 cm ^"1 Absorption NH / OH 1720 and 1710 cm ^{" 1} Absorption C = 0

1598, 1575, 1528 and 1510 cm ^"1 Absorption NH ₂ + Absorption of the aromatic nucleus SM: in ElecroSpray 70eV, in MeOH 283 ⁺ = [M + H] ⁺ 253 ⁺ = [MH-NH ₂ CH ₂ ] ⁺ 226 ⁺ = [MH-NH ₂ (CH ₂ ) ₃ + H] Stage 5: product 8

Product 8

In a 250 ml flask, the product 3 obtained in stage 3 of the preparation described above (1.11 g, 3.54 mmol) is dissolved in 100 ml of anhydrous CH ₂ C1 ₂ , under nitrogen. Product 6 (1.82 g, 3.89 mmol, 1.1 eq) then BOP (1.72 g, 3.89 mmol, 1.1 eq) and DIEA (1.23 ml, 7.08 mmol, 2 eq) are added. The mixture is stirred under a nitrogen atmosphere. After one night, the reaction medium is taken up in CH ₂ C1 ₂ , then washed with water, with NaHC0 ₃ and brine and the organic phase is concentrated. The product is crystallized from 200 ml of AcOEt (Yield = 93%)

The expected product is thus obtained in the form of red crystals. Analyzes :

TLC: Rf = 0.71 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in n jol Absorption NH

1683 and 1678 cm ^"1 Absorption C = 0 1640, 1600 and 1516 cm ^{" 1} Amide II band + Absorption of the aromatic nucleus + Conjugated system + Absorption N0 ₂ NMR: in DMSO

MS: in Elecrospray 70eV and in MeOH 764 ⁺ = [M + H] ⁺ Stage 6: product 9

The Boc groups are deprotected from product 8 obtained in stage 5 above, proceeding as in stage 4 above to obtain product 7. 85eq HCl is used (Yield = Q).

The expected product is thus obtained in the form of purple crystals. Stage 7: product 10

Product 7 Product 6

Product 7 obtained in stage 4 above (0.365 g,

1.03 mmol) is dissolved in 10 ml of CH ₂ C1 ₂ , to which are added product 6 obtained in stage 3 above (1.06 g, 2.26 mmol, 2.2 eq), BOP (1 g, 2.26 mmol, 2.2 eq) and the DIEA (0.8 ml, 4.63 mmol, 4.5 eq). After one night, the reaction medium is taken up in CH ₂ C1 ₂ , then washed with water and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated. The product is chromatographed on silica in CH ₂ Cl ₂ / MeOH = 95: 5 (Yield = 80%). The expected product is thus obtained in the form of white crystals. Analyzes :

TLC: Rf = 0.54 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

3456 cm ^"1 Absorption NH 1709 and 1658 cm ^{" 1} Absorption C = 0

1595 and 1510 cm ^"1 Amide II band + Absorption of the aromatic nucleus NMR: in CDC1 ₃

6.82ppm (triplet, 2H)

SM: in Elecrospray in MeOH 1205 ⁺ = [M + Na] ⁺

855 ⁺ = [M + Na-2 (O- (CH ₂ ) ₃ -NH-COOtBu) -2H] ⁺ or artefact Stage 8: product 11

The procedure is carried out as in stage 3 above to obtain the product 6 (yield = 95%). The expected product is thus obtained in the form of white crystals. Analyzes: TLC: Rf = 0.16 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHCI ₃

3450 cm ^"1 Absorption NH + General absorption OH / NH 1727, 1709 and 1659 cm ^{" 1} Absorption C = 0

1595 and 1511 cm ^"1 Band Amide II + Absorption of the aromatic nucleus

SM: in MeOH

1151, 6 ⁺ = [M + Na] ⁺ 1169, 6 ⁺ = [M + H] ⁺ 1069, 5 ⁺ = [M + H-C0 ₂ tBu + H] ⁺ 969, 6 ⁺ = [M + H-2C0 ₂ tBu + 2H] ⁺

869, 6 ⁺ = [M + H-3C0 ₂ tBu + 3H] ⁺ 769, 6 ⁺ = [M + H-4C0 ₂ tBu + 4H] ⁺ Stage 9: product 12

The procedure is carried out as in step 5 above to obtain product 8 using product 9 obtained in step 6 above in place of product 3 obtained in step 3 of the preparation described above and product 11 obtained in step 8 above in place of product 6 obtained in stage 3 above. Then BOP (0.069 g, 0.5 eq) and DIEA (0.054 ml, 1 eq) are added. The medium is evaporated to dryness and the crystals solubilized in MeOH are passed over Sephadex LH-20 (swollen in MeOH). The crystals are recrystallized from MeOH, then passed by chromatography on silica in

CH ₂ Cl ₂ / MeOH = 95: 5 (Yield = 50%). The expected product is thus obtained in the form of red crystals. Analyzes :

TLC: Rf = 0.45 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in nujol

NH / OH absorptions 1709 and 1684 cm ^"1 Absorption C = 0

1640, 1593 and 1524 cm ^"1 Amide II band + Absorption of the aromatic nucleus + conjugated system + Absorption N0 ₂

NMR: in DMSO-d6

1.81ppm (16H, quintuplet)

8.50ppm (6H, multiplet)

Stage 10: product 13

The Boc groups are deprotected from product 16 obtained in stage 9 above, proceeding as in stage 4 above to obtain product 7. 160 eq HCl are used (Yield = Q).

The expected product is thus obtained in the form of purple crystals. Stage 11: product 14

In a 500 ml flask, 9.9 g of 4-hydroxymethylphenoxy acetic acid (55 mmol) are dissolved in 200 ml of pyridine. 20.37 ml of acetic anhydride (4eq) are introduced over 1 hour at 0 ° C. After 20 h, the reaction is finished. The pyridine is evaporated and then the crude product obtained is diluted in 200 ml of AcOEt which is placed in a separatory funnel. Add 50 ml of IN HCl, then wash 2X with salt water. It is dried over MgSO4, filtered and then concentrated in vacuo.

The product is crystallized from AcOEt

The expected product is thus obtained in the form of a white powder (Yield 50%). Analyzes :

TLC: Rf = 0.20 in CH ₂ Cl ₂ / MeOH = 9: 1

^X H NMR: in CDC1 _3, delta ppm:

8.02 (1H, S large): -COOH

7.32 (2H, d) 6.96 (2H, d): Aromatic H

5.09 (2H, s) HOOC-CH2-0-

4.70 (2H, s) -Ph-CH2-0-

2.12 (3H, s) -CO-CH3-

Stage 12: product 15

Product 15 The procedure is carried out in stage 5 above to obtain product 8 using product 13 obtained in stage 10 above in place of product 3 obtained in stage 3 of the preparation described above and product 14 obtained in stage 11 above in place of the product 6 obtained in stage 3 above.

The reaction medium is left to precipitate, the crystals are filtered through iena and dried .;

The expected product is thus obtained in the form of red crystals (yield = 24%). Analyzes :

TLC: Rf = 0.36 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in nujol

3215 cm ^"1 Absorption NH / OH 1731,1658 and 1635 cm ^{" 1} Absorption C = 0

1591, 1536 and 1512 cm ^"1 Band Amide II + Absorption of the aromatic nucleus + Absorption N0 ₂ NMR: in DMSO-d6 (For unchanged chemical shifts, see product 12)

)

3.28ppm Stage 13: Dendrimer a

In a 50 ml flask, the product is dissolved

15 obtained in stage 12 above (0.86 g, 0.23 mmol) in 20 ml of MeOH, to which are added K ₂ C0 ₃ (0.51 g, 3.69 mmol,

16 eq). The mixture is stirred overnight at room temperature and under a nitrogen atmosphere. The reaction medium is extracted with CH ₂ C1 ₂ and the organic phase is washed with water. The insoluble crystals are found at the interface of the two phases and are filtered on iena, then dried in a desiccator. The expected product is thus obtained in the form of red crystals (yield = 80%). Analyzes :

CCM: Rf = 0 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in nujol

NH / OH absorptions 1657 cm ^"1 C absorption = 0

1589, 1536 and 1509 cm ^"1 Band Amide II + Absorption of the aromatic nucleus

+ Conjugated system + Absorption N0 ₂ NMR: in DMSO-d6 (For unchanged chemical shifts see product 12)

4.39ppm (doublet, 16H)

H)

EXAMPLE 2: divergent pathway for synthesis of dendrimer a (8-branch dendrimer) (FIG. 7) Stage 1: product 16

The product 9 obtained in stage 6 of example 1 (0.46 g, 0.72 mmol) is dissolved in 80 ml of CH ₃ CN, the product 6 obtained in stage 3 of example 1 (1.02 g, 2.18 mmol, 3 eq), BOP (1.06 g, 2.4 mmol, 3.3 eq) and DIEA (0.75 ml, 4.36 mmol, 6 eq) are added. After one night, the medium precipitated. It is heated to 80 ° C to dissolve everything, then left at room temperature to reprecipitate. The crystals are filtered.

The expected product is thus obtained in the form of red crixtals (Yield = 74%). Analyzes :

TLC: Rf = 0.38 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in nujol

NH / OH absorption

1637, 1684 and 1705 cm ^"1 Absorption C = 0 1518, 1528, 1587 and 1599 cm ^{" 1} Amide II band + Absorption of the aromatic nucleus + Absorption N0 ₂ Stage 2: product 17

The Boc groups are deprotected from product 16 obtained in stage 1 above, proceeding as in stage 4 of Example 1 to obtain product 7. 50 eq HCl are used (Yield = Q).

The expected product is thus obtained in the form of purple crystals. Stage 3: product 12

The procedure is carried out as in stage 1 above using the product 17 obtained in stage 2 above in place of the product 9. The expected product is thus obtained in the form of red crystals (yield = 71%) Analyzes:

TLC: Rf = 0.43 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

NH / OH absorption

1638 and 1682 cm ^"1 Absorption C = 0 1518 and 1590 cm ^{" 1} Amide II band + Absorption of the aromatic nucleus + Absorption N0 ₂ Stage 4: product 13

The Boc groups are deprotected from the product 12 obtained in stage 3 above, proceeding as in stage 4 of Example 1 to obtain the product 7. 160 eq HCl is used (Yield = Q). The expected product is thus obtained in the form of purple crystals. Stage 5: product 15

The procedure is carried out as in stage 12 of Example 1 starting from the product 13 obtained in stage 4 above.

The expected product is thus obtained in the form of red crystals (yield = 64%). Analyzes :

TLC: Rf = 0.51 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

3436 cm ^"1 Absorption NH associated 1651, 1674 and 1735 cm ^{" 1} Absorption C = 0 1514, 1536 and 1595 cm ^"1 Amide II band + Absorption of the aromatic nucleus + Absorption N0 ₂ Stage 6: dendrimer a

The procedure is carried out as in stage 13 of Example 1 starting from the product 15 obtained in stage 5 above. The expected product is thus obtained.

EXAMPLE 3: divergent synthesis of dendrimer b (dendrimer with 9 branches) (FIG. 8) Stage 1: product 18

PTBD, CH, CN resin

MethylGallate

The alkylation is carried out using the method using PTBD as in stage 2 of Example 1 using methyl methyl gallate in place of methyl 3,5-dihydroxybenzoate which is reacted under the same conditions with product 4 obtained in stage 1 of example 1. The expected product 18 is thus obtained in the form of white crystals (yield = 80%). Analyzes: TLC: Rf = 0.35 in CH ₂ Cl ₂ / AcOEt = 7: 3 IR: in CHC1 ₃

3457 cm ^"1 Absorption NH 1709 cm ^{" 1} Absorption C = 0 1589 and 1507 cm ^"1 Amide II band + Absorption of the aromatic nucleus NMR: in CDC1 ₃

SM: in MeOH

656 ⁺ = M ⁺

678 ⁺ = [M + Na] ⁺

556 ⁺ = [M + H- C0 ₂ tBu] ⁺

456 ⁺ = 556 ⁺ -BθC

500 ⁺ = 556 ⁺ -tBu

444 ⁺ = 500 ⁺ -tBu

356 ⁺ = 456 ⁺ -BθC

Stage 2:

The procedure is carried out as in stage 3 of example 1 using the product 18 obtained in stage 1 above in place of the product 5 obtained in stage 2 of example 1. The expected product 19 is thus obtained in the form of crystals white (Yield = Q). Analyzes :

TLC: Rf = 0.26 in CH ₂ Cl ₂ / MeOH = 9: 1

IR: in CHC1 ₃

3457 cm ^"1 Absorption NH; 1706 cm ^{" 1} Absorption C = 0; 1507 and

1586 cm ^"1 Band Amide II + Absorption of the aromatic nucleus SM: Electrospray (negative mode) in MeOH 640 ^" = [MH] ^" Stage 3

Product 3

The procedure is carried out as in stage 9 of example 1 using the product 19 obtained in stage 2 above in place of the product 11 obtained in stage 8 of example 1 and using the product 3 obtained in stage 3 of the preparation of the colored part in place of product 9 obtained in stage 6 of Example 1. The expected product is thus obtained in the form of red crystals (yield = 84%). Analyzes :

TLC: Rf = 0.55 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

3453 cm ^"1 Absorption NH; 1706 and 1659 cm ^{" 1} Absorption C = 0; 1493, 1516, 1559, 1588 and 1601 cm ^"1 Amide II band + Absorption of the aromatic nucleus; + Absorption N0 ₂ + Conjugated NMR system: in CDC1 ₃

8.32 and 7.93ppm (AA'BB ')

1.97ppm (multiplet, 6H)

SM: in MeOH

937 ⁺ = [M + H] ⁺ ; 959 ⁺ = [M + Na] ⁺ ; 881 ⁺ = [M + H-tBu] ⁺ ; 837 ⁺ = [M + H-Cθ ₂ tBu] ⁺ ; 781 ⁺ = 881 ⁺ -C0 ₂ tBu; 737 ⁺ = 837 ⁺ -C0 ₂ tBu; 637 ⁺ = 737 ⁺ -C0 ₂ tBu Stage 4: product 21

The Boc groups are deprotected from the product 20 obtained in stage 3 above by proceeding as in stage 4 of Example 1 to obtain product 7. We use 60 eq HCl (Yield = Q). The expected product is thus obtained 21 in the form of purple crystals. Stage 5: product 21a

The procedure is carried out as in stage 3 above, using instead of the product 3 obtained in stage 3 of the preparation of the colored part, the product 21 obtained in stage 4 above which is reacted with the product 19 obtained. in stage 2 of example 3. The expected product 21a is thus obtained. Analyzes

TLC: Rf = 0.58 in CH2C12: MeOH = 8/2 ^X H NMR: in CDC1 _3, delta ppm:

7.87 (2H, d) 8.29 (2H, d) Aromatic H (02N-Ph-N) 7.08 (2H, s) 7.06 (4H, s) 6.97 (2H, s) Aromatic H

6.88 (2H, d) 7.87 (2H, d) Aromatic H (N-Ph-N)

5.20-5.40 (10H, m): -NH-CO- 4.05 (24H, m): -Ph-0-CH2-CH2 3.80-3.10 (28H, m) -Ph- N-CH2-CH2- + -CH2-CH2-N- 3.56 (2H, m): CH2-CH3

1.75-2.10 (24H, m): -CH2-CH2-CH2- 1.42 (81H, s): tBoc 1.26 (3H, t): -CH3-CH2-

MS (FAB): MH ⁺ = [2508, 9] ⁺ _; [MH ⁺ -Cθ ₂ tBu] ⁺ + H = [2408] ⁺ Stage 6: product 21b

The procedure is carried out as in stage 4 above to obtain the deprotection of the Boc groups of the product 21a obtained in stage 5 above. One uses 180 eq HCl (Yield = Q). The expected product 21b is thus obtained in the form of purple crystals. Analyzes

^X H NMR: in CDC1 _3, delta ppm: 8.20 (18H, m): mobile H

8.35 (2H, d) 7.92 (2H, d) Aromatic H (02N-Ph-N)

7.29 (2H, s) 7.26 (4H, s) 7.23 (2H, s): Aromatic H

7.85 (2H, d) 7.01 (2H, d) 6.97 (2H, s): Aromatic H

6.88 (2H, d) 7.87 (2H, d) Aromatic H (N-Ph-N)

5.20-5.40 (4H, m) -NH-CO-

4.12-4.01 (24H, m) -PH-0-CH2-CH2

3.70-3.40 (10H, m): -PH-N-CH2-CH2- + -CH2 -CH2 -NH-CO 3.56 (2H, m): -CH2-CH3 3.00 (18H, m): -CH2 -CH2 -NH2

1, 85 - 2, 20 (24H, m): -CH2 -CH2 -CH2 -

1, 18 (3H, t): - CH3 -CH2 -

MS (EI, 70ev): (M + 2H) ²⁺ = [804] ⁺ Stage 7: product 21c

The procedure is carried out as in stage 12 of example 1 using the product 21b obtained in stage 6 above which is reacted with the product 14 obtained in stage 11 of example 1.

In a 20 ml flask, 114 mg of product 21 b obtained in stage 6 above is placed in 4 ml of anhydrous CH2Cl2. Then introduced 226 mg of BOP (9.9 eq) as well as 100 mg of product 14 obtained in stage 11 of Example 1 (0.052 mmol) then 244 microl of DIEA (27 eq). The reaction is treated after 3 hours by evaporating to dryness. First chromatographed on Sephadex LH 20 in CH2C12 / MeOH: 95/5 then on silica with CH2C12 / MeOH: 97/3 as eluent, increasing the polarity of the eluent up to CH2C12 / MeOH: 95/5. The expected product is thus obtained (Yield 30%).

TLC analyzes: Rf = 0.3 in CH2C12 / MeOH = 95/5

SM (FAB): MH ^{+ =} [3463, 1] ⁺

Stage 8: dendrimer b

The procedure is carried out as in stage 13 of Example 1 using the product 21c obtained in stage 7 above. In a 5 ml flask, 58 mg of product 21 c obtained in stage 7 above (0.016 mmol) are dissolved in 2 ml of

MeOH / CH2C12: 6/4. 41.5 mg of K ₂ C0 ₃ (2 eq) are then introduced.

Stirring is continued for 3 hours. We extract with

CH2C12 then washed with water. The red precipitate which forms at the interface between CH2Cl2 and water is then filtered through iena. The expected product is thus obtained.

Analyzes

TLC: Rf = 0.47 in CH2Cl2 / MeOH = 8/2

^X H NMR: in DMSO, delta ppm: 8.31 (2H, dl): 7.91 (2H, dl): aromatic H (02N-Ph-N)

7.83 (2H, dl): 6.96 (2H, dl): Aromatic H (N-Ph-N)

7, 30-6, 80 (44H, m): Aromatic H

4.49-4.30 (36H, m): -PH-CH2-0- + CO-CH2-0- 3.90-4.10 (24H, m): -PH-Q-CH2-CH2

3.60-3.30 (31H, m): -PH-N-CH2 -CH2- + -CH2 -CH2 -NH-CO + -CH2-CH3 1.75-2.08 (24H, m): - CH2-CH2-CH2- 1.15 (3H, t): -CH3-CH2-

Example 4: Divergent synthesis of dendrimer c (Figure 9) Stage 1: product 22

The procedure is carried out as in stage 9 of Example 1 using product 21 instead of product 9 and product 6 instead of product 11. BOP (0.98 g, 1 eq), DIEA (0.38) is thus used ml, 1 eq) and 50 ml of CH ₃ CN. The mixture is heated to 80 ° and 40 ml of DMF are added. The medium is extracted with CH2Cl2, the organic phase is washed with water, NaHC0 ₃ and salt water, dried over MgS0 ₄ , filtered and concentrated. The crystals are chromatographed in CH2C12 / MeOH = 95: 5. The oil obtained is taken up in AcOEt, washed with water, NaOH, NH ₄ C1 and salt water. Dried over MgSO ₄ , filtered and concentrated.

The expected product 22 is thus obtained in the form of red crystals. (Yield = 50%) Analysis:

TLC: Rf = 0.50 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

3448 cm ^"1 Absorption NH 1708 and 1653 cm ^{" 1} Absorption C = 0

1515 and 1595 cm ^"1 Amide II band + Absorption of the aromatic nucleus + Absorption N0 ₂ NMR: in CDC1 ₃

6.89ppm (2H)

Stage 2: product 23

The Boc groups are deprotected from the product 22 obtained in stage 1 above to obtain the product 23 by proceeding as in stage 4 of Example 1 to obtain the product 7. 100 eq HCl are used (Yield = Q) .

The expected product 23 is thus obtained in the form of purple crystals. Stage 3: product 24

The procedure is carried out as in stage 12 of example 1 by reacting the product 23 obtained in stage 2 above with the product 14 obtained in stage 11 of example 1.

The expected product 24 is thus obtained in the form of red crystals (yield = 65%). Analyzes :

TLC: Rf = 0.44 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in CHC1 ₃

NH / OH absorption

1657 cm ^"1 Absorption C = 0

1509, 1536 and 1589 cm ^'1 Band Amide II + Absorption of the aromatic nucleus

+ N0 ₂ absorption + NMR conjugate system: in CDC1 ₃

NH 7.14ppm

Stage 4: dendrimer c

The procedure is carried out as in stage 13 of example 1 using the product 23 obtained in stage 3 above instead of the product 15 obtained in stage 12 of example 1. The crystals are recrystallized using CHC1 ₃ , MeOH and H ₂ 0. The expected product is thus obtained, ie dendrimer C in the form of red crystals (yield = 80%). Analyzes : CCM: Rf = 0 in CH ₂ Cl ₂ / MeOH = 9: 1 IR: in nujol

NH / OH absorption

1653 cm ^"1 Absorption C = 0

1509, 1539, 1588 and 1600 cm ^"1 Bande Amide II +

Absorption of the aromatic nucleus

+ Absorption N0 ₂ + NMR conjugate system: in DMSO-d6 (The other chemical shifts remain unchanged.)

4.44ppm (12H) 4.39ppm (12H)

SM: FAB

2377 ⁺ = MH ⁺

2399 ⁺ = [M + Na] ⁺ Example 5: use of dendrimer b as a soluble support in organic chemistry Stage 1: product 26

Product 26 dendrimer b

Dendrimer b as prepared in Example 3 (0.35 g, 0.11 mmol) is dissolved in 20 ml of DMF, the product is added (0.50 g, 2.04 mmol, 2 eq / fct ) as well as DCC (0.42 g, 2.04 mmol, 2 eq / fct) and DMAP (0.31 g, 0.25 mmol, 025 eq / fct). The mixture is stirred under a nitrogen atmosphere overnight. The next day, the mixture is heated to 50 ° C. The DCU is filtered on jena. The DMF is evaporated. The crystals are taken up in 5 ml of CH2Cl2 and passed through a Sephadex cartridge swollen in the same solvent. (Yield = 86%; red crystals). Analyzes :

TLC: Rf = 0.27 in CH ₂ Cl ₂ / MeOH = 93: 7 IR: in CHC1 ₃

3429 cm ^"1 NH absorption

1672 and 1725 cm ^"1 Absorption C = 0

1496, 1513, 1539, 1585, 1601 and 1612 cm ^"1 Bande Amide II

+ Absorption of the aromatic nucleus + Absorption N0 ₂ +

NMR conjugate system: in CDC1 ₃

525 / 522ppm

Stage 2: product 27 OH

Product 26 Product 27

Product 26 (244 mg, 0.047 mmol) obtained in stage 1 above is dissolved in 10 ml of DMF. The product 26a (0.109 g, 0.85 mmol, 2 eq / fct), Pd (PPh3) (0.024 g, 0.021 mmol, 0.05 eq / fct) then Na2CO3 (0.53 ml, 1.06 mmol, 2 , 5 eq / fct) are added. The mixture is heated to 110 ° C. and under Argon overnight. The medium is extracted with AcOEt. The organic phase is washed with water, 0.1N NaOH, NH4C1 and brine, dried over MgSO4, filtered and concentrated. A solution of crystals solubilized in CH2C12 is passed through a Sephadex LH20 cartridge. The expected product 27 is thus obtained in the form of red crystals (yield = 52%). Analyzes :

TLC: Rf = 0.37 in CH ₂ Cl ₂ / MeOH = 93: 7 IR: in CHC1 ₃

3427 cm ^"1 NH absorption

1673 and 1718 cm ^"1 Absorption C = 0 1496, 1513, 1539, 1587, 1601 and 1612 cm ^{" 1} Bande Amide II

+ Absorption of the aromatic nucleus + Absorption N0 +

NMR conjugate system: in CDC1 ₃

Stage 3: product 28

Product 27

Product 28

Product 27 (94 mg, 0.019 mmol) obtained in step 2 above is dissolved in 5 ml of a TFA / CH2Cl2 solution (8: 2). After one hour, it is evaporated to dryness. The crystals are taken up in CH2C12, the organic phase is washed with 0.1N NaOH, the two phases are filtered and the aqueous phase is recovered, which is neutralized with HC1-2N. It is extracted with AcOEt, the organic phase is dried over MgSO4, filtered and concentrated. The expected product 28 is thus obtained in the form of white crystals (yield = 45%). Analyzes: TLC: Rf = 0.44 in CH ₂ Cl ₂ / MeOH = 8: 2 IR: in CH Cl ₃

OH absorption of acid type 1734 and 1698 cm ^"1 Absorption C = 0

1600 and 1575 cm ^"1 Absorption of aromatics and the NMR heterocycle: in CDC1 ₃

7.32ppm (dd, 1 H, J = 3 and 5Hz)

7.27ppm (dd, 1 H, J = 1.5 and 3Hz)

7.42 (wide doublet, 1 H)

7.40 (multiplet, 1H) and 7.54ppm (wide triplet, 1H)

SM in El 70eV, direct introduction and in MeOH 204 ⁺ = M ⁺

187 ⁺ = [M-OH] ⁺ Example 6: use of dendrimer c as a soluble support in organic synthesis Stage 1: product 30

Dendrimer c Product 30

The procedure is carried out as in stage 1 of Example 5 using the dendrimer c in place of the dendrimer b and using the product 29 instead of the product 25. We added 2 times leq of acid and DCC.

The expected product 30 is thus obtained in the form of red crystals (yield = 63%). Analyzes :

TLC: Rf = 0.27 in CH ₂ Cl ₂ / MeOH = 93: 7 IR: in nujol

NH / OH absorption

1653 and 1716 cm ^"1 Absorption C = 0 1511, 1533 and 1585 cm ^{" 1} Amide II band + Absorption of the aromatic nucleus NMR: in DMSO-d ₆

Stage 2: product 32

Product 30 DMF

The procedure is carried out as in stage 2 of Example 5 using the product 30 obtained in stage 1 above in place of the product 26 and using the product 31 instead of the product 26a. Two times leq of acid and DCC were added. Sephadex LH-20 is swollen in CH2C12 / MeOH = 95: 5.

The expected product 32 is thus obtained in the form of red crystals (yield = 82%). Analyzes :

TLC: Rf = 0.38 in CH ₂ Cl ₂ / MeOH = 93: 7 IR: in CHC1 ₃

3428 cm ^"1 Absorption NH 1674 and 1710 cm ^{" 1} Absorption C = 0

1489, 1513, 1536, 1592, 1600 and 1607 cm ^"1 Amide II band + Absorption of the aromatic nucleus + Absorption N0 ₂ NMR: in CDC1 ₃

Stage 3: product 33

The procedure is carried out as in stage 3 of Example 5 using the product 32 obtained in stage 2 above in place of the product 27. The dendrimer is soluble in the organic phase. The expected product 33 is thus obtained in the form of white crystals (yield = 50%). Analyzes :

TLC: Rf = 0.26 in CH ₂ Cl ₂ / MeOH = 85:15 IR: in CHC1 ₃

OH absorption

1676 cm ^"1 Absorption C = 0

1560, 1580 and 1608 cm ^"1 Absorption of aromatic nuclei NMR: in CDC1 ₃

SM: in El 70eV, direct introduction and in MeOH

198 ⁺ = M ⁺

181 ⁺ = [M-OH] ⁺

153 ⁺ = [M-COOH] ⁺ 152 ⁺ = [M-COOH-H] ⁺

Example 7: Divergent synthesis of dendrimer dl Stage 1: Synthesis of the product 37 - Preparation of the product 34

pyridine

In a 250 ml flask, 4-hydroxymethylphenol (5 g, 0.04 moles, 1 eq) is solubilized in 100 ml of pyridine. At 0 ° C., under N ₂ , TBDMSCl is introduced (7.28 g, 0.048 moles, 1.2 eq) and allowed to stir at room temperature for 3 hours. The pyridine is evaporated, extracted with 250 ml of AcOEt, washed once with HCl (IN) and twice with H ₂ O-NaCl. The organic phase is dried over MgS0, filtered and concentrated. The product is chromatographed on silica (eluent CH ₂ Cl ₂ / MeOH = 95: 5) in order to obtain a yellow oil (Yield = 57%). Analyzes :

TLC: eluent CH ₂ Cl ₂ / MeOH, 95: 5; Rf: 0.49 ^X H NMR (CDC1 ₃₎

- Product preparation 35

In a 500 ml flask, 34 (5 g, 0.021 moles, 1 eq) is dissolved in 80 ml of DMF, to which are added, under nitrogen, bis 2-bromoethyl ether (14.6 g, 0.063 moles, 3 eq) and the base K ₂ C0 ₃ (9.27 g, 0.067 moles, 3.2 eq). The mixture is stirred at 60 ° C for 19 hours. The reaction medium is taken up in AcOEt, then washed twice; with water, NaHC0 ₃ , H ₂ 0-NaCl. It is dried, filtered and concentrated. The product is chromatographed on silica (eluent CH ₂ C1 ₂ ). A yellow oil is obtained. (YId: 72%). Analyzes :

TLC: eluent CH ₂ Cl ₂ / Cyclohexane, 95: 5; Rf: 0.49 ¹ H NMR (CDC1 ₃ )

SM: direct introduction into El 70 eV

388 ⁺ = M ⁺ (isotopic mass characteristic of the presence of bromine).

331 ⁺ = M ⁺ - (tBu ⁺ = 57 ⁺ ).

287 ⁺ = M ⁺ - (tBu-Si CH ₃ ).

257 ⁺ = M ⁺ - (OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ ).

IR: in CHC1 ₃ 1612, 1587, 1511 cm -1 Absorption of an aromatic,

1252, 839 cm ^"1 : Absorption of an OSi - Preparation of the product 36

Cesium carbonate (7.96 g, 24.4 mmol, 4.5 eq) is quickly introduced into a 500 ml flask under N ₂ at room temperature, followed by methylgallate (1 g, 5.43 mmol). , 1 eq) dissolved in 20 ml of DMF, and finally 35 (9.51 g, 24.4 mmol, 4.5 eq) also dissolved in 20 ml of DMF. The mixture is left stirring at 50 ° C. for 18 hours and at room temperature for 48 hours. The medium is extracted with AcOEt, washed successively with water, NaHC0 ₃ , HCl, NaCl, H ₂ 0, NaHC0 ₃ , NaCl. It is dried, filtered and concentrated. The product is chromatographed on silica (eluent heptane / AcOEt, 7: 3). A yellow oil is obtained. (YId: 70%). Analysis: TLC: eluent heptane / AcOEt, 7: 3, Rf = 0.16 ^X H NMR (CDC1 ₃₎

SM:

1131.6 ⁺ = (M + Na) ⁺

1109.6 ⁺ = (M + H) ⁺

1051.5 ⁺ = (M + H-tBu) ⁺

977.5 ⁺ = (M + H- (O-Si (CH ₃ ) ₂ -C (CH ₃ ) ₃ ) ⁺

845.5 ⁺ = (M + H- ((CH ₂ ) ₂ -0-Ph-CH ₂ -0-Si (CH ₃ ) ₂ C (CH ₃ ) ₃ ) ⁺

IR: in CHC1 ₃

1716 cm ^"1 Absorption of a conjugated ester. 1612, 1587, 1511 cm ^{" 1} : Absorption of an aromatic. 1252, 839 cm ^"1 : Absorption of an OSi. - Preparation of the product 37

In a 30 ml flask, 36 (0.5 g, 0.45 mmol, 1 eq) is dissolved in 4 ml of EtOH. 450 μl of 2N NaOH (2 eq) are introduced. After stirring overnight at room temperature, EtOH is evaporated and the medium is acidified with 500 μl of 2N HCl, extracted with AcOEt and washed three times with water. The organic phase is dried over MgS04, filtered and concentrated. (Yield: 95%, white crystals). Analyzes :

TLC: eluent CH ₂ Cl ₂ / EtOAc, 94: 6, Rf = 0.23 NMR ^X H (CDC1 ₃₎ In the same chemical shift 36 with disappearance of CH ₃ -O-CO signal to 3.87 ppm. SM:

1117.6 ⁺ = (M + Na) ⁺ 1095.6 ⁺ = (M + H) ⁺ 963.5 ⁺ = (M + H- (0-Si (CH ₃ ) ₂ -C (CH ₃ ) ₃ ) ⁺

905.5 ⁺ = (M + H- (0-Si (CH ₃ ) ₂ -C (CH ₃ ) ₃ ) -tBu) ⁺

831.5 ⁺ = (M + H- ((CH ₂ ) ₂ -0-Ph-CH ₂ -0-Si (CH ₃ ) ₂ C (CH ₃ ) ₃ ) ⁺

Stage 2: Product 38 obtained by coupling

In a 50 ml flask, 37 (1.101 g, 1 mmol, 5.8 eq) is dissolved in 10 ml of acetonitrile. The product 21 (0.129 g, 0.173 mmol, 1 eq) is added under N ₂ at ambient temperature, then the BOP (0.444 g, 1 mmol, 5.8 eq) and the DIEA (0.48 ml, 2.66 mmol) , 16 eq). After two days of reaction, the medium is taken up in AcOEt and washed with H2O (X2), NaHCO3. After evaporating under vacuum, 1.0 g of crude product is obtained, which leads to 0.58 g of expected product after purification on a cartridge of Sephadex LH20. Analyzes :

IR: in CHC1 ₃

3520-3440 cm ^"1 : OH / NH absorption

1650cm ^"1 : Amide

1610, 1600, 1588, 1540 and 1512 cm ^"1 : Joint system + N02 + Amide II + Aromatic.

Stage 3: Dendrimer dl obtained by deprotection of the product 38

Dendrimer d1 In a 50 ml flask, 38 (0.200 g, 0.05 mmol, 1 eq) is dissolved in 10 ml of anhydrous THF. 1 ml of a solution of nBuNF in THF (1M) is added under N ₂ at room temperature. The reaction medium is left under stirring at room temperature for 16 h, then evaporated to dryness under vacuum. The residues thus obtained are purified with a cartridge of Sephadex LH20, to give 0.11 g of expected product.

Claims

1) Products of formula (P-Y) characterized in that Y represents a residue of dendrimer and P represents a colored part.

2) Products of formula (P-Y) as defined in claim 1 characterized in that Y represents a dendrimer residue and the colored part P represents: either:

such that R4 represents a phenyl, naphthyl or benzothienyl radical optionally substituted by one or more substituents chosen from the values of R6 and R7 n represents the whole 1 or 2 R5, R6, R7, R8, R9, RIO and R11, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl or alkoxy radical containing at most 4 carbon atoms, a hydroxyl, phenoxy, nitro or amino radical optionally substituted by an acyl radical or by one or two linear or branched alkyl radicals containing at most 4 carbon atoms, this or these alkyl radicals themselves being optionally substituted by a hydroxyl, cyano, acyl, acyloxy or phenyl radical itself optionally substituted by a linear or branched alkyl radical containing at most 4 carbon atoms, the naphthyl radical which R4 can represent being additionally optionally substituted by the radical

wherein R6 has the meaning indicated above, and the salts of said products of formula (P-Y). 3) Products of formula (P-Y) as defined in any one of claims 1 and 2 characterized in that Y represents a residue of dendrimer and the colored part P is such that:

R4 represents: either a naphthyl radical substituted by the radical:

R6 and R7, identical or different, represent a hydrogen atom, a halogen atom or a linear or branched alkyl or alkoxy radical containing at most 4 atoms of carbon,

R8 represents a hydrogen atom,

4) Products of formula (PY) as defined in any one of claims 1 to 3 characterized in that Y represents a residue of dendrimer and the colored part P is chosen from the fragments represented by FIG. 12, and the salts said products of formula (PY).

5) Products of formula (P-Y) as defined in any one of claims 1 to 4, characterized in that Y represents a residue of dendrimer and the colored part P represents the following fragment:

and the salts of said products of formula (P-Y).

6) Products of formula (PY) as defined in any one of claims 1 to 5 characterized in that the colored part P has the meaning indicated in any one of claims 1 to 5 and Y represents a residue of dendrimer chosen from the products of formula (I):

in which :

-0-z-CH ₂ —CH ₂ - _{Yl (χ)}

Z represents - ((CH2) nl-W) n2

W represents the divalent oxygen atom -O- or the amide bond -NH-CO- nl represents an integer from 2 to 6 n2 represents an integer from O to 3 Yi, Y ₂ , Y ₃ and Y identical or different either represent the functions: -OH, -Br, -Cl, -I, -SH, -C0 ₂ H, -C0 ₂ C1, -C0 ₂ Br,

-S0 ₃ H, -S0 ₂ C1, -NH ₂ , and -CH = CH, or represent residues obtained after reaction on these functions of a chosen Linker L among the following values: -2,4-dimethoxy-4 '-hydroxy-benzophenone, -4- (4-hydroxymethyl-3-methoxyphenoxy) -butyric acid, -4-hydroxymethylbenzoic acid, -4-hydroxymethyl-phenoxyacetic acid, ( Li) -3- (4-hydroxymethylphenoxy) -propionic acid, -p- [(R, S) -α- [1- (9H-fluoren-9-yl) mLthoxyformamido] -2,4- dimethoxy-benzyl] - phenoxyacetic acid, -p-hydroxymethylphenol linker, (L ₂ ) -MBHA linker,

-Rink amide linker,

-Sieber liker,

-and trityl linker, and the salts of said products of formula (PY). 7) Products of formula (PY) as defined in any one of claims 1 to 6 characterized in that the colored part P has the meaning indicated in any one of claims 1 to 5 and Y represents a residue of dendrimer chosen from the products of formula (I) as defined in claim 6 in which Z, W, ni, n2, Yι, Y ₂ , Y ₃ and Y ₄ have the meanings indicated in claim 6, and RI, R2 and R3 are such that: either R2 represents hydrogen and RI and R3 are chosen from the values of XI or RI, R2 and R3 represent X2 or X3 and the salts of said products of formula (PY). 8) Products of formula (PY) as defined in any one of claims 1 to 7 characterized in that the colored part P has the meaning indicated in any one of claims 1 to 5 and Y represents a residue of dendrimer chosen from the products of formula (I) as defined in any one of claims 6 and 7 in which: RI, R2, R3, n2, Y _1f Y ₂ , Y ₃ and Y ₄ have the meanings indicated in any one of claims 6 and 7, and Z represents - ((CH2) 3-NH-CO-) n2 or - ((CH2) 2-0-) n2 and the salts of said products of formula (PY). 9) Products of formula (PY) as defined in any one of claims 1 to 8 characterized in that the colored part P has the meaning indicated in any one of claims 1 to 5 and Y represents a residue of dendrimer chosen from the products of formula (I) as defined in any one of claims 6 to 8 in which RI, R2, R3, ni, n2, Y _lt Y ₂ , Y ₃ and Y ₄ have the meanings indicated in l any of claims 6 to 8 and Z represents - (CH2) 3-NH-CO- or - (CH2) 2-0- and the salts of said products of formula (PY).

10) Products of formula (PY) as defined in any one of claims 1 to 9 in which the colored part P has the meaning indicated in any one of claims 1 to 5 and Y represents a residue of dendrimer chosen from the products of formula (I) as defined in any one of claims 6 to 9 in which RI, R2, R3, ni, n2, Z, W, Y _1f Y ₂ , Y ₃ and Y have the meanings indicated in any one of claims 6 to 9, characterized in that when Yi, Y ₂ , Y ₃ and Y ₄ represent a residue obtained after reaction with a Linker L, the Linker L is chosen from the following values: 4-hydroxymethyl- phenoxyacetic acid, (Li) p-hydroxymethylphenol linker, (L ₂ ) Rink amide linker. 11) Products of formula ((PY)) as defined in any one of claims 1 to 10, characterized in that the Linker L represents: the Linker (Li) either:

or the Linker (L ₂ ) either:

and the salts of said products of formula (PY).

12) Products of formula (PY) as defined in any one of claims 1 to 11 corresponding to the formulas of the dendrimers a, b, c, d and dl as defined respectively by FIGS. 1, 2, 3, 4 and 4.1.

13) Process for the preparation of products of formula (P-Y) as defined in any one of claims 1 to 12, characterized in that a product of formula Dl is reacted:

in which R4 represents hydrogen or hydroxyl and alk represents an alkyl radical containing at most 4 carbon atoms, with a product of formula D ₂ :

Br - G - NH-COOtBu (D ₂ )

in which Br represents a bromine atom, G represents the divalent radical - (CH ₂ ) nι- or - ((CH ₂ ) ₂ -0- (CH ₂ ) ₂ ) - and ni represents an integer from 2 to 6, for obtain a product of formula (D ₃ ):

O - G - NH-COOtBu

in which G has the meaning indicated above, product of formula (D ₃ ) which is saponified to obtain the product of formula (D ₄ ):

in which G and R5 have the meanings indicated above or product of formula (D ₃ ) in which the amino functions of the BOC are deprotected to obtain the product of formula (D ₅ ):

in which G and alk have the meanings indicated above, and R6 represents H or -0-G-NH ₂ , CIH then we proceed according to any one of the following paths: 1) According to the so-called convergent path: a) we reacts the product of formula (D ₄ ) as defined above with the product of formula (D ₅ ) as defined above to obtain the product of formula (D ₆ ):

in which G and alk have the meanings indicated above, Ra ₂ represents H or the value of Ra _x or Ra ₃ and Rai and Ra ₃ represent the radical:

in which R5 has the meaning indicated above, product of formula (D ₆ ) which is saponified to obtain the product of formula (D ₇ ):

in which Rai, Ra ₂ and Ra ₃ have the meanings indicated above, b) the product of formula (D ₄ ) is reacted with the product of formula (D ₈ ):

NH ₂ (D ₈ )

in which P has the meaning indicated in any one of claims 1 to 5, to obtain the product of formula (D ₉ ):

in which G, P and R ₅ have the meanings indicated above, and in which the amino functions of BOC are deprotected to obtain the product of formula (Dι ₀ ):

in which G, P and R ₆ have the meanings indicated above, which are reacted with the product of formula (D ₇ ) to obtain the product of formula (Du):

in which Rb ₂ represents H or the value of Rbi or Rb ₃ and Rbi and Rb ₃ represent the radical:

in which G has the meaning indicated above, product of formula (Du) in which the amine functions of BOC are deprotected to obtain the product of formula (Dι ₂ ):

in which Rc ₂ represents H or the value of Rci or Rc ₃ and RCi and Rc ₃ represent the radical:

in which R7 represents H or the radical

with G as defined above 2) According to the divergent route, the product of formula (D ₄ ) as defined above is reacted with the product of formula (D _i0 ) as defined above to obtain the product of formula (D ₁₃ ):

in which P, Ra _x , Ra ₂ and Ra ₃ have the meanings indicated above, product of formula (D _i3 ) in which the amine functions of BOC are deprotected to obtain the product of formula (D _i4 ):

in which P has the meaning indicated above, R ₈ represents H or Rdi or Rd ₃ and Rd _x and Rd ₃ represent the radical

in which G and R6 have the meanings indicated above product of formula (D _i4 ) which is reacted, if necessary or if desired, with the product of formula (D ₄ ) as defined above to obtain the product of formula (Du) as defined above, product of formula (D _i4 ) which, if necessary or if desired, is subjected to a reaction of transformation of the amine NH2 functions into hydroxyl OH function to obtain the product of formula (D _X5 ):

in which P has the meaning indicated above, Rf ₂ represents H or represents Rfi or Rf ₃ and Rfi and Rf ₃ represent the radical:

in which R9 represents H or OG-OH with G having the meaning indicated above, products of formulas (D _i2 ), (D _i4 ) or (Dι ₅ ) as defined above, which can be products of formula (PY) and that, in order to obtain or other products of formula (PY), it is possible, if desired and if necessary, to undergo one or more of the following transformation reactions, in any order: a) a reaction for transforming an alkoxy function into a hydroxyl function, or a hydroxyl function into an alkoxy function, b) an oxidation reaction of an alcohol function into an aldehyde, acid or ketone function, c) a reaction for transforming a halogenated function into an esterified formyl or carboxy function, d) a reaction with the linker L as defined in claim 6, 10 or 11, e) a reaction for removing the protective groups which may carry the protected reactive functions, f) a salification reaction with a mineral or organic acid or with a base to obtain the corresponding salt.

14) Use of the products of formula (P-Y) as defined in any one of claims 1 to 11 as colored dendrimers as soluble supports in organic synthesis.

15) Use of the dendrimers a, b, c, d and dl as defined in claim 12 as colored dendrimers as soluble supports in organic synthesis.