JP2003514970A - Colored polyphenoxydendrimers, novel soluble carriers, methods for their preparation and their use in organic synthesis - Google Patents

Abstract

(57) Summary The present invention relates to compounds of formula (PY) and salts of compounds of formula (PY). Here, P represents a colored portion, and Y represents a dendrimer group of the formula (I). Here, R1, R2 and R3 represents hydrogen or X1, X2, X3 or X4, X1 represents an example wherein (X _1), wherein, Z is _{- ((CH 2) n1 -W} ) n2 - the expressed, wherein, W is represents -O- or -NH-CO-, n1 represents 2 to 6, n2 represents _{0~3, Y 1, Y 2,} Y 3 and Y ₄ is -OH, -NH ₂ or represents e.g. 4-hydroxymethyl-1-phenoxyacetic acid (L _1), p-hydroxymethyl phenol linker (L ₂₎ group obtained after reacting a linker such as.

Description

Detailed Description of the Invention

The present invention relates to colored polyphenoxy dendrimers, novel soluble carriers, a process for their preparation and their use in organic synthesis. More specifically, the subject of the present invention is the use of colored dendrimers as soluble carriers in organic synthesis, these colored dendrimers and a process for their preparation.

[0002] Chemists are increasingly using combinatorial chemistry as a novel technique that allows the synthesis of a large number of substances. The advantage of this technique is that it allows rapid synthesis of very large numbers of substances, but this technique does not allow large amounts of each of these substances to be synthesized. Thus, combinatorial chemistry is a very useful technique for sieving substances that require specific activity, such as affinity for a particular receptor, from a very large number of substances.

On the other hand, in medicinal chemistry substances are subject to further study, for example after being screened for specific activity, especially as identified after sieving, and the screened substances are subjected to a considerable number of tests. So a lot of material is needed. The synthesis of bulk materials is carried out in solution according to standard organic chemistry techniques.

One of the techniques used in combinatorial chemistry is polymer-supported organic synthesis, but a significant length to adapt (mount) a chemical in solution on a solid support. Need time.

German Patent Nos. 2316941 and 2317173 describe the use of large molecules called dendrimers in solution, the utility of which is to bind small molecules to them. And then it is chemically converted, which allows for easier synthesis and isolation of small molecules of interest.

Dendrimers are fractal molecules (also called molecular trees) or cascading molecules. These names reflect that the structures of these compounds are constructed by branching branches in a stepwise sequence from the central core to the production. Dendrimers are therefore dendritic, monodisperse polymers at the interface of standard chemistry and polymer chemistry, and in many areas, for example as catalysts in organometallic chemistry, between carbohydrates and proteins in carbohydrate biology. It is used as a vehicle for biomolecules (eg in agricultural chemistry or pharmacy) to study the interactions of

From 1941, PJ Flory (book titled "les dendrimeres", Cl
ub CRIN ECRIN, 1998) is similar to linear polymers in that it has infinite branch formation, but is obtained as a linear polymer in that it is obtained without intramolecular or intermolecular reactions during the dendritic process. Have envisioned and prepared different new types of macromolecules. This novel concept was embodied by the first synthesis of dendrimers by F. Vogtle (Buhleier, EW Wehner, W .; Vogtle, F., Synthesis, 1978, 155.
-158), especially developed by 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, 1 9, 2466-2468).

The utility of dendrimers as novel carriers in parallel syntheses should be emphasized. Parallel synthesis means, according to standard expressions in chemistry, reactions performed in parallel in different reactors at the same time. The idea of using dendrimers as the soluble carrier derives from the problems encountered when using solid carriers in the synthesis. In fact, the parallel synthesis method has the following drawbacks. • It takes too long to adapt the solution chemical to the solid support. Resins present problems of accessibility and solvation, in which case the loading is generally very low, so the amount of material obtained is not sufficient for pharmacological testing. is there. The reaction cannot be monitored by TLC on solid supports, which is a significant obstacle for chemists.

Dendrimers can overcome some of these problems. -Dendrimers have a large number of outer functional groups and as a result have a very high loading rate. • They also have the advantage of being soluble, unlike solid carriers, and can therefore be considered as protecting groups. -This method does not, in principle, require adapting the chemicals in solution. -Each synthetic intermediate can be characterized by standard techniques (IR, MS, NMR) and the reaction can be rapidly purified by steric exclusion (or ultrafiltration).

The idea that is the subject of the present invention is to prepare new dendrimers with specific characteristics. Thus, the dendrimers according to the invention are colored. This coloring of the dendrimers according to the invention makes the reactions involving such dendrimers much easier to monitor, especially in the purification process. Dendrimers according to the invention contain special amide or ether linkages.

The color of such dendrimers according to the invention is yellow, blue or especially red. Thus, such dendrimers of the present invention provide an additional solution to existing techniques in combinatorial chemistry and / or parallel synthesis, thus allowing increased productivity, especially in organic synthesis.

The subject of the invention is thus a novel dendrimer, which is characterized in particular by the inclusion of colored fragments in the structure. Due to this coloring, various stages of synthesis,
In particular, the purification step of a dendrimer to which a small molecule of the target substance is bound can be visually monitored. The use of such colored dendrimers in solution provides significant and valuable time savings in research activities. The invention therefore relates to a dendrimer characterized in that it contains colored moieties in the structure.

The subject of the invention is therefore the compounds of the formula (PY), characterized in that Y represents a dendrimer residue and P represents a colored moiety. In the compound of formula (P-Y) defined above, Y is for example Starburst (trade name) polyamidoamine (PAMAM) (Tomalia et al., Polymer Journal, 17 , (1), 117-132 (1985).
) Represents a dendrimer residue that can be selected from known dendrimers that can be found in the literature or on the market, to which a colored moiety P as defined in the present invention is added. Such colored dendrimers thus obtained are part of the present invention. The Y dendrimer residue can also be selected from compounds of formula (I) as defined below.

A more particular subject matter of the present invention is that the colored moieties P representing dendrimer residues are

[Chemical 31] Or

[Chemical 32] [Wherein R4 represents a phenyl, naphthyl or benzothienyl group optionally substituted with one or more substituents selected from R6 and R7, n represents an integer 1 or 2, R5, R6, R7, R8, R9, R10 and R11 may be the same or different and each is a hydrogen atom, a halogen atom, a linear or branched alkyl or alkoxy group having at most 4 carbon atoms, a hydroxyl group, Represents an amino group substituted by a phenoxy group, a nitro group, or an acyl group or by one or two straight-chain or branched-chain alkyl groups having at most 4 carbon atoms, where These alkyl groups may themselves be hydroxyl, cyano, acyl, acyloxy or phenyl groups (which may themselves be straight chain or branched chain alkyl groups having up to 4 carbon atoms). In may be substituted optionally with optionally substituted optionally), naphthyl group further following equation may be R4 represents

[Chemical 33] (Wherein R6 has the meaning indicated above), which may be optionally substituted with a group of the above formula] and a compound of formula (P-Y) above and a compound of formula (P-Y)
-Y) in the salt of the compound.

For the definitions of substituents above and below, the definitions used can have the following:

The term alkyl refers to a straight or branched chain group having at most 12 carbon atoms,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec
-Butyl, t-butyl, pentyl, isopentyl, sec-pentyl, t-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, t-hexyl, heptyl, octyl, decyl, undecyl, dodecyl. Alkyl groups having at most 4 carbon atoms are preferred, especially methyl, ethyl, propyl, isopropyl and n-butyl groups.

The term alkoxy means a straight-chain or branched group having at most 12 carbon atoms, for example methoxy, ethoxy, propoxy or isopropoxy, preferably straight-chain, It is also preferably a second or third butoxy.

Halogen means, of course, a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine atoms are preferred. An acyl group preferably means a group having at most 7 carbon atoms, such as acetyl, propionyl, butyryl or benzoyl, but can also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl group. Moreover, a formyl group can also be mentioned. The acyloxy group means a group in which the acyl group has the above-mentioned meaning and is, for example, an acetoxy or propionyloxy group.

By esterified carboxy group is meant, for example, an alkoxycarbonyl group, such as a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, or a group such as a butyl or t-butyloxycarbonyl group. Also, methoxymethyl, ethoxymethyl group; acyloxyalkyl group such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; methyl or ethylmethoxycarbonyloxy group, methyl or ethylisopropyloxycarbonyloxy group Mention may also be made of groups formed with easily cleavable ester residues such as: alkylalkyloxycarbonyloxy groups: A list of such ester groups can be found in EP-A-0034536.

Salt-formed carboxy means, for example, a salt formed with one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. In addition, methylamine, propylamine, trimethylamine, diethylamine,
Mention may also be made of salts formed with organic bases such as triethylamine. The sodium salt is preferred. The amino group can be substituted with one or two alkyl groups selected from the alkyl groups as defined above to form an alkylamino or dialkylamino group as defined above.

An alkylamino group preferably means a group in which alkyl has at most 4 carbon atoms. Mention may also be made of methylamino, ethylamino, propylamino or butyl (straight or branched) amino groups. Similarly, dialkylamino groups preferably mean groups in which the alkyl has at most 4 carbon atoms. Examples thereof include dimethylamino, diethylamino and methylethylamino groups.

The esterified, etherified or protected hydroxyl group is -O-, respectively.
Means _{CO-a 1, a 2 -O} -a 3 or -O-pg group, these are intended to be formed from a hydroxyl group according to well-known conventional method to those skilled in the art, wherein, pg is a protecting group Wherein a ₁ , a ₂ and a ₃ are especially alkyl, alkenyl, alkynyl,
Represents an aryl or arylalkyl group, which has at most 12 carbon atoms and may be optionally substituted, especially as described above for R ₃ .

Examples of pg protecting groups and the formation of protected hydroxyl groups are given in the literature especially to those skilled in the art: Protective Groups in Organic Synthesis, Theo.
doa W. Greene, Harvard University; John Wiley and Sons, Wiley Intersci
Printed by ence Publishers in 1981.

The protecting group for the hydroxyl group that pg can represent can be selected from the following list: for example formyl, acetyl, chloroacetyl, bromacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxy. Acetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. In addition, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, βββ-
Trichloroethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, 1-cyanopropylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl, benzyl,
4-methoxybenzyl, benzohydryl, trichloroethyl, 1-methyl-1-
Methoxyethyl, phthaloyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, p-nitrobenzoyl,
p-t-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl,
A phenylcarbamoyl group and a naphthylcarbamoyl group can also be mentioned. The protecting group pg may especially represent a 2-hexahydropyranyl group, and
It can also represent a derivative of silicon such as trimethylsilyl.

Inorganic or organic acid addition salts of compounds of formula (P-Y) can be, for example, salts formed with the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid. , Phosphoric acid, propionic acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkyl sulfonic acid (eg methanesulfonic acid, Ethanesulfonic acid, propanesulfonic acid), alkyldisulfonic acid (eg methanedisulfonic acid, α,
β-ethanedisulfonic acid), arylmonosulfonic acids (eg benzenesulfonic acid) and aryldisulfonic acids.

If the compound of formula (PY) as defined above contains an amino group salted with an acid, these acid salts are of course also part of the invention. Mention may be made in particular of salts formed with hydrochloric acid or methanesulfonic acid, for example.

A particular subject of the invention is that Y is a dendrimer residue and the colored moiety P
Where R4 is the following formula:

[Chemical 34] A naphthyl group substituted with a group of: a benzothienyl group substituted with nitro or a linear or branched alkoxy group having at most 4 carbon atoms, or a halogen atom, hydroxyl, at most 4 Represents a phenyl group substituted with one or more groups selected from a linear or branched alkyl or alkoxy group having 1 carbon atom and a nitro group, and R5 represents a hydrogen atom, a hydroxyl group, or an acyl group. Represents an amino group optionally substituted by 1 or 2 straight-chain or branched-chain alkyl radicals having at most 4 carbon atoms, which or these alkyl radicals are themselves hydroxyl, cyano or It may be optionally substituted with an acyloxy group, R6 and R7 may be the same or different, and may be a hydrogen atom, a halogen atom or a poly atom. Both represent a linear or branched alkyl or alkoxy group having 4 carbon atoms, R8 represents a hydrogen atom, and R9, R10 and R11 may be the same or different, and are hydrogen atoms; Hydroxyl group; phenoxy group; optionally phenyl group, which itself may be optionally substituted with straight or branched chain alkyl groups having up to 4 carbon atoms.
Or an amino group optionally substituted with a linear or branched alkyl group having at most 4 carbon atoms, which may itself be optionally substituted with a hydroxyl group. And a salt of a compound of formula (P-Y) and a compound of formula (P-Y), characterized in that

A more particular subject of the invention is the abovementioned formula (P-, characterized in that Y represents a dendrimer residue and the colored moiety P is selected from the fragments shown in FIG. Y) and salts of compounds of formula (P-Y).

An even more particular subject matter of the present invention is that Y represents a dendrimer residue and the colored moiety P is of the formula:

[Chemical 35] And a salt of a compound of formula (P-Y) and a compound of formula (P-Y) as defined above.

[0030]   The subject of the invention is also that P has the abovementioned meaning and Y is of the formula (I):

[Chemical 36] {Wherein R1, R2 and R3 may be the same or different, R2 represents a hydrogen atom or is selected from R1 and R3, and R1 and R3
Are X1, X2, X3 and X4 defined as follows:

[Chemical 37] (Where, Z is _{- ((CH 2) n1 -W} ) represents _n2, W is a divalent oxygen atom -O- or represents an amide bond -NH-CO-, n1 represents an integer of 2-6, n2 represents an integer of 0 to 3, Y ₁ , Y ₂ , Y ₃ and Y ₄ may be the same or different, and a functional group —OH,
-Br, -Cl, -I, -SH, -CO 2 H, -CO 2 Cl, -CO 2 Br, -S
O ₃ H, -SO ₂ Cl, or represents -NH ₂ and -CH = CH _2, or one of the following things to these functional groups: - 2,4-dimethoxy-4'-hydroxybenzophenone, & 4- ( 4-hydroxymethyl-3-methoxyphenoxy) butyric acid, 4-hydroxymethylbenzoic acid, 4-hydroxymethylphenylacetic acid (L ₁ ), 3- (4-hydroxymethylphenoxy) propionic acid, p-[( R, S) -α- [1- (9H-fluoren-9-yl) methoxyformamide] -2,4-dimethoxybenzyl] phenoxyacetic acid, p-hydroxymethylphenol linker (L ₂ ), MBHA linker, Rink amide linker, -Sieber linker, -representing a residue obtained after reacting a linker L selected from a trityl linker Characterized in that representing the dendrimer residue selected from the compounds of} is selected from the a) or, in a salt of a compound and a compound of formula (P-Y) of the formula (P-Y).

Accordingly, Y ₁ , Y ₂ , Y ₃ and Y ₄ are functional groups —OH, —Br, —Cl, —I, —SH, —CO ₂ as defined above for the linker L as defined above. H, -CO ₂ Cl, -
It can represent a residue obtained after reaction with CO ₂ Br, —SO ₃ H, —SO ₂ Cl, —NH ₂ or —CH═CH ₂ . These functional gold red, -NH ₂ or -OH functional group. If Y _1, Y _2, Y ₃ and Y ₄ represents -NH _2, the reaction can be carried out on the acid functional group of the linker selected from particular example the list, such as L1 linker. When Y ₁ , Y ₂ , Y ₃ and Y ₄ represent —OH, first convert —OH to a mesylate or equivalent, which is then treated with a linker selected from the above list, such as L2. Can be reacted.

The present invention is also a compound of formula (PY) as defined above, wherein the end opposite to the end attached to the colored moiety P in the dendrimer residue is a linker. It also relates to a covalent bond to a fragment referred to as. Such a linker facilitates the use of the dendrimers of the invention as a soluble carrier in organic syntheses as defined below.

A particular subject of the invention is that the colored part P has the abovementioned meaning and Y is Z, W, n1, n2, Y ₁ , Y ₂ , in the above formula (I). whether Y ₃ and Y ₄ is and R1, R2 and R3 are · R2 is hydrogen have the meanings given above and R1 and R3 are selected from X1, or · R1, R2 and R3 represent an X2 or X3 A compound of formula (PY) and a salt of a compound of formula (PY), characterized in that it represents a dendrimer residue selected from the compounds

A more particular subject of the invention is that the colored part P has the abovementioned meaning, and
Y is, R1 in the above formula (I), R2, R3, n2, Y 1, Y 2, Y 3 and Y ₄
There the means having and Z is _{- ((CH 2) 3 -NH} -CO) n2 - or - ((CH _{2) 2} -
O) _n2- represents a dendrimer residue selected from the compounds of formula (P-Y) and the salts of the compounds of formula (P-Y).

An even more particular subject matter of the present invention is that the colored part P has the abovementioned meaning and Y is R1, R2, R3, n1, n2, Y in the above formula (I). ₁ ,
Y _2, Y ₃ and Y ₄ is and meaning of the Z is _{- (CH 2) 3 -NH-} CO- or - (
Characterized in that representing the dendrimer residue selected from CH ₂₎ compounds representing the ₂ -O-, in a salt of a compound and a compound of formula (P-Y) of the formula (P-Y).

A quite particular subject matter of the invention is that the colored part P has the abovementioned meaning, and
R1 in the Y has the above formula (I), R2, R3, n1, n2, Z, W, Y 1, Y 2
, Y ₃ and Y ₄ represent dendrimer residues selected from the compounds having the meanings given above, Y ₁ , Y ₂ , Y ₃ and Y ₄ represent residues obtained after reaction with the linker L. The linker L is selected from the following: 4-hydroxymethylphenoxyacetic acid (L ₁ ), p-hydroxymethylphenol linker (L ₂ ), Rink amide linker, (P-Y) compound.

The linker L is a linker (L ₁ ), that is,

[Chemical 38] Or a linker (L ₂ ), ie

[Chemical Formula 39] And a salt of the compound of formula (P-Y) and the compound of formula (P-Y) above.

A particular subject of the invention is the abovementioned formula (P-Y), which corresponds to the formulas of dendrimers a, b, c and d defined respectively by FIGS. 1, 2, 3 and 4. In the compound. A particular subject of the invention is the abovementioned formula (corresponding to the formulas of dendrimers a, b, c, d and d1 defined by FIGS. 1, 2, 3, 4 and 4.1, respectively.
P-Y).

Such dendrimers and compounds of formula (PY) according to the invention can be synthesized in two different ways, according to the so-called convergent and branched syntheses. In the branched synthesis method, dendrimer synthesis proceeds by repeating a series of reactions from the core portion to the surface. Therefore, the number of terminal functional groups at the periphery can increase very quickly as the production proceeds. -In the convergent synthesis method, a dendrimer is constructed from the peripheral part toward the core part. In this synthetic mode, there is a limit to the number of reaction sites in each production.

[0040] Thus, subject of the present invention which is also a process for the preparation of compounds of formula as defined above (P-Y), the method is characterized in that: the following formula (D ₁ ):

[Chemical 40] (Wherein R4 represents hydrogen or hydroxyl, alk represents an alkyl group having at most 4 carbon atoms) and a compound of the formula (D ₂ ):

[Chemical 41] (Where, Br represents a bromine atom, G is - (CH _{2) n1} -, or _{- ((CH 2) 2 -O-} (CH 2) 2) - represents a divalent radical, n1 is 2 to 6 Represented by the following formula (D ₃ ):

[Chemical 42] [Wherein G and alk have the above-mentioned meanings and R5 represents a hydrogen atom or a -O-G-NH-COOtBu group (wherein G has the above-mentioned meaning)], following equation was saponified compounds of formula _{(D 3) (D 4)} :

[Chemical 43] (Here, G and R5 have the meanings given above) to give a compound of or Formula (D ₃₎ the BOC amine functional groups in the compounds of deprotecting the formula (D _5):

[Chemical 44] (Wherein G and alk have the meanings given above, and R6 represents H or —O—G—NH ₂ .ClH) and then either of the following routes (1) or (2) Perform the process according to.

(1) According to the so-called convergent route, (a) a compound of the above formula (D ₄ ) is reacted with a compound of the above formula (D ₅ ) to give the following formula (
D ₆ ):

[Chemical formula 45] {Wherein G and alk have the above-mentioned meanings, Ra ₂ represents H or Ra ₁ or Ra ₃ , and Ra ₁ and Ra ₃ are the following formulas:

[Chemical formula 46] (Wherein R5 has the above meaning) and a compound of the formula (D ₆ ) is saponified to obtain a compound of the following formula (D ₇ ):

[Chemical 47] (Wherein Ra ₁ , Ra ₂ and Ra ₃ have the above-mentioned meanings), and (b) the compound of formula (D ₄ ) is replaced by the following formula (D ₈ ):

[Chemical 48] (Wherein, P is meaningful according to claim 1) is reacted with a compound of the formula (D _9):

[Chemical 49] (Wherein G, P and R5 have the above-mentioned meanings), and deprotecting the amine functional group of BOC therein, the following formula (D ₁₀ ):

[Chemical 50] (Wherein G, P and R6 have the above-mentioned meanings), and the compound of the formula (D ₇ ) is reacted with the compound of the following formula (D ₁₁ ):

[Chemical 51] {Where Rb ₂ represents H or Rb ₁ or Rb ₃ , and Rb ₁ and Rb ₃ are of the following formula:

[Chemical 52] (Wherein G has the above meaning) and a compound of formula (D ₁₁ ) is obtained, and the amine functional group of BOC in the compound of formula (D ₁₁ ) is deprotected to obtain the following formula (D ₁₂ ):

[Chemical 53] [Here, Rc ₂ represents H or Rc ₁ or Rc ₃ , and Rc ₁ and Rc ₃ are represented by the following formula:

[Chemical 54] {Where R7 is H or the following formula:

[Chemical 55] (Wherein G is as described above) represents a group] and represents a group].

(2) According to the diffusion route, the compound of the above formula (D ₄ ) is reacted with the compound of the above formula (D ₁₀ ) to give the following formula (D ₁₃ ):

[Chemical 56] (Wherein P, Ra ₁ , Ra ₂ and Ra ₃ have the above-mentioned meanings), and deprotecting the amine functional group of BOC in the compound of formula (D ₁₃ ) D ₁₄ )
:

[Chemical 57] {Where P has the above meaning, R8 represents H or Rd ₁ or Rd ₃ , and Rd ₁ and Rd ₃ are of the following formula:

[Chemical 58] (Wherein, G and R6 have the meanings given above) to give a compound of the representative} the group of compounds of this formula (D ₁₄₎ of the compounds the of formula, if it or desired if necessary the (D ₄₎ To give a compound of formula (D ₁₁ ) as described above, and subjecting the compound of formula (D ₁₄ ) to conversion of NH ₂ amine functionality to OH hydroxyl functionality if necessary or desired. The following formula (D ₁₅ ):

[Chemical 59] [Where P has the above meaning, Rf ₂ represents H or Rf ₁ or Rf ₃ , and Rf ₁ and Rf ₃ are of the following formula:

[Chemical 60] {Wherein R9 represents H or O-G-OH (where G has the meaning given above)}.

The compound of formula (D ₁₂ ), (D ₁₄ ) or (D ₁₅ ) above may be a compound of formula (P-Y), which is another compound of formula (P-Y). If desired or necessary to obtain the following conversion reaction: (a) conversion reaction of an alkoxy function to a hydroxyl function or of a hydroxyl function to an alkoxy function, (b) an aldehyde of an alcohol function. Oxidation reaction to acid or ketone functional group, (c) conversion reaction of halogenated functional group to formyl or esterified carboxy functional group, (d) reaction with linker L as described above, (e) deprotected And (f) one or more of a reaction for removing a protective group which a reactive functional group may have and (f) a salt-forming reaction with an inorganic or organic acid or a base to obtain a corresponding salt in any order. it can.

The above-mentioned reactions (a) to (f), which are carried out as desired or necessary with respect to the compound of the above formula (D ₁₂ ), (D ₁₄ ) or (D ₁₅ ), can be carried out by those skilled in the art. It is a standard reaction which is well known and is therefore conveniently carried out under normal conditions well known to those skilled in the art.

Thus, the synthesis of the compounds of formula (PY) according to the invention described above consists in attaching several branches in a convergent or branched manner in the central part (core part).

Among the dendrimers of formula (PY) according to the invention, dendrimer a has 8 final functional groups, dendrimers b and d have 9 final functional groups and dendrimer c has 6 End functional groups, and therefore these final functional groups are found at the tips of the branches of the dendrimer, which are the anchor points for the molecule to be synthesized, which is used as a soluble carrier.

The synthesis of the dendrimer core is common to all dendrimers.
For the dendrimers a, b, c and d of particular interest according to the invention, the synthesis of the core part of these dendrimers is carried out according to the diagram shown in FIG.
Starting from ed, it is divided into 3 stages.

[0048]   For dendrimer a, the following reaction is also carried out.

[Chemical formula 61]

To synthesize Molecule 5, this method follows the standard alkylation conditions D
It is carried out in MF at 80 ° C. in the presence of K ₂ CO ₃ or preferably in acetonitrile with PTBD resin at ambient temperature.

To construct dendrimer a, the ester functionality of compound 5 is then saponified under standard conditions.

[Chemical formula 62]

Therefore, dendrimer a can be synthesized by two different routes, called the convergent route and the branched route, as shown in the diagrams of FIGS. 6 and 7. The convergent synthesis route of dendrimer a shown in FIG. 6 is a more rapid method. According to the diagram shown in FIG. 7, the synthesis of dendrimer a by the branching route described in Example 2 of the experimental part is compared with the synthesis of dendrimer a by the convergent route described in Example 1 according to the diagram shown in FIG. It should be noted that it includes two additional steps.

To obtain the compound of formula 12, dichloromethane or preferably acetonitrile (solvent used in the coupling of the synthesis of dendrimer b) can be used. It should be noted that this compound precipitates as it forms in the latter solvent and is easily isolated by filtration. The molecule 13 is then coupled with the linker 14.

Dendrimers b and c can likewise be synthesized according to a convergent or branched route as shown below. The steps involved in the convergent synthesis route of dendrimer b are 1
Few. Dendrimer b can be synthesized under the same conditions as dendrimer a. All couplings are carried out in BOP / DIEA and all BOC vapor deprotection is carried out in HCl-AcOEt. The branched synthetic route of dendrimer b is shown in the diagram of FIG.

The above dendrimer c is a “mixed” dendrimer containing a fragment with first three branches and then two branches, providing a compromise between final chain number and molecular weight. The branched synthetic route of dendrimer c is achieved according to the diagram shown in FIG. In the experimental part below, a precise description of the synthesis of dendrimers a by the convergent and branched routes and the synthesis of dendrimers b and c by the branched routes is given in Examples 1-4.

Thus, the colored dendrimers according to the invention, in particular the three different types of dendrimers a, b and c described above, can be synthesized according to two synthetic routes. It should be noted that the so-called branched dendrimer synthesis method described above is preferred.

The invention also relates to the use of the dendrimer according to the invention as a soluble carrier in organic synthesis. The use of the dendrimers of the invention as a soluble carrier in organic synthesis is shown in FIG.
This is illustrated in the diagram shown in.

To study the use of dendrimers as soluble carriers according to the present invention, Suzu
The ki reaction was chosen as a model reaction (Miyaura, N .; Yanagi, Y; Suzuki, A., Synth.
Commun., 1981, 11, 513) (Watanabe, T .; Miyaura, N .; Suzuki, A., Synlet
t, 1992, 207) (Martin, AR; Yang, Y., Acta Chem. Scand., 1993, 47, 22.
1) (Suzuki, A., Pure S Appln. Chem., 1994, 66, 213) (Miyaura, N .; Suzu
ki, A., Chem. Rev., 1995, 95, 2457).

In the experimental part below, examples of the use of dendrimers according to the invention as soluble carriers in organic synthesis are given in Examples 5-6. Examples 5 and 6 particularly relate to the use of dendrimers b or c as soluble carriers in organic synthesis according to the diagram in FIG. The reaction conditions of the diagram shown in FIG. 10 are outlined below.

O- or p-iodobenzoic acid binds to dendrimers with 6 or 9 terminal functional groups (using an excess of reagent (acid, DCC)) by forming an ester bond.
At the end of the reaction, DMF is simply concentrated, redissolved in a small amount of dichloromethane and this solution is passed through a Sephadex LH-20 cartridge (swollen in dichloromethane). The bright red color of this dendrimer allows the purification of the dendrimer through the cartridge to be monitored, thus limiting the use of solvent. Once the cartridge is loaded, this purification takes 20 minutes.

The synthesis can then be continued with the purified dendrimer. According to Suzuki's exemplary reaction, two boric acids are used under standard conditions for this reaction, but in excess of reagents. After the reaction, the extraction step can remove the catalyst and salts. Then, in the same manner as for purification, CH ₂ Cl ₂ / M
The solution of eOH is passed through a cartridge (gel swollen in the same solvent).

After cleaving the dendrimer and the final acid, the separation of the acid-form dendrimer is carried out according to various reaction conditions, for example with a basic resin such as PTBD and Amberlyst A-26. Dendrimers with 9 terminal alcohol functional groups are C
Poorly soluble in H ₂ Cl ₂ (in which dendrimers with 6 terminal functional groups are soluble), it is possible to easily salt this acid in basic medium and then extract with CH ₂ Cl _2. It should be noted that it is also possible. Dendrimers placed at the interface or in the organic solution are easily removed by filtration. The aqueous phase is then acidified and the acid is extracted with ethyl acetate.

The present invention also relates to the use of a compound of formula (PY) above as a colored dendrimer as a soluble carrier in organic synthesis. Thus, when using the compound of the above formula (P-Y) as a soluble carrier in the organic synthesis, is Y _1, Y _2, Y ₃ and Y ₄ in the formula (P-Y) of the present invention Compounds which represent the residue obtained after reaction with the abovementioned linkers are preferred.

In fact, such a linker acts as an anchor (fixation medium) for the molecule synthesized during the organic synthesis in which the dendrimer on the one hand binds and on the other hand the dendrimer acts as a soluble carrier. This structure results in desorption, and when the linker is covalently attached more tightly to the rest of the dendrimer, the molecules synthesized during organic synthesis are more easily desorbed from the dendrimer. . Particularly in the compounds of the present invention, the linker is attached to the dendrimer by an amidation reaction or an esterification reaction.

[0064]   As an example, two diagrams are shown below. If you follow these,
In the linker L1 and the linker L1, the hydroxyl-OH functional group is -OAc.
The linker L2 'corresponding to the one protected with is Y in the above formula (P-Y). ₁ , Y₂, Y₃And Y_FourAre each NH₂Or bound to dendrimer D representing OH
And another dendrimer, namely Y in formula (PY) according to the invention.₁, Y₂, Y₃
And Y_FourRepresents a residue obtained after the reaction with the linker L1 or L2 'described above.
Generate a ndrimer. D-NH₂  + HO-CO-CH₂-O-phenyl-CH₂OH (L1) →
D-NH-CO-CH₂-Phenyl-CH₂OH D-OH + HO-phenyl-CH₂OAc (L2) → D-O-phenyl
-CH₂-OAc

In particular, the invention consists in using the abovementioned dendrimers a, b, c or d as colored dendrimers as soluble carriers in organic synthesis. Quite particularly, the invention also consists in using the abovementioned dendrimers a, b, c, d or d1 as colored dendrimers as soluble carriers in organic synthesis.

When using dendrimers for the synthesis of molecules, particular attention should be paid to the effectiveness of purification of reaction components by steric exclusion chromatography. This purification method is
By avoiding the need for extraction in many reactions, the purification time is very short (about 20 minutes), the amount of solvent is low and the automation by UV detector is not necessary,
It is efficient. Therefore, the synthesis of molecules in solution, achieved by using dendrimers as soluble carriers, is a technology that complements all that has already been used in combinatorial chemistry.

Within the scope of the present invention, by increasing the chain length and incorporating a less reactive ether functional group instead of an amide functional group, the dendrimer can be used under a wider range of conditions, It has been found that it can be soluble in common solvents. In this case, the hindrance is not significant, making it possible to obtain a more complete reaction at the binding level of the linker 14. It should also be noted that dendrimers should not be used under conditions that would alter these dendrimers, such as reagents attacking the nitro group, or too basic conditions.

Accordingly, the present invention is quite particularly based on the fact that the length of the chains constituting the dendrimer represents n1 in particular 2 or 3, or 3 or 4 and even 5 or 6, and n2 in particular 0.
Or 1 or to 2 or 3 with respect to compounds of formula P-Y above.

The present invention is also quite particularly dendrimer of the above formula P-Y, wherein the chains making up the dendrimer contain an amide functional group or, alternatively, an ether functional group rather than an amide functional group, In particular, W has more than -CO-NH amide functional groups.
It also relates to compounds of formula (P-Y) such that they exhibit O-ether functional groups.

The invention therefore relates to the use of the abovementioned dendrimers as soluble carriers in organic synthesis, after which the dendrimers are purified by steric exclusion chromatography or optionally ultrafiltration.

Examples of the use of dendrimers as soluble carriers include chemical synthesis by progressive attachment to dendrimers, or chemical conversion of dendrimer anchored molecules.

In particular, molecules with acid functional groups can be attached to dendrimers by formation of ester bonds and then subjected to chemical conversion. High molecular weight dendrimers can be purified by simple steric exclusion chromatography. The low molecular weight reagents used in excess must be kept in the pores of the gel and the dendrimer will be eluted. Then, by simply desorbing from the dendrimer, FIG.
The purified molecule is obtained as shown in the reaction diagram in 1.

The diagram in FIG. 11 describes the use of dendrimers according to the invention as soluble carriers in organic synthesis. The diagram in FIG. 11 represents a dendrimer of the above formula (PY), in particular the dendrimer a, b, c or d shown in FIGS. 1 to 4, respectively.

The subject of the present invention is therefore the use of the colored dendrimer as a soluble carrier in organic synthesis, characterized in that the color of the dendrimer allows the organic synthesis reaction of interest to be visually observed. And what to do.

To achieve the organic synthesis of such target molecules, the colored dendrimers according to the invention are solubilized and the organic synthesis is carried out with the colored dendrimers as carriers, on which the objective Is progressively synthesized, then the dendrimer to which the synthesized molecule is bound is purified, and the last synthesized molecule is desorbed. All these targeted organic synthesis reactions can be visually monitored by TLC using dendrimer coloration.

A particular subject of the present invention is the use of the colored dendrimers described above as soluble carriers in said organic synthesis, which dendrimers are purified by steric exclusion chromatography in about 20 minutes and Is small, tens of meters
It is about 1 and is characterized in that the detection of the synthesized molecule bound to the dendrimer is visible to the naked eye.

Hereinafter, the present invention will be illustrated by examples, but these do not limit the present invention. In these examples, the compounds shown in the figures, i.e., compound 1, compound 2 to compound 33 along the time line, are shown in the diagram above or below or in the diagram in the figure of the invention. Corresponds to the compound. The figures described below in FIGS. 1 to 12 (a, b, c, d, e, f, g, h) form part of the present invention.

Regarding the analytical results (IR, NMR, MS) described later in the preparation of Experimental Examples 1 to 6,
TLC is performed using Silicagel Merck 60 F ₂₅₄ silica plates and reagents are exposed in UV = 254 nm with phosphomolybdate reagents or iodine depending on the molecule. Terms used below: PTSA = p-toluenesulfonic acid BOC = t-butyloxycarbonyl BOP = benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate DCC = dicyclohexylcarbodiimide DIC = diisopropylcarbodiimide DIEA = diisopropylethylamine DMAP = dimethylaminopyridine HOBT = 1-hydroxybenzotriazole hydrate MsCl = methyl chloride Pd (PPh ₃ ) ₄ = tetrakis (triphenylphosphine) platinum (0) PPh ₃ = triphenylphosphine PPTS = p- Pyridinium Toluenesulfonate PTBD = 1,5,7- linked to polystyrene (crosslinked with 2% DVS)
Triazabicyclo [4.4.0] dec-5-ene TEA = (triethylamine) TFA = trifluoroacetic acid.

Preparation of the colored part of the dendrimer : Compound 3 According to the diagram shown in FIG. 5, the core part of the dendrimer is synthesized by the synthesis of the colored part as follows.

Step 1 : Compound 1

[Chemical formula 63]

Dispers Red 1 (5.10 g, 16.23 mmol) is dissolved in 100 ml anhydrous CH ₂ Cl _{2 in a} 250 ml three-necked flask. TEA (6.77 ml,
48.70 mmol, 3 eq) was added using a syringe, then MsCl (1.
89 ml, 24.35 mmol, 1.5 eq) are added at 0 ° C. After reacting for 1 hour, the reaction medium is taken up in CH ₂ Cl ₂ and then washed with 1N HCl, water and brine. The organic phase is dried over MgSO ₄ , filtered,
Concentrate in a rotary evaporator. (Yield = Q) Thus, the desired compound 1 was obtained in the form of red crystals. Analysis : TLC: Rf = 0.80 (in CH ₂ Cl ₂ / MeOH = 9: 1)

Step 2 : Compound 2

[Chemical 64]

In a 500 ml flask, the compound 1 obtained in the above step 1 (6.36 g, 1
6.22 mmol) is dissolved in 200 ml DMSO. NaN ₃ (1.58
g, 24.33 mmol, 1.5 eq) are added. The reaction medium is stirred under a nitrogen atmosphere 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 in a rotary evaporator (yield = 5%). In this way the expected compound 2 is obtained in the form of red crystals. Analysis : TLC: Rf = 0.48 (in Cyclo / AcOEt = 5: 5)

Step 3 : Compound 3

[Chemical 65]

In a 250 ml flask, the compound 2 (5.35 g, 1
3.41 mmol) is dissolved in 100 ml of THF. PPh ₃ (4.57g
, 17.43 mmol, 1.3 eq) and 410 μl of water (22.79 mmol,
1.7 eq) is added. The reaction medium is heated to 40 ° C. under nitrogen atmosphere overnight. The solvent is evaporated and the product is purified by chromatography on silica (eluent: CH ₂ Cl ₂ / MeOH = 9: 1). (Yield = Q) The desired compound was thus obtained in the form of red crystals.

Analysis : TLC: Rf = 0.17 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3384 cm ⁻¹ NH ₂ absorption 1601, 1589, 1558 and 1517 cm ⁻¹ aroma. Ring absorption + conjugated system +
Absorption of NO ₂ NMR: (CDCl ₃₎

[Chemical formula 66] MS :( electrospray, 70 eV, in ^{MeOH) 314 + = [M +} H] + 297 + = [MH + -NH 3] ++ 271 + = [314 + - (CH 2) 2 -NH 2] +

Example 1 : Convergent synthesis step 1 of dendrimer shown in the diagram of FIG. 6: Compound 4

[Chemical formula 67]

In a 250 ml flask, 3-bromopropylamine hydrobromide (24.
98 g, 110 mmol, 1.1 eq) was dissolved in 100 ml anhydrous CH ₂ Cl _{2 to} which TEA (16.68 ml, 120 mmol, 1.2 eq) was added,
Then di-t-butyl dicarbonate (21.82 g, 100 mmol) is added. Stir overnight at ambient temperature under a nitrogen atmosphere. The reaction medium is taken up in CH ₂ Cl ₂ and then washed with water, 1N-HCL and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated on a rotary evaporator. (Yield 96%) The desired compound was thus obtained in the form of white crystals.

Analysis : TLC: Rf = 0.76 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3459 cm ⁻¹ NH absorption 1710 cm ⁻¹ C═O absorption 1507 cm ⁻¹ amide II band NMR: (CDCl ₃₎

[Chemical 68] MS: (EI 70 eV and direct introduction, in MeOH) 237 ⁺ = M ⁺ (isotopic multiplex character of the presence of bromine) 180 ⁺ = M ⁺ -tBu (tBu ⁺ = 57 ⁺ ) 181 ⁺ = M ⁺ -tBu + H.

Step 2 : Compound 5

[Chemical 69]

To synthesize compound 5, following standard alkylation conditions in DMF in the presence of K ₂ CO ₃ at 80 ° C. or preferably in acetonitrile with PTBD resin at ambient temperature at The method is thus carried out. PTBD resin (1.81 g, 4 mmol, 4 eq) in a 50 ml flask.
Is dissolved in 10 ml of acetonitrile. Methyl 3,5-dihydroxybenzoate (0.168 g, 1 mmol) and compound 4 (0
． 476 g, 2 mmol, 2 eq) are added. Stir for 48 hours at ambient temperature under a nitrogen atmosphere. The resin is filtered on Iena. Concentrate the filtrate. In this way the expected compound is obtained in the form of white crystals.

Analysis : TLC: Rf = 0.45 (in CH ₂ Cl ₂ / AcOEt = 7: 3) IR: (in CHCl ₃ ) 3458 cm ⁻¹ NH absorption 1711 cm ⁻¹ C═O absorption 1598, 1507 and Absorption NMR of 1479 cm ^-1 amide II band + aromatic ring: (CDCl ₃ )

[Chemical 70] MS: (EI 70 eV and directly introduced, in ^{MeOH) 482 + = M + 426} + = M + -tBu + H (57 + = tBu +) 408 + = M + -OtBu-H 382 + = M + -COOtBu + H 309 + = M ⁺ -COOtBu-OtBu + H

Step 3 : Compound 6

[Chemical 71]

The ester functional group of compound 5 obtained in step 2 above is saponified under standard conditions or as follows to give compound 6. In a 100 ml flask, the compound 5 (2.26
g, 4.68 mmol) is dissolved in 24 ml EtOH. 2N-NaOH (
4.68 ml, 9.36 mmol, 2 eq) are added. This reaction medium at 40 ° C.
Heat to overnight. Evaporate the ethanol. This medium was added to 4.68 ml of 2N-H.
Acidify with Cl, then extract with AcOEt and finally wash with water and brine. The organic phase was dried over MgSO _4, filtered and concentrated. In this way the expected compound is obtained in the form of white crystals. (Yield = 98%) Analysis : TLC: Rf = 0.20 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3458 cm ⁻¹ NH / OH absorption 1702 cm ⁻¹ C = O absorption 1597 and 1507 cm ^-1 amide II band + aromatic ring absorption MS: (electrospray, 70 eV in MeOH) 469 ⁺ = [M + H] ⁺ 413 ⁺ = [M-tBu + H] ⁺ 357 ⁺ = [M-2tBu + 2H]. ⁺ 313 ⁺ = [357 ⁺ -CO ₂ ] ⁺

Step 4 : Compound 7

[Chemical 72]

In a 30 ml flask, the compound 5 obtained in step 2 above (0.501 g, 1
0.4 mmol) is dissolved in 5 ml AcOEt. A solution of HCl-AcOEt (6M, 3.47 ml, 20.81 mmol, 20 eq) is added dropwise at 0 ° C. Stir under nitrogen. After 3 hours of reaction, the solvent is evaporated. (Yield = Q
) The desired compound is thus obtained in the form of white crystals. Analysis : TLC: Rf = 0.24 (in CH ₂ Cl ₂ / MeOH = 8: 2) IR: (Nujol method) 3458 cm ⁻¹ NH / OH absorption 1720 and 1710 cm ⁻¹ C═O absorption 1598, 1575, 1528 and 1510 cm ^-1 NH ₂ absorption + aromatic rings absorb MS :( electrospray, 70 eV, in ^{MeOH) 283 + = [M +} H] + 253 + = [MH-NH 2 CH 2] + 226 + = [MH-NH ₂ (CH ₂ ) ₃ + H] ⁺

Step 5 : Compound 8

[Chemical formula 73]

In a 250 ml flask, the compound 3 (
1.11 g, 3.54 mmol) are dissolved under nitrogen in 100 ml of anhydrous CH ₂ Cl ₂ . Compound 6 (1.82 g, 3.89 mmol, 1.1 eq), then BO
P (1.72 g, 3.89 mmol, 1.1 eq) and DIEA (1.23 ml)
, 7.08 mmol, 2 eq.) Are added. Stir under a nitrogen atmosphere. After dawn overnight, the reaction medium is taken up in CH ₂ Cl ₂ and then washed with water, NaHCO ₃
Wash with, wash with brine, and concentrate the organic phase. The product is crystallized from 200 ml AcOEt. The expected compound is thus obtained in the form of red crystals.

Analysis : TLC: Rf = 0.71 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (Nujol method) NH absorption 1683 and 1678 cm ⁻¹ C═O absorption 1640, 1600 and 1516 cm ^{− 1} amide II band + absorption of aromatic ring + conjugated system + NO ₂ absorption NMR: (in DMSO)

[Chemical 74] MS: (electrospray, 70 eV in MeOH) 764 ⁺ = [M + H] ^+.

Step 6 : Compound 9 To obtain compound 7, deprotection of the BOC group of compound 8 obtained in step 5 above is carried out by proceeding as in step 4 above. In this way the expected compound is obtained in the form of violet crystals.

Step 7 : Compound 10

[Chemical 75]

Compound 7 (0.365 g, 1.03 mmol) obtained in Step 4 above was treated with CH ₂
It was dissolved in 10 ml of Cl ₂ and the compound 6 (1.06
g, 2.26 mmol, 2.2 eq), BOP (1 g, 2.26 mmol, 2.
2 eq) and DIEA (0.8 ml, 4.63 mmol, 4.5 eq) are added. After dawn overnight, the reaction medium is taken up in CH ₂ Cl ₂ and then washed with water,
Wash with brine. The organic phase was dried over MgSO _4, filtered and concentrated. The product is chromatographed on silica (CH ₂ Cl ₂ / MeOH = 95: 5). (Yield = 80%) In this way, the desired compound was obtained in the form of white crystals.

TLC: Rf = 0.54 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3456 cm ⁻¹ NH absorption 1709 and 1658 cm ⁻¹ C═O absorption 1595 and 1510 cm ⁻ Absorption NMR of ¹ amide II band + aromatic ring: (CDCl ₃ ).

[Chemical 76] MS :( electrospray in ^{MeOH) 1205 + = [M +} Na] + 855 + = [M + Na-2 (O- (CH 2) 3 -NH-COOtBu) -2H] + or artifact

Step 8 : Compound 11

[Chemical 77]

The procedure is carried out as in step 3 above to give compound 6. (Yield 95%) Thus, the desired compound was obtained in the form of white crystals. Analysis : TLC: Rf = 0.16 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3450 cm ⁻¹ NH absorption + general OH / NH absorption 1727, 1709 and 1659 cm ^{−. 1} C = O absorption 1595 and 1511 cm ^-1 amide II band + aromatic ring absorption MS: (in MeOH) 1151.6 ⁺ = [M + Na] ⁺ 1169.6 ⁺ = [M + H] ⁺ 1069.5 ⁺ = [M + H- CO ₂ tBu + H] ⁺ 969.6 ⁺ = [M + H-2CO ₂ tBu + 2H] ⁺ 869.6 ⁺ = [M + H-3CO ₂ tBu + 3H] ⁺ 769.6 ⁺ = [M + H-4CO ₂ tBu + 4H] ⁺

Step 9 : Compound 12

[Chemical 78]

The procedure is carried out as in step 5 above to give compound 8, except that the compound 9 obtained in step 6 above is used in place of the compound 3 obtained in step 3 of the above preparation, The compound 11 obtained in the above step 8 is used in place of the compound 6 obtained in the above step 3. Then BOP (0.069g, 0.5
Eq) and DIEA (0.054 ml, 1 eq) are added. The medium is evaporated to dryness and the crystals dissolved in MeOH are passed through Sephadex LH-20 (swollen with MeOH). The crystals are recrystallized from MeOH and then chromatographed on silica (CH ₂ Cl ₂ = 95: 5) (yield 50%). The expected compound is thus obtained in the form of red crystals.

Analysis : TLC: Rf = 0.45 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (Nujol method) NH / OH absorption 1709 and 1684 cm ⁻¹ C═O absorption 1640, 1593 and 1524 cm ^-1 amide II band + aromatic ring absorption + conjugated system + NO ₂ absorption NMR: (DMSO-d6)

[Chemical 79]

Step 10 : Compound 13 The BOC group of Compound 16 obtained in Step 9 above is deprotected according to Step 4 above to give Compound 7. Use 160 equivalents of HCl. (Yield = Q) Thus, the desired compound was obtained in the form of purple crystals.

Step 11 : Compound 14 4-hydroxymethylphenoxyacetic acid (55 mmol) is dissolved in 200 ml pyridine in a 500 ml flask. Acetic anhydride 20.37 ml (4.3
7 eq.) Are introduced at 0 ° C. over 1 hour. The reaction is stopped after 20 minutes. The pyridine is evaporated, then diluted into 200 ml of the crude product AcOEt obtained and placed in a separatory funnel. Add 50 ml of 1N HCl, then wash twice with brine, then dry over MgSO ₄ , filter and concentrate under vacuum. The product is AcO
Crystallize from Et. In this way the expected compound is obtained in the form of white crystals. (Yield 50%) Analysis : TLC: Rf = 0.20 (in CH ₂ Cl ₂ / MeOH = 9: 1) ¹ H-NMR (CDCl ₃ , δ, ppm) 8.02 (1H, broad s ): - COOH 7.32 (2H, d): 6.96 (2H, d): aromatic H 5.09 (2H, s): HOOC- CH 2 -O- 4.70 (2H, s): _{-Ph- CH 2 -O- 2.12 (3H,} s): - CO-CH 3 -

Step 12 : Compound 15

[Chemical 80]

The procedure is carried out as in step 5 above to give compound 8, except that compound 13 obtained in step 10 above is used in place of compound 3 obtained in step 3 of the above preparation, Instead of the compound 6 obtained in the above step 3, the compound 14 obtained in the above step 11 is used. The reaction medium is left to settle,
The crystals are filtered on Iena and dried. The expected compound is thus obtained in the form of red crystals. (Yield 24%)

Analysis : TLC: Rf = 0.36 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (Nujol method) 3215 cm ⁻¹ NH / OH absorption 1731, 1658 and 1635 cm ⁻¹ C═O Absorption 1591, 1536 and 1512 cm ^-1 Amide II band + Absorption of aromatic ring + N
O ₂ absorption NMR: (DMSO-d6) (see compound 12 for unchanged chemical shift).

[Chemical 81]

Step 13 : Dendrimer a

[Chemical formula 82]

In a 50 ml flask, the compound 15 obtained in step 12 above (0.8
6 g, 0.23 mmol) was dissolved in 20 ml MeOH and to this was added K ₂ CO ₃ (
0.51 g, 3.69 mmol, 16 eq) are added. Stir overnight at ambient temperature under a nitrogen atmosphere. The reaction medium is extracted with CH ₂ Cl ₂ and the organic phase is washed with water. Insoluble crystals are found at the interface of the two phases, which are filtered on Iena and then dried in a dessicator. The expected compound is thus obtained in the form of red crystals. (Yield 80%)

Analysis : TLC: Rf = 0 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (Nujol method) NH / OH absorption 1657 cm ⁻¹ C═O absorption 1589, 1536 and 1509 cm ⁻¹ amide II band + absorption of aromatic ring + conjugated system + NO ₂ absorption NMR: (DMSO-d6) (see Compound 12 for unchanged chemical shift).

[Chemical 83]

[0117] Example 2: Branching synthesis route for dendrimer a (Dendrimer with 8 branches) (Fig. 7)

Step 1 : Compound 16

[Chemical 84]

Compound 9 (0.46 g, 0.72 mmol) obtained in step 6 of example 1 was dissolved in 80 ml of CH ₃ CN to give compound 6 (1 obtained in step 3 of example 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 dawn overnight, the medium precipitates. It is heated to 80 ° C. to dissolve everything and then left at ambient temperature to reprecipitate. The crystals are filtered. The expected compound is thus obtained in the form of red crystals. (Yield 74%) Analysis : TLC: Rf = 0.38 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (Nujol method) NH / OH absorption 1637, 1684 and 1705 cm ⁻¹ C═O Absorption 1518, 1528, 1587 and 1599 cm ^-1 Amide II band + aromatic ring absorption + NO ₂ absorption

Step 2 : Compound 17 Deprotection of the BOC group of compound 16 obtained in step 1 above is carried out by carrying out as in step 4 of example 1 to obtain compound 7. Use 50 equivalents of HCl. (Yield = Q) Thus, the desired compound was obtained in the form of purple crystals.

Step 3 : Compound 12

[Chemical 85]

The procedure is carried out as in step 1 above, using compound 17 obtained in step 2 above instead of compound 9. The expected compound is thus obtained in the form of red crystals. (Yield 71%) Analysis : TLC: Rf = 0.43 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) NH / OH absorption 1638 and 1682 cm ⁻¹ C═O absorption 1518 and 1590 cm ^-1 amide II band + aromatic ring absorption + NO ₂ absorption

Step 4 : Compound 13 Deprotection of the BOC group of compound 12 obtained in step 3 above is carried out by carrying out as in step 4 of example 1 to obtain compound 7. 160
Use an equivalent amount of HCl. (Yield = Q) Thus, the desired compound was obtained in the form of purple crystals.

Step 5 : Compound 15

[Chemical 86]

The procedure is carried out as in step 12 of example 1, starting from the compound 13 obtained in step 4 above. The expected compound is thus obtained in the form of red crystals. (Yield 64%) Analysis : TLC: Rf = 0.51 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3436 cm ⁻¹ Associated NH absorption 1651, 1674 and 1735 cm ^−1. C = O absorption 1514, 1536 and 1595 cm ^-1 Amide II band + aromatic ring absorption + N
O ₂ absorption

Step 6 : Dendrimer a Starting from compound 15 obtained in step 5 above, the procedure is carried out as in step 13 of example 1. In this way the expected compound is obtained.

Example 3 : Branched synthesis of dendrimer b (dendrimer with 9 branches) (FIG. 8)

Step 1 : Compound 18

[Chemical 87]

In a method using PTBD as in step 2 of example 1, methyl gallate was used instead of methyl 3,5-dihydroxybenzoate, which was obtained in step 1 of example 1 under the same conditions. Alkylation is carried out by reacting with compound 4. In this way the expected compound 18 is obtained in the form of white crystals. (Yield 80%)

[0130] Analysis: TLC: Rf = 0.35 (CH 2 Cl 2 / AcOEt = 7: 3 in) IR: (in CHCl ₃₎ 3457cm ^-1 NH absorption 1709 cm ^-1 C = O absorption 1589 and 1507Cm ^- Absorption NMR of ¹ amide II band + aromatic ring: (CDCl ₃ ).

[Chemical 88] MS: (in MeOH) 656 ⁺ = M ⁺ 678 ⁺ = [M + Na] ⁺ 556 ⁺ = [M + H-CO ₂ tBu] ⁺ 456 ⁺ = 556 ⁺ -BOC 500 ⁺ = 556 ⁺ -tBu 444 ⁺ = 500 ⁺ -tBu. 356 ⁺ = 456 ⁺ -BOC

Step 2 :

[Chemical 89]

Compound 18 obtained in Step 1 above in place of compound 5 obtained in Step 2 of Example 1
Is carried out as in step 3 of example 1. The expected compound 19 is thus obtained in the form of white crystals. (Yield = Q) Analysis : TLC: Rf = 0.26 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3457 cm ⁻¹ NH absorption 1706 cm ⁻¹ C═O absorption 1507 and 1586 cm ^-1 amide II band + aromatic ring of absorbent MS :( electrospray, negative mode, in ^{MeOH) 640 - = [M-} H] -

Step 3 :

[Chemical 90]

Substituting the compound 19 obtained in step 2 above for the compound obtained in step 8 of example 1 and substituting the compound 9 obtained in step 6 of example 1 for the preparation of the colored part Using compound 3 obtained in 3, the procedure is carried out as in step 9 of example 1. The expected compound 20 is thus obtained in the form of red crystals. (Yield 84%)

[0135] Analysis: TLC: Rf = 0.55 (CH 2 Cl 2 / MeOH = 9: 1 in at) IR: (in CHCl ₃₎ 3453cm ^-1 NH absorption 1706 and 1659 cm ^-1 C = O absorption 1493, 1516, 1559, 1588 and 1601 cm ^-1 amide II band + absorption of aromatic ring + NO ₂ absorption + conjugated system NMR: (CDCl ₃ ).

[Chemical Formula 91] MS: (in MeOH) 937 ⁺ = [M + H] ⁺ 959 ⁺ = [M + Na] ⁺ 881 ⁺ = [M + H-tBu] ⁺ 837 ⁺ = [M + H-CO ₂ tBu] ⁺ 781 ⁺ = 881 ⁺ -CO ₂ tBu 737. _{^{+ = 837 + -CO 2 tBu 637}} + = 737 + -CO 2 tBu

Step 4 : Compound 21 Deprotection of the BOC group of compound 20 obtained in Step 3 above is carried out as done in Step 4 of Example 1 to obtain Compound 7. 60 equivalents of H
Cl is used. (Yield = Q) Thus, the desired compound 21 was obtained in the form of purple crystals.

Step 5 : Compound 21a Perform the procedure as in Step 3 above, except that Step 3 of preparation of the colored moiety is
Compound 21 obtained in Step 4 above is used in place of Compound 3 obtained in Step 3 above, and this is reacted with Compound 19 obtained in Step 2 of Example 3. Thus the expected compound 21a is obtained analytical _{TLC: Rf = 0.58 (CH 2} Cl 2: Among ^{MeOH = 8/2) 1 H} -NMR (CDCl 3, δ, ppm) 7.87 (2H , D): 8.29 (2H, d): aromatic H (O ₂ N-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-O- CH 2 -CH 2 - 3.80~ 3.10 (28H, m): - Ph-N- CH 2 -CH 2 - + -C
_{H 2 - CH 2 -N- 3.56 (} 2H, m): - CH 2 -CH 3 1.75~2.10 (24H, m): - CH 2 - CH 2 -CH 2 - 1.42 ( 81H, s): tBOC 1.26 ( 3H, t): - CH 3 -CH 2 - MS (FAB): MH + = [2508.9] + [MH + -CO 2 tBu] + + H = [2408] ⁺

Step 6 : Compound 21b To achieve deprotection of the BOC group of compound 21a obtained in Step 5 above, the procedure is carried out as in Step 4 above. 180 equivalents of HCl are used.
(Yield = Q) Thus, the desired compound 21b was obtained in the form of purple crystals. Analysis ¹ H-NMR (CDCl ₃ , δ, ppm) 8.20 (18H, m): Mobility H 8.35 (2H, d): 7.92 (2H, d): Aromatic H (O ₂ N) -Ph-N
) 7.29 (2H, s): 7.26 (4H, s): 7.33 (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-O- CH 2 -CH 2 - 3.70~3.40 (10H, m): - Ph-N- CH ₂ -CH ₂ - + -C
_{H 2 - CH 2 -NH-CO} 3.56 (2H, m): - CH 2 -CH 3 3.00 (18H, m): - CH 2 - CH 2 -NH 2 1.85~2.20 ( _{24H, m): - CH 2} - CH 2 -CH 2 - 1.18 (3H, t): - CH 3 -CH 2 - MS (EI, 70eV): (MH + + 2H) + + H = [804] +

Step 7 : Compound 21c The procedure is carried out as in Step 12 of Example 1, except that the compound 21b obtained in Step 6 above is reacted with the compound 14 obtained in Step 11 of Example 1. Let Compound 21 obtained in step 6 above in 4 ml of anhydrous CH ₂ Cl ₂
b (114 mg) is placed in a 20 ml flask. Then BOP (226 mg,
9.9 eq.) And compound 14 (100 mg) obtained in step 11 of Example 1 are introduced, followed by DIEA (244 μl, 27 eq.). The reaction is worked up by evaporation to dryness after 3 hours. Chromatography first with Sephadex LH 20 (CH ₂ Cl ₂ / MeOH = 95/5) and then with silica (CH ₂ Cl ₂ / MeOH = 97/3), The polarity of the eluent is increased to CH ₂ Cl ₂ / MeOH = 95/5. In this way the expected compound is obtained. (Yield 30%) Analytical TLC: Rf = 0.3 (in CH ₂ Cl ₂ / MeOH = 95/5) MS (FAB): MH ⁺ = [3463.1] ⁺

Step 8 : Dendrimer b The compound 21c obtained in Step 7 above is worked up as in Step 13 of Example 1. In a 5 ml flask, Compound 21c (58 mg, 0.016 mmol) obtained in Step 7 above was treated with MeOH / CH ₂ Cl ₂ (6/4).
Dissolve in 2 ml. Then K ₂ CO ₃ (41.5 mg, 2 eq) is introduced.
Stir for 3 hours, then extract with CH ₂ Cl ₂ and wash with water. The purified red precipitate at the interface of CH ₂ Cl ₂ and water is then filtered on Iena. In this way the expected compound is obtained. Analysis _{TLC: Rf = 0.47 (CH 2} Cl 2: Among ^{MeOH = 8/2) 1 H} -NMR (DMSO, δ, ppm) 8.31 (2H, bd): 7.91 (2H, bd ): Aromatic H (O ₂ N-Ph
-N) 7.83 (2H, bd): 6.96 (2H, d): aromatic H (N-Ph-N) 7.30-6.80 (44H, m): aromatic H 4.49 ~4.30 (36H, m): - PH-CH 2 -O- + CO-CH 2 -O- 3.90~4.10 (24H, m): - PH-O- CH 2 -CH 2 - 3.60~3.30 (31H, m): - PH-N- CH 2 -CH 2 - + -C
_{H 2 - CH 2 -NH-CO} + - CH 2 -CH 3 1.75~2.08 (24H, m): - CH 2 - CH 2 -CH 2 - 1.15 (3H, t): - CH ₃ -CH ₂ -

Example 4 : Branched synthesis of dendrimer c (FIG. 9) Step 1: Compound 22

[Chemical Formula 92]

Substituting Compound 21 for Compound 9 and Compound 6 for Compound 11,
The operation is carried out as in step 9 of example 1. BOP (0.98 g, 1 equivalent),
DIEA (0.38 ml, 1 eq) using and CH ₃ CN50ml. The reaction medium is heated to 80 ° C. and 40 ml DMF are added. The medium is extracted with CH ₂ Cl ₂ , the organic phase is washed with water, NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated. Chromatography of the crystals (CH ₂ Cl ₂ / MeO
H = 95/5 used). The resulting oil was taken up in AcOEt, washed with water, NaOH, NH ₄ Cl, brine, then MgS.
Dry over O ₄ , filter and concentrate. In this way the expected compound 22 is obtained in the form of red crystals. (Yield 50%)

Analysis : TLC: Rf = 0.50 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) 3448 cm ⁻¹ NH absorption 1708 and 1653 cm ⁻¹ C═O absorption 1515 and 1,595 cm ^-1 amide II band + aromatic ring absorption + NO ₂ absorption NMR: (CDCl ₃ ).

[Chemical formula 93]

Step 2 : Compound 23 Deprotection of the BOC group of compound 22 obtained in step 1 above to give compound 23 is carried out as in step 4 of example 1 to obtain compound 7. . Use 100 equivalents of HCl. (Yield = Q) Thus, the desired compound 23 was obtained in the form of purple crystals.

Step 3 : Compound 24

[Chemical 94]

Compound 23 obtained in step 2 above as in step 12 of example 1
The procedure is carried out by reacting with the compound 14 obtained in step 11 of example 1. In this way the expected compound 24 is obtained in the form of red crystals. (Yield 65%)

Analysis : TLC: Rf = 0.44 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (in CHCl ₃ ) NH / OH absorption 1657 cm ⁻¹ C═O absorption 1509, 1536 and 1589 cm ^-1 Amide II band + aromatic ring absorption + N
O ₂ absorption + conjugated system NMR: (CDCl ₃ )

[Chemical 95]

Step 4 : Dendrimer c

[Chemical 96]

The procedure is carried out as in step 13 of example 1, substituting the compound 23 obtained in step 3 above for the compound 15 obtained in step 12 of example 1. The crystals are recrystallized with CHCl ₃ , MeOH and H ₂ O. In this way the expected compound, dendrimer c, was obtained in the form of red crystals. (Yield 80%)

Analysis : TLC: Rf = 0 (in CH ₂ Cl ₂ / MeOH = 9: 1) IR: (Nujol method) NH / OH absorption 1653 cm ⁻¹ C═O absorption 1509, 1539, 1588 and 1600 cm ^{− 1} NH ₂ absorption + aromatic ring absorption + NO ₂ absorption + conjugated system NMR: (DMSO-d6) (see compound 12 for unchanged chemical shifts).

[Chemical 97] MS: FAB 2377 ⁺ = MH ⁺ 2399 ⁺ = [M + Na] ⁺

Example 5: Use of Dendrimer b as a Soluble Carrier in Organic Chemistry Step 1 : Compound 26

[Chemical 98]

Dendrimer b (0.35 g, 0.11 mmol) prepared in Example 3 was added to D
Dissolved in 20 ml of MF then compound 25 (0.50 g, 2.04 mmol, 2 eq / fct), DCC (0.42 g, 2.04 mmol, 2 eq / fct).
) And DMAP (0.31 g, 0.25 mmol, 025 eq / fct) are added. Stir overnight under nitrogen atmosphere. The next day, the reaction medium is heated to 50 ° C. DC
Filter U over Iena. Evaporate DMF. The crystals are taken up in 5 ml of CH ₂ Cl ₂ and passed through a Sephadex cartridge swollen with the same solvent. (86% yield, red crystals)

Analysis : TLC: Rf = 0.27 (in CH ₂ Cl ₂ / MeOH = 93: 7) IR: (in CHCl ₃ ) 3429 cm ⁻¹ NH absorption 1672 and 1725 cm ⁻¹ C═O absorption 1496, 1513, 1539, 1585, 1601 and 1612 cm ^-1 amide II band + aromatic ring absorption + NO ₂ absorption + conjugated system NMR: (CDCl ₃ ).

[Chemical 99]

Step 2 : Compound 27

[Chemical 100]

Compound 26 obtained in Step 1 above (244 mg, 0.047 mmol)
Is dissolved in 10 ml DMF. Compound 26a (0.109 g, 0.85 mmol, 2 eq / fct), Pd (PPh ₃ ) (0.024 g, 0.021 mmol, 0.05 eq / fct), then Na ₂ CO ₃ (0.53 ml). , 1.06 mmol, 2.5 eq / fct) are added. The reaction medium is heated to 110 ° C. under argon.
Heat to overnight. The medium is extracted with AcOEt. The organic phase is washed with water, 0.
Wash with 1N NaOH, NH ₄ Cl, brine, then dry over MgSO ₄ , filter and concentrate. A solution of crystals in CH ₂ Cl ₂ was added to Sephad
Pass through an ex LH 20 cartridge. The expected compound 27 is obtained in the form of red crystals. (
Yield 52%)

Analysis : TLC: Rf = 0.37 (in CH ₂ Cl ₂ / MeOH = 93: 7) IR: (in CHCl ₃ ) 3427 cm ⁻¹ NH absorption 1673 and 1718 cm ⁻¹ C═O absorption 1496, 1513, 1539, 1587, 1601 and 1612 cm ^-1 amide II band + absorption of aromatic ring + NO ₂ absorption + conjugated system NMR: (CDCl ₃ ).

[Chemical 101]

Step 3 : Compound 28

[Chemical 102]

Compound 27 (94 mg, 0.019 mmol) obtained in step 2 above is dissolved in 5 ml of TFA / CH ₂ Cl ₂ solution (8: 2). After 1 hour, the reaction medium is evaporated to dryness. The crystals were taken out in CH ₂ Cl ₂ and the organic phase was washed with 0.1N-NaO.
Wash with H, filter the two phases, collect the aqueous phase, and neutralize it with 2N HCl. It is extracted with AcOEt, the organic phase is dried over MgSO ₄ , filtered and concentrated. The expected compound 28 is thus obtained in the form of white crystals. (Yield 45%)

Analysis : TLC: Rf = 0.44 (in CH ₂ Cl ₂ / MeOH = 8: 2) IR: (in CHCl ₃ ) Acid type OH absorption 1734 and 1698 cm ⁻¹ C═O absorption 1600 and 1575 cm ^-1 Absorption NMR of aromatic and heterocycles: (CDCl ₃ )

[Chemical 103] MS: (EI 70 eV, direct introduction, in ^{MeOH) 204 + = M + 187} + = [M-OH] +

Example 6 : Use of dendrimer c as a soluble carrier in organic synthesis Step 1 : Compound 30

[Chemical 104]

The procedure is carried out as in step 1 of example 5, substituting dendrimer c for dendrimer b and substituting compound 29 for compound 25. Add 1 equivalent of acid and DCC twice. The expected compound 30 is thus obtained in the form of red crystals. (Yield 63%)

Analysis : TLC: Rf = 0.27 (in CH ₂ Cl ₂ / MeOH = 93: 7) IR: (Nujol method) NH / OH absorption 1653 and 1716 cm ⁻¹ C═O absorption 1511, 1533 and Absorption NMR of 1585 cm ^-1 amide II band + aromatic ring: (DMSO-d6)

[Chemical 105]

Step 2 : Compound 32

[Chemical formula 106]

Compound 30a obtained in Step 1 above was used in place of compound 26 to obtain compound 26a
The procedure is carried out as in step 2 of example 5, substituting compound 31 for
1 equivalent of acid and DCC were added twice. Sephadex LH-20 is CH ₂ Cl ₂ / MeO
Swell at H = 95: 5. In this way the expected compound 32 is obtained in the form of red crystals. (Yield 82%)

Analysis : TLC: Rf = 0.38 (in CH ₂ Cl ₂ / MeOH = 93: 7) IR: (in CHCl ₃ ) 3428 cm ⁻¹ NH absorption 1674 and 1710 cm ⁻¹ C═O absorption 1489, 1513, 1536, 1592, 1600 and 1607 cm ^-1 amide II band + aromatic ring absorption + NO ₂ absorption NMR: (CDCl ₃ ).

[Chemical formula 107]

Step 3 : Compound 33

[Chemical 108]

The procedure is carried out as in step 3 of example 5, substituting compound 32 obtained in step 2 above for compound 27. This dendrimer is soluble in the organic phase. The expected compound 33 is thus obtained in the form of white crystals. (Yield 50%) Analysis : TLC: Rf = 0.26 (in CH ₂ Cl ₂ / MeOH = 85: 15) IR: (in CHCl ₃ ) OH absorption 1676 cm ⁻¹ C═O absorption 1560, 1580 and Absorption NMR of 1608 cm ^-1 aromatic nucleus: (in CDCl ₃ ) MS: (EI, 70 eV, direct introduction and in MeOH) 198 ⁺ = M ⁺ 181 ⁺ = [M-OH] ⁺ 153 ⁺ = [M-COOH] ⁺ 152 ⁺ = [M-COOH-H] ⁺

Example 7 : Branching Synthesis of Dendrimer d1 Step 1: Synthesis of Compound 37 / Preparation of Compound 34

[Chemical 109]

In a 250 ml flask, 4-hydroxymethylphenol (5 g, 0.0
4 mol, 1 eq) is dissolved in 100 ml of pyridine. Introduce TBDMSCl (7.28 g, 0.048 mol, 1.2 eq) under N ₂ at 0 ° C. and stir at ambient temperature for 3 h. Evaporate pyridine then AcOEt 250m
Extract with l, wash once with HCl (1N) and twice with H ₂ O—NaCl.
The organic phase was dried over MgSO _4, filtered and concentrated. The product was chromatographed on silica (eluent CH ₂ Cl ₂ / MeOH = 95: 5) to give a yellow oil. (Yield 57%)

Analysis : TLC: (eluent = CH ₂ Cl _{2 /} MeOH, 95/5) Rf = 0.49 ¹ H-NMR (CDCl ₃ ).

[Table 1]

[0171] .Preparation of compound 35

[Chemical 110]

In a 500 ml flask, compound 34 (5 g, 0.021 mol, 1 eq) was dissolved in 80 ml of DMF to which bis (2-bromoethyl) ether (14
． 6 g, 0.063 mol, 3 eq) and K ₂ CO ₃ bases (9.27 g, 0.067
Mol, 3.2 eq) is added under nitrogen. The reaction medium is stirred at 60 ° C. for 19 hours. The reaction medium is taken up in AcOEt and then washed twice with water,
Washed with washed with NaHCO _3, H ₂ O-NaCl, dried, filtered and concentrated. The product is chromatographed on silica (eluent = CH ₂ Cl ₂ ). A yellow oil was obtained. (Yield 72%)

Analysis : TLC: (eluent = CH ₂ Cl ₂ / cyclohexane, 95/5) Rf = 0.49 ¹ H-NMR (CDCl ₃ ).

[Table 2] MS: (EI, 70 eV, direct introduction) 388 ⁺ = M ⁺ (isotopic multiplex characteristic of the presence of bromine) 331 ⁺ = M ⁺ -(tBu ⁺ = 57 ⁺ ) 287 ⁺ = M ⁺ -(tBu-SiCH ₃ ). ^{257 + = M + - (OSi} (CH 3) 2 C (CH 3) 3) IR: (CHCl 3 in) 1612,1587 and 1511cm ^-1: absorption of the aromatic nucleus 1252,839cm ^-1: OSi absorption

[0174] .Preparation of compound 36

[Chemical 111]

In a 500 ml flask at room temperature under N ₂ cesium carbonate (7.96 g
, 24.4 mmol, 4.5 eq) were introduced rapidly, followed by methyl gallate (1
g, 5.43 mmol, 1 eq) dissolved in 20 ml DMF was added and finally compound 35 (9.51 g, 24.4 mmol, 4.5 eq) was also dissolved in 20 ml DMF. Add Stir at 50 ° C. for 18 hours and then at ambient temperature for 48 hours. This medium is extracted with AcOEt, water,
Wash successively with NaHCO ₃ , HCl, NaCl, H ₂ O, NaHCO ₃ , NaCl, then dry, filter and concentrate. The product is chromatographed on silica (eluent = heptane / AcOEt, 7: 3). A yellow oil was obtained. (70% yield)

Analysis : TLC: (eluent = heptane / AcOEt, 7/3) Rf = 0.16 ¹ H-NMR (CDCl ₃ ).

[Table 3] ^{MS: 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 -O-Ph-CH 2 -O-Si (CH 3) 2 C (
^{_{CH 3) 3) + IR:}} ( in CHCl ₃₎ 1716cm ^-1: absorption of the conjugated ester 1612,1587,1511cm ^-1: absorption of the aromatic nucleus 1252,839cm ^-1: OSi absorption

[0177] .Preparation of compound 37

[Chemical 112]

In a 30 ml flask, compound 36 (0.5 g, 0.45 mmol, 1 eq) is dissolved in 4 ml EtOH. 450 μl of 2N NaOH (2 eq) is introduced. After stirring overnight at ambient temperature, EtOH is evaporated, the medium is acidified with 500 μl of 2N HCl and then extracted with AcOEt and washed 3 times with water. The organic phase was dried over MgSO _4, filtered and concentrated. (95% yield, white crystals) Analysis: TLC :( eluent ^{_{= CH 2 Cl 2 /AcOEt,94/6)Rf=0.23 1 H}} -NMR (CDCl 3) CH at 3.87ppm ₃ -O- Same chemical shift as compound 36 except that the CO signal disappeared: 1117.6 ⁺ = (M + Na) ⁺ 1095.6 ⁺ = (M + H) ⁺ 963.5 ⁺ = (M + H- (O-Si (CH ₃ )). _{2 -C (CH 3) 3)} + 905.5 + = (M + H- (O-Si (CH 3) 2 -C (CH 3) 3) -tBu) + 831.5 + = (M + H - ((CH _{2) 2 -O-Ph-CH} 2 -O-Si (CH 3) 2 C (
CH ₃ ) ₃ ) ⁺

Step 2 : Compound 38 obtained by coupling

[Chemical 113]

[0180]   In a 50 ml flask, compound 37 (1.101 g, 1 mmol, 5.8 equiv.
Amount) is dissolved in 10 ml of acetonitrile. Compound 21 (0.129 g, 0
． 173 mmol, 1 eq), then BOP (0.444 g, 1 mmol, 5.
8 eq) and DIEA (0.48 ml, 2.66 mmol, 16 eq) with N 2₂under
At ambient temperature. After 2 days of reaction, the medium was taken up in AcOEt.
Take out, wash with water (twice), NaHCO.₃Wash with. After evaporating under vacuum
, 1.0 g of crude product was obtained, which was purified on a Sephadex LH20 cartridge
Afterwards 0.58 g of the expected compound is obtained.analysis : IR: (CHCl₃During)   3520-3440 cm^-1  OH / NH absorption   1650 cm^-1  Amide   1610, 1600, 1588, 1540 and 1512 cm^-1: Conjugate system + NO ₂ + Amide II + aromatic ring

Step 3 : Dendrimer d1 obtained by deprotection of compound 38

[Chemical 114]

In a 50 ml flask, compound 38 (0.200 g, 0.05 mmol, 1
Equivalent) is dissolved in 10 ml of anhydrous THF. THF at ambient temperature under N ₂
1 ml of a solution of nBu ₄ NF in (1M) is added. The reaction medium is stirred for 16 hours at ambient temperature and then evaporated to dryness under vacuum. The residue thus obtained was purified by Sephadex LH20 to obtain 0.11 g of the desired compound.

[Brief description of drawings]

[Figure 1]   1 represents the chemical formula of dendrimer a according to the present invention.

[Fig. 2]   3 represents the chemical formula of dendrimer b according to the present invention.

[Figure 3]   1 represents the chemical formula of dendrimer c according to the present invention.

[Figure 4]   3 represents the chemical formula of dendrimer d according to the present invention.

[Figure 4.1]   3 represents the chemical formula of dendrimer d1 according to the invention.

FIG. 5 is a diagram outlining the synthesis of core moieties for dendrimers a, b, c and d according to the present invention.

[Figure 6]   1 is a diagram outlining a convergent synthesis of dendrimer a according to the present invention.

[Figure 7]   1 is a diagram showing an outline of branched synthesis of dendrimer a according to the present invention.

[Figure 8]   1 is a diagram outlining a branched synthesis of dendrimer b according to the present invention.

[Figure 9]   1 is a diagram outlining a branched synthesis of dendrimer c according to the present invention.

FIG. 10 is a diagram outlining an example of the use of dendrimers b or c according to the invention as soluble carriers in organic synthesis.

FIG. 11 is a diagram outlining an example of the use of the dendrimers according to the invention as soluble carriers in organic synthesis.

FIG. 12a   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

FIG. 12b   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

FIG. 12c   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

FIG. 12d   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

FIG. 12e   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

FIG. 12f   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

Figure 12g   7 is an example of a moiety P in a compound of formula (P-Y) according to the invention.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C09B 69/10 C09B 69/10 AB (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AE, AG, AL, AU, BA, BB, BG, BR, BZ, CA, CN, CR, CU, CZ, DM, DZ, E. , GD, GE, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV, MA, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, TT, UA, US, UZ, VN, YU, ZA

Claims (15)

[Claims] 1. A compound of formula (P-Y), characterized in that Y represents a dendrimer residue and P represents a colored moiety. 2. Y represents a dendrimer residue and the colored moiety P is Or [Chemical 2] [Wherein R4 represents a phenyl, naphthyl or benzothienyl group optionally substituted with one or more substituents selected from R6 and R7, n represents an integer 1 or 2, R5, R6, R7, R8, R9, R10 and R11 may be the same or different and each is a hydrogen atom, a halogen atom, a linear or branched alkyl or alkoxy group having at most 4 carbon atoms, a hydroxyl group, Represents an amino group substituted by a phenoxy group, a nitro group, or an acyl group or by one or two straight-chain or branched-chain alkyl groups having at most 4 carbon atoms, where These alkyl groups may themselves be hydroxyl, cyano, acyl, acyloxy or phenyl groups (which may themselves be straight chain or branched chain alkyl groups having up to 4 carbon atoms). In may be substituted optionally with optionally substituted optionally), naphthyl groups may be further substituted formula ## STR3 ## which may R4 represents (Wherein R6 has the meaning given above) optionally substituted with a group of], or a compound of formula (P-Y) according to claim 1 or A salt of a compound of formula (P-Y). 3. In the colored moiety P, where Y is a dendrimer residue and R4 is of the formula: A naphthyl group substituted with a group of: a benzothienyl group substituted with nitro or a linear or branched alkoxy group having at most 4 carbon atoms, or a halogen atom, hydroxyl, at most 4 Represents a phenyl group substituted with one or more groups selected from a linear or branched alkyl or alkoxy group having 1 carbon atom and a nitro group, and R5 represents a hydrogen atom, a hydroxyl group, or an acyl group. Represents an amino group optionally substituted by 1 or 2 straight-chain or branched-chain alkyl radicals having at most 4 carbon atoms, which or these alkyl radicals are themselves hydroxyl, cyano or It may be optionally substituted with an acyloxy group, R6 and R7 may be the same or different, and may be a hydrogen atom, a halogen atom or a poly atom. Both represent a linear or branched alkyl or alkoxy group having 4 carbon atoms, R8 represents a hydrogen atom, and R9, R10 and R11 may be the same or different, and are hydrogen atoms; Hydroxyl group; phenoxy group; optionally phenyl group, which itself may be optionally substituted with straight or branched chain alkyl groups having up to 4 carbon atoms.
Or an amino group optionally substituted with a linear or branched alkyl group having at most 4 carbon atoms, which may itself be optionally substituted with a hydroxyl group. The compound of formula (P-Y) or the compound of formula (P-Y) according to claim 1 or 2, characterized in that
) Compound salt. 4. Y represents a dendrimer residue and the colored portion P is shown in FIG.
A compound of formula (P-Y) or a salt of a compound of formula (P-Y) according to any of claims 1 to 3, characterized in that it is selected from the fragments shown in 2. 5. Y represents a dendrimer residue and the colored moiety P is of the formula: A compound of formula (P-Y) or a salt of a compound of formula (P-Y) according to any of claims 1 to 4, characterized in that it represents a fragment of 6. P has the meaning according to any one of claims 1 to 5 and Y is the following formula (I): {Wherein R1, R2 and R3 may be the same or different, R2 represents a hydrogen atom or is selected from R1 and R3, and R1 and R3
Are X1, X2, X3 and X4 defined as follows: (Where, Z is _{- ((CH 2) n1 -W} ) represents _n2, W is a divalent oxygen atom -O- or represents an amide bond -NH-CO-, n1 represents an integer of 2-6, n2 represents an integer of 0 to 3, Y ₁ , Y ₂ , Y ₃ and Y ₄ may be the same or different, and a functional group —OH,
-Br, -Cl, -I, -SH, -CO 2 H, -CO 2 Cl, -CO 2 Br, -S
O ₃ H, -SO ₂ Cl, or represents -NH ₂ and -CH = CH _2, or one of the following things to these functional groups: - 2,4-dimethoxy-4'-hydroxybenzophenone, & 4- ( 4-hydroxymethyl-3-methoxyphenoxy) butyric acid, 4-hydroxymethylbenzoic acid, 4-hydroxymethylphenylacetic acid (L ₁ ), 3- (4-hydroxymethylphenoxy) propionic acid, p-[( R, S) -α- [1- (9H-fluoren-9-yl) methoxyformamide] -2,4-dimethoxybenzyl] phenoxyacetic acid, p-hydroxymethylphenol linker (L ₂ ), MBHA linker, Rink amide linker, -Sieber linker, -representing a residue obtained after reacting a linker L selected from a trityl linker Characterized in that representing the dendrimer residue selected from the compounds of} is selected from the a) or claim 1
A compound of formula (P-Y) or a salt of a compound of formula (P-Y) according to any one of claims 1 to 5. 7. The colored part P has the meaning according to any one of claims 1 to 5, and Y is Z, W, n1, n2, Y in formula (I) according to claim 6. ₁ ,
Y ₂ , Y ₃ and Y ₄ have the meanings of claim 6 and R 1, R 2 and R 3 are: R 2 is hydrogen and R 1 and R 3 are selected from X 1, or R 1, R 2 and R 3 are A compound of formula (P-Y) or formula (P-Y) according to any of claims 1 to 6, characterized in that it represents a dendrimer residue selected from compounds which either represent X2 or X3. -Y)
Salt of the compound. 8. The colored portion P has the meaning according to any one of claims 1 to 5, and Y is R1, R2, R3, n2 in the formula (I) according to claim 6.
Y ₁ , Y ₂ , Y ₃ and Y ₄ have the meanings of claims 6 and 7 and Z is-((CH ₂ ) ₃
-NH-CO) _n2 - or _{- ((CH 2) 2 -O} ) n2 - , wherein the representing the dendrimer residue selected from the compounds represented the formula according to claim 1 A compound of (P-Y) or a salt of a compound of formula (P-Y). 9. The colored part P has the meaning according to any of claims 1 to 5 and Y is R1, R2, R3, n1, in the formula (I) according to claim 6.
_{n2, Y 1, Y 2,} Y 3 and Y ₄ is and Z have the meanings of any of claims 6-8 _{- (CH 2) 3 -NH-} CO- or - (CH _{2) 2} - A compound of formula (P-Y) or a salt of a compound of formula (P-Y) according to any of claims 1 to 8, characterized in that it represents a dendrimer residue selected from compounds representing O-. . 10. The colored portion P has the meaning according to any one of claims 1 to 5, and Y is R1, R2, R3, n1, in the formula (I) according to claim 6.
_{n2, Z, W, Y 1} , Y 2, Y 3 and Y ₄ represent a dendrimer residue selected from compounds having the meanings of any of claims _{6~9, Y 1, Y 2,} Y ₃ and Y ₄ represent the residue obtained after reaction with the linker L, which linker L is: 4-hydroxymethylphenoxyacetic acid (L ₁ ), p-hydroxymethylphenol linker (L ₂ ), a formula (P-Y) according to any one of claims 1 to 9, characterized in that it is selected from Rink amide linkers.
) Compound. 11. The linker L is a linker (L ₁ ), that is, Or a linker (L ₂ ), that is The compound of formula (P-Y) or the salt of the compound of formula (P-Y) according to any one of claims 1 to 10, wherein 12. A dendrimer a, b, c, d and d1 defined by FIGS. 1, 2, 3, 4 and 4.1, respectively, corresponding to the formulas 1 to 11.
A compound of formula (P-Y) according to any one of the above. 13. A method for producing the compound of formula (PY) according to any one of claims 1 to 12, which comprises the following formula (D ₁ ): (Wherein R4 represents hydrogen or hydroxyl, and alk represents an alkyl group having at most 4 carbon atoms), a compound of the formula (D ₂ ): (Where, Br represents a bromine atom, G is - (CH _{2) n1} -, or _{- ((CH 2) 2 -O-} (CH 2) 2) - represents a divalent radical, n1 is 2 to 6 Represented by the following formula (D ₃ ): [Wherein G and alk have the above-mentioned meanings and R5 represents a hydrogen atom or a -O-G-NH-COOtBu group (wherein G has the above-mentioned meaning)], The compound of the formula (D ₃ ) is saponified to give the following formula (D ₄ ): (Wherein G and R5 have the above-mentioned meanings) or by deprotecting the amine functional group of BOC in the compound of formula (D ₃ ) by the following formula (D ₅ ): ] (Wherein G and alk have the meanings given above, and R6 represents H or —O—G—NH ₂ .ClH) and then either of the following routes (1) or (2) Carry out the process according to
(1) According to the so-called convergent route, (a) the compound of the above formula (D ₄ ) is reacted with the compound of the above formula (D ₅ ) to give the following formula (
D ₆ ): [Chemical formula 15] {Where G and alk have the meanings given above, Ra ₂ represents H or Ra ₁ or Ra ₃ , and Ra ₁ and Ra ₃ are of the formula: (Wherein R5 has the above meaning) and a compound of the formula (D ₆ ) is saponified to obtain a compound of the following formula (D ₇ ): (Wherein Ra ₁ , Ra ₂ and Ra ₃ have the above-mentioned meanings), and (b) the compound of the formula (D ₄ ) is converted into the following formula (D ₈ ): (Wherein P has the meaning defined in any one of claims 1 to 5) and reacted with a compound of the following formula (D ₉ ): (Wherein G, P and R5 have the above-mentioned meanings), and deprotecting the amine functional group of BOC therein, the following formula (D ₁₀ ): (Wherein G, P and R6 have the above-mentioned meanings), and the compound of formula (D ₇ ) is reacted with the compound of formula (D ₁₁ ): {Where Rb ₂ represents H or Rb ₁ or Rb ₃ , and Rb ₁ and Rb ₃ are of the following formula: (Wherein G has the above meaning) and a compound of formula (D ₁₁ ) is obtained, and the amine functional group of BOC in the compound of formula (D ₁₁ ) is deprotected to obtain the following formula (D ₁₂ ): Chemical 23] [Wherein Rc ₂ represents H or Rc ₁ or Rc ₃ , and Rc ₁ and Rc ₃ are represented by the following formula: {Where R7 is H or the following formula: (Wherein G is as described above) represents a group of], and (2) according to the diffusion route, the compound of formula (D ₄ ) is replaced by the compound of formula (D ₄ ). D ₁₀ ) to react with a compound of the following formula (D ₁₃ ): (Wherein P, Ra ₁ , Ra ₂ and Ra ₃ have the above-mentioned meanings), and deprotecting the amine functional group of BOC in the compound of formula (D ₁₃ ) D ₁₄ )
: [Chemical 27] {Where P has the above meaning, R8 represents H or Rd ₁ or Rd ₃ , and Rd ₁ and Rd ₃ are of the following formula: (Wherein, G and R6 have the meanings given above) to give a compound of the representative} the group of compounds of this formula (D ₁₄₎ of the compounds the of formula, if it or desired if necessary the (D ₄₎ To give a compound of formula (D ₁₁ ) as described above, and subjecting the compound of formula (D ₁₄ ) to conversion of NH ₂ amine functionality to OH hydroxyl functionality if necessary or desired. The following formula (D ₁₅ ): [Where P has the above-mentioned meaning, Rf ₂ represents H or Rf ₁ or Rf ₃ , and Rf ₁ and Rf ₃ are of the following formula: {Wherein, R9 is (here, G has the meaning of the) H or O-G-OH represent} to give a compound of representing] a group of the formula (D _12), (D ₁₄ ) Or (D ₁₅ ) can be a compound of formula (P-Y) which, if desired or necessary, provides a subsequent conversion reaction to give another compound of formula (P-Y). : (A) conversion reaction of an alkoxy functional group to a hydroxyl functional group or of a hydroxyl functional group to an alkoxy functional group, (b) oxidation reaction of an alcohol functional group to an aldehyde, acid or ketone functional group, (c) Conversion reaction of halogenated functional group to formyl or esterified carboxy functional group, (d) reaction with linker L according to claim 6, 10 or 11, (e) that deprotected reactive functional group has Removal of a protecting group, (f) Inorganic or Characterized in that can be subjected in any order one or more of the salt-forming reaction with an organic acid or base, the manufacturing method. 14. Use of a compound of formula (PY) according to any of claims 1 to 11 as a colored dendrimer as a soluble carrier in organic synthesis. 15. Use of dendrimer a, b, c, d or d1 according to claim 12 as a colored dendrimer as a soluble carrier in organic synthesis.