HU190382B - Improved process for preparing salts of adriamicine - Google Patents

Abstract

Process for Hydrogen Halide Salts of Adriamycin for the preparation of the halonic salt of daunomycin bromination and the resulting 14-bromo derivative hydrolysis by daunomycin hydrogen halide salt in anhydrous organic solvent C 1-5 orthoalkanoate or 1-5 in the presence of a C 1 -C 6 alkyl ester with bromine reacting at 0-20 ° C, preferably at 8 ° C, 3-30 hours, preferably 5 hours, is formed 14-bromo in an organic solvent system after precipitation in acetone, hydrogen bromide in acetone and reacting in the presence of alkali formate, then the reaction mixture is changed to a pH value in two steps is extracted with chloroform and a the target product is obtained in the form of a hydrogen halide salt; and then optionally cleaned.

Description

BACKGROUND OF THE INVENTION The present invention relates to an improved process for the preparation of the hydrochloride salt of adriamycin by reacting the hydrogen halide salt of daunomycin with bromine in anhydrous organic solvent system in the presence of a trialkyl orthoformate at 0-20 C for ⁵ hours, preferably 8 C. over, the resulting 14-bromo derivative in acetone with hydrogen bromide and alkáliformiát presence after precipitation with organic solvent, and then the reaction mixture ¹⁰ while varying the pH of the two steps of chloroform extraction, and the aimed product was recovered as a hydrogen halide salt, and then optionally purified.

As it is known adriamycin antitumor effects' ⁵ sú antibiotic which is used as a hydrogen halide salt of the treatment of cancer - can be produced directly by fermentation (. Belgian Patent 3,773th No. 71), or semi-synthetic methods, the daunomicinbői (1,917,874 U.S. Patent Nos. 4,102, 4,198 and 4,012,448 to U.S. Pat.

The starting daunomicinből and preparation of daunomycinone and 7-dezoxidaunomicinon as intermediate processes involving extremely tak BO- ny Olula ²⁵ as the starting compound in addition to chemical conversion of adriamycin sugar component, also include the attachment of the molecule include Å.

Easier adriamycin daunomicinből known to the skilled pseudo- ³⁰ (FRG Patent Specification 1 917 874 c.) For the 14-halo-daunomycin derivatives of the molecule without affecting the sugar.

The method may be performed in the chloroform solution of bromine in brominated directly, while iodine historically ³⁵ Tenon halogenation the daunosamine amino group protected by an acyl derivative, or Schiff base formation.

The simplest methods for the production of adriamycin from daunomycin, which appear to be the simplest, have shown in the reproduction experiments on direct bromination of daunomycin that daunosamine and the C-14-containing side chain are readily cleaved and 14-bromo-daunomycin and other soluble without yielding decomposition products, the bromination reaction yields a fairly low yield of 58-59%. Given that the molecule is sensitive to acids, alkalis, and susceptible to oxidation, the exchange of the bromine atom of 14-bromo-daunomycin to the hydroxyl group and the product purification result in new losses, so that the yield of adriamycin based on the starting daunomycin is %.

It is an object of the present invention to provide a semi-synthetic process for the production of adriamycin, starting from daunomycin, which provides a simpler and more economical process for the production of a finished product of appropriate quality. 60

In our attempts to develop the present invention, it has been found that when the bromination of daunomycin is suitable for ketal formation e.g. in the presence of triethyl orthoformate, the molecule proves to be much more stable, the deacetylation does not occur, and the breakdown of the glycoside bond is also less experienced, so that the 14-bromo-daunomycin derivative can be obtained with significantly better yields. The bromine atom is attacked by the C-8 carbon atom of the daunomycin molecule, which results in the molecule being deacetylated. Experimental experience has shown that triethyl orthoformate, which interacts with the hydroxyl group on the carbon atom of the daunomycin molecule and the keto group on the carbon atom 13, in the presence of bromine in the presence of bromine, is found to be most suitable for this purpose. and thereby inhibit side reactions and alkyl cleavage.

It has been found to be advantageous to use triethyl orthoformate in an excess of 1: 3-4 molar to daunomycin hydrochloride, thereby increasing the yield of the 14-bromo-daunomycin derivative.

According to our procedure, the 14-bromo-daunomycin derivative need not be prepared, since the acetone solution of the 14-bromo-daunomycin protected with a five-membered ring ketal treated with 0.25 normal hydrogen bromide can be used directly to replace the bromine atom with the hydroxyl group.

From our experimental experience, we have found it preferable to convert the bromine atom directly to the hydroxy group with sodium hydroxide via the 14-formyloxy derivative. In fact, the hydrolysis of the 14-formyloxy derivative at pH 7.6-8.0 provides less favorable conditions for the adriamycin less resistant to alkalis than the pH 10.3 used for the alkaline treatment.

Prior to the alkaline hydrolysis of 14-formyloxy-daunomycin, it is advisable to extract the reaction mixture with chloroform at pH 3.5-4.0 to remove the clay-like degradation products.

The pH for hydrolysis is adjusted to pH 7.6-8.0 with 5% sodium bicarbonate solution, the resulting adriamycin base is recovered from the reaction mixture by repeated chloroform extraction, and after concentration of the combined extract with hydrochloric acid methanol. Adriamycin hydrochloride is formed which is precipitated with ether from the solution.

The adriamycin hydrochloride obtained by this process is used alone, optionally after purification, in the preparation of pharmaceutical compositions. The adriamycin obtained by the process of the invention is purified in a manner known per se. The present invention is illustrated by the following examples, without, however, limiting the invention.

Example 1

1.4 g daunomycin hydrochloride (2.48 mmol) were dissolved in a mixture of 20 mL of anhydrous methanol, 56 mL of anhydrous dioxane and 1.4 mL of anhydrous triethyl orthoformate (8.47 mmol). To this solution was added 0.5 g (3.16 mmol) of bromine in 5.4 ml of anhydrous chloroform, the flask was sealed and kept at 8 ° C for 5 hours.

190,382

The reaction mixture was poured into 280 ml of diethyl ether and 120 ml of petroleum ether, the precipitate was filtered off, the impurities were washed three times with 30 ml of diethyl ether, then dissolved in 40 ml of acetone and 40 ml of 0.25 N aqueous hydrogen bromide. is maintained at 25 ° C. A solution of sodium formate (2.0 g, 29.4 mmol) in deionized water (20 mL) was added and the mixture was stirred at 25 ° C for 48 hours.

The reaction mixture was adjusted to pH 3.7 with 1 N hydrochloric acid and extracted with chloroform (5 x 50 mL). Subsequently, the aqueous phase was adjusted to pH 7.6 with 5% sodium bicarbonate solution and the Adriamycin base was extracted with chloroform. The extraction was continued until the chloroform extract was colored. The combined chloroform extracts were washed with deionized water (5% by volume) and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solution was concentrated in vacuo to a volume of 50 ml. The free base is converted into the hydrochloride salt using a calculated amount of 0.6 N hydrochloric acid in methanol and then separated with 500 ml of diethyl ether. The precipitate was filtered off, washed with diethyl ether (4 x 30 mL), and dried in vacuo at room temperature. yield; 0.61 g (42.4%) of Adriamycin hydrochloride having the following quality characteristics:

C ₂₇ H 11 NO ₁ HCl (Ms: 580.0)

Calculated% Found%

C 55.9 55.52

H, 5.21 5.10

N, 2.42 2.04

Cl, 6.11 6.24

m.p .; 202-206 'C (decomposes)

Tlc

Layer; Kieselgel 60 (Merck 5724) impregnated with 1% oxalic acid solution.

Solvent: Upper phase of n-butanol-acetic acid-water 4: 1: 5.

Development to 10 cm

The sample has an R _f value of 0.33

IRISH. spectrum (PERKIN-ELMER type 397, KBr tablet)

v cm ¹ 3420 2980-2920 Assignment O-H band (hydrogen bonding) NH ₃ ⁺ and O-H band (hydrogen bonding) binding) 1725 C = O ketone 1615 and 1580 C = O (intrahydrogen bond, out- non) 1280 C-O-C (ether) 1115 C - Oh hello. alcohol 1070 C-O chair. alcohol 1010 C — O Prim. alcohol N.m.r. spectrum (BRUKER WP 200 SY pulse FT), Ή-NMR, DMSO-d6, room temperature (del. ta, ppm) 250 MHz (Ppm) Asszignáció 1.17 3H, d, CH ₃ -5 ' 1.6 / 1.9 2H, m, CH ₂ -2 ' 2.15 2H, m, CH3-9

2.9 / 3.00 2H, AB, CH ₂ -7 3.7 1H, m, H-4 ' 4.0 3H, s, OCH3 4.2 1H, m, H-5 ' 4.58 / 4.61 2H, AB, CH ₂ -14 4.9 1H, m, H-10 5.3 1H, m, H-1 ' 7.65 1H, m, H-3 7.9 5H, tn, H-4, H-2, NH ₃ ⁺ 13.25 1H, bs, OH-6 14.05 1H, s, OH-11 ™ C-NMR (50.3 MHz, D ₂ O, 310 K) (Ppm) carbon 217.1 13 188.1 (12), (5) * 163.0 1 158.2 11 156.6 6 139.2 3 136.4 (10a), (4a), (6a) * 122.0 (4) (2)) 121.3 (12a) 1 * 113.1 (5a), (IIa) * 101.5 1 ' 78.5 8 71.1 10 69.8 (4 ') k 68.9 (5 ') 67.1 14 59.1 OCH ₃ 49.6 3 ' 37.9 9 34.8 7 30.4 2 ' 18.5 5 '

*: Interchangeable appropriations

Example 2

1.4 g (2.48 mmol) of daunomycin hydrochloride were dissolved in a mixture of 40 mL of anhydrous methanol and 0.55 mL (8.7 mmol) of anhydrous methyl formate. To the resulting solution was added a solution of bromine (0.5 g, 3.16 mmol) in chloroform (5.4 mL) and held at 10 ° C for 4.5 hours.

The reaction mixture was poured into a mixture of diethyl ether (280 mL) and petroleum ether (120 mL), and the precipitate was filtered and washed with diethyl ether (3 x 30 mL). The product was dissolved in a mixture of 40 ml of acetone and 40 ml of 0.25 N aqueous hydrobromic acid solution and kept at 25 ° C for 17 hours.

A solution of sodium formate (2.0 g, 29.4 mmol) in deionized water (20 mL) was added and the solution was stirred at 25 ° C for 48 hours. The reaction mixture thus obtained was worked up as in Example 1.

Yield: 0.55 g (38.6%).

The test results for the final product identification were the same as in the first example.

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Example 3

Daunomycin Hydrochloride (0.70 g, 1.24 mmol) was dissolved in a mixture of 10 mL of anhydrous methanol in 30 mL of anhydrous dioxane and 0.42 mL (4.30 mmol) of ethyl acetate. To the solution was added 0.25 g (1.58 mmol) of bromine

A solution of 2.7 ml of anhydrous chloroform was added and the mixture was kept at 6 ° C for 6 hours.

The reaction mixture was poured into a mixture of 140 mL of diethyl ether and 60 mL of petroleum ether, the precipitate was collected and washed three times with 15 mL of diethyl ether. The product was dissolved in a mixture of 20 ml of acetone and 20 ml of 0.24 N aqueous hydrobromic acid and kept at 25 ° C for 17 hours. Then, a solution of 1.0 g (14.7 mmol) of sodium formate in 10 ml of deionized water was added and the solution was kept at 25 ° C for 48 hours. The pH of the reaction mixture was adjusted to 3.7. Extract with 1 N hydrochloric acid and then with chloroform. After extraction, the aqueous layer was adjusted to pH 7.6, extracted with 5% sodium bicarbonate solution, and the Adriamycin base was extracted with chloroform. Extraction is continued until the chloroform layer is colorless.

The chloroform extracts were washed with deionized water and dried over sodium sulfate.

After filtration of the sodium sulfate, the solution was concentrated to 25 ml. A solution of 0.6 N hydrochloric acid in anhydrous methanol from the free base forms a hydrochloride salt which is separated from the solution with 250 ml of diethyl ether. The filtered crystals were washed with diethyl ether (4 x 15 mL) and dried in vacuo at room temperature.

Yield: 0.29 g (40.3%).

The test results for the final product identification were the same as in the first example.

Example 4

Daunomycin hydrochloride (0.70 g, 1.24 mmol) was dissolved in a mixture of 10 mL of anhydrous methanol, 30 mL of dioxane and 0.8 mL (4.35 mmol) of triethyl orthoacetate. A solution of bromine (0.25 g, 1.58 mmol) in anhydrous chloroform (2.7 mL) was added and the solution was heated at 6 ° C for 6 hours.

The reaction mixture was poured into a mixture of diethyl ether (140 mL) and petroleum ether (60 mL), the precipitated crystals were filtered off and the impurities were washed with diethyl ether (3 x 15 mL). The material thus obtained was dissolved in acetone (20 ml) and aqueous hydrobromic acid (20 ml) and kept at 25 ° C for 17 hours. A solution of sodium formate (1.0 g, 14.7 mmol) in deionized water (10 mL) was added and stirred at 25 ° C for 48 hours.

The resulting reaction mixture was worked up as in Example 3.

Yield: 0.30 g (41.7%).

₁₅ The ^δ results for the final product identification were the same as in the first example.

Claims (4)

_2Q Claims A process for the preparation of hydrogen halide salts of adriamycin by bromination of the hydrogen halide salt of daunomycin and hydrolysis of the resulting 14-bromo derivative, characterized in that the hydrogen halide salt of dauno ²⁵ micins in anhydrous organic solvent is C 1-5 orthoalkanoate; reaction with bromine in the presence of a C szénat alk alkyl ester at 0 ° C to 20 ° C, preferably at 8 ° C, for 3 to 30 hours, preferably 5 hours, after precipitation of the 14-bromo derivative in an organic solvent system with hydrogen bromide and alkaline formate; and the reaction mixture is extracted with chloroform in two steps while adjusting the pH and the target product ³⁵ is recovered as the hydrogen halide salt and optionally purified. 2. A process according to claim 1, wherein the anhydrous organic solvent is a 1: 2 to 5 mixture of methanol and dioxane. ⁴⁰ The process according to claim 1, wherein the C 1-5 orthoalkanoate is triethylorthoformate. 4. The process according to claim 1, wherein the alkali formate is sodium formate 45 are used. Without drawing