FI83311B - An improved process for preparing a therapeutically active sodium salt of the disodium salt of 5,5'-[(2- hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1- benzopyran-2-carboxylic acid] - Google Patents

Description

8331 1 IMPROVED METHOD OF THERAPEUTICALLY EFFECTIVE 5,5 '- [(2-HYDROXY-1,3-PROPANEDIYL) BIS (OXY)] BIS (4-OXO-4H-1-BENZOPYRANE-2-CARBOXYXAMIC ACID DYNAMIC ACID)

ETT FÖRBÄTTRAT FÖRFARANDE FÖR FRAMSTÄLLNING AV TERÄPEUTISKT VERKSAMT SODRIUMSALT AV 5,5 · - [(2-HYDROXI-1,3-PROPANDIYL) -BIS (OXI)] BIS [4-OXO-4H-1-BENZOPYRAN]

The present invention relates to an improved process for the disodium salt of cromoglycate, i.e. 5.51 - [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid, used as an asthma drug. ] of formula (I), Q 0 -CH 2 -CH-CH 2 -a o

OH

„I lOj jj — C-ONa N <3u * C-k. s '/ il II 0 0 0 10 by hydrolysis of 5,5' - [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid diethyl ester] by dialkyl, trialkyl, or sterically hindered primary amine in aqueous dimethylformamide, methanol, or ethanol to give, as intermediates, highly soluble cromoglycate ammonium salts of the reaction mixture. .

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Background of the invention

The preparation of the disodium salt of cromoglycate has been previously described e.g. British Patent Publication Nos. GB 1,144,905 and GB 1,144,906, in which 5,5 '- [(2-hydroxy-1,3-propanediyl) bis- (oxy)] bis [4-oxo-4H-1-benzopyran-2- carboxylic acid diethyl ester] is converted to the disodium salt of 5,5 '- ((2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid] by classical basic ester hydrolysis in which the reagent a 5 N NaOH solution in ethanol is used.

However, this method has the disadvantage that it is difficult to obtain a benign final product, due to the fact that the finished product does not withstand the basic conditions prevailing in such ordinary lye hydrolysis, but the final product is partially decomposed therein. Thus, the disodium salt of cromoglycate has been found to decompose in 5 N NaOH solution as follows: 0 P-CH -CH-CH - 0

Il 2 1 2 I

o QH 'W'! VP ΟΟί-ν, ^ 1.

o 0-CH2-CH-CH2-0 o ° (fiö) Oils 5N NaOH,

NaQ-C-S „/ XX * <^ 'kr,>, - C-ONa o o 2.

3 8331 1 o o-ch_-ch-ch7-o ° / c \ Λ 0H / Ok ch3 JQ] 0 \ oX = '^ SH NagH- HQ /: -3Ma 3.

o o-ch ^ -ch-ch7-o fl s "iC" '*'

m '0H

4.

When ester hydrolysis is carried out as described above, up to more than 2% of decomposition products are formed in the final product, consisting mainly of decomposition product no. 3 and oxalate. If the reaction temperature is kept too high and the reaction time is too long, larger amounts of decomposition products no. 4 and consequently more oxalate. Alternatively, using the milder sodium hydrogen carbonate hydrolysis disclosed in Patent Application No. 800823, also produces harmful amounts of decomposition products.

Since both the decomposition product no. 3 that the oxalate as well as the final product 15, i.e. the disodium salt of cromoglycate, are all very soluble in water, they are also almost impossible to separate economically.

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Since the amount of oxalate in the final product is directly proportional to the degree of degradation of the final product, the American Pharmacopoeia USP XXI, pp. 252-253 as well as the British Pharmacopoeia, BP 80, pp. This limit is difficult to fall below when performing ester hydrolysis in the classical manner described above, especially on an industrial scale where temperature variations and gradients of the reaction mixture are difficult to precisely control and control.

10 This fact is very important from an economic point of view, as the whole batch of expensive pharmaceutical raw material can easily be completely rejected due to its slightly too high oxalate content.

It is almost economically impossible to purify such a batch of drug raw material by chemical means.

When performing ester hydrolysis by the process of the invention, the above-mentioned problems can be completely eliminated. The final product does not contain measurable amounts of the above degradation products no. 3 and no. 4 and therefore also oxalate.

In our experiments in which 20 disodium salts of cromoglycate were prepared in parallel by the method according to the invention and in patent application no. According to the method disclosed in 800823, in which the diethyl ester of the compound was hydrolyzed with 1.5% sodium hydrogen carbonate in aqueous ethanol, liquid chromatographic analyzes showed that the sodium cromoglycate prepared by the method of the present invention had a concentration of 99.9%.

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Hydrolysis with sodium bicarbonate gave a product which, according to the same method of analysis, contained 1.8% degradation product which exceeded about 3 times the maximum requirements of the USP XXI Pharmacopoeia (<0.5%) for organic impurities. Thus, even using the mildest previously known hydrolysis method, it is not possible to produce an acceptable end product without cumbersome and expensive additional purification operations. The chromatograms for the liquid chromatographic analysis are shown in the appendix, Figure 1 and Figure 2.

The chromatogram of the pure end product (batch no. 89H735) prepared by the process of the invention is shown in Figure 1 and the chromatogram of the impure final product prepared with sodium bicarbonate (batch no. MD9293) is shown in Figure 2 with a retention time of 1.37 and a concentration of 1.8%. .

.5 Vigorous alkaline treatment, such as sodium hydroxide solution, gives even more decomposition products to the final product.

The liquid chromatographic method used a Spherisorb C 18 column and 50% acetonitrile / H 2 O + 1% acetic acid + 1% triethylamine as eluent at a flow rate of 1 ml / min. The wavelength of the UV detector was 254 mm.

The process of the invention hydrolyses 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid diethyl ester] dialkyl, tri- 5 alkyl, or sterically hindered primary amine, preferred

trialkylamine in an aqueous solution of dimethylformamide or 70-80% methanol or ethanol by refluxing the reaction mixture for 2-8 h.

c 83311

O

O O -CH_-CH-CH -O O R,

ΑΛ 2 in 2 11 R> N

»Jjo o \ s * y c2h5o-c ~ k0A ^ c ^ ^ \ 0> -c-oc2h5 - Q p-CH2-CH-CH2-0 0 RNH SocJL) 0I 00-CM" N ^ R'2 Na00CCH3 0 D-CH_-CH-CHo-O o i iH li

NaOOC__X jJ — COONa

II

wherein R 1 and R 2 may be H or a lower alkyl group, R 3 may be a lower straight chain or branched alkyl group.

Primary straight chain amines are not properly suited for this purpose because they form predominantly amides with the ester. However, sterically hindered primary amines, such as tert. butylamine, work as well as tertiary amines as desired. Secondary amines also form some amides.

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After the first reaction of the formula II, highly soluble ammonium salts of cromoglycate are formed in the reaction solution used. The reaction solution is treated with activated carbon and filtered, after which the disodium salt of cromoglycate 5 is crystallized from the hot filtrate by adding sodium acetate dissolved in water or an aqueous solution of 70-80% methanol or ethanol. The reaction solution is then slowly cooled to about 15 ° C.

The crystallized final product, i.e. the disodium salt of cromoglycate, is recovered from the reaction mixture by filtration.

An advantage of the process of the invention over conventional basic hydrolysis of the ester with 5N NaOH is the very gentle treatment of the cromoglycate ester with a dialkyl, trialkyl or sterically hindered primary amine which hydrolyzes the ester completely without degrading the cromoglycate. Thus, no measurable amounts of decomposition products no. 3 and no. 4 and therefore also oxalate. Another advantage is the good solubility of the ammonium salts of cromoglycate formed in the first reaction step in the solution solution used in the reaction, in dimethylformamide or preferably in an aqueous solution of 70-80% methanol or ethanol, which allows the reaction solution to be treated with activated carbon. This gives a very pure solution without any significant losses of the final product. The final product is very pure and is suitable for use in special pharmaceutical preparations.

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The invention is best illustrated by examples.

Example 1 25 g of 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid diethyl ester], 250 ml of methanol, 50 ml water and 20 ml of triethylamine 5 are transferred to a 0.5 l beaker. The mixture is refluxed for about 4 hours. The mixture is allowed to cool, after which 1.0 g of activated carbon is added. The activated carbon is filtered off and the filtrate is heated to boiling. To the hot filtrate is added a solution of 9.5 g of sodium acetate dissolved in 50 ml of 80% methanol in water. The mixture is allowed to cool for approx.

15-20 ° C, whereupon the disodium salt of cromoglycate precipitates. The crystallized product is collected by filtration and the filtrate is washed first with 80% methanol in water and then with 100% methanol. The yield is 23 g of 5,5 - ((2-hydroxy-1,3-15-propanediyl) bis (oxy)] bis (4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt] (95% of theory).

Example 2 25 g of 5,5 * - [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid diethyl ester], 250 ml of ethanol, 70 Transfer 1 ml of water and 15 ml of diethylamine to a 0,5 L beaker. The mixture is refluxed for about 2 hours.

The mixture is allowed to cool, after which 1.0 g of activated carbon is added. The activated carbon is filtered off and the filtrate is heated to boiling. To the hot filtrate is added a solution of 9.5 g of sodium acetate dissolved in 20 ml of water.

The mixture is allowed to cool to about 15-20 ° C, whereupon the disodium salt of cromoglycate precipitates. The crystallized product is collected by filtration and the filtrate is washed first with a 70% ethanol-water solution and then with 95% ethanol. The yield is 21 g of 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis- [4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt] (90% of theory). ).

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Example 3 25 g of 5,5 '- ((2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-1-benzopyran-2-carboxylic acid diethyl ester], 200 ml of dimethylformamide (DMF) , 30 ml of water and 35 ml of tributyl-amine are transferred to a 0.5 L beaker and the mixture is refluxed for about 2 hours at 80 [deg.] C. The mixture is allowed to cool to about 15-20 [deg.] C., then 1 The activated carbon is filtered off and the filtrate is heated to about 70 [deg.] C. A solution of 9.5 g of sodium acetate dissolved in 20 g of water is added to the hot filtrate and the mixture is allowed to cool to about 15-20 [deg.] C. The disodium salt of cromoglycate precipitates, the crystallized product is collected by filtration and the filtrate is washed with 50 ml of dimethylformamide and then with 50 ml of methanol.

The yield is 20 g of 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] - bis (4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt] (85.7% of theory).

Example 4 25 g of 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-20 4H-1-benzopyran-2-carboxylic acid diethyl ester], 250 ml of methanol, 50 ml of water and 15 ml of tert. transfer the butylamine to a 0.5 L beaker. The mixture is refluxed for approx.

2 h. The mixture is allowed to cool to about 15-20 ° C, after which 1.0 g of activated carbon is added. The activated carbon is filtered off and the filtrate is heated to boiling. To the hot filtrate is added a solution of 9.5 g of sodium acetate dissolved in 50 ml of 80% methanol in water. The mixture is allowed to cool to about 15-20 ° C, whereupon the disodium salt of cromoglycate precipitates. The crystallized product is collected by filtration and the filtrate is washed first with 80% methanol-water solution and then with 100% methanol.

The yield is 22 g of 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] - bis [4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt] (90% of theory).

Claims (2)

83311 10 Claim