ES2365919T3 - PROCEDURE FOR THE PREPARATION OF RENT AND ARILDIFOSPHONIC ACIDS AND SALTS OF THE SAME. - Google Patents

Abstract

Monosodium salt of ibandronic acid in the amorphous form.

Description

The present invention relates to a process for the preparation of diphosphonic acids, in particular risedronic, zoledronic and ibandronic acids. The invention further relates to a monosodium salt of ibandronic acid in the amorphous form, pharmaceutical compositions and a process for the preparation thereof.

Diphosphonic acids or salts thereof are used in therapy to inhibit bone resorption.

Monosodium ibandronate, for example, is used in particular for the treatment and prevention of osteoporosis, hypercalcemia associated with neoplasms, Paget's disease and related pathologies.

Monosodium ibandronate is currently available in the market in the anhydrous crystalline form [RN = 13884481-2] and monohydrate [RN = 138926-19-9].

The preparation of ibandronic acid and salts thereof is disclosed in US 4927814 and DE 3623397.

One of the main problems related to the synthesis of diphosphonic acids is the solidification of the reaction mixture, which makes it difficult to carry out the reaction on an industrial scale and does not provide satisfactory yields (the yields are generally about 50%).

In particular, the production of risedronic, zoledronic and ibandronic acid requires starting materials that are expensive and not readily available.

US 4927814 discloses the preparation of 1-hydroxy-3- (N-methyl-N-pentylamino) propane-1,1-diphosphonic acid (ibandronic acid) by the reaction of 3- (N-methyl-N-pentylamino acid) ) propionic with phosphorus trichloride and phosphorous acid in chlorobenzene. The solvent is removed at the end of the reaction by decantation and first the resulting solid mass is hydrolyzed with hydrochloric acid, then filtered, concentrated to a semi-fluid mass and purified through a resin (Amberlite IR 120). These operations are particularly difficult and dangerous when carried out on an industrial scale.

US 5583122 discloses 1-hydroxy-2- (3-pyridyl) ethane-1,1-diphosphonic acid (risedronic acid), but its preparation is not given as an example. In contrast, the patent discloses the synthesis of an isomer, 1-hydroxy-2- (2-pyridyl) ethane-1,1-diphosphonic acid, by reacting (2-pyridyl) acetic acid with phosphorous acid and phosphorus trichloride in chlorobenzene. At the end of the reaction, the mixture solidifies and the solvent must be removed by decantation. This operation is difficult to carry out on an industrial scale and the addition of water necessary to hydrolyze the solid mass is dangerous. The yield amounts to 52%.

EP 1243592 discloses the synthesis of risedronic acid following the same general procedure as US 5583122, starting from (3-pyridyl) acetic acid hydrochloride. The product is isolated in 50% yield, without adding solvents to promote precipitation.

US 4939130 discloses the synthesis of 1-hydroxy-2- (1-imidazolyl) ethane-1,1-diphosphonic acid (zoledronic acid) by the reaction of (1-imidazolyl) acetic acid hydrochloride with phosphorus trichloride and 85% phosphoric acid in chlorobenzene. Also in this case a semisolid mass is separated from the reaction mixture and the chlorobenzene must be removed by decantation.

J. Org. Chem. 1995, 60, 8310-8312, mentions that the use of phosphorus oxychloride and phosphorous acid causes solidification of the reaction mixture.

IT 1230503 discloses the preparation of 8-amino-1-hydroxyoctane-1,1-diphosphonic acid by reacting 8-amino-octanoic acid with a mixture of phosphorous acid and phosphorus trichloride, with or without solvents. When no solvent is used, the optimal molar ratio of 8-amino-octanoic acid: phosphorous acid: phosphorus trichloride is 1: 3: 1.5.

Description of the invention

It has now been discovered that the reaction of a carboxylic acid with phosphorus oxychloride and phosphorous acid in well defined reasons always leads to a fluid mass that can be meticulously stirred and is suitable for industrial production.

Accordingly, the present invention relates to a process for the preparation of diphosphonic acids of the general formula (I)

image 1

where m is an integer from 1 to 8 and R is a formula residue

image 1

In which R1 and R2 are independently selected from hydrogen or C1-C5 alkyl, or

R is a 5- or 6-membered aromatic ring, optionally containing one or more heteroatoms selected from N, O, S, preferably imidazolyl or pyridyl, 15 by the reaction of a carboxylic acid of the general formula (II)

R (CH2) mCOOH

(II)

20 in which R and m are as defined above,

with a mixture of phosphorous acid and phosphorus oxychloride, in the absence of solvents and with a molar ratio of carboxylic acid: phosphorus oxychloride: phosphorous acid of 1: 2-4: 8-12, preferably 1: 3: 10. The process is particularly suitable for the preparation of the following acids:

ibandronic acid (m = 2, R = R1R2N-in which R1 = CH3 R2 = CH3 (CH2) 4)

image 1

zoledronic acid (m = 1, R = imidazol-1-yl)

image 1

35 risedronic acid (m = 1, R = pyrid-3-yl)

image 1

and it is particularly advantageous because, thanks to the absence of solvents and the fluidity of the reaction mixture, it not only does not imply a high risk, but also provides much higher yields than those reported in the literature, usually 60% or more.

The ibandronic acid obtained with the method of the invention can conveniently be transformed into the sodium salt, in particular the amorphous form, which is an additional aspect of the invention. It has been found in fact that the monosodium salt of the amorphous ibandronic acid is particularly suitable for pharmaceutical use. More particularly, oral pharmaceutical preparations have improved bioavailability compared to those currently available in the market.

Amorphous monosodium ibandronate can be obtained with conventional methods. For example, ibandronic acid can be salified with hydroxide, carbonate or sodium bicarbonate, preferably sodium hydroxide, to give an aqueous solution which, after optional filtration, is lyophilized. As an alternative to lyophilization, the product can be spray dried. Monosodium ibandronate obtained in this way is an amorphous white powder with a water content of less than 3-4%, usually less than 2%. Freeze drying and spray drying conditions (concentration, temperature, time, pressure) are not critical and can be determined according to the production plant.

The following examples show typical operating conditions and can be adjusted within wide ranges of the reported values, for example within a range of ± 20-30%.

The amorphous monosodium ibandronate thus obtained can be formulated in conventional pharmaceutical preparations, in particular suitable for oral administration. The doses are the same as those of the formulations already available in the market and can be optionally reduced thanks to the improved bioavailability of the salt.

The invention will be illustrated below in more detail by means of some examples.

Examples

Example 1 - Preparation of risedronic acid

Phosphorus oxychloride (28.8 g, 0.19 mol) is slowly added to a mixture of (3-pyridyl) acetic hydrochloride (10 g, 0.06 mol) and phosphorous acid (47 g, 0.58 mol) . The fluid mixture is heated to 60-70 ° C for 24 hours, then 60 ml of water is added at the same temperature. The mixture is refluxed for 6 hours, and 0.3 g of charcoal is added and filtered hot through Celite. 160 ml of acetone are added to the clarified solution. The resulting precipitate is filtered, suspended in 50 ml of water, dissolved at pH 7.5 (+/- 0.2) with 30% sodium hydroxide. The resulting solution is acidified to pH 0.8 (+/- 0.2) and the precipitate is filtered and dried under vacuum at 40-50 ° C until a constant weight is obtained. 9.8 g of pure risedronic acid are obtained (yield: 60%).

Example 2 - Preparation of zoledronic acid

Following the same procedure as in Example 1, using (1-imidazolyl) acetic hydrochloride as a starting material, zoledronic acid is obtained (yield: 62%).

Example 3 - Preparation of ibandronic acid

Following the same procedure as in Example 1, using 3- (N-methyl-N-pentylamino) propionic acid as the starting material, ibandronic acid is obtained (yield: 59%).

Example 4

Ibandronic acid (10 g) is suspended in water (200 ml) and 1 M NaOH is added until pH 4.3-4.4. The clear solution is filtered through a 0.22 micron filter, frozen to -40 ° C and lyophilized (<100 mbar, 040 ° C), to give amorphous monosodium ibandronate with a water content of less than 2%.

Example 5

Ibandronic acid (10 g) is suspended in water (200 ml) and 1 M NaOH is added until pH 4.3-4.4. The clear solution is filtered through a 0.22 micron filter and transported under pressure to a spray dryer (nozzle temperature = 180-200 ° C). Amorphous monosodium ibandronate identical to that of example 1 is obtained.

Claims (2)

1. Monosodium salt of ibandronic acid in the amorphous form.

Salt according to claim 1, with a water content of less than 2% by weight.

3. Pharmaceutical compositions containing the salt of claims 1 or 2, in admixture with suitable excipients.

Method for the preparation of the salt of claims 1 or 2, which comprises salting the ibandronic acid with sodium hydroxide, carbonate or bicarbonate in an aqueous solution, followed by lyophilization.

or "spray dry" the resulting aqueous solution.