Indian Patents. 253975:A DENDRITIC MACROMOLECULE AND A PROCESS THEREOF

Title of Invention	A DENDRITIC MACROMOLECULE AND A PROCESS THEREOF
Abstract	The present invention is in relation to a dendritic molecule having symmetrically sited branches. The branch points are tertiary amines linked together with oxygen atom of ether and the heteroatoms are separated by a substituted or non-substituted linear three methylene linker. In addition the invention also provides a process to prepare such dendritic macromolecules.

Full Text	FIELD OF INVENTION The present invention is in relation to dendritic macromolecules. More particularly, the present invention is in relation to establishing constitutionally new dendritic macromolecules, presenting many surface functional groups, each functional group presenting a unique reactivity pattern. These new dendritic macromolecules are capable of acting as base platforms for further modifications, aided by, for example, surface functional groups or the defined inner cavities present within these dendritic macromolecules. BACKGROUND AND PRIOR ART OF THE INVENTION Dendritic macromolecules represent a new type of polymeric architecture which has become popular in a variety of studies, including application level, in the last two decades. The branches-upon-branches is an unique architectural feature of these macromolecules and they enjoy being the most monodispersed of all synthetic macromolecules. The systematic studies of the dendritic macromoleules may be traced back first to the series of the so-called poly (amido amine) or Starburst dendrimers, pioneered by Tomalia and co-workers, Polym. J. (Tokyo), 117 (1985), U.S.Pat. No.4,507,466; U.S.Pat. No.4,558,320 and U.S.Pat. No. 4,737,550. These dendrimers possess primarily an amide as the linkage unit and a tertiary amine as the branch point. Another popula-dendritic macromolecular series is the poly (propylene imine) dendrimers, advanced by Meijer and de Brabander-van den Berg, Angew. Chem. Int. Ed. Engl. 1308 (1993), WO 93/14147, U.S. Pat. No. 5,698,662. In this poly(propylene imine) dendrimer series, there is no heteroatom or linker functionalties between the branch points, that are constituted by tertiary amines. The branch points are separated typically by alkylene units. Other popular dendrimers studied extensively, are by Frechet and co-workers, J. Am. Chem. Soc. 7638 (1990); Majoral and co-workers. Science, 1981 (1997) and Frechet and co-workers U.S. Pat. No. 5,041,516. Low molecular weight dendritic molecules with ether linkages and imine branch points wherein the molecular weight is less than 3600 g/mol, with ester units at the surfaces has been described in, Rama Krishna and Jayaraman, J. Org. Chem. 2003, 9694. Each dendrimer is characterized by their unique constitution and thus attendant physico-chemical and biological properties differ significantly. Although there exists a number of dendrimers, the ones that have been utilized in a wide range of studies remain limited. The poly(amido amine) and poly(propylene imine) dendrimers are the most studied dendritic macromolecules, in general. Due to the physico-chemical properties that reside with the molecular constitution of the dendrimers, identification of new monomers and synthesis of new dendrimers are important target areas in the branch of polymer/macromolecular science and technology. A large number of technologically important utilities such as those in power, energy, healthcare, medial, engineering, consumer goods, environmental, electronics and optoelectronics are expected to benefit by the unique architectural characteristics of the dendritic macromolecules. OBJECTS OF THE PRESENT INVENTION The principal object of the present invention is in relation to preparation of dendritic macromolecules. Another object of the present invention is to prepare dendritic macromolecules with ether linkages and tertiary amine branch points. Yet another object of the present invention is to develop a process for the preparation of dendritic macromolecules with ether linkages and tertiary amine branch points. STATEMENT OF INVETNION Accordingly, the present invention provides a dendritic macromolecule having symmetrically sited branches, wherein the branch points are tertiary amines, the branches linked together through linkers comprising oxygen atom corresponding to an ether, and the heteroatoms are separated by a substituted or non-substituted linear three methylene linker; and a process for preparing a dendritic macromolecule comprises steps of; reacting the alcohol units of the lower dendritic molecule to react with molar equivalents of a,P-unsaturated nitrile, in the presence of an alkali, to install nitrile groups at the surfaces of the dendritic macromolecule; converting nitrile groups at the surfaces of the dendritic macromolecule to the corresponding amines, mediated by supported metal catalysts and hydrogen gas; subjecting the resulting amine functional groups to react with a,p-unsaturated esters; converting ester units present at the surfaces of the dendritic macromolecule to the corresponding alcohol units, mediated by metal hydride reagents; to prepare a higher generation dendritic molecule. DETAILED DESCRIPTION OF THE INVENTION The present invention is in relation to a dendritic macromolecule having symmetrically sited branches, wherein the branch points are tertiary amines, the branches linked together through linkers comprising oxygen atom corresponding to an ether, and the heteroatoms are separated by a substituted or non-substituted linear three methylene linker. In another embodiment of the present invention, wherein the number of symmetrically sited branches, are ranging from 3 to 8 and the number of peripheral groups ranging from 16 to 512. In yet another embodiment of the present invention, wherein the substituents on the linkers are selected from a group comprising an alkyl, branched alkyl and aryl group. In still another embodiment of the present invention, wherein the alkyl, branched alkyl and aryl substituents in the linear three methylene linker are present on two adjacent methylene groups and the third unsubstituted methylene group is present on left to the heteroatoms. In still another embodiment of the present invention, wherein the functional group present at the periphery of the dendritic macromolecule is selected from a group comprising alcohol, amine, ester, nitrile and carboxylic acid or a combination thereof. In still another embodiment of the present invention, wherein said molecule is useful in the delivery of drug molecules, fragrant molecules, antibodies, antigens, nucleotides, nucleosides, peptides, proteins and as lubricants in automotive oils. In still another embodiment of the present invention, wherein repeating unit of the dendritic macromolecule is: The present invention is in relation to a process for preparing a dendritic macromolecule comprises steps of, i. reacting the alcohol units of the lower dendritic molecule to react with molar equivalents of α ,β -unsaturated nitrile, in the presence of an alkali, to install nitrile groups at the surfaces of the dendritic macromolecule; ii. converting nitrile groups at the surfaces of the dendritic macromolecule to the corresponding amines, mediated by supported metal catalysts and hydrogen gas; iii. subjecting the resulting amine functional groups to react with a,P- unsaturated esters, iv. converting ester units present at the surfaces of the dendritic macromolecule to the corresponding alcohol units, mediated by metal hydride reagents; to prepare a higher generation dendritic molecule. In another embodiment of the present invention, wherein the lower dendritic molecule is one generation lower than the target dendritic molecule. In yet another embodiment of the present invention, wherein the molar equivalents of α ,βunsaturated nitrile is 50 molar equivalent per unit of the hydroxyl group present in the dendritic molecule: In still another embodiment of the present invention, wherein the alkali used is 40% aqueous solution of sodium hydroxide; In still another embodiment of the present invention, wherein the catalyst is selected from a group of metal supported catalysts such as Raney alloys; preferably Raney Cobalt. In still another embodiment of the present invention, wherein the concentration of nitrile ranges between 0.01 mM and 4.0 mM. In still another embodiment of the present invention, wherein the metal hydride reagent is selected from a range of metal hydride reagents preferably lithium aluminum hydride. In still another embodiment of the present invention, is useful in the delivery of drug molecules, fragrant molecules, antibodies, antigens, nucleotides, nucleosides, peptides, proteins and as lubricant in automotive oils. The innovation deals with the preparation of dendritic macromolecules wherein the characteristics of the preparation are (i) reaction of an α ,β-unsaturated nitrile with a compound presenting a number of hydroxyl groups at the surfaces, in the presence of an alkali; (ii) reduction of the compound resuhing from step (i) to a compound containing several symmetrically substituted amine functional groups, by supported metal catalysts; (iii) reacting the compound resuhing from step (ii) with an a,P-unsaturated ester, leading to the formation of several symmetrically substituted ester functional groups at the surfaces; (iv) subjecting the compound resuhing from step (iii) to a reduction reaction with a metal hydride based reagent, so as to form a product with several symmetrically substituted hydroxyl group containing dendritic macromolecule. The number of the hydroxyl group present in the dendritic macromolecule, after the above four steps, is to a maximum of twice that number present in the compound used in step (i). This invention describes dendritic macromolecules with a well-defined chemical constitution. The chemical constitution comprises a linkage group and a branching group. The presence of both the linkage group and the branching group are required simultaneously in the chemical constitution of the dendritic macromolecules of this invention. An α ,β-unsaturated ester and a nitrile act as the monomers. These two types of monomers are taken through covalent bond formation and subsequent functional group conversions. While the covalent bond formations create the unique linkage and the branching groups, the functional group conversion generates a different functional group capable of undergoing the covalent bond formation, leading to the formation of the linkage and branching groups. The functional group conversions and the covalent bond formations are conducted alternatively to prepare the dendritic macromolecules of the present invention. Every symmetrically sited branching group is considered to constitute a generation. Thus the branching group nearest to the central atom or unit or the core of the dendritic structure is treated as the first generation. The next symmetrically placed branching groups are treated to complete the second generation dendritic structure. The progressive next symmetrically place branching groups are treated to complete the third generation dendritic structure and so on. With the branching group multiplicity of 2 and the central atom or unit or core of the dendritic macromolecule multiplicity of 2, the maximum number of surface groups possible in each generation is twice the number that is present in the corresponding immediate lower generation dendritic structure. Thus, the first generation dendritic structure with 2 symmetrically placed branching groups can have at the maximum 4 surface functionalities or units; the second generation dendritic structure with 4 symmetrically placed branching groups can have at the maximum 8 surface functionalities or units; the third generation dendritic structure with 8 symmetrically placed branching groups can have at the maximum 16 surface functionalities or units; the fourth generation dendritic structure with 16 symmetrically placed branching groups can have at the maximum 32 surface functionalities or units; the fifth generation dendritic structure with 32 symmetrically placed branching groups can have at the maximum 64 surface functionalities or units; the sixth generation dendritic structure with 64 symmetrically placed branching groups can have at the maximum 128 surface functionalities or units; the seventh generation dendritic structure with 128 symmetrically placed branching groups can have at the maximum 256 surface functionalities or units and the eighth generation dendritic structure with 256 symmetrically placed branching groups can have at the maximum 512 surface functionalities or units. The functionalities, that undergo covalent bond formation upon reaction with nitriles and esters in the present invention, are primarily alcohols and amines. These functional groups are generated in prior reactions through the type chemical reactions called functional group conversions. In the embodiment of the present invention, the alcohol and amine functional groups are present, many in numbers, at the surfaces of the low molecular weight dendritic scaffolds of the type described in Rama Krishna and Jayaraman, J. Org. Chem. 2003, 9694. The low molecular weight dendritic scaffolds disclosed in this publication are incorporated as a reference, in the present invention. Repetitive and consecutive reactions, corresponding to the conversion of (i) esters to alcohols; (ii) alcohols to ethers, possessing pendant nitriles; (iii) nitriles to primary amines and (iv) primary amines to tertiary amines, possessing pendant esters, constitute to be the integral steps involved in the construction of the dendritic macromolecules of the present invention. When there are x number of functional groups on the surfaces of a low molecular weight dendritic molecule, namely the esters and the nitriles, performing the above reactions will provide either twice or less number x of the functionalities or units, corresponding to the next higher generation. For example, when third generation dendritic molecule possessing 16 alcohol functionalities is taken through the above repetitive reactions, then a fourth generation dendritic structure with either 32 or less number of alcohol functionalities at the surfaces is obtained at the end of the sequential reactions described above. The repetitive and consecutive reactions of the present invention are performed by (i) a,p-unsaturated ester and nitrile as monomers and (ii) supported metal catalysts and metal hydrides as the reagents. Examples of a,p-unsaturated esters are linear and branched alkyl esters and aryl esters, the most preferred among them is tert-butyl acrylate. Example of a,P-unsaturated nitriles are a series of alkyl and aryl substituted acrylonitriles, the most preferred among them is unsubstituted acrylonitrile. In the first embodiment of the invention, the low molecular weight dendritic scaffolds of molecular weight less than 3600 g mol"', with ester units present at the surfaces, as described in Rama Krishna and Jayaraman, J. Org. Chem. 2003, 9694, are used as the initiator to construct the dendritic macromolecules. The number of ester units at the peripheries vary between 4 and 16, depending on the chosen low molecular weight dendritic scaffold. Accordingly, the molecular weights of the dendritic scaffolds are in the range of 600-3600 g mol-1 The functional group conversion, namely, a reduction, provides alcohol functionalities at the peripheries, the number of such groups vary between 4 and 16. Formula 1 describes the structure of the dendritic macromolecule of this embodiment 1 as: According to the formula 1, the product of the third generation dendritic structure contains x number of alcohol units and 16-x number of ester units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 1 contains 16 alcohol units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain hydroxyl units in the progression (i) x number of alcohol units in the fourth generation dendritic structure and 32-x number of ester units, with more preferable x being 32; (ii) x number of alcohol units in the fifth generation dendritic structure and 64-x number of ester units, with more preferable x being 64; (iii) x number of alcohol units in the sixth generation dendritic structure and 128-x number of ester units, with more preferable x being 128; (iv) x number of alcohol units in the seventh generation dendritic structure and 256-x number of ester units, with more preferable x being 256; (v) JC number of alcohol units in the eighth generation dendritic structure and 512-x number of ester units, with more preferable jc being 512. The dendritic macromolecules carrying alcohol functionalities at the surfaces, either fully or partially as described above, are proceeded further to generate larger dendritic structure, through reaction of the alcohol functionalities with a, (3-unsaturated nitriles. This reaction provides saturated P-cyano ethyl ethers, wherein the alcohol units are converted to p-cyano ethyl ethers. Formula 2 provides an example of the second embodiment of the invention, as follows: According to the formula 2, the product contains x number of nitrile units and \6-x number of alcohol units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 2 contains 16 nitrile units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain nitrile units in the progression (i) x number of nitrile units in the fourth generation dendritic structure and 32-x number of alcohol units, with more preferable x being 32; (ii) x number of nitrile units in the fifth generation dendritic structure and 64-X number of alcohol units, with more preferable x being 64; (iii) x number of nitrile units in the sixth generation dendritic structure and 128-x number of alcohol units, with more preferable x being 128; (iv) x number of nitrile units in the seventh generation dendritic structure and 256-x number of alcohol units, with more preferable x being 256; (v) X number of nitrile units in the eighth generation dendritic structure and 512-x number of alcohol units, with more preferable x being 512. The reaction of the conversion of the alcohol functionalities to the nitrile functionalities requires the presence of an alkali and a solvent. The alkalis that can be used include NaOH, KOH, Ca(OH)2 and Mg(0H)2. The most preferred among these alkalis is an aqueous solution of NaOH. In the subsequent preparations, the nitrile functionalities present at the surfaces of dendrimers are proceeded through a functional group conversion, by which the nitrile functionalities are converted to primary amine functionalities through a reduction. Formula 3 provides an example of the third embodiment of the present invention, as follows: According to the formula 3, the product contains x number of amine units and \6-x number of nitrile units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 3 contains 16 amine units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain amine units in the progression (i) x number of amine units in the fourth generation dendritic structure and 32-X number of nitrile units, with more preferable x being 32; (ii) x number of amine units in the fifth generation dendritic structure and 64-X number of nitrile units, with more preferable x being 64; (iii) x number of amine units in the sixth generation dendritic structure and 128-x number of nitrile units, with more preferable x being 128; (iv) x number of amine units in the seventh generation dendritic structure and 256-A: number of nitrile units, with more preferable x being 256; (v) x number of amine units in the eighth generation dendritic structure and 512-x number of nitrile units, with more preferable x being 512. In the fourth embodiment of the invention, the amine functionalities present in the surface of the dendritic macromolecules are subjected through a chemical reaction with an a,p-unsaturated ester, leading to the formation of ester functionalities at the surfaces. The number of ester functionalities thus formed will be up to twice the number of amine funcionalities present in the starting material of this reaction. Formula 4 provides an example of this embodiment of invention, as follows: According to the formula 4, the product contains x number of ester units and 32-x number of amine units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 4 contains 16 ester units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain ester units in the progression (i) x number of ester units in the fourth generation dendritic structure and 32-x number of amine units, with more preferable x being 32; (ii) x number of ester units in the fifth generation dendritic structure and 64-x number of amine units, with more preferable x being 64; (iii) x number of ester units in the sixth generation dendritic structure and 128-x number of amine units, with more preferable x being 128; (iv) x number of ester units in the seventh generation dendritic structure and 256-x number of amine units, with more preferable x being 256; (v) x number of ester units in the eighth generation dendritic structure and 512-x number of amine units, with more preferable x being 512. The present invention also relates to the process of preparation of the dendritic macromolecules described in the above steps. Embodiment 1: A substantial number of alcohol units is reacted with α ,β-unsaturated nitriles, in the presence of an alkali, so as to provide nitrile containing dendritic macromolecules. Embodiment 2: A substantial number of nirtiles resulting from embodiment 2 is reduced to amine units, with the aid of supported metal catalysts. Embodiment 3: A substantial number of amine units resulting from embodiment 3 is reacted with an α ,β-unsaturated ester, resulting in the formation of the ester functionalized dendritic macromolecules. The ester functionalized dendritic macromolecules can be taken through, repeating the cycle from embodiments 1 to 4. Embodiment 4; The ester functionalized dendritic macromolecules is reduced to alcohol units, with a metal hydride. The products formed in each step can be stopped to provide the dendritic macromolecules with defined functionality at the surfaces. The reaction of the alcohol terminated dendrimers with α ,β-unsaturated nitriles is conducted with excess nitrile, in the presence of an alkali. Excess nitrile is generally up to 50 molar equivalent per unit of the hydroxyl group present in the dendritic macromolecule, more preferable being 1-4 molar equivalents of nitrile per unit of the hydroxyl group present in the dendritic macromolecule. The most preferable alkali is an aqueous solution of NaOH (40%) for this reaction. After the reaction is completed, the reaction mixture is filtered through a celite pad, diluted with CHCl3, washed with water and solvents removed under reduced pressure. The byproduct, bis(cyanoethyl ether), present in the crude product, is removed by a liquid-liquid extraction of the present invention. Thus, a solution of the crude product in MeOH:H2O is taken through liquid-liquid extraction with hexane. The extraction process removes most of the bis(2-cyano ethyl ether). The remaining byproduct is removed by column chromatography, using alumina matrix. The substantially nitrile functionalized dendritic macromolecules are subjected to reduction, using supported metal catalysts, such as Raney alloys, the more preferable among the Raney alloys being Raney cobalt. The reduction requires positive pressure of hydrogen gas, maintained at a higher pressure. The reaction is conducted in water, an alcohol such as MeOH may be added if required. The concentration of the nitrile compound in water is between 0.01-4.0 mM, more preferably between 0.1-0.4 mM. The weight ratio of the nitrile compound to the supported metal catalyst is generally 1:15 and, most preferably in the range of 1:3 to 1:7. The hydrogen gas pressure is generally in the range of 20-70 atm, more preferably between 40-50 atm. The reaction temperature is generally maintained between 60-85 °C, more preferably at - 70 °C. After the reaction, the supported metal catalyst can be removed by filtration. Alternatively, a magnetic pellet picker can be used to remove the catalyst. The amine resulting from the above step is taken through reaction with an a,P-unsaturated esters, the most preferable ester being tert-butyl acrylate. Alcoholic solvents can be used generally to conduct the reaction of amine functionalized dendrimers, the most preferable solvent is MeOH, The ratio of tert-butyl acrylate to each amine functionalities present at the surfaces of the dendritic macromolecule is in the range of 1:1 to 200:1. Most preferable ratio is in the range of 5-60 molar equivalent of tert-butyl acrylate per one unit of amine present at the surfaces. At the end of the reaction, the excess tert-butyl acrylate can be recovered by distillation. Column chromatography, using neutral alumina matrix, of the crude product is carried out usually to obtain the pure ester functionalized dendritic macromolecules. The reduction of esters to alcohols is performed in a solvent and in the presence of a metal hydride. Suitable metal hydrides are lithium aluminium hydride, alkyl derivatives of lithium aluminium hydride, combination of lithium borohydride and AICI3. The preferable metal hydride among these is lithium aluminium hydride. The solvents for the reduction are THF, diethyl ether, dioxane, toluene and hexanes. The most preferable solvent is THF. The molar ratio of metal hydride generally is 0.5 to 4 per one ester unit, the preferable molar ratio of the metal hydride is 2 per unit of ester. After the conversion of the surface ester functionalities to alcohol functionalities in the dendritic macromolecules, the isolation of the pure product is achieved by differential solubility, according to this invention. When lithium aluminium hydride is used as the reducing agent, the byproducts LiOH and A1(0H)3, arising after the work-up of the reaction, are removed by: (i) washing the crude product with water; (ii) filtration; (iii) removal of water under reduced pressure; (iv) washing the product with MeOH; (v) filtration; (vi) removal of MeOH under reduced pressure and (vii) extraction of the product with CHCI3 and removal of the solvents under reduced pressure. If required, the above process is repeated to eliminate any inorganic byproducts that may still remain. The embodiments 1-4 described above are necessary to complete the constitution of the dendritic macromolecules of the present invention. Thus, each cycle involves a set of four distinct reactions to complete the cycle. Thus, initiating from a low molecular weight dendritic molecule with 16 ester functionalities at the surfaces requires full five cycles to reach a dendritic macromolecule presented with 512 ester functionalities at the surfaces, wherein complete reactivities of the functional groups occurred at the surfaces of the dendritic macromolecule. The dendritic macromolecules of this invention can be used in many applications. Various applications, in such areas as, medical, healthcare, environmental, catalysis, engineering, electronics and opto-electronics are targeted for promotion of better performances, characteristics and efficiencies through the dendrimer technology. The important molecular feature available for the dendritic macromolecules is the presence of large of number of dense peripheral functional groups. This large number of peripheral functional groups provides the opportunity for attaching, for example, drug molecules, fragrant molecules, antibodies, antigens, nucleotides, nucleosides, peptides, proteins and carbohydrate ligands etc. Also, the low viscosity of the dendritic macromolecules, in comparison to random polymers of the similar molecular weights, may find applications in the area of, for example, lubricants in automotive oils. Another important physical attribute of these new class of dendrimers is that their radius is considerably larger than dendrimers of the type as described in U.S.Pat. No.4,507,466; U.S.Pat. No.4,558,320 and U.S.Pat. No. 4,737,550, relating to the poly(amido amine) series of dendrimers and WO 93/14147, U.S. Pat. No. 5,698,662, relating to the poly(propylene imine) series of dendrimers. The radius of a particular generation of the dendrimers of the present invention would relate to next higher generation of, for example, the poly(amido amine) dendrimers. This important physical attribute of the dendrimers of the present invention originates from the larger linkers lengths, connecting the branch functionalities. The utility of the larger radius of the dendrimers, with attendant lesser molecular weights, can be envisaged in applications such as drug delivery. The dendritic base platforms with larger sizes and lesser molecular weights will have beneficial effects upon conjugation with drugs. The larger through-bond distances between the branch functionalities of the present invention also allow them to be more flexible and less rigid. The presence of ether and amine functionalities of the dendrimers of this invention makes them analogous to the functionalities present individually in polymers such as poly(ethylene glycol) and poly(ethylene imine). The lower toxicity profile of these types of functionalities make the molecules derived from thereof to be invoked in applications, such as, drug delivery vehicles, drug formulations, skin care formulations, gene delivery vehicles, vehicles for conjugation with pharmacologically important nucleosides, nucleotides, peptides, proteins, carbohydrates and other synthetic agents. The series of the dendrimers have defined internal voids and cavifies that can encapsulate small molecules, relevant in, for example, enhancing the bioavailablity of a drug, or a drug encapsulation or a toxic chemical encapsulation or a biocide encapsulation etc. Thus, from the point of view of various applications, lower generation dendrimers of the present invention can be utilized in place of higher generation dendrimers of the type as described in above disclosures, in order, for example, to avoid toxicity towards biological objects. The technology of the instant Application is further elaborated with the help of following examples. However, the examples should not be construed to limit the scope of the invention. Example: 1 A mixture of the 16-alcohol functionalized dendritic macromolecule (5.0 g) and of aq 40 % NaOH (0.4 mL) was added with acrylonitrile (2.15 mL), at 0 °C and stirred at room temperature for 15 h. Additional amount of acrylonitrile (2.15 mL) was added portion wise, and this additional amount was added again after 8 h of stirring and the reaction was monitored (TLC alumina matrix; eluant: 6 % MeOH/ CHCI3, Rf of the required 16-nitrile functionalized dendritic macromolecule: 0.45). The solution was filtered through celite using chloroform, and washed with water and the solvents evaporated under reduced pressure. The crude reaction mixture was dissolved in aqueous MeOH, subjected to liquid-liquid extraction with hexane to remove -70 % of bis(2-cyano ethyl ether). Finally, the reaction mixture was subjected to column chromatography (neutral alumina, 100-300 mesh size), afforded the 16-nitrile functionalized dendritic macromolecule, as a colorless gummy liquid. Yield: 6.33 g. Example: 2 In a 2 L hydrogenation reactor vessel, a mixture of sixteen nitrile-functionalized dendritic macromolecule (1.5 g) in distilled water (1.2 L) and Raney Co (Aldrich Inc. USA) (4.0 g) was hydrogenated in the presence of hydrogen gas (46 atm.). The temperature was maintained in the range of 70-75 °C. After 3.5 h, the reaction mixture was cooled and the spent Raney cobalt was recovered using a magnetic pellet picker. Methanol was added to wash the compound from catalyst and to remove the catalyst from pellet picker, flushed with water and the water layer was concentrated at 55 °C under reduced pressure. For easy removal of water, azeotrope mixture was formed by adding dioxane solvent and evaporated quickly. To the resulting reaction mixture methanol was added and filtered. The filtrate was concentrated and dried to afford the corresponding 16 amine-functionalized dendritic macromolecule. Yield: 1.53 g. Example: 3 A solution of 16 amine terminated dendritic macromolecule (1.53 g) in methanol (50 mL) and tert-butyl acrylate (filtered through pad of alumina prior to the addition) (10 mL) was stirred vigorously for 72 h. The reaction was monitored (TLC alumina matrix, eluant: 3 % MeOH/ CHCI3, Rf of the 32 ester functionalized dendritic macromolecule: 0.52). Excess tert-butyl acrylate and methanol were removed under reduced pressure after completion of the reaction. Addition of petroleum ether helped to precipitate the polar impurity and it was separated by filtration through filter paper. Subsequent evaporation of the solvent afforded the 32 ester terminated dendritic macromolecule. Further purification was performed by column chromatography (neutral alumina; eluant: CHCI3: MeOH), to afford the 32 ester functionalized dendritic macromolecule. Yield: 3.15 g. Example: 4 A solution of 32-ester functionalized dendrimer (4.0 g) in THF (150 mL) was added dropwise to a suspension of LiAlH4 (1.34 g) in THF (50 mL), over a period of 15 min at 0 °C and the stirring was continued for 4 h at room temperature. After completion of the reaction, the mixture was cooled to 0 °C, quenched with ice, diluted with water, passed through celite, and the filtrate concentrated under reduced pressure. The crude reaction mixture was added with MeOH, filtered, and the filtrate concentrated. The resulting reaction mixture was extracted CHCI3. Removal of the solvents afforded the 32-alcohol functionalized dendritic macromolecule. Yield: 2.76 g. Example; 5 A mixture of the 32-alcohol functionalized dendritic macromolecule (5.0 g) and of aq 40 % NaOH (0.4 mL) was added with acrylonitrile (2.02 mL), at 0 °C and stirred at room temperature for 15 h. Additional amount of acrylonitrile (2.02 mL) was added portion wise, and this additional amount was added again after 8 h of stirring and the reaction was monitored (TLC alumina matrix; eluant: 6 % MeOH/ CHCI3, Rf of the required 32-nitrile functionalized dendritic macromolecule: 0.6). The solution was filtered through celite using chloroform, and washed with water and the solvents evaporated under reduced pressure. The crude reaction mixture was dissolved in aqueous MeOH, subjected to liquid-liquid extraction with hexane to remove -70 % of bis(2-cyano ethyl ether). Finally, the reaction mixture was subjected to column chromatography (neutral alumina, 100-300 mesh size), afforded the 32-nitrile functionalized dendritic macromolecule, as a colorless gummy liquid. Yield: 5.23 g. Example: 6 In a 2 L hydrogenation reactor vessel, a mixture of 32 nitrile-functionalized dendritic macromolecule (1.0 g) in disfilled water (1.2 L) and Raney Co (Aldrich Inc. USA) (5.0 g) was hydrogenated in the presence of hydrogen gas (46 atm.). The temperature was maintained in the range of 70-75 °C. After 3.5 h, the reaction mixture was cooled and the spent Raney cobah was recovered using a magnetic pellet picker. Methanol was added to wash the compound from catalyst and to remove the catalyst from pellet picker, flushed with water and the water layer was concentrated at 55 °C under reduced pressure. For easy removal of water, azeotrope mixture was formed by adding dioxane solvent and evaporated quickly. To the resulting reaction mixture methanol was added and filtered. The filtrate was concentrated and dried to afford the corresponding 32 amine-functionalized dendritic macromolecule. Yield: 1.01 g. Example: 7 A solution of 32 amine terminated dendritic macromolecule (1.01 g) in methanol (50 mL) and tert-butyl acrylate (filtered through pad of alumina prior to the addition) (10 mL) was stirred vigorously for 72 h. The reaction was monitored (TLC alumina matrix, eluant: 3 % MeOH/ CHCI3, Rf of the 64 ester functionalized dendritic macromolecule: 0.66). Excess /er/-butyl acrylate and methanol were removed under reduced pressure after completion of the reaction. Addition of petroleum ether helped to precipitate the polar impurity and it was separated by filtration through filter paper. Subsequent evaporation of the solvent afforded the 64 ester terminated dendritic macromolecule. Further purification was performed by column chromatography (neutral alumina; eluant: CHCI3: MeOH), to afford the 64 ester functionalized dendritic macromolecule. Yield: 1.70 g. WE CLAIM: 1. A dendritic macromolecule having symmetrically sited branches, wherein the branch points are tertiary amines, the branches linked together through linkers comprising oxygen atom of an ether, and the heteroatoms are separated by a substituted or non-substituted linear three methylene linker. 2. The dendritic macromolecule as claimed in claim 1, wherein the number of symmetrically sited branches, are ranging from 3 to 8 and the number of peripheral groups ranging from 16 to 512. 3. The dendritic macromolecule as claimed in claim 1, wherein the substituents on the three methylene linkers are selected from a group comprising an alkyl, branched alkyl and aryl group. 4. The dendritic macromolecule as claimed in claim 1, wherein the alkyl, branched alkyl and aryl substituents in the linear three methylene linker are present on two adjacent methylene groups and the third unsubstituted methylene group is present on left to the heteroatoms. 5. The dendritic macromolecule as claimed in claim 1, wherein the functional group present at the periphery of the dendritic macromolecule is selected form a group comprising alcohol, amine, ester, nitrile and carboxylic acid or a combination thereof. 6. The dendritic macromolecule as claimed in claim 1, wherein said molecule is useful in the delivery of drug molecules, fragrant molecules, antibodies, antigens, nucleotides, nucleosides, peptides, proteins and as lubricant in automotive oils. 7. The dendritic macromolecule as claimed in claim 1, wherein repeating unit of the dendritic macromolecule is: 8. A process for preparing a dendritic macromolecule comprises steps of: i. reacting the alcohol units of the lower dendritic molecule to react with molar equivalents of α, β -unsaturated nitrile, in the presence of an alkali, to install nitrile groups at the surfaces of the dendritic macromolecule; ii. converting nitrile groups at the surfaces of the dendritic macromolecule to the corresponding amines, mediated by supported metal catalysts and hydrogen gas; iii. subjecting the resulting amine functional groups to react with α ,β -unsaturated esters; and iv. converting ester units present at the surfaces of the dendritic macromolecule to the corresponding alcohol units, mediated by metal hydride reagents; to prepare a higher generation dendritic molecule. 9. The process as claimed in claim 8, wherein the lower dendritic molecule is one generation lower than the target dendritic molecule 10. The process as claimed In claim 8, wherein the molar equivalents of α, β - unsaturated nitrile is 50 molar equivalent per unit of the hydroxyl group present in the dendritic molecule: 11. The process as claimed in claim 8, wherein the alkali used is 40% aqueous solution of sodium hydroxide; 12. The process as claimed in claim 8, wherein the catalyst is selected from a group of metal supported catalysts such as Raney alloys; preferably Raney Cobalt. 13. The process as claimed in claim 8(ii), wherein the concentration of nitrile ranges between 0.01 mM and 4.0 mM. 14. The process as claimed in claim 8, wherein the metal hydride reagent is selected from a range of metal hydride reagents preferably lithium aluminum hydride. 15. A dendritic molecule and the process of its preparation substantially as herein

Full Text

FIELD OF INVENTION
The present invention is in relation to dendritic macromolecules. More particularly, the present invention is in relation to establishing constitutionally new dendritic macromolecules, presenting many surface functional groups, each functional group presenting a unique reactivity pattern. These new dendritic macromolecules are capable of acting as base platforms for further modifications, aided by, for example, surface functional groups or the defined inner cavities present within these dendritic macromolecules. BACKGROUND AND PRIOR ART OF THE INVENTION
Dendritic macromolecules represent a new type of polymeric architecture which has become popular in a variety of studies, including application level, in the last two decades. The branches-upon-branches is an unique architectural feature of these macromolecules and they enjoy being the most monodispersed of all synthetic macromolecules.
The systematic studies of the dendritic macromoleules may be traced back first to the series of the so-called poly (amido amine) or Starburst dendrimers, pioneered by Tomalia and co-workers, Polym. J. (Tokyo), 117 (1985), U.S.Pat. No.4,507,466; U.S.Pat. No.4,558,320 and U.S.Pat. No. 4,737,550. These dendrimers possess primarily an amide as the linkage unit and a tertiary amine as the branch point. Another popula-dendritic macromolecular series is the poly (propylene imine) dendrimers, advanced by Meijer and de Brabander-van den Berg, Angew. Chem. Int. Ed. Engl. 1308 (1993), WO 93/14147, U.S. Pat. No. 5,698,662. In this poly(propylene imine) dendrimer series, there is no heteroatom or linker functionalties between the branch points, that are constituted by tertiary amines. The branch points are separated typically by alkylene units. Other popular dendrimers studied extensively, are by Frechet and co-workers, J. Am. Chem. Soc. 7638 (1990); Majoral and co-workers. Science, 1981 (1997) and Frechet and co-workers U.S. Pat. No. 5,041,516. Low molecular weight dendritic molecules with ether linkages and imine branch points wherein the molecular weight is less than 3600 g/mol, with ester units at the surfaces has been described in, Rama Krishna and Jayaraman, J. Org. Chem. 2003, 9694.
Each dendrimer is characterized by their unique constitution and thus attendant physico-chemical and biological properties differ significantly. Although there exists a

number of dendrimers, the ones that have been utilized in a wide range of studies remain limited. The poly(amido amine) and poly(propylene imine) dendrimers are the most studied dendritic macromolecules, in general. Due to the physico-chemical properties that reside with the molecular constitution of the dendrimers, identification of new monomers and synthesis of new dendrimers are important target areas in the branch of polymer/macromolecular science and technology. A large number of technologically important utilities such as those in power, energy, healthcare, medial, engineering, consumer goods, environmental, electronics and optoelectronics are expected to benefit by the unique architectural characteristics of the dendritic macromolecules.
OBJECTS OF THE PRESENT INVENTION
The principal object of the present invention is in relation to preparation of dendritic
macromolecules.
Another object of the present invention is to prepare dendritic macromolecules with
ether linkages and tertiary amine branch points.
Yet another object of the present invention is to develop a process for the preparation of
dendritic macromolecules with ether linkages and tertiary amine branch points.
STATEMENT OF INVETNION
Accordingly, the present invention provides a dendritic macromolecule having symmetrically sited branches, wherein the branch points are tertiary amines, the branches linked together through linkers comprising oxygen atom corresponding to an ether, and the heteroatoms are separated by a substituted or non-substituted linear three methylene linker; and a process for preparing a dendritic macromolecule comprises steps of; reacting the alcohol units of the lower dendritic molecule to react with molar equivalents of a,P-unsaturated nitrile, in the presence of an alkali, to install nitrile groups at the surfaces of the dendritic macromolecule; converting nitrile groups at the surfaces of the dendritic macromolecule to the corresponding amines, mediated by supported metal catalysts and hydrogen gas; subjecting the resulting amine functional
groups to react with a,p-unsaturated esters; converting ester units present at the

surfaces of the dendritic macromolecule to the corresponding alcohol units, mediated by metal hydride reagents; to prepare a higher generation dendritic molecule.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is in relation to a dendritic macromolecule having symmetrically
sited branches, wherein the branch points are tertiary amines, the branches linked
together through linkers comprising oxygen atom corresponding to an ether, and the
heteroatoms are separated by a substituted or non-substituted linear three methylene
linker.
In another embodiment of the present invention, wherein the number of symmetrically
sited branches, are ranging from 3 to 8 and the number of peripheral groups ranging
from 16 to 512.
In yet another embodiment of the present invention, wherein the substituents on the
linkers are selected from a group comprising an alkyl, branched alkyl and aryl group.
In still another embodiment of the present invention, wherein the alkyl, branched alkyl
and aryl substituents in the linear three methylene linker are present on two adjacent
methylene groups and the third unsubstituted methylene group is present on left to the
heteroatoms.
In still another embodiment of the present invention, wherein the functional group
present at the periphery of the dendritic macromolecule is selected from a group
comprising alcohol, amine, ester, nitrile and carboxylic acid or a combination thereof.
In still another embodiment of the present invention, wherein said molecule is useful in
the delivery of drug molecules, fragrant molecules, antibodies, antigens, nucleotides,
nucleosides, peptides, proteins and as lubricants in automotive oils.
In still another embodiment of the present invention, wherein repeating unit of the
dendritic macromolecule is:

The present invention is in relation to a process for preparing a dendritic macromolecule comprises steps of,
i. reacting the alcohol units of the lower dendritic molecule to react with
molar equivalents of α ,β -unsaturated nitrile, in the presence of an alkali,
to install nitrile groups at the surfaces of the dendritic macromolecule; ii. converting nitrile groups at the surfaces of the dendritic macromolecule
to the corresponding amines, mediated by supported metal catalysts and
hydrogen gas; iii. subjecting the resulting amine functional groups to react with a,P-
unsaturated esters, iv. converting ester units present at the surfaces of the dendritic
macromolecule to the corresponding alcohol units, mediated by metal
hydride reagents; to prepare a higher generation dendritic molecule. In another embodiment of the present invention, wherein the lower dendritic molecule is one generation lower than the target dendritic molecule.
In yet another embodiment of the present invention, wherein the molar equivalents of α ,βunsaturated nitrile is 50 molar equivalent per unit of the hydroxyl group present in the dendritic molecule:
In still another embodiment of the present invention, wherein the alkali used is 40% aqueous solution of sodium hydroxide;
In still another embodiment of the present invention, wherein the catalyst is selected from a group of metal supported catalysts such as Raney alloys; preferably Raney Cobalt.
In still another embodiment of the present invention, wherein the concentration of nitrile ranges between 0.01 mM and 4.0 mM.
In still another embodiment of the present invention, wherein the metal hydride reagent is selected from a range of metal hydride reagents preferably lithium aluminum hydride.
In still another embodiment of the present invention, is useful in the delivery of drug molecules, fragrant molecules, antibodies, antigens, nucleotides, nucleosides, peptides, proteins and as lubricant in automotive oils.
The innovation deals with the preparation of dendritic macromolecules wherein the characteristics of the preparation are (i) reaction of an α ,β-unsaturated nitrile with a

compound presenting a number of hydroxyl groups at the surfaces, in the presence of an alkali; (ii) reduction of the compound resuhing from step (i) to a compound containing several symmetrically substituted amine functional groups, by supported metal catalysts; (iii) reacting the compound resuhing from step (ii) with an a,P-unsaturated ester, leading to the formation of several symmetrically substituted ester functional groups at the surfaces; (iv) subjecting the compound resuhing from step (iii) to a reduction reaction with a metal hydride based reagent, so as to form a product with several symmetrically substituted hydroxyl group containing dendritic macromolecule. The number of the hydroxyl group present in the dendritic macromolecule, after the above four steps, is to a maximum of twice that number present in the compound used in step (i).
This invention describes dendritic macromolecules with a well-defined chemical constitution. The chemical constitution comprises a linkage group and a branching group. The presence of both the linkage group and the branching group are required simultaneously in the chemical constitution of the dendritic macromolecules of this invention. An α ,β-unsaturated ester and a nitrile act as the monomers. These two types of monomers are taken through covalent bond formation and subsequent functional group conversions. While the covalent bond formations create the unique linkage and the branching groups, the functional group conversion generates a different functional group capable of undergoing the covalent bond formation, leading to the formation of the linkage and branching groups. The functional group conversions and the covalent bond formations are conducted alternatively to prepare the dendritic macromolecules of the present invention.
Every symmetrically sited branching group is considered to constitute a generation. Thus the branching group nearest to the central atom or unit or the core of the dendritic structure is treated as the first generation. The next symmetrically placed branching groups are treated to complete the second generation dendritic structure. The progressive next symmetrically place branching groups are treated to complete the third generation dendritic structure and so on. With the branching group multiplicity of 2 and the central atom or unit or core of the dendritic macromolecule multiplicity of 2, the maximum number of surface groups possible in each generation is twice the number that is present in the corresponding immediate lower generation dendritic structure. Thus, the first generation dendritic structure with 2 symmetrically placed

branching groups can have at the maximum 4 surface functionalities or units; the second generation dendritic structure with 4 symmetrically placed branching groups can have at the maximum 8 surface functionalities or units; the third generation dendritic structure with 8 symmetrically placed branching groups can have at the maximum 16 surface functionalities or units; the fourth generation dendritic structure with 16 symmetrically placed branching groups can have at the maximum 32 surface functionalities or units; the fifth generation dendritic structure with 32 symmetrically placed branching groups can have at the maximum 64 surface functionalities or units; the sixth generation dendritic structure with 64 symmetrically placed branching groups can have at the maximum 128 surface functionalities or units; the seventh generation dendritic structure with 128 symmetrically placed branching groups can have at the maximum 256 surface functionalities or units and the eighth generation dendritic structure with 256 symmetrically placed branching groups can have at the maximum 512 surface functionalities or units.
The functionalities, that undergo covalent bond formation upon reaction with nitriles and esters in the present invention, are primarily alcohols and amines. These functional groups are generated in prior reactions through the type chemical reactions called functional group conversions.
In the embodiment of the present invention, the alcohol and amine functional groups are present, many in numbers, at the surfaces of the low molecular weight dendritic scaffolds of the type described in Rama Krishna and Jayaraman, J. Org. Chem. 2003, 9694. The low molecular weight dendritic scaffolds disclosed in this publication are incorporated as a reference, in the present invention. Repetitive and consecutive reactions, corresponding to the conversion of (i) esters to alcohols; (ii) alcohols to ethers, possessing pendant nitriles; (iii) nitriles to primary amines and (iv) primary amines to tertiary amines, possessing pendant esters, constitute to be the integral steps involved in the construction of the dendritic macromolecules of the present invention. When there are x number of functional groups on the surfaces of a low molecular weight dendritic molecule, namely the esters and the nitriles, performing the above reactions will provide either twice or less number x of the functionalities or units, corresponding to the next higher generation. For example, when third generation dendritic molecule possessing 16 alcohol functionalities is taken through the above repetitive reactions, then a fourth generation dendritic structure with either 32 or less

number of alcohol functionalities at the surfaces is obtained at the end of the sequential reactions described above.
The repetitive and consecutive reactions of the present invention are performed by (i) a,p-unsaturated ester and nitrile as monomers and (ii) supported metal catalysts and metal hydrides as the reagents.
Examples of a,p-unsaturated esters are linear and branched alkyl esters and aryl esters, the most preferred among them is tert-butyl acrylate. Example of a,P-unsaturated nitriles are a series of alkyl and aryl substituted acrylonitriles, the most preferred among them is unsubstituted acrylonitrile.
In the first embodiment of the invention, the low molecular weight dendritic scaffolds of molecular weight less than 3600 g mol"', with ester units present at the surfaces, as described in Rama Krishna and Jayaraman, J. Org. Chem. 2003, 9694, are used as the initiator to construct the dendritic macromolecules. The number of ester units at the peripheries vary between 4 and 16, depending on the chosen low molecular weight dendritic scaffold. Accordingly, the molecular weights of the dendritic scaffolds are in the range of 600-3600 g mol-1 The functional group conversion, namely, a reduction, provides alcohol functionalities at the peripheries, the number of such groups vary between 4 and 16. Formula 1 describes the structure of the dendritic macromolecule of this embodiment 1 as:

According to the formula 1, the product of the third generation dendritic structure contains x number of alcohol units and 16-x number of ester units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 1 contains 16 alcohol units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain hydroxyl units in the progression (i) x number of alcohol units in the fourth generation dendritic structure and 32-x number of ester units, with more preferable x being 32; (ii) x number of alcohol units in the fifth generation dendritic structure and 64-x number of ester units, with more preferable x being 64; (iii) x number of alcohol units in the sixth generation dendritic structure and 128-x number of ester units, with more preferable x being 128; (iv) x number of alcohol units in the seventh generation dendritic structure and 256-x number of ester units, with more preferable x being 256; (v) JC number of alcohol units in the eighth generation dendritic structure and 512-x number of ester units, with more preferable jc being 512. The dendritic macromolecules carrying alcohol functionalities at the surfaces, either fully or partially as described above, are proceeded further to generate larger dendritic structure, through reaction of the alcohol functionalities with a, (3-unsaturated nitriles. This reaction provides saturated P-cyano ethyl ethers, wherein the alcohol units are converted to p-cyano ethyl ethers. Formula 2 provides an example of the second embodiment of the invention, as follows:

According to the formula 2, the product contains x number of nitrile units and \6-x number of alcohol units present at the surfaces of the dendritic macromolecules. More

preferably, the product in formula 2 contains 16 nitrile units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain nitrile units in the progression (i) x number of nitrile units in the fourth generation dendritic structure and 32-x number of alcohol units, with more preferable x being 32; (ii) x number of nitrile units in the fifth generation dendritic structure and 64-X number of alcohol units, with more preferable x being 64; (iii) x number of nitrile units in the sixth generation dendritic structure and 128-x number of alcohol units, with more preferable x being 128; (iv) x number of nitrile units in the seventh generation dendritic structure and 256-x number of alcohol units, with more preferable x being 256; (v) X number of nitrile units in the eighth generation dendritic structure and 512-x number of alcohol units, with more preferable x being 512.
The reaction of the conversion of the alcohol functionalities to the nitrile functionalities requires the presence of an alkali and a solvent. The alkalis that can be used include NaOH, KOH, Ca(OH)2 and Mg(0H)2. The most preferred among these alkalis is an aqueous solution of NaOH.
In the subsequent preparations, the nitrile functionalities present at the surfaces of dendrimers are proceeded through a functional group conversion, by which the nitrile functionalities are converted to primary amine functionalities through a reduction. Formula 3 provides an example of the third embodiment of the present invention, as follows:

According to the formula 3, the product contains x number of amine units and \6-x number of nitrile units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 3 contains 16 amine units. In addition to the

example given above, the larger generation dendritic macromolecules of this invention contain amine units in the progression (i) x number of amine units in the fourth generation dendritic structure and 32-X number of nitrile units, with more preferable x being 32; (ii) x number of amine units in the fifth generation dendritic structure and 64-X number of nitrile units, with more preferable x being 64; (iii) x number of amine units in the sixth generation dendritic structure and 128-x number of nitrile units, with more preferable x being 128; (iv) x number of amine units in the seventh generation dendritic structure and 256-A: number of nitrile units, with more preferable x being 256; (v) x number of amine units in the eighth generation dendritic structure and 512-x number of nitrile units, with more preferable x being 512.
In the fourth embodiment of the invention, the amine functionalities present in the surface of the dendritic macromolecules are subjected through a chemical reaction with an a,p-unsaturated ester, leading to the formation of ester functionalities at the surfaces. The number of ester functionalities thus formed will be up to twice the number of amine funcionalities present in the starting material of this reaction. Formula 4 provides an example of this embodiment of invention, as follows:

According to the formula 4, the product contains x number of ester units and 32-x number of amine units present at the surfaces of the dendritic macromolecules. More preferably, the product in formula 4 contains 16 ester units. In addition to the example given above, the larger generation dendritic macromolecules of this invention contain ester units in the progression (i) x number of ester units in the fourth generation dendritic structure and 32-x number of amine units, with more preferable x being 32;

(ii) x number of ester units in the fifth generation dendritic structure and 64-x number of amine units, with more preferable x being 64; (iii) x number of ester units in the sixth generation dendritic structure and 128-x number of amine units, with more preferable x being 128; (iv) x number of ester units in the seventh generation dendritic structure and 256-x number of amine units, with more preferable x being 256; (v) x number of ester units in the eighth generation dendritic structure and 512-x number of amine units, with more preferable x being 512.
The present invention also relates to the process of preparation of the dendritic
macromolecules described in the above steps.
Embodiment 1: A substantial number of alcohol units is reacted with α ,β-unsaturated
nitriles, in the presence of an alkali, so as to provide nitrile containing dendritic
macromolecules.
Embodiment 2: A substantial number of nirtiles resulting from embodiment 2 is
reduced to amine units, with the aid of supported metal catalysts.
Embodiment 3: A substantial number of amine units resulting from embodiment 3 is
reacted with an α ,β-unsaturated ester, resulting in the formation of the ester
functionalized dendritic macromolecules. The ester functionalized dendritic
macromolecules can be taken through, repeating the cycle from embodiments 1 to 4.
Embodiment 4; The ester functionalized dendritic macromolecules is reduced to
alcohol units, with a metal hydride.
The products formed in each step can be stopped to provide the dendritic
macromolecules with defined functionality at the surfaces.
The reaction of the alcohol terminated dendrimers with α ,β-unsaturated nitriles is
conducted with excess nitrile, in the presence of an alkali. Excess nitrile is generally up
to 50 molar equivalent per unit of the hydroxyl group present in the dendritic
macromolecule, more preferable being 1-4 molar equivalents of nitrile per unit of the
hydroxyl group present in the dendritic macromolecule. The most preferable alkali is
an aqueous solution of NaOH (40%) for this reaction. After the reaction is completed,
the reaction mixture is filtered through a celite pad, diluted with CHCl3, washed with
water and solvents removed under reduced pressure. The byproduct, bis(cyanoethyl
ether), present in the crude product, is removed by a liquid-liquid extraction of the
present invention. Thus, a solution of the crude product in MeOH:H2O is taken through

liquid-liquid extraction with hexane. The extraction process removes most of the bis(2-cyano ethyl ether). The remaining byproduct is removed by column chromatography, using alumina matrix.
The substantially nitrile functionalized dendritic macromolecules are subjected to reduction, using supported metal catalysts, such as Raney alloys, the more preferable among the Raney alloys being Raney cobalt. The reduction requires positive pressure of hydrogen gas, maintained at a higher pressure. The reaction is conducted in water, an alcohol such as MeOH may be added if required. The concentration of the nitrile compound in water is between 0.01-4.0 mM, more preferably between 0.1-0.4 mM. The weight ratio of the nitrile compound to the supported metal catalyst is generally 1:15 and, most preferably in the range of 1:3 to 1:7. The hydrogen gas pressure is generally in the range of 20-70 atm, more preferably between 40-50 atm. The reaction temperature is generally maintained between 60-85 °C, more preferably at - 70 °C. After the reaction, the supported metal catalyst can be removed by filtration. Alternatively, a magnetic pellet picker can be used to remove the catalyst. The amine resulting from the above step is taken through reaction with an a,P-unsaturated esters, the most preferable ester being tert-butyl acrylate. Alcoholic solvents can be used generally to conduct the reaction of amine functionalized dendrimers, the most preferable solvent is MeOH, The ratio of tert-butyl acrylate to each amine functionalities present at the surfaces of the dendritic macromolecule is in the range of 1:1 to 200:1. Most preferable ratio is in the range of 5-60 molar equivalent of tert-butyl acrylate per one unit of amine present at the surfaces. At the end of the reaction, the excess tert-butyl acrylate can be recovered by distillation. Column chromatography, using neutral alumina matrix, of the crude product is carried out usually to obtain the pure ester functionalized dendritic macromolecules. The reduction of esters to alcohols is performed in a solvent and in the presence of a metal hydride. Suitable metal hydrides are lithium aluminium hydride, alkyl derivatives of lithium aluminium hydride, combination of lithium borohydride and AICI3. The preferable metal hydride among these is lithium aluminium hydride. The solvents for the reduction are THF, diethyl ether, dioxane, toluene and hexanes. The most preferable solvent is THF. The molar ratio of metal hydride generally is 0.5 to 4 per one ester unit, the preferable molar ratio of the metal hydride is 2 per unit of ester.

After the conversion of the surface ester functionalities to alcohol functionalities in the dendritic macromolecules, the isolation of the pure product is achieved by differential solubility, according to this invention. When lithium aluminium hydride is used as the reducing agent, the byproducts LiOH and A1(0H)3, arising after the work-up of the reaction, are removed by: (i) washing the crude product with water; (ii) filtration; (iii) removal of water under reduced pressure; (iv) washing the product with MeOH; (v) filtration; (vi) removal of MeOH under reduced pressure and (vii) extraction of the product with CHCI3 and removal of the solvents under reduced pressure. If required, the above process is repeated to eliminate any inorganic byproducts that may still remain.
The embodiments 1-4 described above are necessary to complete the constitution of the dendritic macromolecules of the present invention. Thus, each cycle involves a set of four distinct reactions to complete the cycle. Thus, initiating from a low molecular weight dendritic molecule with 16 ester functionalities at the surfaces requires full five cycles to reach a dendritic macromolecule presented with 512 ester functionalities at the surfaces, wherein complete reactivities of the functional groups occurred at the surfaces of the dendritic macromolecule.
The dendritic macromolecules of this invention can be used in many applications. Various applications, in such areas as, medical, healthcare, environmental, catalysis, engineering, electronics and opto-electronics are targeted for promotion of better performances, characteristics and efficiencies through the dendrimer technology. The important molecular feature available for the dendritic macromolecules is the presence of large of number of dense peripheral functional groups. This large number of peripheral functional groups provides the opportunity for attaching, for example, drug molecules, fragrant molecules, antibodies, antigens, nucleotides, nucleosides, peptides, proteins and carbohydrate ligands etc. Also, the low viscosity of the dendritic macromolecules, in comparison to random polymers of the similar molecular weights, may find applications in the area of, for example, lubricants in automotive oils. Another important physical attribute of these new class of dendrimers is that their radius is considerably larger than dendrimers of the type as described in U.S.Pat. No.4,507,466; U.S.Pat. No.4,558,320 and U.S.Pat. No. 4,737,550, relating to the poly(amido amine) series of dendrimers and WO 93/14147, U.S. Pat. No. 5,698,662, relating to the poly(propylene imine) series of dendrimers. The radius of a particular

generation of the dendrimers of the present invention would relate to next higher generation of, for example, the poly(amido amine) dendrimers. This important physical attribute of the dendrimers of the present invention originates from the larger linkers lengths, connecting the branch functionalities. The utility of the larger radius of the dendrimers, with attendant lesser molecular weights, can be envisaged in applications such as drug delivery. The dendritic base platforms with larger sizes and lesser molecular weights will have beneficial effects upon conjugation with drugs. The larger through-bond distances between the branch functionalities of the present invention also allow them to be more flexible and less rigid. The presence of ether and amine functionalities of the dendrimers of this invention makes them analogous to the functionalities present individually in polymers such as poly(ethylene glycol) and poly(ethylene imine). The lower toxicity profile of these types of functionalities make the molecules derived from thereof to be invoked in applications, such as, drug delivery vehicles, drug formulations, skin care formulations, gene delivery vehicles, vehicles for conjugation with pharmacologically important nucleosides, nucleotides, peptides, proteins, carbohydrates and other synthetic agents. The series of the dendrimers have defined internal voids and cavifies that can encapsulate small molecules, relevant in, for example, enhancing the bioavailablity of a drug, or a drug encapsulation or a toxic chemical encapsulation or a biocide encapsulation etc. Thus, from the point of view of various applications, lower generation dendrimers of the present invention can be utilized in place of higher generation dendrimers of the type as described in above disclosures, in order, for example, to avoid toxicity towards biological objects.
The technology of the instant Application is further elaborated with the help of following examples. However, the examples should not be construed to limit the scope of the invention. Example: 1
A mixture of the 16-alcohol functionalized dendritic macromolecule (5.0 g) and of aq 40 % NaOH (0.4 mL) was added with acrylonitrile (2.15 mL), at 0 °C and stirred at room temperature for 15 h. Additional amount of acrylonitrile (2.15 mL) was added portion wise, and this additional amount was added again after 8 h of stirring and the reaction was monitored (TLC alumina matrix; eluant: 6 % MeOH/ CHCI3, Rf of the required 16-nitrile functionalized dendritic macromolecule: 0.45). The solution was

filtered through celite using chloroform, and washed with water and the solvents evaporated under reduced pressure. The crude reaction mixture was dissolved in aqueous MeOH, subjected to liquid-liquid extraction with hexane to remove -70 % of bis(2-cyano ethyl ether). Finally, the reaction mixture was subjected to column chromatography (neutral alumina, 100-300 mesh size), afforded the 16-nitrile functionalized dendritic macromolecule, as a colorless gummy liquid. Yield: 6.33 g.
Example: 2
In a 2 L hydrogenation reactor vessel, a mixture of sixteen nitrile-functionalized dendritic macromolecule (1.5 g) in distilled water (1.2 L) and Raney Co (Aldrich Inc. USA) (4.0 g) was hydrogenated in the presence of hydrogen gas (46 atm.). The temperature was maintained in the range of 70-75 °C. After 3.5 h, the reaction mixture was cooled and the spent Raney cobalt was recovered using a magnetic pellet picker. Methanol was added to wash the compound from catalyst and to remove the catalyst from pellet picker, flushed with water and the water layer was concentrated at 55 °C under reduced pressure. For easy removal of water, azeotrope mixture was formed by adding dioxane solvent and evaporated quickly. To the resulting reaction mixture methanol was added and filtered. The filtrate was concentrated and dried to afford the corresponding 16 amine-functionalized dendritic macromolecule. Yield: 1.53 g.
Example: 3
A solution of 16 amine terminated dendritic macromolecule (1.53 g) in methanol (50 mL) and tert-butyl acrylate (filtered through pad of alumina prior to the addition) (10 mL) was stirred vigorously for 72 h. The reaction was monitored (TLC alumina matrix, eluant: 3 % MeOH/ CHCI3, Rf of the 32 ester functionalized dendritic macromolecule: 0.52). Excess tert-butyl acrylate and methanol were removed under reduced pressure after completion of the reaction. Addition of petroleum ether helped to precipitate the polar impurity and it was separated by filtration through filter paper. Subsequent evaporation of the solvent afforded the 32 ester terminated dendritic macromolecule. Further purification was performed by column chromatography (neutral alumina; eluant: CHCI3: MeOH), to afford the 32 ester functionalized dendritic macromolecule. Yield: 3.15 g.

Example: 4
A solution of 32-ester functionalized dendrimer (4.0 g) in THF (150 mL) was added dropwise to a suspension of LiAlH4 (1.34 g) in THF (50 mL), over a period of 15 min at 0 °C and the stirring was continued for 4 h at room temperature. After completion of the reaction, the mixture was cooled to 0 °C, quenched with ice, diluted with water, passed through celite, and the filtrate concentrated under reduced pressure. The crude reaction mixture was added with MeOH, filtered, and the filtrate concentrated. The resulting reaction mixture was extracted CHCI3. Removal of the solvents afforded the 32-alcohol functionalized dendritic macromolecule. Yield: 2.76 g.
Example; 5
A mixture of the 32-alcohol functionalized dendritic macromolecule (5.0 g) and of aq 40 % NaOH (0.4 mL) was added with acrylonitrile (2.02 mL), at 0 °C and stirred at room temperature for 15 h. Additional amount of acrylonitrile (2.02 mL) was added portion wise, and this additional amount was added again after 8 h of stirring and the reaction was monitored (TLC alumina matrix; eluant: 6 % MeOH/ CHCI3, Rf of the required 32-nitrile functionalized dendritic macromolecule: 0.6). The solution was filtered through celite using chloroform, and washed with water and the solvents evaporated under reduced pressure. The crude reaction mixture was dissolved in aqueous MeOH, subjected to liquid-liquid extraction with hexane to remove -70 % of bis(2-cyano ethyl ether). Finally, the reaction mixture was subjected to column chromatography (neutral alumina, 100-300 mesh size), afforded the 32-nitrile functionalized dendritic macromolecule, as a colorless gummy liquid. Yield: 5.23 g.
Example: 6
In a 2 L hydrogenation reactor vessel, a mixture of 32 nitrile-functionalized dendritic macromolecule (1.0 g) in disfilled water (1.2 L) and Raney Co (Aldrich Inc. USA) (5.0 g) was hydrogenated in the presence of hydrogen gas (46 atm.). The temperature was maintained in the range of 70-75 °C. After 3.5 h, the reaction mixture was cooled and the spent Raney cobah was recovered using a magnetic pellet picker. Methanol was added to wash the compound from catalyst and to remove the catalyst from pellet picker, flushed with water and the water layer was concentrated at 55 °C under reduced pressure. For easy removal of water, azeotrope mixture was formed by adding dioxane solvent and evaporated quickly. To the resulting reaction mixture methanol was added

and filtered. The filtrate was concentrated and dried to afford the corresponding 32 amine-functionalized dendritic macromolecule. Yield: 1.01 g.
Example: 7
A solution of 32 amine terminated dendritic macromolecule (1.01 g) in methanol (50 mL) and tert-butyl acrylate (filtered through pad of alumina prior to the addition) (10 mL) was stirred vigorously for 72 h. The reaction was monitored (TLC alumina matrix, eluant: 3 % MeOH/ CHCI3, Rf of the 64 ester functionalized dendritic macromolecule: 0.66). Excess /er/-butyl acrylate and methanol were removed under reduced pressure after completion of the reaction. Addition of petroleum ether helped to precipitate the polar impurity and it was separated by filtration through filter paper. Subsequent evaporation of the solvent afforded the 64 ester terminated dendritic macromolecule. Further purification was performed by column chromatography (neutral alumina; eluant: CHCI3: MeOH), to afford the 64 ester functionalized dendritic macromolecule. Yield: 1.70 g.

WE CLAIM:
1. A dendritic macromolecule having symmetrically sited branches, wherein the branch points are tertiary amines, the branches linked together through linkers comprising oxygen atom of an ether, and the heteroatoms are separated by a substituted or non-substituted linear three methylene linker.
2. The dendritic macromolecule as claimed in claim 1, wherein the number of
symmetrically sited branches, are ranging from 3 to 8 and the number of
peripheral groups ranging from 16 to 512.
3. The dendritic macromolecule as claimed in claim 1, wherein the substituents on
the three methylene linkers are selected from a group comprising an alkyl,
branched alkyl and aryl group.
4. The dendritic macromolecule as claimed in claim 1, wherein the alkyl,
branched alkyl and aryl substituents in the linear three methylene linker are
present on two adjacent methylene groups and the third unsubstituted methylene
group is present on left to the heteroatoms.
5. The dendritic macromolecule as claimed in claim 1, wherein the functional
group present at the periphery of the dendritic macromolecule is selected form a
group comprising alcohol, amine, ester, nitrile and carboxylic acid or a
combination thereof.
6. The dendritic macromolecule as claimed in claim 1, wherein said molecule is
useful in the delivery of drug molecules, fragrant molecules, antibodies,
antigens, nucleotides, nucleosides, peptides, proteins and as lubricant in
automotive oils.
7. The dendritic macromolecule as claimed in claim 1, wherein repeating unit of
the dendritic macromolecule is:

8. A process for preparing a dendritic macromolecule comprises steps of:
i. reacting the alcohol units of the lower dendritic molecule to react with molar equivalents of α, β -unsaturated nitrile, in the presence of an alkali, to install nitrile groups at the surfaces of the dendritic macromolecule;
ii. converting nitrile groups at the surfaces of the dendritic macromolecule to the corresponding amines, mediated by supported metal catalysts and hydrogen gas;
iii. subjecting the resulting amine functional groups to react with α ,β -unsaturated esters; and
iv. converting ester units present at the surfaces of the dendritic macromolecule to the corresponding alcohol units, mediated by metal hydride reagents; to prepare a higher generation dendritic molecule.
9. The process as claimed in claim 8, wherein the lower dendritic molecule is one
generation lower than the target dendritic molecule
10. The process as claimed In claim 8, wherein the molar equivalents of α, β -
unsaturated nitrile is 50 molar equivalent per unit of the hydroxyl group present
in the dendritic molecule:
11. The process as claimed in claim 8, wherein the alkali used is 40% aqueous
solution of sodium hydroxide;
12. The process as claimed in claim 8, wherein the catalyst is selected from a group
of metal supported catalysts such as Raney alloys; preferably Raney Cobalt.
13. The process as claimed in claim 8(ii), wherein the concentration of nitrile
ranges between 0.01 mM and 4.0 mM.
14. The process as claimed in claim 8, wherein the metal hydride reagent is selected
from a range of metal hydride reagents preferably lithium aluminum hydride.
15. A dendritic molecule and the process of its preparation substantially as herein

Documents:

1435-che-2007 form-3 25-01-2011.pdf

1435-che-2007 amended claims 25-01-2011.pdf

1435-che-2007 amended pages of specification 25-01-2011.pdf

1435-CHE-2007 CORRESPONDENCE OTHERS 10-02-2012.pdf

1435-che-2007 examination report reply received 25-01-2011.pdf

1435-che-2007 other patent document 25-01-2011.pdf

1435-che-2007-abstract.pdf

1435-che-2007-claims.pdf

1435-che-2007-correspondnece-others.pdf

1435-che-2007-description(complete).pdf

1435-che-2007-form 1.pdf

1435-che-2007-form 3.pdf

1435-che-2007-form 5.pdf

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Patent Number

253975

Indian Patent Application Number

1435/CHE/2007

PG Journal Number

37/2012

Publication Date

14-Sep-2012

Grant Date

10-Sep-2012

Date of Filing

04-Jul-2007

Name of Patentee

INDIAN INSTITUTE OF SCIENCE

Applicant Address

DEPARTMENT OF ORGANIC CHEMISTRY BANGALORE 560 012

Inventors:

#	Inventor's Name	Inventor's Address
1	NARAYANASWAMY JAYARAMAN	C/O INDIAN INSTITUTE OF SCIENCE DEPARTMENT OF ORGANIC CHEMISTRY BANGALORE 560 012
2	GOVINDASAMY JAYAMURUGAN	C/O INDIAN INSTITUTE OF SCIENCE DEPARTMENT OF ORGANIC CHEMISTRY BANGALORE 560 012

PCT International Classification Number

A61K31/785

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA