RO112355B1 - 4-amino-hydroxybutyliden-1,1-biphosphonic acid or for its salts improved preparation process - Google Patents

Abstract

The invention relates to a process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts through it; a) reaction of 4-aminobutyric acid with a mixture of phosphorous acid and PCI3 in the presence of methanesulfonic acid; b) contacting the reaction mixture, resulting in step a), with a hydrolysis mixture aqueous solution, wherein the pH is maintained between 4 and 10, during contacting; c) recovery of 4-amino-1-hydroxybutylidene acid. This compound is used in the treatment and prevention of resorption diseases a bones.

Description

The invention relates to a process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof. This compound is used in the form of pharmaceutical preparations for the treatment and prevention of bone resorption diseases, such as malignant hypercalcemia, Paget's disease and osteoporosis.

According to US 4407761, the preparation of 4-amino-hydroxy-butylidene 1,1-bisphosphonic acid is accomplished by bisphosphonating an aminocarboxylic acid with phosphonation reagents and then cooling the reaction mixture by adding a strong non-oxidizing acid, preferably hydrochloric acid, concentrated. with heating, to hydrolyze the phosphorus intermediate products, formed until the final product is obtained. However, problems arise in this direction, because the bisphosphonation reaction mixture does not remain homogeneous and local solidifications occur. This solidification results in variable outputs, which partly results from the exothermic nature of the reaction, due to the development of hot spots. Moreover, in order to prepare the sodium salt, using the preceding process, it is necessary to isolate 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and an additional step to convert it to monosodium salt. Next, the use of concentrated hydrochloric acid, on cooling, whose smoke presents an environmental problem, is also required.

US Patent 4922007 indicates the use of methanesulfonic acid to overcome the problems of inhomogeneity and solidification associated with bisphosphonation phases, but it uses water cooling, with uncontrolled pH, which leads to the presence of a strongly acid and corrosive hydrolysis mixture which requires the use of vessels. of reaction, expensive, glass, with their inherent pressure limits.

The present invention solves these problems by using methanesulfonic acid, which allows the bisphosphonation reaction to remain fluid and homogeneous and to use an aqueous cooling medium with a controlled pH, between 4 and 10, followed by hydrolysis, which eliminates the need for acid use. hydrochloric concentrate, upon cooling. The present invention also eliminates the need to manipulate the hydrolysis mixture of a corrosive acid product, in this context a stainless steel hydrolysis equipment may be better used than the glass equipment. The glass equipment has inherent pressure limitations which is not the case with stainless steel. This is a great advantage in the current process, because it has been found that by driving the hydrolysis under pressure, the speed of the hydrolysis can be greatly increased.

It has been found that, upon cooling, a pH above 1 O results in a lower production, due to the formation of intermediate products, which exist at hydrolysis and a pH below 4 causes much longer hydrolysis times. At the same time, it was found that ABP is unstable at a pH greater than 8, thus limiting reaction times and hydrolysis times at higher pHs.

According to this invention, there is provided a process for the preparation of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid or salts thereof consisting of:

a) reaction of 4-aminobutyric acid with a mixture of phosphoric acid and PCI ₃ in the presence of methanesulfonic acid, after which

b) contact the mixture resulting in step a] with an aqueous hydrolysis mixture, where the pH is maintained within 4 to 10, during contact; and then

c) the 4-amino-1 hydroxybutylidene-1,1-bisphosphonic acid or its salts are recovered.

The reaction may be further conducted by controlling the pH during cooling with water in a restricted range, for example 6-8, maintaining the temperature between 0 and 20 ° C and then heating the hydrolysis mixture to 50 ° C, by refluxing or under pressure, long enough to ensure complete hydrolysis of said product.

The process of the present invention provides pure crystallized 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid, or salts thereof, which can be obtained with

RO 112355 High efficiency. The invention comprises bisphosphonation of an aminoalcancarboxylic acid with phosphonated reagents, in the presence of methanesulfonic acid, cooling the reaction mixture with a mixture of aqueous hydrolysis, maintaining the pH from 4 to 10, hydrolysing the intermediate phosphorus products, forming and recovering from the acid process. 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid or the salts thereof. The compound can be crystallized directly from the reaction mixture, with a yield of over 90% after the pH of the hydrolysis has been controlled and adjusted to 4.3 without further purification. Among the aminoalkanecarboxylic acids that can be used is 4-aminobutyric acid. The bisphosphonation reaction generally occurs at temperatures ranging from 45 to 125 ° C, preferably at about 65 ° C.

Generally 1 to 3, or generally 2 moles of H ₃ PO _3, and generally 1 to preferably 4 moles of PCIt per 1 mol of aminocarboxylic acid are generally used.

Smaller amounts of 4-aminobutyric acid may be used which limit the formation of the ABP fraction and decrease the hydrolysis times required. If desired, inert organic diluents, which do not solubilize the reaction product, in particular chlorinated hydrocarbons such as chlorobenzene, tetrachlorethane, tetrachlorethylene and trichlorethylene, may be used in reaction with mentansulfonic acid.

After the product formation reaction, the reaction mixture is cooled, for example immersed in a hydrolysis mixture in water. The cooling conditions are such that the pH is controlled in the pH range 4 to 10 and is preferably controlled in a narrower pH range for example 6-8. By controlling the pH in this way, it was found that the production of ABP can be increased.

Aqueous hydrolysis mixtures may contain basic or acidic compounds, or buffering agents.

Representative examples include sodium, potassium and lithium hydroxides, carbonates, bicarbonates, bisubstituted phosphates, monosubstituted phosphates, borates, oxalates, tartarates, phthalates, phosphoric acid salts and the like, and mixtures thereof.

Preferably, the hydrolysis mixture is a buffered solution, preferably a phosphate or bicarbonate buffered solution in the pH range 6-8.

The pH of the resulting cooling mixture can also be controlled during hydrolysis by simultaneous additions of a basic reagent, such as sodium hydroxide.

The cooling temperature is set in the range of D ... 90 ° C and preferably at 0 ... 20 ° C.

The time required for the cooling immersion process will vary according to the volumes used.

After cooling to pH and controlled temperature, the resulting mixture is stirred and heated in the temperature range from 50 ° C to reflux temperature and preferably to reflux temperature of about 105-110 ° C to complete and ensure complete hydrolysis.

The ratio of the volume of the reaction mixture in step a) to phosphonation and the volume of the hydrolysis mixture in water in the cooling step b) is about 1 to 5.

Alternatively, the hydrolysis mixture may be partially concentrated to about half the initial volume by distillation at atmospheric or reduced pressure, diluted with water to about the initial volume and then refluxed. This process substantially reduces hydrolysis time.

As an alternative, the hydrolysis mixture can be heated to 110-165 ° C in a pressure-sealed vessel. It also substantially reduces hydrolysis times.

It should be noted that at a pH of about 7-8, the ABP product begins to undergo degradation resulting in product loss and thus it is preferred that the desired hydrolysis process be carried out in the pH 6-8 range.

The reaction is represented schematically as follows:

RO 112355 Bl

1) PCI ₃ / H ₃ P0 ₃ / ch ₃ so ₃ h

H _a NCH _a CH ₂ CH ₂ C0 ₂ H2) H _a 0, pH = 4-10

3) NaOH

C ₄ H _g N0 ₂

MW 103.12

The monosodium trihydrate salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid described herein is used as a pharmaceutical compound for the treatment and prevention of bone resorption diseases. Such diseases as malignant hypercalcemia, Paget's disease and osteoporosis are treated with good results, with monosodium trihydrate salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid manufactured in accordance with the process of this invention. 25

Other pharmaceutically acceptable salts such as, for example, calcium, potassium salts may be prepared in accordance with the processes of the present invention and are included for this purpose. 30

The present invention has the advantage of obtaining a pure drug compound with high productivity.

The following are examples of embodiments of the invention. 35

Example 1. Hydrolysis with uncontrolled pH. Preparation of the monosodium salt trihydrate of 4-amino-1-hydroxybutylidene-1 -1- biophosphonic acid.

The bisphosphonation phase is performed as follows: 40

A mechanical shaker, a thermocouple, an additional funnel and a reflux condenser were circulated to a 250 ml glass vessel, with a brine circulating at -20 ° C. The system was connected 45 to a caustic gas purifier that exerts a pressure of 0.035-0.07 kgf / cm ² on the system. The system was fueled with nitrogen and charged with 20 g (0.19 mol] aminobutyric acid, 80 ml 50 methanesulfonic acid and 24 g [O, 29 mol] phosphorous acid. For larger operations, methanesulfonic acid can be charged the first, followed by 4-aminobutyric acid and phosphorous acid. After mixing, the heat of neutralization 55 and that of the solution rise

O OH \\ / + P-ON _a

I ^a

- H ₃ N-CH ₂ -CH ₂ -DH ₃ H ₂ 0 ₂ -DOH

P-0 z \

O OH

C ₄ H ₁₂ NNa0 ₇ P ₂ .3H ₂ 0

MW 325.13 reaction temperature at 75 ° C. The suspension was allowed to mature 15 min at 7075 ° C resulting in a clear, colorless solution. The solution was cooled to 35 ° C and then 40 ml (0.46 mol] phosphorus trichloride (PCI3) was added carefully after 20 min. The reaction was then heated to 65 ° C and allowed to mature at this temperature. for 20 h. The reaction should not be allowed to exceed B5 ° C. The reaction mixture is auto-heated to above 85 ° C and under adiabatic conditions the temperature will increase permanently.At about 150 ° C an exothermic reaction accompanied by a large For this reason it is recommended that the reaction mixture be cooled immediately with cold water when the temperature reaches 85 ° C.

The hydrolysis phase is thus achieved.

The reaction mixture is then cooled to 25 ° C and 200 ml deionized water is added after 5 minutes. The flask was rinsed with an additional 100 ml of water and the combined, strongly acidic solution (pH below zero) was aged for 5 h at 95-100 ° C.

The reaction mixture was then cooled to 20 ° C and maintained at 2O-25 ° C, while the pH was adjusted to 4.3 with about 80 ml of 50% NaOH. The resulting white slurry was then cooled to 0-5 ° C and aged for 1 h. The pH is readjusted to 4.3 if necessary and the slurry aged at 0-5 ° c for a further 2 h. The product was collected by filtration, then washed with 2 x 50 ml of cold water (0-5 ° C) and 100 ml of 95% ethyl alcohol. After cooling to 40 ° C at constant weight, 56.4 g (90%) of product were obtained.

Example 2. For the controlled pH hydrolysis the following compounds are used:

RO 112355 4 g aminobutyric acid, 160 ml methanesulfonic acid, 35 g phosphoric acid and 80 ml phosphorus tricolor.

The phase of the bisphosphonation reaction is performed as follows:

The above reagents were mixed and heated at 65 ° C for 5 h analogous to the working method of Example 1.

The hydrolysis phase is performed as follows:

The reaction mixture was cooled for more than 35 minutes by dropwise to a solution of 10 g Na _P HP0 ₄ in one liter of water at pH = 7. The pH during cooling of the reaction mixture was maintained between 6 and 7 by simultaneous addition of 25% sodium hydroxide and kept below 25 ° C by ice cooling. After the cooling was complete, the pH was adjusted to 7 and the solution was concentrated to 1080 ml by atmospheric distillation (100-104 ° C) for 3 h. At this point the reaction was subdivided into two parts A and B.

Part A, being 630 ml, was further concentrated to 450 ml after adjusting the pH to 4.3. The solution was aged overnight at ambient temperature, during which time the product crystallized. The suspension was aged at 0 ° C for 2 h, then filtered, washed with 100 ml of cold water, 100 ml of 1: 1 water / ethanol and 100 ml of 100% ethanol and dried, yielding 20.5 g (56% product). ).

Part B being 450 ml, it was treated at reflux temperature for another 16 h before adjusting the pH to 4.3 and concentrating to 300 ml. The product was isolated as above resulting in 16.5 g (63% product) of ABP.

This example illustrates that the above bisphosphonation reaction in combination with cooling by buffering decreases the amount of ABP and phosphonates that are much more difficult to hydrolyze, thus reducing the time required for hydrolysis.

Example 3. The following compounds are used for hydrolysis at controlled pH: 60 g 4-aminobutyric acid, 240 ml methanesulfonic acid, 4B g phosphoric acid and 120 ml phosphorus trichloride.

The bisphosphonation is performed as follows:

The reaction was conducted analogously using the procedure described in Example 1 (65 ° C overnight) with the above amount of reagents. The total reaction volume was 430 ml. The reaction mixture was subdivided into aliquots before cooling.

The hydrolysis phase with cooling was performed as follows:

The aliquots were cooled in 100 ml of water while at the same time 20% sodium hydroxide was added to maintain a pH of 6-1 O. The pH was adjusted to various values between 4-10 and its reaction mixture. refluxed for a period of time adequate to produce an isolated product (see below). The pH was then adjusted to 7 and the resulting solution was filtered. The pH was then adjusted to 4.3 and the solution matured overnight while the product was crystallized. The slurry was then aged at 0 ° C for 2 h and then filtered. The resulting agglomerated material was washed with water, then with ethanol and finally dried. In the table below, the yields obtained by working through the process according to the invention are given.

RO 112355 Bl

Aliquot pH Duration of reflux Product resulted 50 ml 11 1 day 9.6 g (44%) 46 ml 10 2 days 11.4 g (56%) 20 ml 9 2 days 5.0 g (54%) 23 ml 8 6 days 6.8 g (66%) 21 ml 7 10 days 6.6 g (72%) 21 ml 7 10 days 7.2 g (78%) 21 ml 7 Five days 7.0 g [78%) 2 21 ml 7 42 hours4 2.4 g [75%) 3 21 ml 6 11 days 6.8 g (74%) ml 5 day ⁵ g (%) ml 4 day ⁵ g (%) ml 3 day ⁵ g (%)

1. The temperature is between 105-11 15 0 ° C in 1 atmosphere.

2. An equal volume of ethanol was used in crystallization.

3. It was partially concentrated by atmospheric distillation to about 20 half volume, diluted with an equal volume of water and then refluxed.

4. After cooling it was refluxed to 140 ° C in a closed pressure vessel.

5. After 12 days, the hydrolysis mixture was analyzed by phosphorous NMR. Reactions at pH = 5 and pH = 4 indicate incomplete hydrolysis mixtures. The reaction at pH = 3 indicates a mixture of incomplete hydrolysis and a significantly longer hydrolysis time for completion.

This example illustrates that the product can be cooled and hydrolyzed under neutral and basic conditions with good yield, but at higher pH values, the resulting quantities are lower due to complete degradation of the product.

Claims (5)

1. Acid preparation process 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its salts, characterized in that [a] 4-aminobutyric acid is reacted with a mixture of phosphorous acid and PCI ₃ in the presence of methanesulfonic acid, after which b) the obtained mixture is brought into contact with a mixture of hydrolysis and water, represented by a phosphate buffer solution, monosodium phosphate or disodium phosphate, where the pH is kept in the range 6 ... 8, at a temperature between 50 ° C and the boiling temperature, preferably □ ... 90 ° C and more preferably O ... 20 ° C and finally c) 4-amino-1hydroxybutylidene-1,1-bisphosphonic acid or its salts are recovered. Process according to Claim 1, characterized in that the trihydrated monosodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is recovered. Process according to claim 1, characterized in that the 4-amino-1-hydroxybutylidene1,1-bisphosphonic acid is recovered. 4. Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof, characterized in that [a] 4RO 112355 Bl (R) aminobutyric acid is reacted with a mixture of phosphoric acid and PCt ₃ in the presence of methanesulfonic acid at a temperature of 65 ° C, after which b) the resulting mixture is brought into contact with aqueous phosphate buffer solution, at a temperature between 0 ... 2O ° C, maintaining the pH between 6 ... 8 during the reaction, followed by heating the resulting mixture to the boiling point and c) finally 5 recovers 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its salts.