AU700833B2

AU700833B2 - Medicinal products and pure preparations of melarsomine dihydrochloride, process for obtaining them and intermediate products obtained

Info

Publication number: AU700833B2
Application number: AU56149/96A
Authority: AU
Inventors: Jean-Pierre Etchegaray; Robert Floch; Patrick Lubert; Regine Jackie Anne-Marie Mazars; Gerard Wolf
Original assignee: Merial SAS
Current assignee: Boehringer Ingelheim Animal Health USA Inc
Priority date: 1991-12-02
Filing date: 1996-06-21
Publication date: 1999-01-14
Anticipated expiration: 2012-11-27
Also published as: AU5614996A

Description

p:\OPER\MJC\DIV29720.173 21/6/96 -2- This application is a divisional of Application No.

29720/93, the entire contents of which is incorporated herein by reference.

The parent invention relates to medicinal products comprising pure preparations of melarsomine dihydrochloride as active principle, in particular as an antiparasitic and more especially macrofilaricidal and trypanocidal agent.

The parent invention also relates to a new process for the synthesis of melarsomine dihydrochloride, and to the pure preparations of melarsomine dihydrochloride. This application relates to novel intermediate products obtained in this process.

Organoarsenic derivatives are known as macrofilaricidal and trypanocidal agents. A large number of organoarsenic derivatives have been synthesised and tested in different forms, such as, for example, the compounds described in Patent US-A-2,659,723.

Organoarsenic derivatives, melaminylthioarsenates, form the subject of Patent US-A-4,514,390, including melarsomine dihydrochloride (cysteamine melaminylthioarsenate dihydrochloride), bis(2-aminoethyl) 4- T( 4,6-diamino-, 3, 5-triazin-2-yl) amino]phenyldithioarsonite hydrochloride, of formula:

H

2 N S (CH 2 2

NH

2 N N H As .2HC N S(CH 2 )2NH 2

H

2

N

-3- This derivative is obtained by reacting melarsen oxide dihydrate or arsenone and cysteamine hydrochloride together in an ethanolic medium at the boiling point (Example 1 of Patent US-A-4,514,390 cited above).

According to Patent US-A-2,295,574, diaminochlorotriazine (DCT) may be used for the synthesis of arsenical compounds. DCT was synthesised for the first time by Liebig (Annalen der Pharmazie, Volume 10, 1834, page 43).

Moreover, trichlorotriazine (TCT) also constitutes a known starting point for the synthesis of arsenical compounds. Thus, according to Patent US-A-295,574, it is known to synthesise melarsen acid hydrochloride (MAH) starting from 2,4,6-trichloro-1,3,5triazine, which is reacted with arsanilic acid in an aqueous medium, and the reaction product is then converted to MAH in the presence of ammonia solution and hydrochloric acid at between 110 and 130°C.

According to Patent US-A-2,390,091, MAH can itself be used in condensation reactions to synthesise substituted 1,3,5-triazinyl-(6)-aminophenyl arsenical compounds.

Apart from the degree of efficacy of the arsenical derivatives, the two main problems are tolerance with e.

respect to the active principle and the mode of administration. In effect, most arsenical derivatives in subcutaneous or intramuscular injection cause inflammations or necroses, and they should hence preferably be administered intravenously.

The process according to Patent US-A-4,514,390 cited above makes use of an excess of thiol in an attempt to bring about the most complete possible reaction and hence to decrease to the maximum extent the amount of toxic melarsen oxide dihydrate in the final product.

Other considerable drawbacks lie in the synthesis processes, namely, in particular, the presence of substantial reaction residues which must necessarily be eliminated, requiring costly steps of purification and then of treatment of the mother liquors and effluents therefrom.

Thus, the preferred objective of the parent invention is to provide new medicinal products based on melarsomine dihydrochloride preparations of high purity, capable of being administered by various routes including the intramuscular and subputaneous routes.

Another preferred objective of the parent in Pntion is to provide a process for the production of these pure preparations, and in particular such a process possessing optimised reaction conditions in order, in particular, to yield intermediate products of high purity and to limit to the maximum extent the reaction residues and thus the purification phases and the volume of the mother liquors therefrom.

Thus, the subject of the parent invention is a medicinal product comprising as active principle a preparation of melarsomine dihydrochloride, the preparation having a purity of between 98.5 and 100%.

*e The medicinal product according to the invention is preferably in lyophilised form, to be redissolved at the time of use. The assay of the solution remains stable for at least 72 hours at 4 0 C protected from light. A standard lyophilisation stabiliser, for example glycine, may optionally be combined therewith.

The subject of the parent invention is also,a process that permits the production of preparations according to the invention for making the abovementioned medicinal products, characterised in that: step 1, trichlorotriazine (TCT) is converted to diaminochlorotriazine (DCT) in an ammoniacal medium; step 2, the DCT is converted to melarsen acid hydrochloride (MAH) in the presence of arsanilic acid; step 3, the MAH is reduced to melarsen oxide dihydrate; and step 4, the melarsen oxide dihydrate is converted to melarsomine dihydrochloride in the presence of cysteamine hydrochloride.

Preferably, in step 1: the TCT is reacted with an ammonia solution in two substeps, the first comprising the gradual addition of TCT to the ammonia solution under conditions that limit the reaction temperature to below approximately 20"C, and preferably to a temperature of the order of 0 to 5°C approximately, throughout this first substep, while, in the second substep, the reaction is completed by bringing the temperature of the solution obtained to between 20 and 90"C approximately, and preferably to approximately 40 0 C, and the diaminochlorotriazine (DCT) obtained is then purified by washing with hot water, in particular by resuspension in hot water, in particular in water at 90-95"C approximately, to solubilise the impurities.

Preferably: step 2: in an aqueous medium, the DCT is converted to melarsen acid hydrochloride in the presence of arsanilic acid, and the MAH is then precipitated in an acid medium; step 3: the melarsen acid hydrochloride, previously dried or otherwise, is reduced in an aqueous or preferably an organic medium, such as the alcohols tertiary butanol, isopropanol, ethanol, methanol, or in *a an aqueous-alcoholic medium, in the presence of a reducing agent such as SOCl 2 NaHSO3, H 2 SO, or SO 2 and optionally of traces of potassium iodide, in the presence of acid or otherwise, to give melarsen oxide dihydrate, which is then dried or otherwise; -6step 4: the dry or wet melarsen oxide dihydrate is suspended in water and then brought into contact with cysteamine hydrochloride to give melarsomine dihydrochloride, which may thereafter be recovered in solid form by crystallisation at low temperature or the like, followed by drying. Advantageously, the sterile melarsomine dihydrochloride may be recovered by lyophilisation and packaged.

As a variant, the process for the synthesis of melarsomine dihydrochloride, in which the latter is prepared from trichlorotriazine (TCT), proceeding via diaminochlorotriazine (DCT), then melarsen acid hydrochloride (MAH) and then melarsen oxide dihydrate, comprises at least one of the abovementioned steps 1 to 4.

It is of great importance that the DCT used in step 2 is of high purity if it is desired to decrease the formation of impurities in the following steps, these conditions also being necessary for obtaining a final product of suitable purity. The process according to the invention as a whole makes it possible very advantageously to dispense with the customary steps of purification of arsenical derivatives which generate large e* volumes of mother liquors requiring treatment. Intermediate reaction products of high purity, a condition of the synthesis of a very pure melarsomine dihydrochloride, oo. and large gains in productivity and in yield are the consequences thereof.

According to the parent invention: step 2 may advantageously be performed at a temperature of between 0 and 95°C, until dissolution of the arsanilic acid is complete, which may be assessed by *t the change in the turbidity of the solution; step 3 may advantageously be performed at a temperature of the order of 10 to 60°C or 65°C, and in particular 30 to 40 0 C, with a gradual injection of SO 2 as reducing agent in the proportion of 4.4 to 20 g, and in particular 12 to 15 g, approximately of SO 2 per 25 g of melarsen acid, until a homogeneous medium is obtained; step 4 may advantageously be carried out at a temperature of between 20 and 100°C approximately, in particular between 40 and 50"C and especially at approximately 40°C, until dissolution of the melarsen oxide dihydrate is complete. Advantageously, step 4 is performed with approximately 1 mol of melarsen oxide dihydrate per 2 mol of cysteamine hydrochloride.

Advantageously, step 3 is performed in a volume of 100 to 200 ml approximately of methanol per 10 to 60 g approximately of dry or wet melarsen acid, and in particular approximately 25 g.

Preferably, in step 1, from 30 to 200 g approximately, and in particular from 50 to 70 g approximately, of TCT are reacted per litre of ammonia solution containing, in particular, from 5 to 28 weight/weight approximately of NH 3 and in particular from 15 to 20 weight/weight. For reasons of heat transfer and of viscosity of the medium, it is advantageous to work with between 50 to 70 g of TCT per litre of ammonia solution.

The TCT is advantageously introduced over a period of more than 40 min, and in particular of approximately 120 min, in continuous or discontinuous fashion, into the ammonia solution whose initial temperature is between 0 and 20"C approximately, and in particular Sbetween 0 and 5°C approximately, it being necessary for the temperature to be maintained in this range throughout the operation.

In the second substep of step 1, the solution is preferably heated to between 20 and 90°C approximately for from 10 to 180 min approximately, and preferably to approximately 40'C for approximately 90 min.

This synthesis process makes it possible to obtain a melarsomine dihydrochloride having a purity of greater than 98.5 and which can reach 100 which is capable of being administered by various routes such as the oral, intravenous, intramuscular and subcutaneous routes.

The subject of the parent invention is hence also the melarsomine dihydrochloride preparations obtained by the process according to the invention, having a purity of between 98.5% and 100%.

The subject of the parent invention is also the melarsomine dihydrochloride preparations of purity between 98.5 and 100%.

The purified preparations of diaminochlorotriazine

(DCT)

obtained in this process are also novel.

This process makes it possible, in effect, to obtain a DCT of purity greater than 99.5%. DCT preparations having such a purity may be used, in particular as intermediate products.

The purified preparations of melarsen acid hydrochloride (MAH) obtained in the process of the invention are also novel.

This process makes it possible, in effect, to produce a MAH of purity greater than 99%. The MAH preparations having such a purity may be used, in particular as intermediate products.

The purified preparations of melarsen oxide dihydrate obtained in the process of the invention are also novel.

This process makes it possible, in effect, to produce a melarsen oxide dihydrate of purity greater than 99%. The melarsen oxide dihydrate preparations having such a purity may be used, in particular as intermediate products.

p:\OpER\MJC\6149-96SPE 19/11/98 -9- Accordingly in a first aspect of the present invention there is provided a process for the synthesis of diaminochlorotriazine (DCT) wherein trichlorotriazine (TCT) is converted to DCT in an ammoniacal solution, in two substeps, the first comprising the gradual addition of TCT to the ammoniacal solution comprising an excess of ammonia with respect to TCT, under conditions that limit the reaction temperature to below approximately 20 C throughout this first substep, while, in the second substep, the reaction is completed by bringing the temperature of the solution obtained to between 20 and 90 0 C approximately, and the DCT obtained is then purified by washing with hot water.

The TCT is reacted with an ammonia solution in two substeps, the first comprising 10 the gradual addition of TCT to the ammonia solution under conditions that limit the reaction temperature to below approximately 20°C, and preferably to a temperature of the order of 0 to 5°C approximately, throughout this first substep, while, in the second substep, the *O reaction is completed by bringing the temperature of the solution obtained to between 20 and 90 0 C approximately, and preferably to approximately 40°C and the diaminochlorotriazine 15 (DCT) obtained is then purified by washing with hot water.

o A purified preparation of DCT obtained in accordance with the process of the first aspect of the invention is also provided.

The invention further provides a DCT preparation of purity greater than 99.5%.

In a second aspect of the invention there is provided a process for the synthesis of S 20 melarsen acid hydrochloride (MAH) wherein DCT is converted to MAH in the presence of arsanilic acid. The MAH is preferably precipitated in an acid medium.

S* Preferably the conversion of DCT to MAH is performed at a temperature of between 9 and 95°C, until dissolution of the arsanilic acid is complete.

A purified preparation of MAH obtained in accordance with the second aspect of the invention is also provided.

The invention further provides a MAH preparation of purity greater than 99%.

P:\OPER\MJC\DIV29 7 20.173- 21/6/96 In a third aspect of the invention there is provided a process for the preparation of melarsen oxide dihydrate

(MO)

wherein MAH is reduced to MO.

Preferably the MAH, previously dried or otherwise, is reduced in the presence of a reducing agent, and optionally of traces of potassium iodide, to give MO.

The invention further provides a MO preparation of purity greater than 99%.

The invention will now be described in greater detail below. Reference may be made to Figure 1, illustrating diagrammatically in a general manner the steps of the process according to the invention. The abbreviations therein have the following meanings: TCT: trichlorotriazine DCT: diaminochlorotriazine AA arsanilic acid MAH: melarsen acid hydrochloride MO melarsen oxide dihydrate CH cysteamine hydrochloride MH melarsomine dihydrochloride.

Figure 2 shows the impurities (impurities I, II, X, X', Z and melamine) which may be produced during steps 1, 2 and 3 of the process, and identifies them by their structural formulae.

Assay of diaminochlorotriazine: reverse-phase high pressure liquid chromatography in comparison with a reference series.

-11- Assay of melarsen acid hydrochloride: high pressure liquid chromatography in comparison with an arsanilic acid and melarsen acid series.

Assay of melarsen oxide dihydrate: high pressure liquid chromatography in comparison with a melarsen oxide and melarsen acid series.

Assay of melarsomine dihydrochloride: ultraviolet adsorption spectrophotometry in comparison with a reference series, and high pressure liquid chromatography in comparison with a melarsomine dihydrochloride reference.

Step i. Production of 2-chloro-4,6-diaminotriazine.

Examples 1 and 2 below do not follow the conditions of the invention. They are given by way of comparison.

Comparative Example 1: The whole of the TCT charge (Fluka commercial product, product no. 28620, purity 98 is added to the ammonia solution at 20 C. The temperature of the 0 i 20 reaction medium rapidly rises to 75 0 C. The trichlorotriazine concentration is 150 g/kg. The reaction time is 1 hour.

The finished product contains two impurities, the percentages of which are 15.4 for I and 8.2 for II respectively. The formulae of I and II are given in Figure 2.

The phases of purification in water at 20*C and did not enable the contents of impurities to be lowered to less than 4 30 Melamine is formed (Figure but is removed by washing with water.

Comparative Example 2: TCT is added during 20 min to an ammonia solution at 9"C. The temperature of the reaction medium rises from 9 to 30"C. The concentration of trichlorotriazine in suspension is 193 g/l. When the addition is complete, the temperature falls to 20 0 C, and is then raised to 45"C and maintained at this value for 1 h 30 min.

-12- The contents of impurities are 0.6 for I and for II. Purification with water enables the level of impurity II to be lowered to 3.5 Example 3: TCT is added during 40 min to an ammonia solution at 4 0 C. The temperature of the reaction medium rises from 4 to 11°C and is maintained below 12*C for 4 hours. The final concentration of trichlorotriazine equivalent in suspension is 65 g/l. The temperature of the medium is then raised to 38 0 C and maintained for 210 minutes. The contents of impurities are 3.2 for I and 2.8 for II.

Purification with water enables the levels of I to be lowered to 0.6 and of II to 1.8 Example 4: TCT is added during 40 mih to an ammonia solution at 10°C, in which it occurs in suspension. The temperature of the reaction medium never exceeds 13"C throughout the addition. When the addition is complete, the temperature of the medium is brought to 40 0 C and then maintained for 1 hour. The final concentration of TCT equivalent (suspended solid) is 65 g/l. The solid is then purified in water at 90'C for 1 hour. The contents of impurities are 0.1 for I and 0.4 for II.

Example TCT is added during 120 min in 4 steps to an :..ammonia solution at 4°C. Throughout the addition period, the temperature of the reaction medium does not exceed 4 to 5°C. The medium is then heated to 40°C with maintenance of this temperature for 90 minutes. The 30 concentration of trichlorotriazine equivalent is 60 g/1.

The wet solid obtained is purified in water at 90-95"C.

The impurities I and II are no longer detected and lie at values relative to contents below 0.1 Step 2.

The wet or dry and ground 2-chloro-4,6-diaminotriazine is used to synthesise melarsen acid hydrochloride from p-arsanilic acid (SIGMA commercial product, no. A 9268, purity 99 The reaction which takes -13place at between 0 and 95°C in an aqueous medium is finished when dissolution is complete. The MAH is precipitated by adding a hydrochloric acid solution. The level of impurities in the melarsen acid hydrochloride is dependent on the degree of purity of the 2-chloro-4,6diaminotriazine

(DCT).

With the DCT of Example 1, the percentage of impurities is 0.4 for X and 4 for X' (see Figure 2).

With the DCT of Example 4, X is 0.3 and X' is r r r r r r 0.2 Step 3: Example 6: Methanol (kg/kg MAH) KI (kg/kg MAH) HC1, 35-37% (kg/kg MAH) Temperature SO2 (kg/kg

MAH)

Time of SO2 injection SO, flow rate (kg/kg MAH/h) 20 Reaction time Water Sodium hydroxide, 30.5% (1/kg MAH) Purification stages Volume of mother liquors (1/kg MAH): Yield 6.4 0.032 0.19 0.485 1 to 2 h 0.320 5 to 25 h 24 1 1.4 none 50 to 90 to This process is characterised by a low consumption of KI and of SO z which has greater solubility in methanol than in water. It is, furthermore, injected into the reaction medium, which improves gas-liquid transfer and hence the kinetics.

At the end of the reaction in methanol, the medium is clear, enabling the end of the reaction to be assessed. The absence of a purification phase is reflected very positively in the productivity and yield of the reaction and limits considerably the volume of mother liquors.

-14- The melarsen oxide is precipitated in the aqueous-alcoholic phase at between pH 8 and 10, and preferably at pH 9, with sodium hydroxide.

Example 7: 200 ml of methanol, 25 g of dry melarsen acid and 0.8 g of KI are placed in a 250-ml reactor. The medium is heated to 30°C and the temperature is maintained at this value throughout the reaction. 14.6 g of sulphur dioxide are injected in the course of 1 h 30 min into the methanolic solution, which is stirred using a turbo-mixer. The degrees of conversion of melarsen acid hydrochloride to melarsen oxide are 0.47 in 270 min and 0.98 in 1,320 min.

The melarsen oxide is precipitated under the same conditions as in Example 6.

Example 8: 100 ml of methanol, 25 g of dry melarsen acid, 0.8 g of KI and 4 ml of 35 hydrochloric acid are placed in a 250-ml reactor. The medium is heated to 40"C and maintained at this value throughout the reaction. 15 g of 20 sulphur dioxide are injected in the course of 1 h 30 min.

The degrees of conversion are 0.93 in 270 min and 0.97 in 1,320 min. The melarsen oxide is precipitated as above.

Example 9: 200 ml of methanol, 25 g of dry melarsen acid, 0.8 g of KI and 4 ml of 35 hydrochloric acid are placed in a 250-ml reactor. The medium is heated to 30°C and the temperature is maintained at this value throughout the reaction. 12 g of sulphur dioxide are injected in the course of 1 h 30 min into the methanolic solution, which 30 is stirred according to Example 7. The degrees of conversion of melarsen acid hydrochloride to melarsen oxide are 0.94 in 270 min and 0.99 in 1,320 min. The melarsen oxide is precipitated as above.

The products derived from Examples 1 and 4, converted to melarsen acid hydrochloride, were treated according to Example 9 to give two samples 1' and 4' of melarsen oxide dihydrate. 1' contains 3 of an impurity Z, and 0.2 of the same impurity Z (see Figure 2).

Example Process of Example 9, without iodine. The reaction is slower.

Step 4.

The reaction is performed on the basis of approximately 1 mol of melarsen oxide dihydrate per 2 mol of cysteamine hydrochloride: Example 11: 1 kg of melarsen oxide dihydrate is dispersed in a solution of cysteamine hydrochloride (FLUKA, Aldrich) at a concentration of 0.83 kg/kg of water, which is stirred.

kg of water is added and the temperature of the reaction is maintained at 40 0 C until dissolution has taken place.

The solution obtained is cooled to 0"C and seeded with stirring with a batch of melarsomine dihydrochloride in order to initiate crystallisation.

After 10 to 20 hours, the solid is recovered and 20 then washed with 3 litres of ethanol.

After drying at 60 0 C for between 10 and 20 hours, the purities of the melarsomine dihydrochloride preparations obtained from 1' and 4' are 96.8 and 100 respectively.

As a variant, it is also possible to suspend 1 kg .of melarsen oxide dihydrate in 0.5 kg of water, and then to add the cysteamine hydrochloride solution.

-16- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

950515 ,p:\opcdsb,29720.spc, 12 p:\OpER\MJC\56149-96.SPE 19/11198 -17- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS 1. A process for the synthesis of diaminochlorotriazine (DCT) wherein trichlorotriazine (TCT) is converted to DCT in an ammoniacal solution, in two substeps, the first comprising the gradual addition of TCT to the ammoniacal solution comprising an excess of ammonia with respect to TCT, under conditions that limit the reaction temperature to below approximately 20°C throughout this first substep, while, in the second substep, the reaction is completed by bringing the temperature of the solution obtained to between 20 and approximately, and the DCT obtained is then purified by washing with hot water.

S2. A process according to claim 1 wherein, in step 1, from 30 to 200 g approximately •of TCT are reacted per litre of ammoniacal solution.

3. A process according to claim 2 wherein from 50 to 70 g approximately of TCT are 15 reacted per litre of ammoniacal solution.

4. A process according to any one of claims 1 to 3 wherein the TCT is introduced over a period of more than 40 min.

20 5. A process according to claim 4 wherein the TCT is introduced over a period of Sapproximately 120 min.

6. A process according to any one of claims 1 to 5 wherein the reaction temperature is limited to a temperature of the order of 0 to 5'C approximately throughout the first substep.

7. A process according to any one of claims 1 to 6 wherein the second substep, the temperature of the solution is brought to approximately 8. A process according to any one of claims 1 to 7 wherein the initial temperature of M O ammoniacal solution is between 0 and 20°C approximately.

Claims

9. A process according to claim 8 wherein the initial temperature of the ammoniacal solution is between 0 and 5°C approximately. A process according to any one of claims 1 to 6 wherein, in the second substep, the solution is heated to between 20 and 90C approximately from 10 to 180 min approximately.
11. A process according to any one of claims 1 to 7 wherein, in the second substep, the solution is heated to approximately 40"C for approximately 90 min. 10 12. A process according to any one of claims 1 to 11 wherein the DCT obtained is purified by suspension in water at 90-95 C approximately. 0
13. A purified preparation of DCT obtained by the process according to any one of claims S. 1 to 12.
14. A process for synthesis of melarsen acid hydrochloride (MAH) wherein DCT preparation according to claim 13 is converted to MAH in the presence of arsanilic acid. *99999
15. A process according to claim 14 wherein the MAH is precipitated in an acid medium.
16. A process according to claim 14 or 15 wherein the conversion is performed at a temperature of between 0 and 95 C until dissolution of the arsanilic acid is complete.
17. A purified preparation of MAH obtained by the process according to any one of claims 14 to 16.
18. A process for the preparation of melarsen oxide dihydrate (MO) wherein MAH gc~Eis~- gc~Eis~- P:\OPERMJC\56149-96.SPE 24/11/98
19- according to claim 17 is reduced to MO, by reaction of MAH in an aqueous, aqueous- alcoholic or organic medium then followed by precipitation to recover the melarsen oxide. 19. Process according to claim 18, wherein the reaction is conducted in an organic medium selected from the group consisting of tertiary butanol, isopropanol, ethanol and methanol. Process according to claim 19, wherein it is carried out with methanol as organic medium.
21. Process according to claim 20, characterized in that it is performed in a volume of 100 to 200 ml of methanol per 10 to 60 g.
22. A process according to any one of claims 18 to 21 wherein the MAH, dried or otherwise, is reduced in the presence of SO 2 to give MO.
23. A process according to any one of claims 18 to 22 wherein the reduction is performed in the presence of traces of potassium iodide. 20 24. A process according to any one of claims 18 to 23 wherein the reduction is performed at a temperature in the order of 10 to 60"C with a gradual injection of SO 2 as reducing agent in the proportion of 4.4 to 20 g approximately of SO 2 per 25 g of melarsen acid, the reaction being continued until a homogeneous medium is obtained.
25. A process according to claim 24 wherein 12 to 15 g of SO z per 25 g of melarsen acid is injected.
26. A process according to claim 24 or claim 25 wherein the reduction is carried out at a temperature of 30* and P:\OPER\MJC\56149-96.SPE 24/1198
27. A process according to any one of claims 18 to 26, characterized in that the melarsen oxide dihydrate is precipitated in the aqueous-alcoholic phase at between pH 8 and 10 with sodium hydroxide.
28. Purified preparation of Melarsen oxide dihydrate obtained by the process according to any one of claims 18 to 27.
29. A process according to any one of claims 1, 14 or 18 substantially as hereinbefore described with reference to any one of the examples. DATED this 24th day of November, 1998 Merial By DAVIES COLLISON CAVE Patent Attorneys for the Applicant *.I P:\OPER\MJC\DIV29720.173 21/6/96 ABSTRACT The invention provides processes for the synthesis of intermediates useful in the synthesis of melarsomine dihydrochloride. Purified preparations of the intermediates are also provided.