SU1017701A1 - Process for preparing aldehyde derivatives of polyglycols - Google Patents

Abstract

A method for producing aldehyde derivatives of polyglycols by oxidizing the latter and isolating the target product, characterized in that in order to simplify the process and its versatility, polyethylene glycol of the general formula R (OCH2CH2) OH, where R H, CH, p 4, is used as polyglycols. -1200, and oxidation are a mixture of chromium nitroxide, water and pyridine by the overhang ratio of 1:

Description

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The invention relates to a method for producing aldehyde derivatives of polyglycols that are used to synthesize polyglycol derivatives of the enzymes asparaginase, phenylalanine-NHJ-lyse, ureae, which have been used in enzyme therapy in the treatment of leukemia and other diseases. Moreover, enzyme preparations based on aldehyde derivatives of polyethylene glycol exhibit greater activity and stability.

The main methods for the preparation of aldehyde glycol derivatives were nitrate dehydrogenation and oxidation.

A method of producing aldehyde polyglycol derivatives, in particular ethoxyacetaldehyde, is obtained by dehydrogenating ethylene glycol monoethyl ether over activated copper catalyst. The process proceeds at atmospheric pressure and 370 ° C. The output of ethoxyacetaldehyde 70-75% tl.

The disadvantage of this method is the relatively low yield of the target product.

There is also known a method for producing aldehyde derivatives — polyethylene glycol, in particular glyoxal, by oxidizing ethylene glycol with air with oxygen or oxygen-containing gas in the presence of Pt, Pd, -Ci, and P-containing catalysts at 50–100 ° C and pressure of 100 atm in the vapor phase. The output of glyoxal is 65-80%, conversion of ethylene glycol is 27-38% i23.

The disadvantage of this method is the complexity of the process due to the use of a multi-component catalyst and high pressure. The closest to the invention is a method for producing aldehyde derivatives of polyglycols, in particular glyoxal, by oxidizing ethylene glycol with atmospheric oxygen at 6 so C in the presence of metallic

silver. The yield of the target product is 70% SPZ.

The disadvantage of this method is the complexity of the process. due to the use of scarce and expensive silver, high temperature, as well as the impossibility of obtaining aldehyde derivatives of glycols by means of thermo-oxidative degradation.

The goal is achieved by the fact that according to the method of producing aldehyde derivatives of polyglycols, polyethylene glycol of the general formula is used as polyglycols

R (OCH, OH,

where, snch,

4-1200,

and oxidation are carried out with a mixture of chromium trioxide, water and pyridine, taken in

a weight ratio of 1: (1-1.1): J (3.3-100), respectively, at 20–25 ° C for 20–24 h in pi medium; )go to.

The method is carried out as follows.

0.045–9 g of chromic anhydride is dissolved in 0.05–9 ml of water and added, with stirring and cooling (), to 4.5–30 ml pyridine. Gradually, 3 g of oxidized polyethylene glycol (PEG) is added to the system and maintained at 20–25 ° C for 2024 hours. The end of the reaction is controlled by color change. CrO ions are precipitated from the reaction medium and the desired product is isolated.

PEG oxidation by the proposed method proceeds with high selectivity without destruction and crosslinking of macromolecules, which is confirmed by gel permeation chromatography. The presence of aldehyde groups is confirmed by IR-spectrum1 (1640 V-oscillations

i C-O, qualitative reaction with 2,4-dinitrophenylhydrazine (orange), photometric titration.

The proposed method allows to simplify the process by eliminating the use of the catalyst, reducing the temperature, as well as the advantage of its versatility, i.e. obtaining aldehyde derivatives of polyethylene glycols, which could not be obtained in a known manner.

Example 1: Dialdehyde PEG6000. ,

0.3 g (CCH mol) CrOe in 0.3 ml of water is poured with stirring and cooling to 300 ml of pyridine. A solution of 3 g (5-10 mol) of PEG-6000 in 6 ml of pyridine was added to the resulting mixture and kept for 24 hours. Then the solution was dialyzed in water for 4 days, followed by removal of the zodia by freeze drying. The output of dialdehyde PEG-6000 quantitative.

Example 2. Dialdehyde PEG20000. .

0.09 g (9-10 mol) CrOjB 0.1 ml of water is poured with stirring and cooling to 9 ml of pyridine. To the resulting mixture is added a solution of 3 g (15-10 mol) of PEG-20,000 in 7 ml of pyridine. Further carrying out the reaction and the selection of the product is similar to example 1. The output of dialdehyde PEG20000 quantitative.

Froze Dialdehyde PEG400001 f

0.045 g (45-10 mol) of CrO, in 0.5 ml of water is poured with stirring and cooling to 4.5 ml of pyridine. To the resulting mixture is poured 3 g (75.) of PEG-40,000 in 7.5 ml of pyridine. Further reaction

and the precipitation of the target product is analogous to Example 1. The yield of dialdehyde PEG-40000 is quantitative.

PRI me R 4. Dialdehyde PEG2000.

0.9 g (9-10 mol) of OOj in 1 ml of water is poured with stirring and cooling to 15 ml of pyridine. To the resulting mixture is added a solution of 3 g (15-10 mol) of PEG-2000 in 5 ml of pyridine. Purification of the target product is carried out on a column filled with Sepliadex, washed out with methanol, which is then removed on a rotary evaporator. PEG-200 dialdehyde outlet: 0 1, Vg (70%).

PRI me R 5. Dialdehyde methoxyPEG-750. s

1.2 g (1210 mol) of CrO3 in 1.2 ml of WATER are added with stirring and cooling (0-5) to 15 ml of pyridine. A solution is added to the resulting mixture. 3 g (4 -10 mol) of methoxy-PEG.-750 in 5 ml of pyridine. Further carrying out the reaction and the selection of the target product as in example 4. The yield of dialdehyde methoxy-PEG-7501 1.6 g (60%)

PRI me R 6. Dishestide ethylene glycol-tetra.,

9 g (9.) of CrO in 9 ml of water was added under stirring and cooling (0-5) to 30 ml of pyridine. To the resulting mixture is added a solution of 3 g (0.015 mol) of tetraethylene glycol in 2 ml of pyridine and kept at 25 ° C for 20 hours. Then 20 ml: water is added to the contents, acidified with 1N HC1 solution to pH 6.0 and at 50- 60 ° CgO ions are precipitated with an excess of dry barium nitrate, and Cr ions are precipitated with excess. The precipitates are filtered and extracted in a stem bed with boiling acetone for 48 hours. Water and pyridine are removed from the mother liquor on a rotary evaporator, the residue is combined with the acetone fraction and acetone is again removed on a rotary evaporator. The remaining oxidation product is further purified on a column filled with silica gel L 40/100 L and then washed with a system of butanol-acetic acid 1 water (4: 1: 5), followed by removal of the solvents on a rotary evaporator. The output of dialdehyde ethylene glycol - tetra 0.8 g (40%).

Claims (1)

METHOD FOR ALDEHYDE DERIVATIVES polyglycols oxidation of the latter and the desired product isolation, characterized in that in order to simplify the process and its versatility, as polyglycols using polyethylene glycol of general formula u (OCH ₂ CH _{z) and} OH · where R = H, CHj, η = 4-1200, and the oxidation is carried out with a mixture of chromium trioxide, water and pyridine with a weight ratio of 1: (1-1.1) :( 3.3-100), respectively, at 20-25 ° C for 20-24 hours in the medium pyridine. 18