CZ302248B6 - Polyethylene glycol oxybenzoic acids and process of their preparation - Google Patents

Abstract

The present invention relates to polyethylene glycol oxybenzoic acids of the general formula I, in which Ri1 denotes CHi3, 3-carboxyphenyl or 4-carboxyphenyl and Ri2 represents 3-carboxyphenyl or 4-karboxyfenyl with average molecular weight of polyethyleneglycol chin ranging from 2000 to 40 000. The invention further relates to a process for preparing polyethylene glycol oxybenzoic acids of the general formula I, the preparation process being characterized in that a polyethyleneglycol chain (PEG) or {alpha}-methoxy polyethyleneglycol chain (mPEG), having at least one terminal atom activated by a well leaving group, is subjected to nucleophilic substitution on that terminal carbon atom with excess of 3- or 4-alkoxycarbonylphenolate, which generates itself directly in the reaction medium. After reaction finish, excess of the nucleophilic agent is removed, the obtained alkyl esters of {alpha}-(4- or 3-carboxyphenyloxy)-{omega}-methoxy polyethylene glycols, {alpha}-(4- or 3-carboxyphenyloxy)polyethylene glycols or {alpha}, {omega}-bis(4- or 3-carboxyphenyloxy)polyethylene glycols are then subjected to acid- or base-catalyzed hydrolysis to yield polyethylene glycol oxybenzoic acid of the general formula I, which is then isolated from the reaction mixture.

Description

Polyethylene glycol oxybenzoic acids and process for their preparation

Technical field

The invention relates to polyethylene glycoloxybenzoic acids and to a process for their preparation.

BACKGROUND OF THE INVENTION

In recent years, the number of applications of polyethylene glycols [polyethylene glycol: PEG; α-methoxypolyethylene glycol: mPEG], which have a carboxyl functionality at the chain end. These products are used to synthesize polyethylene glycol drug conjugates or to prepare block copolymers for a variety of applications. [Cólfen H .: Macromot. Rapid

Commun. 22, 219 (2001); Greenwald RB, Choe YH, McGuire J., Conover CD: Adv. Drug Delivery Rev. 55, 217 (2003); HartusJ. M., Chess R. B .: Nat. Roar. Drug. Discov. 3, 214 (2003); Veronese FM, Pasut G., Drug Discov. Today 10, 1451, 2005; Sedlák M .: Collect. Czech. Chem. Commun. 70, 269, 2005]. A number of methods are described in both patent and non-patent literature to prepare polyethylene glycols bearing a terminal carboxyl functional group linked via the aliphatic residue -CH ₂ - [Martinez AJ, Greenwald RB: US 5605976; Chem. Abstr. 126, 225710 (1997); Sedlák M., Antonietti M., Cólfen H .: Macromol. Chem. Phys. 199, 247 (1998); Masson C., Shennaman D., Bessodes M., J. Polymer. Sci. A., Polymer Chem. 39, 4022 (2001); BS Bullets, Gopalkrishna M .: US 2000-477263, Chem. Abstr. 135, 6020 (2001); Fishman A. Acton A., Lee-Ruff E .: Synth. Commun. 34, 2309 (2004); Ma G., Su Z. Li, X .: CN 1011-3367

Chem. Abstr. 144, 156676, 2006.]. A disadvantage of the methods currently used is often incomplete conversion of terminal hydroxyl groups. Oxidation processes degrade the polyethylene glycol chain [Harris J. M: J. Macromol. Sci .. Rev. Macromol. Chem. Phys. C25, 325,1985.].

SUMMARY OF THE INVENTION

The present invention relates to polyethylene glycoloxybenzoic acids of the formula I,

wherein R ¹ is CH ₃ , 3-carboxyphenyl (

.COOH) or 4-carboxyphenyl (

YY ^COOW

R ² is 3-carboxyphenyl () or 4-carboxyphenyl (- _h, an average molecular weight in the range poíyethylenglykolového chain 2000-40 000th

Polyethylene glycol (PEG; mPEG) having an ether-linked benzene ring at the chain end with a carboxyl functional group located at the 3 or 4 position is not yet described in the literature. The carboxyl functional group thus positioned has a similar pX _and (-5) value as the carboxyl group bonded directly to the terminal -CH ₂ - group of the polyethylene glycol chain. The advantage of our polyethylene glycol oxybenzoic acids is the presence of a hydrophobic aromatic linker (spacer), which in many cases increases the conversion of reactions taking

Substituted by the ends of the polyethylene glycol chain, as compared to functional groups attached directly to the polyethylene glycol chain [Benaglia M., Cinquini M., Cozzy F., Tocco G .: Tetrahedron Lett. 43, 3391 (2002); Tocco G., Begala M., Delogu G., Meli G., Picciau C., Poddá G .: Synlett, 1296, 2005.]. A great advantage is also the possibility of quick and easy control of reactions by means of signals of aromatic hydrogen atoms ^. 1 H NMR spectrum.

The present invention further provides a process for the preparation of polyethylene glycol oxybenzoic acids of the formula I having an ether-linked benzene ring attached at the end of the chain further carrying a carboxyl functional group located at the 3 or 4 position, which comprises the polyethylene glycol chain (PEG) or α-methoxypolyethylene glycol. a chain (mPEG) having at least one terminal carbon atom activated by a well-leaving group will undergo nucleophilic substitution at that terminal carbon atom with an excess of 3- or 4-alkoxycarbonylphenolate (i.e., the phenolate anion of the 3-hydroxybenzoic or 4-hydroxybenzoic acid alkyl ester) which is generated directly in the reaction medium, after the reaction, the excess nucleophilic reagent formed by the alkyl esters of α- (4- or 3-carboxyphenyloxy) -m-methoxypolyethylene glycols, α- (4- or 3-carboxyphenyloxy) polyethylene glycols or α, ω - bis (4- or 3-carboxyphenyloxy) polyethylene glycol The compounds of this invention are subjected to acid or base catalyzed hydrolysis to give polyethylene glycol oxybenzoic acid of formula (I) which is then isolated from the reaction mixture.

It is a feature of the invention that well-leaving groups are selected from the group consisting, in particular, of Br, Cl, OSO ₂ CH ₃ , OSO ₃ CF ₃ , OSO ₂ C 6, H ₅ , OSO ₂ C ₆ H ₄ CH ₃ .

It is also a feature of the invention that the 3- or 4-alkoxycarbonyl phenoxy is generated directly in the reaction medium by treating the 3-hydroxybenzoic or 4-hydroxybenzoic acid alkyl ester with dry sodium, potassium or cesium carbonate. Suitable alkyl esters are methyl, ethyl, propyl esters.

It is also a feature of the invention that a 15 to 20 fold excess of 3- or 4-alkoxycarbonylphenolate is used for nucleophilic substitution.

It is a further feature of the invention that the nucleophilic substitution is carried out under an inert atmosphere in the melt of the respective substituted polyethylene glycol using a 15 to 20-fold excess of the corresponding 3- or 4-alkoxycarbonylphenolate. A molar excess of the nucleophilic reagent guarantees complete conversion upon substitution.

A further feature of the invention is that, after nucleophilic substitution, the mixture is dissolved in a solvent selected from the group consisting, in particular, of dichloromethane, chloroform, benzene, toluene, xylene and ethyl acetate, the excess of the corresponding 3-hydroxy benzoic esters or % aqueous sodium hydroxide solution and the solvent was evaporated.

After evaporation of the solvent, acid- or base-catalyzed hydrolysis of the resulting .alpha .- (4- or 3-carboxyphenyloxy) -1o-methoxypolyethylene glycols and .alpha.-.alpha.-bis (4- or 345 carboxyphenyloxy) polyethylene glycols is carried out to give the corresponding polyethylene glycol oxybenzoic acids.

The final isolation of the products from the aqueous phase can be accomplished in several ways, for example after neutralization and acidification of the reaction mixture by extraction with a solvent selected from the group consisting of dichloromethane, chloroform, benzene, toluene, xylene and ethyl acetate, evaporation of the solvent and recrystallization, preferably recrystallization from propane-2- olu. Prior to extraction, the pH should be adjusted to about 1-2, since the product is an acid with a pK _and about 5. Another variant of product isolation is dialysis followed by lyophilization. When using dialysis, it is not necessary to extract the excess of 3-hydroxybenzoic or 4-hydroxybenzoic acid esters with a 5% aqueous sodium hydroxide solution, but the dialysis solution needs to be neutralized, i.e. adjust the pH to about 7.

-2 GB 302248 B6

Summary reaction scheme of the whole reaction:

^ho <3 ^ ⁰ oz

Β7-, β2) (m) PEG-X

1) M ₂ CO ₃ (m) PEG HO 1 / H ₂ O - Y (H ⁺ / H ₂ O) ^Jn

OZ

M: Na, K, Cs

Z: CH ₃ , C ₂ H _{5 and} C ₃ H ₇

X: Br.CI, OSO ₂ CH ₃ , OSO ₂ CF 3 OSO ₂ C _e H ₅ , OSO ₂ C ₆ H ₄ CH ₃

The invention is further illustrated by the following examples without being limited thereto.

Examples 1 H NMR spectra were measured on a Bruker AVANCE 500 instrument at a frequency of 500 MHz. The spectra were calibrated for residual solvent signal: CDCl 3 (7.25 ppm).

I5 Example 1

Preparation of α- (4-carboxyphenyloxy) - <o -methoxypolyethylene glycol (M = 2000)

Melt of 2g (1 mmol) of α-methoxy-α-4-toluenesulfonylpolyethylene glycol (M = 2000), 2.3 g (15 mmol) of methyl 4-hydroxy benzoate, 1.6 g (15 mmol) of sodium carbonate were heated with stirring under argon at 65 ° C for 48 h. After cooling, the reaction mixture was dissolved in 150 mL of dichloromethane, filtered with Celite and extracted with 1 x 30 mL of 5% aqueous sodium hydroxide solution and 1 x 30 mL of saturated sodium chloride solution. After drying, the dichloromethane was evaporated to dryness in a water bath. The residue was dissolved in 150 ml of 1M hydrochloric acid and refluxed for 4 hours. After cooling, the solution was saturated with sodium chloride and extracted with 5 x 50 mL dichloromethane. The combined extracts were dried, evaporated and crystallized from propan-2-ol. 1.7 g of product (85%) were obtained. 1 H NMR (CDCl ₃ , ppm) δ: 3.36 (s; 3H, CH ₂ -O): 3.52-4.27 (m; 188 H, (CH ₂ CH ₂ -O) ₄₇ ); 3.83 (t; 74.5 Hz, 2H, ΟΗ ₂ -β); 4.15 (t, J 4.5 Hz, 2H, CH ₂ -a); 6.89 (d; J 8.8 Hz, 2H-aroma); 7.96 (d; J 8.8 Hz, 2H-arom).

Example 2

Preparation of α- (3-carboxyphenyloxy) -to-methoxypolyethylene glycol (M = 2000)

A melt of 2g (1 mmol) of α-methoxy-o-trifluoromethanesulfonylpolyethylene glycol (M = 2000), 2.7 g (15 mmol) of ethyl 3-hydroxybenzoate, 2.1 g (15 mmol) of potassium carbonate was heated under stirring to argon. 65 ° C for 48 h. After cooling, the reaction mixture was dissolved in 150 ml of chloroform, filtered with Celite and extracted with 1 x 30 ml of 5% aqueous sodium hydroxide solution and 1 x 30 ml of saturated sodium chloride solution. After drying, the dichloromethane was evaporated to dryness in a water bath. The residue was dissolved in 150 ml of 1M hydrochloric acid and refluxed for 4 hours. After cooling, the solution was saturated with sodium chloride and extracted with 5 x 50 mL dichloromethane. The combined extracts were dried, evaporated and crystallized from propan-2-ol. 1.8 g of product (91%) were obtained. 1 H NMR (CDCl 3, ppm) δ: 3.36 (s; 3H, CH ₃ -O); 3,52- 4.27 (m, 188 H, (CH ₂ -CH ₂ -O) _47); 3.83 (t; 74.5 Hz, 2H, CTT-β); 4.15 (t, 74.5 Hz, 2H, CH ₂ -a); 6.91 (m, 1H-arom); 7.18 (m, 1H-arom); 7.48 (m, 2H, m).

-3 CZ 302248 B6

Example 3

Preparation of N - (4-carboxyphenyloxy) o -methoxypolyethylene glycol (M = 5000)

Melt 5g (1 mmol) of α-broin-o-methoxypolyethylene glycol (M = 5000), 2.7 g (15 mmol) of methyl 4-hydroxybenzoate, 2.1 g (15 mmol) of potassium carbonate were heated under stirring under argon atmosphere. After cooling, the reaction mixture was dissolved in 200 ml of dichloromethane, filtered with Cellite and extracted with 1 x 50 ml of 5% aqueous sodium hydroxide solution and 1 x 50 ml of saturated sodium chloride solution. After drying, the dichloromethane was evaporated to dryness in a water bath. The residue was dissolved in 50 ml of 5M sodium hydroxide and stirred at room temperature for 5 hours. After cooling and adjusting the pH to 1-2, the solution was saturated with sodium chloride and extracted with 5 x 60 mL of dichloromethane. The combined extracts were dried, evaporated and crystallized from propan-2-ol. 4.6 g of product (92%) were obtained.

1 H NMR (CDCl 3, ppm) δ: 3.36 (s; 3H, CH ₃ -O); 3,52- 4.27 (t n; 460 H _{(CH2 -CH2} -O), _5); 3.83 (l, .7 4.5 Hz, 2H, CH ₂ - [3); 4.15 (t, J 4.5 Hz, 2H, CH ₂ -a); 6.89 (d; J 8.8 Hz, 2H-aroma); 7.96 (d; J 8.8 Hz, 2H-arom).

2o Example 4

Preparation of α- (3-carboxyphenyloxy) -1-methoxypolyethylene glycol (M = 5000)

Melt of 5 g (1 mmol) of a-methoxy-co-methansulfonylpolyethylenglykolu (M ^_ 5000), 2.5 g (15 mmol) of ethyl 3-hydroxybenzoate, 2.1 g (15 mmol) potassium carbonate was heated with stirring under an argon atmosphere 65 ° C for 48 h. After cooling, the reaction mixture was dissolved in 200 mL of dichloromethane, filtered with Cellite and extracted with 1 x 50 mL of 5% aqueous sodium hydroxide solution and 1 x 50 mL of saturated sodium chloride solution. After drying, the dichloromethane was evaporated to dryness in a water bath. The residue was dissolved in 150 ml of 1M hydrochloric acid and refluxed for 4 hours. After cooling, the solution was saturated with sodium chloride and extracted with 5 x 60 mL of dichloromethane. The combined extracts were dried, evaporated and crystallized from propan-2-ol. Yield: 4.4 g (88%). 1 H NMR (CDCl ₂ , ppm) δ: 3.36 (s; 3H, CH 3 -O); 3.52 to 4.27 (m, 460 H, (CH ₂ -CH ₂ O), _15); 3.83 (t ./4,5 Hz, 2H, _CH2-P); 4.15 (t; J 4.5 Hz, 2H, CHrd); 6.91 (m, 1H-arom); 7.18 (m, 1H-arom); 7.48 (m, 2H-aroma).

Example 5

Preparation of α, t-bis (4-carboxyphenyloxy) polyethylene glycol (M = 10,000)

A melt of 10 g (1 mmol) of α, ω-bismethanesulfonylpolyethylene glycol (M = 10,000), 2.3 g (15 mmol) of methyl 4-hydroxybenzoate, 2 g (15 mmol) of potassium carbonate was heated to 70 ° under argon with stirring. After cooling, the reaction mixture was dissolved in 250 ml of dichloromethane, filtered with Cellite and extracted with 1 x 50 ml of 5% aqueous sodium hydroxide solution and 1 x 50 ml of saturated sodium chloride solution. After drying, the dichloromethane was evaporated to dryness in a water bath. The residue was dissolved in 50 ml of 5M sodium hydroxide and stirred at room temperature for 5 hours. After cooling and adjusting the pH to 1-2, the solution was saturated with sodium chloride and extracted with 5 x 60 mL of dichloromethane. The combined extracts were dried, evaporated and crystallized from propan-2-ol. 8.9 g of product (87%) were obtained.

1 H NMR (CDCl 3, ppm) δ: 3.52-4.27 (m; 460 H, (CH ₂ -CH ₂ -O), _δ ); 3.83 (t, / 4.5 Hz, 2H, _CH2 β); 4.15 (t, / 4.5 Hz, 2H, CH ₂ -a); 6.89 (d; δ 8.8 Hz, 2H-aroma); 7.96 (d; δ 8.8 Hz, 2H-arom).

-4 CZ 302248 B6

Example 6

Preparation of α, ω-bis (3-carboxyphenyloxy) polyethylene glycol (M = 10,000)

WITH

A melt of 10 g (1 mmol) of α.ω-dibromopolyethylene glycol (M = 10,000), 3 g (20 mmol) of methyl 3-hydroxybenzoate, 2.8 g (20 mmol) of potassium carbonate was heated to 70 with stirring under argon. After cooling, the reaction mixture was dissolved in 100 ml of 5M sodium hydroxide and stirred at room temperature for 5 hours. After pH adjustment of 77, the solution was also dialyzed through a membrane (Spectra / Por; MWCO 5000). After lyophilization, 9.3 g of product (91%) were obtained. 1 H NMR (CDCl 3, ppm) δ: 3.52-4.27 (m; 460 H, (CH ₂ -CH ₂ -O), _δ ) ; 3.83 (t;

./4,5 Hz, 2H, CH ₂ -p); 4.15 (t; J 4.5 Hz, 2H, CH 2 -a); 6.91 (m, 1H-arom); 7.18 (m; 1H-aroma); 7.48 (m, 2H -arom).

Example 7

Preparation of α, ω - bi with (4-carboxyphenyl loxy) polyethylene glycol (M = 20 000)

A melt of 20 g (1 mmol) of α, ω-bisbenzenesulfonylpolyethylene glycol (M = 20,000), 3.6 g (20 mmol) of propyl 4-hydroxybenzoate, 3.6 g (20 mmol) of potassium carbonate was heated under stirring to argon atmosphere. 70 ° C for 48 h. After cooling, the reaction mixture was dissolved in 100 mL of 5M sodium hydroxide and stirred at room temperature for 5 hours. After pH adjustment of 77, the solution was dialyzed through a membrane (Spectra / Por; MWCO 10,000). After lyophilization, 18.4 g of product (93%) were obtained. ¹ HNMR (CDCl 3, ppm) δ; 3.52 to 4.27 (m, 932 H (CH ₂ -CH ₂ -O) _2, 33); 3.83 (t, J4,5 Hz, 2H, CH ₂ -P); 4.15 (t, J 4.5 Hz, 2H, CH _2); 6.89 (d, J 8.8 Hz, 2H arom); 7.96 (d, J 8.8 Hz, 2H-arom).

Example 8

Preparation of α, ω-bis (3-carboxyphenyloxy) polyethylene glycol (M ~ 20,000)

A melt of 20 g (1 mmol) of α, ω-bisbenzenesulfonylpolyethylene glycol (M = 20,000), 3 g (20 mmol) of 35 methyl 3-hydroxybenzoate, 3.6 g (20 mmol) of potassium carbonate was heated under stirring to argon. 70 ° C for 48 h. After cooling, the reaction mixture was dissolved in 100 mL of 5M sodium hydroxide and stirred at room temperature for 5 hours. After pH adjustment of 7, the solution was dialyzed through a membrane (Spectra / Por; MWCO 10,000). After freeze-drying, 18.9 g of product (95%) were obtained. 1 H NMR (CDCl 3, ppm) δ: 3.52-4.27 (m; 932 H, (CH 2 O 4 CH 2 -O 4)); 3.83 (t; J 4.5 Hz, 2H, CH 3 -β); 4.15 (t; J 4.5 Hz, 2H, CHwx); 6.91 (m; 1H-aroma): 7.18 (m; 1H-aroma); 7.48 (m, 2H-aroma).

Example 9

Preparation of α, ω-bis (4-carboxyphenyloxy) poly ethylene glycol (M = 40,000)

A melt of 20 g (0.5 mmol) of α, ω-bis-methanesulfonylpolyethylene glycol (M = 40,000), 1.5 g (10 mmol) of methyl 4-hydroxybenzoate, 3.3 g (10 mmol) of cesium carbonate was heated under stirring under argon. The reaction mixture was dissolved in 100 mL of 5M sodium hydroxide and stirred at room temperature for 5 hours. After pH-7 adjustment, the solution was dialyzed through a membrane (Spectra / Por; MWCO 10,000). After lyophilization, 19.2 g of product (96%) were obtained. H HNMR (CDCh, ppm) δ: 3.52 - 4.27 (m; 1840 H,

(CH ₂ -CH ₂ -O) ₄₆₀ ); 3.83 (t, J4,5 Hz, 2H, CH ₂ -p); 4.15 (t; J 4.5 Hz, 2H, CH2-hx); 6.89 <d; J 8.8 Hz, 2H arom); 7.96 (d, J 8.8 Hz, 2H-aroma).

Example 10

Preparation of tx, 10-bis (3-carboxyphenyloxy) polyethylene glycol (M = 40,000)

A melt of 20 g (0.5 mmol) of α, ω-bismethanesulfonylpolyethylene glycol (M = 40,000), 1.5 g (10 mmol) of methyl 3-hydroxybenzoate, 3.3 g (10 mmol) of cesium carbonate was heated under stirring Argon atmosphere at 70 ° C for 48 h. After cooling, the reaction mixture was dissolved in 100 mL of 5M sodium hydroxide and stirred for 5 hours at room temperature.

After treatment with pIL-7, the solution was dialyzed through a membrane (Spectra / Por; MWCO 10,000). After freeze-drying, 18 g of product (90%) were obtained. 1 H NMR (CDCl 3, ppm) δ: 3.52-4.27 (m; 1840 H, is (CH ₃ -CH ₂ -O) _{4 (} , o); 3.83 (t; .4.5) Hz, 2H, CH ₂ -P), 4.15 (t .74,5 Hz, 2H, CH ₂ -N); 6.91 (m, 1Harom), 7.18 (m, 1 H arom) 7.48 (m, 2H-aroma).

Industrial applicability

The polyethylene glycol oxybenzoic acids prepared by the process can be used as intermediates for the preparation of drug conjugates (e.g., cytostatics, antifungals), for the preparation of block copolymers or for the synthesis and stabilization of nanoparticles of various character.

Claims (10)

PATENT CLAIMS COOH Wherein R ¹ is CH ₃ , 3-carboxyphenyl () or 4-carboxyphenyl (TX coc 1), COOH R ² is 3-carboxyphenyl () or 4 carboxyphenyl (ω-cooh), with an average molecular weight of the polyethylene glycol chain of from 2000 to 40,000. 2. A process for the preparation of polyethylene glycol oxybenzoic acids of the formula I, characterized in that the PEG polyethylene glycol chain or the .alpha.-methoxypolyethylene glycol chain of mPEG having at least one activated terminal leaving group is subjected to nucleophilic substitution at that terminal carbon by an excess of 3- or 445 alkoxycarbonylphenophate. which is generated directly in the reaction medium, after the reaction, the excess nucleophilic reagent formed by the alkyl esters of α- (4- or 3-carboxyphenyloxy) -ceta-methoxy polyethylene glycols, α- (4- or 3-carboxyphenyloxy) polyethylene glycols, or α, α-, The bis (4- or 3-carboxyphenyloxy) polyethylene glycols are then subjected to acid or base catalysis Hydrolysis to give the polyethylene glycol oxybenzoic acid of formula (1), which is then isolated from the reaction mixture. Method according to claim 2, characterized in that the good leaving groups are selected 5 in particular comprising Br, Cl, OSO2CH3, OSO2CF3, OSO2C6H5, OSO2C6H4CH3. Process according to claim 2 or 3, characterized in that the 3- or 4-alkoxycarbonylphenolate is generated directly in the reaction medium by treating the alkyl ester of 3-hydroxybenzoic acid or 4-hydroxybenzoic acid with dry sodium, potassium or cesium carbonate. Process according to claim 4, characterized in that the alkyl esters are preferably methyl, ethyl, propyl esters. Method according to any one of claims 2 to 5, characterized in that it is nucleophilic 15 substitutions employ a 15 to 20 fold excess of 3- or 4-alkoxycarbonylphenolate. The method according to any one of claims 2 to 6, characterized in that the nucleophilic substitution is carried out under an inert atmosphere in the melt of polyethylene glycol or α-methoxy polyethylene glycol having a terminal carbon atom activated by a well-leaving group, wherein: 20, use a 15 to 20 fold excess of the corresponding 3- or 4-alkoxycarbonyl phenolate. Process according to any one of claims 2 to 7, characterized in that, after nucleophilic substitution, the mixture is dissolved in a solvent selected from the group consisting, in particular, of dichloromethane, chloroform, benzene, toluene, xylene and ethyl acetate, excess of the corresponding 3-hydroxybenzoic esters; -hydroxy benzoic acid was removed by extraction with 5% (w / w) aqueous sodium hydroxide solution and the solvent was evaporated. Process according to any one of claims 2 to 8, characterized in that the final isolation of the polyethylene glycol benzoic acid of the formula I from the aqueous phase is carried out by The values are between 1 and 2 followed by extraction with a solvent selected from the group consisting of dichloromethane, chloroform, benzene, toluene, xylene and ethyl acetate, evaporation of the solvent and subsequent recrystallization, preferably recrystallization from propan-2-ol. Method according to any one of claims 2 to 8, characterized in that the final insulation is applied The polyethylene glycol oxybenzoic acid of the formula I is carried out by neutralizing the resulting reaction mixture and then by dialysis followed by lyophilization.