ADINAZOLAM METHANESULFONATE

Abstract: Crystalline adinazolam methanesulfonate which is essen­ tially non-hygroscopic is a novel product. It can be prepared by mixing adinazolam free base and methanesulfonic acid in anal­ kanol/alkyl acetate mixture, heating the mixture to remove alkanol and any water, and separating the precipitate after cooling.

Description: This invention relates to a salt form of adinazolam, and its preparation. Adinazolam is 8-chloro- 1- (dimethylamino) methyl- 6- phenyl-4H-s-triazolo [4,3-a] [1, 4lbenzodiazepine. Adinazolam and its methanesulfonate salt are described and claimed in US-A-4250094. The salt is being clinically lly studied for use in the treatment of human patients suffering fran acute depression and psychotic disorders including schizophrenia. To be in a ccooercially-acceptable potable form, adinazolam methane sulfonate should be in a stable, crystalline form which can stand in bulk containers without aggregation, to facilitate subsequent handling. Its production should minimise or eliminate concern about toxicological safety to plant personnel and, ultimately, the patient, resulting fran the use of solvents which may be present, in small amountst in the crystal lattice of the product. There should be minimal by-product formation, e.g. as the result of local excesses of methanesulfonic acid, especially in the presence of water which may be introduced with the crystallisation solvents or in the crystal lattice of the adinazolam starting material. A novel product of the invention is essentially non-hygroscopic adinazolam methanesulfonate. The product may be prepared in a non-hygroscopic, crystal form, essentially free of ring-opened by-product and undesirable solvent residues. A process according to the invention, for preparing crystalline, essentially non-hygroscopic adinazolam methanesulfonate, comprises mixing adinazolam free base into a liquid mixture of methanol or ethanol and a C46 alkyl acetate, e.g. butyl, pentyl or hexyl acetate, adding to the mixture methanesulfonic acid diluted in a low-boiling liquid such as methanol or ethanol, the amount of methanesulfonic acid not to exceed the molar amount of adinazolam in the resulting mixture, heating the resulting mixture to a temperature sufficient to dissolve at least some of the adinazolam in the mixture, to promote formation of adinazolam methanesulfonate salt and for a time sufficient to remove essentially all of the C1 to C2-al-kanol and any water in the mixture, cooling the resulting mixture to precipitate and crystallize the adinazolam methanesulfonate from the mixture, and separating the resulting adinazolam methanesulfonate salt from the liquid mixture. DETAILED DESCRIPTION OF THE INVENTION This invention provides essentially non-hygroscopic adinazolam methanesulfonate salt, per se, and describes both direct and indirect processes for preparing it. The adinazolam methanesulfonate salt of this invention can be prepared from adinazolam free base or from various hydrated adinazolam acid salt forms, after freeing the adinazolam from any non-methanesulfonate salt forms. The preferred, direct method for preparing essentially non-hygroscopic adinazolam methanesulfonate comprises mixing from about 1 percent to about 15 percent, by weight, of adinazolam free base into a liquid mixture of butyl acetate or pentyl acetate or hexyl acetate by way of mixture of adinazolam into a C1 to C2-alkanol so that the resulting adinazolam C1 to C2-alkanol/C4 to C6-alkyl acetate mixture is present preferably in a proportion, v/v, of from 1 to 15 parts of the C1 to C2-alkanol to 99 to 85 parts of the C4-C6-alkyl acetate, or mixtures thereof, heating the mixture, if necessary, to effect solution of the adinazolam, adding to the adinazolam in the C1 to C2-alkanol/ C4-C6-alkyl acetate or solution the methanesulfonic acid diluted with a C1 to C2-alkanol in a slow controlled manner to minimize localized concentrations of methanesulfonic acid, to an amount just short of stoichiometric equivalency of the methanesulfonic acid relative to the adinazolam concentration in the mixture, and heating the mixture at a temperature sufficient to distill off the methanol or ethanol and essentially all of any water present in the mixture. Heating of these mixtures at a temperature of from about 1100C. to about 1200C. for about 1-1/2 hours to about several hours at atmospheric pressure is sufficient to remove the methanol or ethanol and essentially all of the water present in the mixture. It has been found that it is necessary to add methanol or ethanol for the adinazolam free base or hydrated methanesulfonate salt thereof to the C4 to C6-alkyl acetate to increase the solubility of the adinazolam in the mixture. The amount of C1 to C2-alkanol added is not critical beyond providing the enhanced solubility property to the solvent mixture because the mixture is heated to distill or azeotrope off the C1 to C2-alkanol and any water in the mixture. Amounts of C1 to C2-alkanol ranging from about 10 to about 15 percent v/v, based upon the amount of C4 to C6-alkyl acetate, are generally sufficient. A solvent mixture containing about a 9:1 v/v C4 to C6-alkyl acetate or to C1 to C2-alkanol , is preferred. Methanol is the preferred Ci to C2-alkanol. Also, maintaining the adinazolam free base concentration in the solvent mixture equal to or higher than the stoichiometric concentration of the methanesulfonic acid helps to ensure reproducibility of high quality, non-hygroscopic adinazolam methanesulfonate salt product yields. Such processing also minimizes formation of the yield lowering ring opened by-products in the mixture, probably due to the combined presence of excess methanesulfonic acid and water in the mixture, which conditions are sought to be avoided herein. The concentration of adinazolam free base or its equivalent hydrated adinazolam methanesulfonate starting material can be mixed with one or the other of the solvent mixture components, and then the other solvent component can be added. The concentration of the adinazolam in the solvent mixture can vary from dilute (concentrations of adinazolam down below or near 1 percent w/v adinazolam in solvent mixture volume) to more concentrated (concentration of adinazolam up near 15 percent w/v, on the same basis as above) for pilot or plant scale operation of the process. Experiments have been conducted employing fast, one-shot or slow, dropwise, controlled addition of methanesulfonic acid to 1 percent and 10 percent, respectively, of adinazolam free base in a 9:1 v/v butyl acetate/methanol solvent mixture, at 230C. until the adinazolam/methanesulfonic acid stoichiometric ratio in the mixture reached the indicated ratios, below. TABLE Run Adinazolam/ Adinazolam: Ring Ring A. 1% adinazolam/ H3CSO3H Addition Opened volume (a) Ratio Rate (e) Impurity (b) I. - 1.05 Fast LTd 0.2% II. 0.83 Fast Nd 8% III. 1.00 Fast LT 0.2% IV. 0.91 Slow N 6% B. 10% adinazolam/ volume I. 0.83 Fast 3.8% II. 1.04 Fast LT 0.2% III. 0.92 Slow 4.1% IV. (c) 1.01 Fast 0.5% V. 1.01 Fast LT 0.1% Footnotes: a - All runs conducted in solvent mixture of butyl acetate/ methanol b - Area percent, based upon adinazolam content c - This adinazolam starting material contained 3 percent w/v of N-[E4-(2-benzoyl-4-chlorophenyl )-5-E(dimethyl amino)methyl]- 4H-1,2,4-triazol-3-yl]methyl)phthal imide d - LT = less than; - = about. e - Fast = methane sulfonic acid added rapidly in a single portion Slow = methane sulfonic acid added in a controlled dropwise fashion The studies at the lower concentration levels allowed more uniform sampling of the reaction slurries; the data for the higher concentration studies are more in line with expected plant conditions. Data from both low and higher concentration studies are reasonably consistent; slight variations in the semi-quantitative results can be attributed to non-uniform sampling of the mixtures. From these data, it is significant that in cases where adinazolam free base was present even in slight excess, relative to the molar content of methanesulfonic acid, the presence of ring-opened impurity in the product was always less than 0.2 percent. A leveling of the amount of ring-opened impurity is seen over time since any localized regions of high methanesulfonic acid acidity are neutralized as the hot slurry thins. The data show that in runs where the methanesulfonic acid is present in excess, relative to the adinazolam free base content, without exception, unacceptably high levels of the ringopened impurity were found in the isolated adinazolam methanesulfonate product. To avoid problems associated with the presence of ringopened impurity in isolating the crystalline non-hygroscopic adinazolam methanesulfonate product, therefore, it is desirable to maintain the stoichiometric ratio of methanesulfonic acid to adinazolam in these dehydrating solvent systems to less than 1, that is, the amount of methanesulfonic acid used is deliberately kept slightly lower or no higher than its molar equivalent of adinazolam free base. As used herein, non-hygroscopic adinazolam methanesulfonate salt is salt which does not have water of hydration in its crystal structure above about 0.15 percent, by weight, or which does not take up water from the atmosphere, or which does not form hard clumps of crystal aggregates of adinazolam methanesulfonate salt upon standing in storage containers awaiting further processing. Another, but less preferred method or process for preparing nonhygroscopic adinazolam methanesulfonate salt is to dissolve adinazolam free base in methanol, with the aid of heat, if necessary, for the concentration of adinazolam in methanol which is desired, cool the solution to about room temperature, add the methanesulfonic acid in methanol to form the hydrated adinazolam methanesulfonate salt, which precipitates when the mixture is cooled to about 0 C. The precipitated hydrated adinazolam methanesulfonate salt can be separated from the liquid phase and mixed with a high boiling liquid (i.e., a b.p. over about llO"C.) such as xylene, toluene, cyclohexanone, or Skellysolve V (a brand of petroleum solvent, which consists essentially of mixed C8 and Cg aliphatic hydrocarbons, boiling at about 240"-290"C.). Xylene is representative of this group. The adinazolam methanesulfonate/high boiling solvent mixture is set for distillation, and the mixture is heated until water or a water/solvent azeotrope ceases to be collected in condensing apparatus connected thereto. Then the mixture is cooled to room temperature or below to precipitate and crys talli-ze the non-hygroscopic adinazolam methanesulfonate salt, which can then be separated and dried by conventional means to a desired degree of dryness. This latter method is not preferred because approximately 0.1 to about 0.2 percent by weight of xylene or other solvent can be detected in this type of non-hygroscopic adinazolam methanesulfonate salt crystal product. Recent investigations by persons concerned with toxicological and occupational safety have recommended xylene not be used, but that butyl acetate, or a C5 or C6-alkyl acetate would be preferred over the use of the other above named solvents for this recrystallization process. Residual solvent levels of either butyl acetate, or a C5 or C6-alkyl acetate, not exceeding 0.1 percent by weight, thereof, based upon the weight of the adinazolam in the finished non-hydroscopic adinazolam methanesulfonate crystalline product are not considered to represent a significant toxicological hazard at this time. However, efforts should be made to minimize, if not eliminate, the presence of any of these residual solvents. The invention is further exemplified by the following detailed examples which are not intended to be limiting. Example 1 In a 10 ml. round bottomed flask fitted with a magnetic stir bar and a condenser there was placed 150 mg of hydrated adinazolam methanesulfonate salt and 5 ml. of reagent grade xylene. The stirring mixture was heated in an oil bath over 1.33 hr. to reflux, and maintained at reflux temperature for about 1 hour to remove water from the mixture. The oil bath temperature varied from about 1200C. to 1650C. The resulting mixture was then cooled to 200C., the adinazolam methanesulfonate solids were removed by filtration, washed with 1 ml. of reagent grade xylene, dried in a vacuum oven at about 50"C. for about 16 hours to constant weight, about 140 mg. The filtration was excellent. The yield of non-hygroscopic adinazolam methanesulfonate was thus about 93 percent; m.p. 2420--2450C., a brown melt. Example 2 This example exemplifies the procedure of Example 1, using xylene, on a larger scale. To a 1-liter 3-necked round-bottomed flask there was added 48.98 g. of hydrated adinazolam methanesulfonate and 750 ml. of reagent grade xylene. The slurry was heated and stirred at reflux, about 1360C., for 2 hours. A Dean-Stark trap apparatus was used to azeotropically remove any water present. Only a few drops of water was collected from this batch of adinazolam methanesulfonate starting material. However, the distillate was turbid when cooled. The resulting slurry was cooled over 1.33 hour to about +15"C. and the adinazolam methanesulfonate salt was collected by filtration. The filtration was excellent. The filtered salt was washed with 100 ml. of room temperature xylene. The washed salt was then air dried at room temperature for ten minutes and then dried in a vacuum oven at 1020C. for 136 hours to give 44.55 g., 95 percent recovery of adinazolam methanesulfonate non-hygroscopic salt, m.p. 2440-2450C. Example 3 To a flask apparatus of the type described in Example 1 there was added 150 mg. of hydrated adinazolam methanesulfonate and 5 ml. of reagent grade butyl acetate. The mixture was heated on an oil bath to reflux for about 1 hour and then cooled to 200C. The solids were collected by filtration, washed with 1 ml. of butyl acetate, and dried in a vacuum oven at about 50"C. for 16 hours to constant weight of 131 mg. The filtration was excellent. The yield was about 87 percent, but with cooling the yield should be about equivalent to that of xylene. The excellent filtration was about comparable to that of the adlnazolamethanesulfonate salt from xylene. Butyl acetate or butanol can be used to replace the use of xylene in such crystallization to obtain non-hygroscopic adinazolam methanesulfonate. Example 4 To a 5-liter 3-neck round-bottom flask equipped with a distillation head, a nitrogen gas inlet, an addition funnel, an overhead stirrer and a hot oil bath heating means there was added 300 g. of adinazolam free base, 3.6 liters of n-butyl acetate and 300 ml. of methanol. The resulting mixture was warmed to 30"C. to dissolve all solids. Then, while stirring rapidly, 77.7 g. of methanesulfonic acid was added slowly via the dropping funnel. The resulting mixture was stirred, and the internal temperature of the flask contents was gradually raised to 1100C. while monitoring the amount of methanol distillate coming from the reaction vessel. After 0.5 hours at an internal temperature of 110"-1150C. (with no further observable distillate coming over), a sample of the resulting reaction mixture is removed, the solid salt thereof is isolated, and its melting point is checked. Any melting activity in the temperature range of 1800-195"C. indicates incomplete conversion of adinazolam to its desired non-hygroscopic adinazolam methanesulfonate salt form. When the melting point of the solid salt sample is in the range of 242"-2460C, the salt forming reaction and crystal form interchange is complete. When the reaction is complete, the resulting mixture is cooled to ambient temperature, filtered to separate the solid adinazolam methanesulfonate non-hygroscopic salt product, washed with butyl acetate and dried in a vacuum oven at 500C. overnight. The resulting non-hygroscopic adinazolam methanesulfonate salt is profile quality, at least 99.6 percent pure by high pressure liquid chromatography analyses means. The yield is about 361 g., 98 percent, based on methanesulfonic acid. Example 5 LARGE SCALE To a large reaction vessel, there is charged 4.44 kg. (12.61 moles) of adinazolam free base. The atmosphere of the vessel is rendered inert by removing air therefrom with a nitrogen gas flow and then 60 kg. of methanol is pulled into the inerted reaction vessel. The resulting mixture is heated to 40"C. whereupon a solution develops. The solution is filtered at 400C. through a sterile filter pad followed by a 2 gallon methanol rinse. The filtered solution is transferred back into the clean reaction vessel, cooled to 250C. and then treated over 5 minutes with a solution of 1,263 g. (13.14 mole) of methanesulfonic acid in 7.3 liters of methanol. At the end of the addition of the methanesulfonic acid solution, the mixture is cooled to OOC. is begun. After about 10 minutes of cooling a white precipitate will be observed which thickens somewhat and then thins out. The reactor vessel contents are filtered at 0 C. to a damp filter cake. The filter cake (hygroscopic form of adinazolam methanesulfonate salt) is transferred back to the reaction vessel and mixed with 25-30 gallons of xylene. The resulting mixture in the vessel is set for distillation, and the mixture is heated and distilled (with the use free of free steam in the vessel jacket, and then with pressure steam in the vessel jacket) until the reaction vessel pot temperature is 1350C. Distillation starts at about 700C. with a water/xylene azeotrope distillate. At 1350C., the reaction vessel and its contents are switched to a reflux mode and refluxed for 0.5 hour at 1350C. The contents of the reaction vessel are then cooled slowly to room temper ature. The contents of the vessel are then filtered and washed with 3 gallons of Skellysolve B brand of mixed hexanes. The filtered solids, non-hygroscopic adinazolam methanesulfonate salt are dried in vacuo at 70"C. for 2 days. The yield of non-hygroscopic adinazolam methanesulfonate salt from this procedure is about 4.44 to 78.6 percent. The characteristic non-hygroscopic form of adinazolam methanesulfonate is shown by an infrared (IR) spectrum of a sample of this salt form product. Example 6 LARGE SCALE, PREFERRED PROCESS To a large, pilot plant scale, stainless steel reactor vessel, from which air is removed with nitrogen gas, there is added 9.2 kg. of adinazolam free base via the reactor manhole, while using a ventilation duct. The chemical operator should use gloves, a respirator and face shield protection equipment. The reactor manhole cover is closed and the reactor vessel is evacuated of air by flushing with itrogen. Then 96.8 kg. of n-butyl acetate is pulled into the reactor vessel by vacuum from a grounded drum. Then 7.3 kg. of absolute methanol is pulled into the reactor vessel from a grounded drum. The reactor vessel contents are stirred and heated to 350C. to dissolve the adinazolam solids in the mixture. While continuing to heat the mixture 2.382 kg. of methanesulfonic acid is pulled into the reaction vessel with vacuum from a glass bottle connected with polyethylene tubing. The vacuum is broken with nitrogen gas. The resulting mixture is stirred rapidly (the mixture becomes thick), and is heated slowly to 1100C. while methanol and any water in the mixture is distilled off. After 2 hours of heating the stirred mixture at 1100C. a sample of the reaction mixture is taken and checked by melting point for completion of the reaction. When the melting point of the adinazolam methanesulfonate salt in the sample is 2420-2460C., the reaction is considered complete. The solids should be free-flowing and settle quickly when the reaction is complete and stirring is discontinued. The resulting reaction mixture is cooled to room temperature and the solids are filtered via a 20-inch stainless steel, grounded filter. The filtered solids are rinsed with butyl acetate. The resulting crystalline adinazolam methanesulfonate salt is dried in a vacuum oven at 50"C. for three days. The yield of non-hygroscopic adinazolam methanesulfonate is 11.0 kg. (94 percent yield).

Claims: CLAIMS 1. Crystalline adinazolam methanesulfonate which is essentially non-hygroscopic. 2. A process for preparing crystalline, essentially non-hygroscopic adinazolam methanesulfonate, which comprises: (i) adding adinazolam free base and methanesulfonic acid, diluted in a law-boiling liquid, to a mixture of methanol or ethanol and a C46 alkyl acetate, such that the molar ratio of methanesulfonic acid to adinazolam is no greater than 1; (ii) heating the resultant mixture to a temperature sufficient to dissolve sate at least of the adinazolam free base and for a time sufficient to remove substantially all the methanol or ethanol and any water; and (iii) cooling the resultant mixture and separating the precipitated crystalline adinazolam methanesulfonate. 3. A process according to claim 2, in which the adinazolam free base is added before the methanesulfonic acid.

Inventors: MEULMAN, PAUL ALLEN, NICHOLS, STEVE, TIFFANY, BURRIS DWIGHT
Applicants: THE UPJOHN COMPANY
Application year: 1984
Main classification: C07D487
IPC codes: C07D487