Title of Invention	A SINGLE STEP PROCESS FOR THE PREPARATION OF FOLY (OXYALKYLENE)-ALPHA, OMEGA- DICARBOXYLIC ACIDS.
Abstract	The present invention provides a single step process for the preparation of poly (oxyalkylene)- alpha, omega- dicarboxylic acids which comprises reacting the corresponding poly (oxyalkylene glycol) with an oxidizing agent in form of Jone" reagent comprising of aqueous solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 , in a polar solvent, quenching the reaction by adding known free radical scavenger, removing oxidation by-products from reaction mixture by adsorbing them on an adsorbing agent to obtain product in the solution, evaporating the clear solution to obtain products- poly (oxyalkylene)- alpha, omega-diacrboxylic acids. The product has wide application in various branches of chemistry as water soluble polymer support, polymeric drug carrier, stabilizer and antistatic agent in polyamides.

Title of Invention

A SINGLE STEP PROCESS FOR THE PREPARATION OF FOLY (OXYALKYLENE)-ALPHA, OMEGA- DICARBOXYLIC ACIDS.

Abstract

The present invention provides a single step process for the preparation of poly (oxyalkylene)- alpha, omega- dicarboxylic acids which comprises reacting the corresponding poly (oxyalkylene glycol) with an oxidizing agent in form of Jone" reagent comprising of aqueous solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 , in a polar solvent, quenching the reaction by adding known free radical scavenger, removing oxidation by-products from reaction mixture by adsorbing them on an adsorbing agent to obtain product in the solution, evaporating the clear solution to obtain products- poly (oxyalkylene)- alpha, omega-diacrboxylic acids. The product has wide application in various branches of chemistry as water soluble polymer support, polymeric drug carrier, stabilizer and antistatic agent in polyamides.

Full Text	This invention relates to a single step process for the preparation of poly (oxyalkylene)-alpha, omega-dicarboxylic ' acids having formula HO2CCH2O(CH2CHRO)nCH2C02H, wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer of from 100 to about 2500. More particularly the invention relates to the process for preparation of poly (oxyalkylene)-alpha, omega- dicarboxylic acids by oxidation of corresponding poly (oxyalkylene glycol)s in the presence of an oxidizing agent. Poly (oxyalkylene)-alpha, omega- dicarboxylic acids are finding ever increasing applications in various branches of chemistry. Some of the applications are as follows. 1) Water soluble polymer support for Merrifield type peptide synthesis (R.P. Garfield and G.M. Ananthramaiah, J. Am. Chem. Soc. 101, 3394 (1979), G.P. Royer, Methods Enzymol. 136, 302 (1987)). 2) Polymeric drug carriers- prodrugs (K. Ulbrich and J. Kopecek, Macromol. Chem. 187, 1131 (1986), T. Ouchi, Y. Hogihara, K. Takahashi, Y. Takano and I. Igarashi, Drug Design and Discovery, 9, 93 (1992), R.B. Greenwald, C.W. Gilbert, A. Pendri, C.D. Conover, J. Xia and A. Martinez, J. Med. Chem. 39, 424 (1996), S. Zalipski, C. Gilon and A. Zilkha, Eur. Polym. J. 19, 1177 (1983), M. Pecher, J. Strohalm and K. Ulbrich, Makromol. Chem. Phys. 198, 1009 (1997)). 3) Antistatic agents in polyamides (I. Jan and C. Frantisek, Czech. CS. 234,832). 4) Conjugates with enzyme - metal ion for improved stability and activity of enzymes (Y. Tukayuki, M. Takeshi, T. Katsunobu, S. Yuji, T. Yukata and I. Yuji, Biochem. Biophys. Res. Commun. 145, 908 (1987), N. Veyarma, M. Nakata and A. Nakamura, Polym. J. (Tokkyo) 17, 721 (1985), T. Katsunobu, 0. Kimiko, Y. Takayuki, S. Yuji, K. Yoh, M. Ayako and I. Yuji, J. Biotechnol. 8, 135 (1988)). 5) Conjugates with hemoglobin for oxygen carrying blood substitute (A. Yabuki, K. Yamaji, H. Ohki and Y. Iwashita, Transfusion (Philadelphia) 30,516(1990). 6) Conjugates with lipids for improved longevity in blood circulation (B. Gabriele and C. Greger, Biochem. Biophys. Acta. 1146, 157 (1993). 7) Surface modifying agents for transition metal alluminides (D.M. Zehner, Surf. Rev. Lett. 3, 1637 (1996). 8) Stabilizer for water based epoxy formulations (H.E. Fried and C.J. Stark, PCT Intl. Appl. WO 9619, 514) and so on. In order to meet these growing requirements for poly (oxyalkylene)-alpha, omega- dicarboxylic acids, various methods for their preparation have been developed so far which can broadly be classified into following two types. 1. Carboxymethylation of poly (oxyalkylene glycol)s In this method of preparation, terminal hydroxymethyl groups of poly (oxyalkylene glycol)s are derivatized with carboxymethyl groups (-CH2-COOH groups) so as to obtain poly (oxyalkylene)-alpha,omega- dicarbcxylic acids This method essentially involves following steps A) Activation of terminal hydroxyl groups by reacting poly (oxyalkylene glycol)s with strong bases such as potassium tertiary butoxide, silver oxide, sodium hydroxide etc. 3 i Reaction of alcoholate so obtained with reagents like bromo ethyl acetate, caloroethyl acetate etc. C) Saponification of ethyl ester followed by acidification of reaction mixture. D) Isolation of product. The above method has been used by various researchers (R.P. Garfield and G.M. Ananthramaiah, J. Am. Chem. Soc. 101, 3394 (1979), K. Ulbrich, J. Strohalm and J. Kopecek,.Makromol. Chem. 187, 1131 (1986), M. Pecher, J. Strohalm and K. Ulbrich, Makromol. Chem. Phys. 198, 1009 (1997), A.F. Buckmann, M. Morr and J. Goete, Makromol. Chem. 182, 1379 (1981), I. Keiji, I. Yuji and 0. Taketashi, Eur. Pat. Appl. EP. 206,448, A.J. Martinez and R.B. Greenwald, U.S. US 5605976A). Since this method of preparation for poly (oxyalkylene)-alpha,omega- dicarboxylic acids is a multistep process involving specialty reagents, it is not attractive for large scale production. 2. Oxidation of poly (oxyalkylene glycol)s A number of patents which are based on this technique have "resn filed. Japanese patent, Japan Kokai 7300,528 discloses the preparation of low molecular weight poly (oxyethylene)-alpha,omega- dicarboxytic acids by oxidation of poly (ethylene glycol)s using oxygen and concentrated nitric acid as oxidizing agent in an autoclave at 80 °C under 3 Kg /cm' pressure (E. Yonemitsue, T. Icshiki, Y. Kijima and T. Matsumoto, Japan Kokai "300,528). Low molecular weight poly (ethylene glycol)s have also been oxidized using Platinum / charcoal catalysts and oxygen under pressure at 50 °C in a column reactor (Sanyo Chemical Industries Ltd. Jpn. Kokai Tokkyo Koho JP 8258,642). Preparation of poly (oxyethylene)-alpha,omega- dicarfacxyiic acids by oxidation of poly (etliylene glycol)s hi presence of cobali acetate quadrahdrate, using oxygen under pressure at 140 °C and using a mxture of catalysts viz. copper acetate, ammonium venadate, nitric acid and fonzaldehyde at 50 to 90 °C has also been reported (Nikka Chemical Industry Co. Ltd. Jpn. Kokai Tokkyo Koho JP 5901,443 and W. Disteldorf,' W. Eisfeli and H. Hellbach, Gen. Offen. DE. 3,209,434, respectively). Czechoslovakian patent CS. 234,832 discloses the preparatiea of poly (oxyethylene)-alpha,omega- dicarboxylic acids of molecular weighs in the range of 1000 to 3000 by oxidation of corresponding poly (ethylecs g!ycol)s using potassium dichromate and sulfuric acid at 70 °C (I. Jan and C. rrantisek, Czech. CS. 234,832). Microbial oxidation of poly (ethylene grycol)s of molecular weights from 200 to 2000 by Rhinocladiella actrovirens bas been reported, wherein, the time period required for oxidation was upto 14 days (M. Shuichi, Y. Nobuo and Y. Sadao, Makromol. Chem. Rapid. Commun. 10, 63 (1989) ). Recently, US patent No. 5,256,819 has disclosed preparation of poly (oxyalkylene)-alpha, omega- dicarboxylic acids of wide range of molecular weights by oxidation of corresponding poly (oxyalkylene glycol)s using oxygen, nitric acid and 2,2,6,6 tetramethylpiperidine-1-oxyl as oxidizing agent (H.E. Fried U,S US5,256,819) Most of the above cited oxidation processes required either harsh reaction conditions such as high temperature, pressure etc. or specialty reagents like stable free radicals- 2,2,6,6 tetramethylpiperidine- 1- oxyl. Also in most of the cases conventional work up procedures which involve neutralization of oxidizing agents, concentration of solvents, removal of oxidation by-products and isolation of products, are followed. Thus there is a need to develop a simpler method for oxidation of poly (oxyalkylene glycoDs having wide range of molecular weights to corresponding dicarboxylic acids. It is therefore an object of the present invention to provide a single step process for the preparation of poly (oxyalkylene)-alpha.omega- dicarboxylic acids of low to very high molecular weights in high yields by oxidation of corresponding glycols using commonly available oxidizing agents under mild reaction conditions such as room temperature, atmospheric pressure etc. Another object of the invention is to provide a simpler method for removing the oxidation by-products from reaction mixture and thus obviate the conventional work up procedures. As compared to above mentioned various oxidizing agents, Jone's reagent, which is a mixture of chromium trioxide and sulfuric acid and water, is a strong oxidizing agent which oxidizes hydroxymethyl groups to carboxyl groups at temperatures in the range of 10 °C to room temperature (25 °C) (L.S. Loeffler, S.F. Britcher and W. Baumgarten, J. Med. Chem. 13, 926 (1970). Despite such strong oxidizing power, Jone's reagent has not been used in oxidation of poly (oxyalkylene glycol)s to corresponding dicarboxylic acids. It has now been found that poly (oxyalkylene)-alpha,omega- dicarboxylic acids can be produced in high yields by oxidation of poly (oxyalkylene glycol)s using Jone's reagent as oxidizing agent in suitable solvent at room temperature. Accordingly, the present invention provides a single step process for the preparation of poly (oxyalkylene)- alpha, omega- dicarboxylic acids of the formula HO2CCH2O(CH2CHRO)nCH:CO2H, wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer of from 100 to 2500, which comprises reacting the corresponding poly (oxyalkylene glycol) with an oxidizing agent in form of Jone' reagent comprising of aqueous solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 , in a polar solvent at a temperature in the range of 100°C to room temperature for a period ranging between 1 hour to 12 hours, quenching ihe reaction by adding known free radical scavenger. removing oxidation by-products from reaction mixture by adsorbing them on an adsorbing agent to obtain product in the solution, evaporating the clear solution to obtain products- poly (oxyalkylene)- alpha, omega-diacrboxylic acids. In another embodiment of the present invention , poly(oxyalkylene glycol)s used is such as compounds of the formula HOCH2O(CH2CHRO)nCH2OH wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer which represents the average numbers of oxyalkylene groups, preferably from 100 to 250 In yet another embodiment of the present invention , the oxidizing agent used is such as Jone's reagent (chromium trioxide and sulfuric acid dissolved in water) consisting of aqueous water solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 respectively or a combination of two separate components i.e. water solution of chromium trioxide and concentrated sulfuric acid In still another embodiment of the present invention , poly (oxyalkylene glycol) is for use in the present invention are commercially available polyethylene glycol)s of molecular weight 4000, 6000, 20,000, 1,00,000 and monomethoxy poly(ethylene glycol) of molecular weight 5000. In yet another embodiment the free radical scavenger used may be such as isopropyl alcohol, mercaptoethanol. In still another embodiment the solvent used may be such as acetonitrile, dichloromethane, chloroform, benzene, acetone, tetrahydrofuran, dioxane, cyclohexanone. In another embodiment the weight ratio of poly (oxyalkylene glycol) to solvent may be in the range from about 1:5 to 1:200, more preferably in the range from about 1:10 to 1:100. In an another embodiment of the present invention, the adsorbing agents used may be such as Fuller's Earth, Kiesleger, ion exchange resins, activated charcoal. In a feature of the present invention the adsorbing agent required for efficient adsorption of chromium salts from reaction mixture is typically in the range of about 10 % to 30 % of the weight of poly (oxyalkylene glycol) taken t for the reaction. Adsorption process typically requires 2 to 3 hours stirring of reaction mixture after adsorbing agent is added in the reaction mixture. Subsequently the reaction mixture is filtered to obtain clear and colorless solution which is then evaporated in vacuo to obtain products. In a feature of the present invention, in order to oxidize on mole of hydroxymethyl groups, the amount of Jone's reagent used contains 1 mole chromium trioxide and 1.75 moles sulfuric acid, dissolved in water. In another feature of the present invention, the process of the present invention is typically conducted under mild conditions. Poly (oxyalkylene glycol) is dissolved in suitable solvent and the appropriate amount of Jone's reagent is added to it and the reaction mixture is'stirred at room temperature for a period of about 1 hour to 12 hours. After stirring the reaction mixture for the above mentioned time period, the reaction is quenched by adding isopropyl alcohol as free radical scavenger. Blue green colored chromium salts are formed in the reaction mixture as result of oxidation. These salts form a fine suspension which is difficult to separate from the reaction mixture by conventional filtration, especially in the case of high molecular weight poly (oxyalkylene glycols). Thus in order to remove these oxidation by-products the process of the instant invention uses the method of adsorption of the salts from reaction mixture onto an adsorbing agent. hi an another feature of die present invention, the adsorption process conditions vary depending upon the molecular weight of poly (oxyaikylene)-alpha,omega- dicarboxylic acid prepared by the process of the instant invention, e.g. for poly (oxyalkylene)-alpha,omega- dicarboxylic acids of molecular weights 4000 and 6000, a large fraction of chromium salts can be filtered out of reaction mixture, rendering less amount of adsorbing agent to be used for the treatment. But poly (oxyalkylene)-alpha,omega- dicarbcxylic acids of molecular weights 20,000 and 1,00,000, chromium salts formed after the reaction a fine suspension which is practically inseparable and thus required the above mentioned adsorption process for its removal. The ranges and limitations provided in the instant specification and claims are those which are believed to particularly point out and distinctly claim the present invention. It is however understood that other ranges and limitations which perform substantially the same function in the same or substantially the same manner to obtain the same or substantially die same results are intended to be within the scope of the instant invention as defined by the instant specification and claims. The process of the instant invention will be further described by the following examples which are provided for illustration and are not to be construed as limiting the invention. Example-1 PREPARATION OF OXIDIZING AGENT (JONE'S REAGENT) Jone's reagent was synthesized according to the following procedure. 70 g CrO3 was dissolved in 500 ml distilled water and the solution was stirred with magnetic needle at 10 ° to 15 ° C (ice - water bath). To this solution, 61 ml cone. H2S04 was added in small portions. After the addition was over, the solution was stirred for additional 10 minutes and allowed to come to room temperature. Jone's reagent so prepared was stored at room temperature and used in syntheses of all poly (oxyalkylene)-alpha,omega- dicarboxylic acids. EXAMPLE-2 . Preparation of poly (oxyehtylene) 4000 - alpha,omega- dicarboxylic acid : 40 g poly (ethylene glycol) 4000 (0.01 M) was taken in a I liter capacity round bottom flask and 400 ml acetone was added to it. Contents of the flask were heated in a heating mantle to obtain clear, homogeneous solution. The solution was allowed to attain room temperature. To this solution, 17 ml Jone's reagent (containing 0.02 M chromium trioxide) was added in a single portion and the reaction mixture was stirred at room temperature (~ 25 °C) with magnetic needle. Within few minutes after the addition, blue - green colored chromium salts (oxidation by-products) precipitated out in the form of a fine suspension in acetone solution. Stirring of the reaction mixture was continued overnight (12 hrs). Then the reaction was quenched by adding 5 ml isopropyl alcohol (free radical scavenger). To the above suspension of chromium salts (not separable by filtration), 4 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 4000) was added and stirred with magnetic needle for two hours. This was then filtered on Buckner funnel to obtain colourless, clear acetone solution. Clear acetone solution was concentrated in vacuo to a viscous liquid. This was poured in petty dish and allowed to cool to room temperature at which it solidified. Residual moisture from the product so obtain was removed by drying it in vacuum desiccator for 48 hours. The product was obtained in the form of a white powder. Oxidation of hydroxymethyl groups to carboxyl groups was quantified by estimating acid values of all the products. The results are listed in Table 1. EXAMPLE-3 Preparation of monomethoxy poly (oxyethylene) 5000 - monocarboxylic acid: 50 g monomethoxy poly (ethylene glycol) 5000 (0.01 M) was dissolved in 400 ml acetone as mentioned in the example 1. To this solution, 8.5 ml Jone's reagent (containing 0.01 M chromium trioxide) was added in a single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyi alcohol. Chromium salts formed were removed from reaction mixture by adding 5 g finely powdered activated charcoal (10 % of the wt. of t monomethoxy poly (polyethylene glycol) 5000), stirring for two hours and filtering it to obtain colourless acetone solution. The solution was concentrated in vacuo and white powdered product was isolated as mentioned in example 1. EXAMPLE-4 Preparation of poly (oxyethylene) 6000 - alpha,omega- dicarboxylic acid : 60 g poly (ethylene glycol) 6000 (0.01 M) was dissolved in 400 ml acetone. To this solution, 17 ml Jone's reagent (containing 0.02 M chromium trioxide) was added in a single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyl alcohol. Chromium salts formed were removed from reaction mixture by adding 6 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 6000), stirring for rwo hours and filtering it to obtain colourless acetone solution. The solunon was concentrated in vacuo and white powdered product was isolated as mentioned in example 1. EXAMPLE-5 Preparation of poly (oxyethylene) 20000 -alpha,omega- dicarboxylic acid : 200 g poly (ethylene glycol) 20000 (0.01 M) was dissolved in 800 ml acetone. To this solution, 17 ml Jone's reagent (containing 0.02 M chromium trioxide) was added in a -single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyl alcohol. Chromium salts formed were removed from reaction mixture by adding 20 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 20000), stirring for two hours and filtering it to obtain colourless acetone solution. The solution was concentrated in vacuo and white powdered product was isolated as mentioned in example 1. EXAMPLE-6 Preparation of poly (oxyethylene) 1,00,000 -alpha,omega- dicarboxylic acid : 50 g poly (ethylene glycol) 1,00,000 (0.5 milimoles) was dissolved in 1000 ml acetone. To this solution, 1 ml Jone's reagent (containing 1.0 milimole chromium trioxide) was added in a single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyl alcohol. Chromium salts formed were removed from reaction mixture by adding 5 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 1,00,000), stirring for two hours and filtering it to obtain colourless acetone solution. The solution was concentrated in vacuo and white powdered product was isolated as mentioned in example 1. Table 1 Data for oxidation of poly (oxyalkylene glycol)s to poly (oxyalkylene)-alpha, omega- dicarboxylic acids by Jone's reagent. (Table Removed) (Theoretical acid values are calculated assuming that poly (oxyalkylene glycol)s used are monodisperse. e.g. molecular weight of poly (ethylene glycol) 6000 was assumed to be 6000 which is infact in the range of 6000 to 7500 ) Advantages of the present invention are: 1) The process of the present invention allows the oxidation of low to very high molecular weight poly (oxyalkylene glycols) under very mild conditions i.e. at room temperature and atmospheric pressure, unlike high temperature and pressure used in the conventional processes. 2) The process of the present invention uses easily available and inexpensive oxidizing agent. 3) The process of the present invention provides a simple work up procedure to isolate the products as compared to tedious conventional work up procedures. We Claim: 1. A single step process for the preparation of poly (oxyalkylene)- alpha, omega- dicarboxylic acids of the formula HO2CCH2O(CH2CHRO)nCH2CO2H, wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer of from 100 to 2500, which comprises reacting the corresponding poly (oxyalkylene glycol) with an oxidizing agent in form of Jone' reagent comprising of aqueous solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 , in a polar solvent at a temperature in the range of 10°C to room temperature for a period ranging between 1 hour to 12 hours, quenching the reaction by adding known free radical scavenger, removing oxidation by-products from reaction mixture by adsorbing them on an adsorbing agent to obtain product in the solution, evaporating the clear solution to obtain products- poly (oxyalkylene)- alpha, omega-diacrboxylic acids. 2. A process as claimed in claim 1, wherein, poly(oxyalkylene glycol)s used is such as compounds of the formula HOCH2O(CH2CHRO)nCH2OH wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer which represents the average numbers of oxyalkylene groups, preferably from 100 to 2500. 3. A process as claimed in claim 1 -2, wherein, the oxidizing agent used is such as Jone's reagent (chromium trioxide and sulfuric acid dissolved in water) consisting of aqueous water solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 respectively or a combination of two separate components i.e. water solution of chromium trioxide and concentrated sulfuric acid. 4. A process as claimed in claim 1-3, wherein, poly (oxyalkylene glycol) is for use in the present invention are commercially available poly( ethylene glycol)s of molecular weight 4000, 6000, 20,000, 1,00,000 and monomethoxy poly(ethylene glycol) of molecular weight 5000. 5. A process as claimed in claim 1 - 4, wherein free radical scavenger used is such as iporropyl alcohol, mercaptocthanol. 6. A process as claimed in claim 1-5, wherein, the polar solvent used is such as acetonitrile, dichloromethane, chloroform, benzene, acetone, tetrahydrofuran, dioxane, cyclohexanone. 7. A process as claimed in claim 1 -6 ,wherein the weight ratio of poly (oxyalkylene glycol) to solvent is in the range from about 1:5 to 1:200, more preferably in the range from about 1:10 to 1:100. 8. A process as claimed in claim 1-7, wherein the adsorbing agents used is such as Fuller's Earth, Kiesleger, ion exchange resins, activated charcoal. 9. A process for the preparation of poly (oxyalkylene)-alpha, omega-dicarboxylic acids of substantially described herein with reference to examples contained therein.

Full Text

This invention relates to a single step process for the preparation of poly (oxyalkylene)-alpha, omega-dicarboxylic ' acids having formula HO2CCH2O(CH2CHRO)nCH2C02H, wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer of from 100 to about 2500. More particularly the invention relates to the process for preparation of poly (oxyalkylene)-alpha, omega- dicarboxylic acids by oxidation of corresponding poly (oxyalkylene glycol)s in the presence of an oxidizing agent.
Poly (oxyalkylene)-alpha, omega- dicarboxylic acids are finding ever increasing applications in various branches of chemistry. Some of the applications are as follows.
1) Water soluble polymer support for Merrifield type peptide synthesis
(R.P. Garfield and G.M. Ananthramaiah, J. Am. Chem. Soc. 101, 3394
(1979), G.P. Royer, Methods Enzymol. 136, 302 (1987)).
2) Polymeric drug carriers- prodrugs (K. Ulbrich and J. Kopecek,
Macromol. Chem. 187, 1131 (1986), T. Ouchi, Y. Hogihara, K.
Takahashi, Y. Takano and I. Igarashi, Drug Design and Discovery, 9, 93
(1992), R.B. Greenwald, C.W. Gilbert, A. Pendri, C.D. Conover, J. Xia
and A. Martinez, J. Med. Chem. 39, 424 (1996), S. Zalipski, C. Gilon

and A. Zilkha, Eur. Polym. J. 19, 1177 (1983), M. Pecher, J. Strohalm and K. Ulbrich, Makromol. Chem. Phys. 198, 1009 (1997)).
3) Antistatic agents in polyamides (I. Jan and C. Frantisek, Czech. CS.
234,832).
4) Conjugates with enzyme - metal ion for improved stability and activity
of enzymes (Y. Tukayuki, M. Takeshi, T. Katsunobu, S. Yuji, T. Yukata
and I. Yuji, Biochem. Biophys. Res. Commun. 145, 908 (1987), N.
Veyarma, M. Nakata and A. Nakamura, Polym. J. (Tokkyo) 17, 721
(1985), T. Katsunobu, 0. Kimiko, Y. Takayuki, S. Yuji, K. Yoh, M.
Ayako and I. Yuji, J. Biotechnol. 8, 135 (1988)).
5) Conjugates with hemoglobin for oxygen carrying blood substitute (A.
Yabuki, K. Yamaji, H. Ohki and Y. Iwashita, Transfusion (Philadelphia)
30,516(1990).
6) Conjugates with lipids for improved longevity in blood circulation (B.
Gabriele and C. Greger, Biochem. Biophys. Acta. 1146, 157 (1993).
7) Surface modifying agents for transition metal alluminides (D.M. Zehner,
Surf. Rev. Lett. 3, 1637 (1996).
8) Stabilizer for water based epoxy formulations (H.E. Fried and C.J. Stark,
PCT Intl. Appl. WO 9619, 514) and so on.

In order to meet these growing requirements for poly (oxyalkylene)-alpha, omega- dicarboxylic acids, various methods for their preparation have been developed so far which can broadly be classified into following two types.
1. Carboxymethylation of poly (oxyalkylene glycol)s
In this method of preparation, terminal hydroxymethyl groups of poly (oxyalkylene glycol)s are derivatized with carboxymethyl groups (-CH2-COOH groups) so as to obtain poly (oxyalkylene)-alpha,omega- dicarbcxylic acids This method essentially involves following steps A) Activation of terminal hydroxyl groups by reacting poly (oxyalkylene glycol)s with strong bases such as potassium tertiary butoxide, silver oxide, sodium hydroxide etc. 3 i Reaction of alcoholate so obtained with reagents like bromo ethyl acetate, caloroethyl acetate etc. C) Saponification of ethyl ester followed by acidification of reaction mixture. D) Isolation of product.
The above method has been used by various researchers (R.P. Garfield and G.M. Ananthramaiah, J. Am. Chem. Soc. 101, 3394 (1979), K. Ulbrich, J. Strohalm and J. Kopecek,.Makromol. Chem. 187, 1131 (1986), M. Pecher, J. Strohalm and K. Ulbrich, Makromol. Chem. Phys. 198, 1009 (1997), A.F. Buckmann, M. Morr and J. Goete, Makromol. Chem. 182, 1379 (1981), I. Keiji, I. Yuji and 0. Taketashi, Eur. Pat. Appl. EP. 206,448, A.J. Martinez and R.B. Greenwald, U.S. US 5605976A). Since this method of preparation for poly (oxyalkylene)-alpha,omega- dicarboxylic acids is a multistep process involving specialty reagents, it is not attractive for large scale production.

2. Oxidation of poly (oxyalkylene glycol)s
A number of patents which are based on this technique have "resn filed. Japanese patent, Japan Kokai 7300,528 discloses the preparation of low molecular weight poly (oxyethylene)-alpha,omega- dicarboxytic acids by oxidation of poly (ethylene glycol)s using oxygen and concentrated nitric acid as oxidizing agent in an autoclave at 80 °C under 3 Kg /cm' pressure (E. Yonemitsue, T. Icshiki, Y. Kijima and T. Matsumoto, Japan Kokai "300,528). Low molecular weight poly (ethylene glycol)s have also been oxidized using Platinum / charcoal catalysts and oxygen under pressure at 50 °C in a column reactor (Sanyo Chemical Industries Ltd. Jpn. Kokai Tokkyo Koho JP 8258,642). Preparation of poly (oxyethylene)-alpha,omega- dicarfacxyiic acids by oxidation of poly (etliylene glycol)s hi presence of cobali acetate quadrahdrate, using oxygen under pressure at 140 °C and using a mxture of catalysts viz. copper acetate, ammonium venadate, nitric acid and fonzaldehyde at 50 to 90 °C has also been reported (Nikka Chemical Industry Co. Ltd. Jpn. Kokai Tokkyo Koho JP 5901,443 and W. Disteldorf,' W. Eisfeli and H. Hellbach, Gen. Offen. DE. 3,209,434, respectively).
Czechoslovakian patent CS. 234,832 discloses the preparatiea of poly (oxyethylene)-alpha,omega- dicarboxylic acids of molecular weighs in the range of 1000 to 3000 by oxidation of corresponding poly (ethylecs g!ycol)s using potassium dichromate and sulfuric acid at 70 °C (I. Jan and C. rrantisek, Czech. CS. 234,832). Microbial oxidation of poly (ethylene grycol)s of molecular weights from 200 to 2000 by Rhinocladiella actrovirens bas been

reported, wherein, the time period required for oxidation was upto 14 days (M. Shuichi, Y. Nobuo and Y. Sadao, Makromol. Chem. Rapid. Commun. 10, 63 (1989) ). Recently, US patent No. 5,256,819 has disclosed preparation of poly (oxyalkylene)-alpha, omega- dicarboxylic acids of wide range of molecular weights by oxidation of corresponding poly (oxyalkylene glycol)s using oxygen, nitric acid and 2,2,6,6 tetramethylpiperidine-1-oxyl as oxidizing agent (H.E. Fried U,S US5,256,819)
Most of the above cited oxidation processes required either harsh reaction conditions such as high temperature, pressure etc. or specialty reagents like stable free radicals- 2,2,6,6 tetramethylpiperidine- 1- oxyl. Also in most of the cases conventional work up procedures which involve neutralization of oxidizing agents, concentration of solvents, removal of oxidation by-products and isolation of products, are followed. Thus there is a need to develop a simpler method for oxidation of poly (oxyalkylene glycoDs having wide range of molecular weights to corresponding dicarboxylic acids.
It is therefore an object of the present invention to provide a single step process for the preparation of poly (oxyalkylene)-alpha.omega- dicarboxylic acids of low to very high molecular weights in high yields by oxidation of corresponding glycols using commonly available oxidizing agents under mild reaction conditions such as room temperature, atmospheric pressure etc.

Another object of the invention is to provide a simpler method for removing the oxidation by-products from reaction mixture and thus obviate the conventional work up procedures.
As compared to above mentioned various oxidizing agents, Jone's reagent, which is a mixture of chromium trioxide and sulfuric acid and water, is a strong oxidizing agent which oxidizes hydroxymethyl groups to carboxyl groups at temperatures in the range of 10 °C to room temperature (25 °C) (L.S. Loeffler, S.F. Britcher and W. Baumgarten, J. Med. Chem. 13, 926 (1970). Despite such strong oxidizing power, Jone's reagent has not been used in oxidation of poly (oxyalkylene glycol)s to corresponding dicarboxylic acids. It has now been found that poly (oxyalkylene)-alpha,omega- dicarboxylic acids can be produced in high yields by oxidation of poly (oxyalkylene glycol)s using Jone's reagent as oxidizing agent in suitable solvent at room temperature.
Accordingly, the present invention provides a single step process for the preparation of poly (oxyalkylene)- alpha, omega- dicarboxylic acids of the formula HO2CCH2O(CH2CHRO)nCH:CO2H, wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer of from 100 to 2500, which comprises reacting the corresponding poly (oxyalkylene glycol) with an oxidizing agent in form of Jone' reagent comprising of aqueous solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 , in a polar solvent at a temperature in the range of 100°C to room temperature for a period ranging between 1 hour to 12 hours, quenching ihe reaction by adding known free radical scavenger.

removing oxidation by-products from reaction mixture by adsorbing them on an adsorbing agent to obtain product in the solution, evaporating the clear solution to obtain products- poly (oxyalkylene)- alpha, omega-diacrboxylic acids.
In another embodiment of the present invention , poly(oxyalkylene glycol)s used is such as compounds of the formula HOCH2O(CH2CHRO)nCH2OH wherein R is hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule and n is an integer which represents the average numbers of oxyalkylene groups, preferably from 100 to 250
In yet another embodiment of the present invention , the oxidizing agent used is such as Jone's reagent (chromium trioxide and sulfuric acid dissolved in water) consisting of aqueous water solution of chromium trioxide and sulfuric acid in the molar proportion of 1:1 to 1:1.75 respectively or a combination of two separate components i.e. water solution of chromium trioxide and concentrated sulfuric acid
In still another embodiment of the present invention , poly (oxyalkylene glycol) is for use in the present invention are commercially available polyethylene glycol)s of molecular weight 4000, 6000, 20,000, 1,00,000 and monomethoxy poly(ethylene glycol) of molecular weight 5000.

In yet another embodiment the free radical scavenger used may be such as isopropyl alcohol, mercaptoethanol.
In still another embodiment the solvent used may be such as acetonitrile, dichloromethane, chloroform, benzene, acetone, tetrahydrofuran, dioxane, cyclohexanone.
In another embodiment the weight ratio of poly (oxyalkylene glycol) to solvent may be in the range from about 1:5 to 1:200, more preferably in the range from about 1:10 to 1:100.
In an another embodiment of the present invention, the adsorbing agents used may be such as Fuller's Earth, Kiesleger, ion exchange resins, activated charcoal.
In a feature of the present invention the adsorbing agent required for efficient adsorption of chromium salts from reaction mixture is typically in the range of about 10 % to 30 % of the weight of poly (oxyalkylene glycol) taken
t
for the reaction. Adsorption process typically requires 2 to 3 hours stirring of reaction mixture after adsorbing agent is added in the reaction mixture.

Subsequently the reaction mixture is filtered to obtain clear and colorless solution which is then evaporated in vacuo to obtain products.
In a feature of the present invention, in order to oxidize on mole of hydroxymethyl groups, the amount of Jone's reagent used contains 1 mole chromium trioxide and 1.75 moles sulfuric acid, dissolved in water.
In another feature of the present invention, the process of the present invention is typically conducted under mild conditions. Poly (oxyalkylene glycol) is dissolved in suitable solvent and the appropriate amount of Jone's reagent is added to it and the reaction mixture is'stirred at room temperature for a period of about 1 hour to 12 hours. After stirring the reaction mixture for the above mentioned time period, the reaction is quenched by adding isopropyl alcohol as free radical scavenger. Blue green colored chromium salts are formed in the reaction mixture as result of oxidation. These salts form a fine suspension which is difficult to separate from the reaction mixture by conventional filtration, especially in the case of high molecular weight poly (oxyalkylene glycols). Thus in order to remove these oxidation by-products the process of the instant invention uses the method of adsorption of the salts from reaction mixture onto an adsorbing agent.

hi an another feature of die present invention, the adsorption process conditions vary depending upon the molecular weight of poly (oxyaikylene)-alpha,omega- dicarboxylic acid prepared by the process of the instant invention, e.g. for poly (oxyalkylene)-alpha,omega- dicarboxylic acids of molecular weights 4000 and 6000, a large fraction of chromium salts can be filtered out of reaction mixture, rendering less amount of adsorbing agent to be used for the treatment. But poly (oxyalkylene)-alpha,omega- dicarbcxylic acids of molecular weights 20,000 and 1,00,000, chromium salts formed after the reaction a fine suspension which is practically inseparable and thus required the above mentioned adsorption process for its removal.
The ranges and limitations provided in the instant specification and claims are those which are believed to particularly point out and distinctly claim the present invention. It is however understood that other ranges and limitations which perform substantially the same function in the same or substantially the same manner to obtain the same or substantially die same results are intended to be within the scope of the instant invention as defined by the instant specification and claims.
The process of the instant invention will be further described by the following examples which are provided for illustration and are not to be construed as
limiting the invention.

Example-1 PREPARATION OF OXIDIZING AGENT (JONE'S REAGENT)
Jone's reagent was synthesized according to the following procedure. 70 g CrO3 was dissolved in 500 ml distilled water and the solution was stirred with magnetic needle at 10 ° to 15 ° C (ice - water bath). To this solution, 61 ml cone. H2S04 was added in small portions. After the addition was over, the solution was stirred for additional 10 minutes and allowed to come to room temperature. Jone's reagent so prepared was stored at room temperature and used in syntheses of all poly (oxyalkylene)-alpha,omega- dicarboxylic acids.
EXAMPLE-2 . Preparation of poly (oxyehtylene) 4000 - alpha,omega- dicarboxylic acid :
40 g poly (ethylene glycol) 4000 (0.01 M) was taken in a I liter capacity round bottom flask and 400 ml acetone was added to it. Contents of the flask were heated in a heating mantle to obtain clear, homogeneous solution. The solution was allowed to attain room temperature. To this solution, 17 ml Jone's reagent (containing 0.02 M chromium trioxide) was added in a single portion and the reaction mixture was stirred at room temperature (~ 25 °C) with magnetic needle. Within few minutes after the addition, blue - green colored chromium salts (oxidation by-products) precipitated out in the form of a fine suspension in acetone solution. Stirring of the reaction mixture was continued overnight (12 hrs). Then the reaction was quenched by adding 5 ml isopropyl alcohol (free radical scavenger). To the above suspension of chromium salts

(not separable by filtration), 4 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 4000) was added and stirred with magnetic needle for two hours. This was then filtered on Buckner funnel to obtain colourless, clear acetone solution. Clear acetone solution was concentrated in vacuo to a viscous liquid. This was poured in petty dish and allowed to cool to room temperature at which it solidified. Residual moisture from the product so obtain was removed by drying it in vacuum desiccator for 48 hours. The product was obtained in the form of a white powder.
Oxidation of hydroxymethyl groups to carboxyl groups was quantified by estimating acid values of all the products. The results are listed in Table 1.
EXAMPLE-3 Preparation of monomethoxy poly (oxyethylene) 5000 - monocarboxylic acid:
50 g monomethoxy poly (ethylene glycol) 5000 (0.01 M) was dissolved in 400 ml acetone as mentioned in the example 1. To this solution, 8.5 ml Jone's reagent (containing 0.01 M chromium trioxide) was added in a single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyi alcohol. Chromium salts formed were removed from reaction mixture by adding 5 g finely powdered activated charcoal (10 % of the wt. of
t
monomethoxy poly (polyethylene glycol) 5000), stirring for two hours and filtering it to obtain colourless acetone solution. The solution was concentrated in vacuo and white powdered product was isolated as mentioned in example 1.

EXAMPLE-4 Preparation of poly (oxyethylene) 6000 - alpha,omega- dicarboxylic acid :
60 g poly (ethylene glycol) 6000 (0.01 M) was dissolved in 400 ml acetone. To this solution, 17 ml Jone's reagent (containing 0.02 M chromium trioxide) was added in a single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyl alcohol. Chromium salts formed were removed from reaction mixture by adding 6 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 6000), stirring for rwo hours and filtering it to obtain colourless acetone solution. The solunon was concentrated in vacuo and white powdered product was isolated as mentioned in example 1.
EXAMPLE-5 Preparation of poly (oxyethylene) 20000 -alpha,omega- dicarboxylic acid :
200 g poly (ethylene glycol) 20000 (0.01 M) was dissolved in 800 ml acetone. To this solution, 17 ml Jone's reagent (containing 0.02 M chromium trioxide) was added in a -single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyl alcohol. Chromium salts formed were removed from reaction mixture by adding 20 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 20000), stirring for two hours and filtering it to obtain colourless acetone solution. The solution was

concentrated in vacuo and white powdered product was isolated as mentioned in example 1.
EXAMPLE-6 Preparation of poly (oxyethylene) 1,00,000 -alpha,omega- dicarboxylic acid :
50 g poly (ethylene glycol) 1,00,000 (0.5 milimoles) was dissolved in 1000 ml acetone. To this solution, 1 ml Jone's reagent (containing 1.0 milimole chromium trioxide) was added in a single portion and the reaction mixture was stirred with magnetic needle overnight at room temperature. Then the reaction was quenched by adding 5 ml isopropyl alcohol. Chromium salts formed were removed from reaction mixture by adding 5 g finely powdered activated charcoal (10 % of the wt. of poly (ethylene glycol) 1,00,000), stirring for two hours and filtering it to obtain colourless acetone solution. The solution was concentrated in vacuo and white powdered product was isolated as mentioned in example 1.

Table 1
Data for oxidation of poly (oxyalkylene glycol)s to poly (oxyalkylene)-alpha, omega- dicarboxylic acids by Jone's reagent.

(Table Removed)
(Theoretical acid values are calculated assuming that poly (oxyalkylene glycol)s used are monodisperse. e.g. molecular weight of poly (ethylene glycol) 6000 was assumed to be 6000 which is infact in the range of 6000 to 7500 )
Advantages of the present invention are:
1) The process of the present invention allows the oxidation of low to very high molecular weight poly (oxyalkylene glycols) under very mild conditions i.e. at room temperature and atmospheric pressure, unlike high temperature and pressure used in the conventional processes.
2) The process of the present invention uses easily available and inexpensive
oxidizing agent.
3) The process of the present invention provides a simple work up procedure
to isolate the products as compared to tedious conventional work up
procedures.

We Claim:
1. A single step process for the preparation of poly (oxyalkylene)- alpha, omega-
dicarboxylic acids of the formula HO2CCH2O(CH2CHRO)nCH2CO2H, wherein R
is hydrogen, methyl or mixtures of hydrogen and methyl on the individual
molecule and n is an integer of from 100 to 2500, which comprises reacting the
corresponding poly (oxyalkylene glycol) with an oxidizing agent in form of
Jone' reagent comprising of aqueous solution of chromium trioxide and sulfuric
acid in the molar proportion of 1:1 to 1:1.75 , in a polar solvent at a temperature
in the range of 10°C to room temperature for a period ranging between 1 hour to
12 hours, quenching the reaction by adding known free radical scavenger,
removing oxidation by-products from reaction mixture by adsorbing them on an
adsorbing agent to obtain product in the solution, evaporating the clear solution to
obtain products- poly (oxyalkylene)- alpha, omega-diacrboxylic acids.
2. A process as claimed in claim 1, wherein, poly(oxyalkylene glycol)s used is such
as compounds of the formula HOCH2O(CH2CHRO)nCH2OH wherein R is
hydrogen, methyl or mixtures of hydrogen and methyl on the individual molecule
and n is an integer which represents the average numbers of oxyalkylene groups,
preferably from 100 to 2500.
3. A process as claimed in claim 1 -2, wherein, the oxidizing agent used is such as
Jone's reagent (chromium trioxide and sulfuric acid dissolved in water)
consisting of aqueous water solution of chromium trioxide and sulfuric acid in the
molar proportion of 1:1 to 1:1.75 respectively or a combination of two separate
components i.e. water solution of chromium trioxide and concentrated sulfuric
acid.
4. A process as claimed in claim 1-3, wherein, poly (oxyalkylene glycol) is for use
in the present invention are commercially available poly( ethylene glycol)s of
molecular weight 4000, 6000, 20,000, 1,00,000 and monomethoxy poly(ethylene
glycol) of molecular weight 5000.
5. A process as claimed in claim 1 - 4, wherein free radical scavenger used is such
as iporropyl alcohol, mercaptocthanol.

6. A process as claimed in claim 1-5, wherein, the polar solvent used is such as
acetonitrile, dichloromethane, chloroform, benzene, acetone, tetrahydrofuran,
dioxane, cyclohexanone.
7. A process as claimed in claim 1 -6 ,wherein the weight ratio of poly (oxyalkylene
glycol) to solvent is in the range from about 1:5 to 1:200, more preferably in the
range from about 1:10 to 1:100.
8. A process as claimed in claim 1-7, wherein the adsorbing agents used is such as
Fuller's Earth, Kiesleger, ion exchange resins, activated charcoal.
9. A process for the preparation of poly (oxyalkylene)-alpha, omega-dicarboxylic
acids of substantially described herein with reference to examples contained
therein.

Documents:

2516-del-1998-abstract.pdf

2516-del-1998-claims.pdf

2516-del-1998-correspondence-others.pdf

2516-del-1998-correspondence-po.pdf

2516-del-1998-description (complete).pdf

2516-del-1998-form-1.pdf

2516-del-1998-form-19.pdf

2516-del-1998-form-2.pdf

2516-del-1998-form-3.pdf

2516-del-1998-petition-138.pdf

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Patent Number

215035

Indian Patent Application Number

2516/DEL/1998

PG Journal Number

10/2008

Publication Date

07-Mar-2008

Grant Date

20-Feb-2008

Date of Filing

26-Aug-1998

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	BHALCHANDRA SHRIPAD LELE	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA.
2	MOHAN GOPALKRISHNA KULKARNI	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA.

PCT International Classification Number

C07D 209/76

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA