Method for synthesizing phentolamine mesylate

Abstract

The present invention provides a method for synthesizing phentolamine mesylate from phentolamine and methanesulfonic acid in the presence of acetone and water. The method of the present invention provides highly pure phentolamine mesylate.

Description

Field of the Invention

[0001] The present invention provides a method for synthesizing phentolamine mesylate from phentolamine and methanesulfonic acid in the presence of acetone and water. The method of the present invention provides highly pure phentolamine mesylate. Background of the Invention

[0002] Phentolamine mesylate is a non-selective α-adrenergic receptor antagonist approved by the Food and Drug Administration (FDA) for reversing soft tissue anesthesia. Phentolamine mesylate is also approved by the FDA for preventing or controlling hypertensive episodes in patients with pheochromocytoma and for treating dermal necrosis following intravenous administration or extravasation of norepinephrine.

[0003] Continued research has been conducted on phentolamine mesylate for new indications. Thus, an improved synthesis of phentolamine is needed to produce highly pure products. Summary of the Invention

[0004] The present invention provides a method for preparing phentolamine mesylate, which comprises:

[0005] (a) reacting compound 1 with methanesulfonic acid in the presence of acetone and water under conditions effective to prepare a first mixture comprising phentolamine mesylate;

[0006]

[0007] (b) mixing the first mixture and methyl tert-butyl ether to prepare a second mixture; and

[0008] (c) precipitating phentolamine mesylate from the second mixture ("the method of the present invention").

[0009] The present invention further provides phentolamine mesylate prepared by the method of the present invention ("the compound of the present invention").

[0010] The present invention further provides a pharmaceutical composition comprising the compound of the present invention (each composition is "the composition of the present invention").

[0011] The present invention further provides a method for inhibiting the contraction of iris smooth muscle, the method comprising administering an effective amount of the compound of the present invention to a subject in need thereof.

[0012] The present invention further provides a method for reducing the pupil diameter, the method comprising administering an effective amount of the compound of the present invention to a subject in need thereof.

[0013] The present invention further provides a method for improving contrast sensitivity or visual acuity, the method comprising administering an effective amount of the compound of the present invention to a subject in need thereof.

[0014] The present invention further provides a method for treating blurred or night vision impairment, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0015] The present invention further provides a method for treating or reversing pharmacologically induced mydriasis, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0016] The present invention further provides a method for treating presbyopia, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] Definition

[0018] The term "about", when immediately preceding a numerical value, means that numerical value ± up to 20%. For example, "about" a numerical value means that numerical value ± up to 20%, and in certain embodiments, ± up to 19%, ± up to 18%, ± up to 17%, ± up to 16%, ± up to 15%, ± up to 14%, ± up to 13%, ± up to 12%, ± up to 11%, ± up to 10%, ± up to 9%, ± up to 8%, ± up to 7%, ± up to 6%, ± up to 5%, ± up to 4%, ± up to 3%, ± up to 2%, ± up to 1%, ± up to less than 1% or any other value or range of values therebetween.

[0019] Throughout this specification, numerical ranges are provided for certain quantities. These ranges include all subranges subsumed therein. Thus, a range "from 50 to 80" includes all possible ranges subsumed therein (e.g., 51 - 79, 52 - 78, 53 - 77, 54 - 76, 55 - 75, 60 - 70, etc.). Additionally, all values within a given range can be endpoints of ranges subsumed thereby (e.g., the range 50 - 80 includes ranges with endpoints such as 55 - 80, 50 - 75, etc.).

[0020] The term "pharmaceutically acceptable salt" includes acid and base addition salts. Pharmaceutically acceptable salts can be obtained by reacting a compound of the present invention acting as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Pharmaceutically acceptable salts can also be obtained by reacting a compound of the present invention acting as an acid with an inorganic or organic base to form a salt, for example, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, trimethylamine, etc. In certain embodiments, the pharmaceutically acceptable salt is a zinc salt. Those skilled in the art will further recognize that pharmaceutically acceptable salts can be prepared by reacting a compound of the present invention with a suitable inorganic or organic acid or base via any of a number of known methods.

[0021] The term "solvate" refers to a solvation complex. Solvates can be formed by solvation (the combination of solvent molecules with the molecules or ions of a compound of the present invention), or solvates can be aggregates containing solute ions or molecules or solvent molecules. The solvent can be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, hexahydrates, etc. Solvates can be formed by hydration, including via the absorption of moisture. Pharmaceutically acceptable salts can also be solvates. In the case of obtaining a solvate by crystallization from a solvent, the solvent can be an alcohol, such as methanol or ethanol; an aldehyde; a ketone, such as acetone; or an ester, such as ethyl acetate.

[0022] Unless otherwise specified, all weight percentages (i.e., "weight percentage" and "weight %" and w / w) mentioned herein are relative to the total weight of the mixture or composition, as appropriate.

[0023] "Impurities" as used herein are compounds or substances other than phentolamine mesylate.

[0024] As used herein, "isolated" means separated from a chemical synthesis reaction mixture. In certain embodiments, the isolated phentolamine mesylate is at least 95% pure and contains no more than 5% of one or more impurities. "Is at least x% pure" means that the compound of the present invention comprises no more than (100 - x)% of one or more impurities. In certain embodiments, the isolated phentolamine mesylate is at least 96%, at least 97%, at least 98% or at least 99% pure and contains no more than 4%, no more than 3%, no more than 2% or no more than 1% of impurities, respectively. In certain embodiments, if present, the one or more impurities are present as a weight percentage in phentolamine mesylate. In certain embodiments, if present, the one or more impurities are present as a mole percentage in phentolamine mesylate. In certain embodiments, if present, the one or more impurities are present as a volume percentage in phentolamine mesylate.

[0025] The method of the present invention

[0026] The present invention provides a method for preparing phentolamine mesylate, which comprises:

[0027] (a) reacting compound 1 with methanesulfonic acid in the presence of acetone and water under conditions effective to prepare a first mixture comprising phentolamine mesylate;

[0028]

[0029] (b) mixing the first mixture and methyl tert-butyl ether to prepare a second mixture; and

[0030] (c) precipitating phentolamine mesylate from the second mixture.

[0031] In certain embodiments of the method of the present invention, the method further comprises the step of: (d) separating phentolamine mesylate from the second mixture, wherein the separation provides isolated phentolamine mesylate. In certain embodiments, the separation is filtration and the isolated phentolamine mesylate is the filtered phentolamine mesylate. In certain embodiments, the filtered phentolamine mesylate is washed with methyl tert-butyl ether.

[0032] In certain embodiments of the method of the present invention, the method further comprises the step of: (e) drying the separated phentolamine mesylate to provide dried phentolamine mesylate. In certain embodiments, the separated phentolamine or the filtered phentolamine is dried using a rotary evaporator. In certain embodiments, the separated phentolamine or the filtered phentolamine is dried using a rotary evaporator at a temperature of about 30 °C to about 50 °C. In certain embodiments, the separated phentolamine or the filtered phentolamine is dried using a rotary evaporator at a temperature of about 30 °C to about 40 °C. In certain embodiments, the drying comprises freeze-drying. In certain embodiments, the drying comprises drying using a rotary evaporator followed by freeze-drying. In certain embodiments, the drying continues until the weight loss of the dried product does not exceed 0.5% of the weight of the separated phentolamine mesylate being dried.

[0033] In certain embodiments of the method of the present invention, the ratio of acetone to water is from about 5:1 (by volume) to about 15:1 (by volume). In certain embodiments, the ratio of acetone to water is from about 10:1 (by volume) to about 12:1 (by volume). In certain embodiments, the ratio of acetone to water is about 11:1 (by volume). In certain embodiments, the ratio of acetone to water is about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1 or about 15:1 (by volume).

[0034] In certain embodiments of the method of the present invention, the concentration of Compound 1 is from about 0.2 moles per liter of acetone and water to about 0.4 moles per liter of acetone and water. In certain embodiments, the concentration of Compound 1 is about 0.3 moles per liter of acetone and water. In certain embodiments, the concentration of Compound 1 is about 0.2 moles per liter, about 0.25 moles per liter, about 0.3 moles per liter, about 0.35 moles per liter or about 0.4 moles per liter of acetone and water.

[0035] In certain embodiments of the method of the present invention, the acetone and water do not contain an alcohol solvent. In certain embodiments of the method of the present invention, the first mixture does not contain an alcohol solvent. In certain embodiments of the method of the present invention, the second mixture does not contain an alcohol solvent. In certain embodiments of the method of the present invention, the acetone and water, the first mixture and the second mixture do not contain an alcohol solvent. In certain embodiments, the method of the present invention is carried out in the absence of an alcohol solvent. In certain embodiments, the alcohol solvent is isopropanol, n-propanol, ethanol or methanol.

[0036] In certain embodiments of the method of the present invention, acetone and water do not contain toluene. In certain embodiments of the method of the present invention, the first mixture does not contain toluene. In certain embodiments of the method of the present invention, the second mixture does not contain toluene. In certain embodiments of the method of the present invention, the acetone and water, the first mixture and the second mixture do not contain toluene. In certain embodiments, the method of the present invention is carried out in the absence of toluene.

[0037] In certain embodiments of the method of the present invention, the acetone and water are at or adjusted to a temperature of about 15°C to about 25°C. In certain embodiments, immediately before reacting compound 1 with methanesulfonic acid, the acetone and water are at or adjusted to a temperature of about 15°C to about 25°C.

[0038] In certain embodiments of the method of the present invention, compound 1 forms a solution with acetone and water and methanesulfonic acid is added to the solution. In certain embodiments, compound 1 forms a solution with acetone and water, and methanesulfonic acid is added dropwise to the solution. In certain embodiments, compound 1 forms a solution with acetone and water, methanesulfonic acid is added to the solution, and the addition of methanesulfonic acid causes the temperature of the solution to rise to about 40°C to about 50°C. In certain embodiments, compound 1 forms a solution with acetone and water, methanesulfonic acid is added to the solution, and after the complete addition of methanesulfonic acid, the first mixture is stirred for about 30 minutes. In certain embodiments, compound 1 forms a solution with acetone and water, methanesulfonic acid is added to the solution, and after the complete addition of methanesulfonic acid, the first mixture is stirred for at least about 30 minutes.

[0039] In certain embodiments of the method of the present invention, compound 1 forms a solution with acetone and water and the solution is added to methanesulfonic acid. In certain embodiments, compound 1 forms a solution with acetone and water, and the solution is added dropwise to methanesulfonic acid. In certain embodiments, compound 1 forms a solution with acetone and water, the solution is added to methanesulfonic acid, and the addition of the solution causes the temperature of the solution to rise to about 40°C to about 50°C. In certain embodiments, compound 1 forms a solution with acetone and water, the solution is added to methanesulfonic acid, and after the complete addition of the solution, the first mixture is stirred for about 30 minutes. In certain embodiments, compound 1 forms a solution with acetone and water, the solution is added to methanesulfonic acid, and after the complete addition of the solution, the first mixture is stirred for at least about 30 minutes.

[0040] In certain embodiments of the method of the present invention, Compound 1 forms a suspension with acetone and water, and methanesulfonic acid is added to the suspension. In certain embodiments, Compound 1 forms a suspension with acetone and water, and methanesulfonic acid is added dropwise to the suspension. In certain embodiments, Compound 1 forms a suspension with acetone and water, methanesulfonic acid is added to the suspension, and the addition of methanesulfonic acid causes the temperature of the suspension to rise to about 40 °C to about 50 °C. In certain embodiments, Compound 1 forms a suspension with acetone and water, methanesulfonic acid is added to the suspension, and after the complete addition of methanesulfonic acid, the first mixture is stirred for about 30 minutes. In certain embodiments, Compound 1 forms a suspension with acetone and water, methanesulfonic acid is added to the suspension, and after the complete addition of methanesulfonic acid, the first mixture is stirred for at least about 30 minutes.

[0041] In certain embodiments of the method of the present invention, Compound 1 forms a suspension with acetone and water, and the suspension is added to methanesulfonic acid. In certain embodiments, Compound 1 forms a suspension with acetone and water, and the suspension is added dropwise to methanesulfonic acid. In certain embodiments, Compound 1 forms a suspension with acetone and water, the suspension is added to methanesulfonic acid, and the addition of the suspension causes the temperature of the suspension to rise to about 40 °C to about 50 °C. In certain embodiments, Compound 1 forms a suspension with acetone and water, the suspension is added to methanesulfonic acid, and after the complete addition of the suspension, the first mixture is stirred for about 30 minutes. In certain embodiments, Compound 1 forms a suspension with acetone and water, the suspension is added to methanesulfonic acid, and after the complete addition of the suspension, the first mixture is stirred for at least about 30 minutes.

[0042] In certain embodiments of the method of the present invention, the first mixture is clear. In this context, "clear" means that all visible solids are completely dissolved. In certain embodiments, the first mixture is heated at about 45 °C and stirred until the first mixture becomes clear. In certain embodiments, the first mixture is heated at about 45 °C and stirred at about 45 °C until the first mixture becomes clear.

[0043] In certain embodiments of the method of the present invention, the method includes reacting 1 molar equivalent of Compound 1 with about 0.9 molar equivalent to about 1.5 molar equivalents of methanesulfonic acid. In certain embodiments, the method includes reacting 1 molar equivalent of Compound 1 with about 1.1 molar equivalents of methanesulfonic acid. In certain embodiments, the method includes reacting 1 molar equivalent of Compound 1 with about 0.9 molar equivalent, about 1.0 molar equivalent, about 1.1 molar equivalent, about 1.2 molar equivalent, about 1.3 molar equivalent, about 1.4 molar equivalent, or about 1.5 molar equivalents of methanesulfonic acid.

[0044] In certain embodiments, the mixing includes adding methyl tert-butyl ether to the first mixture. In certain embodiments, the mixing includes adding the first mixture to methyl tert-butyl ether.

[0045] In certain embodiments of the method of the present invention, immediately prior to mixing the first mixture and methyl tert-butyl ether, the first mixture is at or adjusted to a temperature of about 15°C to about 25°C.

[0046] In certain embodiments of the method of the present invention, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 15°C to about -25°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 15°C to about -15°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 5°C to about -25°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 5°C to about -15°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 15°C to about 8°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 14°C to about 5°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 0°C to about -15°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 3°C to about -3°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the second mixture to a temperature of about 0°C. In certain embodiments, precipitating phentolamine mesylate from the second mixture includes cooling the methyl tert-butyl ether-diluted mixture to a temperature of about -20°C.

[0047] In certain embodiments of the method of the present invention, precipitating phentolamine mesylate includes cooling the second mixture to a first temperature of about 15°C to about -15°C, stirring the second mixture at the first temperature for about 1 hour, and then further cooling the second mixture to a second temperature of about -20°C. In certain embodiments, the first temperature is about 15°C to about -5°C. In certain embodiments, the first temperature is about 15°C to about 0°C. In certain embodiments, the first temperature is about 14°C to about 8°C. In certain embodiments, the first temperature is about 3°C to about -3°C.

[0048] In certain embodiments, the second mixture is cooled to the first temperature at an average rate of from about 0.5 °C / min to about 2 °C / min. In certain embodiments, the second mixture is cooled to the first temperature at an average rate of from about 1 °C / min to about 1.5 °C / min. In certain embodiments, the second mixture is cooled to the first temperature at an average rate of about 1.33 °C / min. In certain embodiments, it takes from about 5 minutes to about 60 minutes to cool the second mixture to the first temperature. In certain embodiments, it takes from about 10 minutes to about 45 minutes to cool the second mixture to the first temperature. In certain embodiments, it takes from about 10 minutes to about 30 minutes to cool the second mixture to the first temperature. In certain embodiments, it takes about 15 minutes to cool the second mixture to the first temperature.

[0049] In certain embodiments, the second mixture is cooled from the first temperature to the second temperature at an average rate of from about 0.5 °C / min to about 2 °C / min. In certain embodiments, the second mixture is cooled from the first temperature to the second temperature at an average rate of from about 0.75 °C / min to about 1.5 °C / min. In certain embodiments, the second mixture is cooled from the first temperature to the second temperature at an average rate of about 1 °C / min. In certain embodiments, it takes from about 5 minutes to about 60 minutes to cool the second mixture from the first temperature to the second temperature. In certain embodiments, it takes from about 10 minutes to about 45 minutes to cool the second mixture from the first temperature to the second temperature. In certain embodiments, it takes from about 10 minutes to about 30 minutes to cool the second mixture from the first temperature to the second temperature. In certain embodiments, it takes about 20 minutes to cool the second mixture from the first temperature to the second temperature.

[0050] In certain embodiments of the method of the present invention, the purity of the compound of the present invention is at least about 98% (wt%), and the compound of the present invention contains no more than about 2% impurities (wt%). In certain embodiments, the purity of the compound of the present invention is from about 95.0% to 100%, and the compound of the present invention contains from 0% to about 5% impurities. In certain embodiments, the purity of the compound of the present invention is from about 98% to 100%, and the compound of the present invention contains from 0% to about 2% impurities. In certain embodiments, the purity of the compound of the present invention is about 98%, about 98.5%, about 99%, about 99.5% or 100%, and the compound of the present invention contains about 2%, about 1.5%, about 1%, about 0.5% or 0% impurities respectively after drying. In certain embodiments, the purity of the compound of the present invention is about 99.5%, about 99.9% or about 99.95%, and the compound of the present invention contains about 0.5%, about 0.1% or about 0.05% impurities respectively after drying. In certain embodiments, the purity of the compound of the present invention is about 98%, about 98.5%, about 99%, about 99.5% or 100%, and the compound of the present invention contains about 2%, about 1.5%, about 1%, about 0.5% or 0% impurities respectively after drying by rotary evaporator. In certain embodiments, the purity of the compound of the present invention is about 99.5%, about 99.9% or about 99.95%, and the compound of the present invention contains about 0.5%, about 0.1% or about 0.05% impurities respectively after drying by rotary evaporator. In certain embodiments, the purity of the compound of the present invention is about 98%, about 98.5%, about 99%, about 99.5% or 100%, and the compound of the present invention contains about 2%, about 1.5%, about 1%, about 0.5% or 0% impurities respectively after lyophilization. In certain embodiments, impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, impurities are determined by titration.

[0051] In certain embodiments, the determination of the purity of the compound of the present invention by HPLC includes comparing the compound of the present invention obtained from the method of the present invention with a reference sample of phentolamine mesylate of a tested purity. In certain embodiments, the purity of the compound of the present invention obtained from the method of the present invention is determined by HPLC to be from about 95% to about 102%, and in certain embodiments, from about 95% to about 100%. In certain embodiments, the purity of the compound of the present invention determined by HPLC only takes into account impurities detectable by the HPLC method used. In certain embodiments, the purity of the compound of the present invention determined by HPLC does not take into account the presence of solvents, if any.

[0052] In certain embodiments of the method of the present invention, the purity of the compounds of the present invention is determined by HPLC using a mobile phase that is 0.5 g / L ammonium acetate in a water:acetonitrile (67:33) solution. In certain embodiments, the HPLC method used in determining the purity of the compounds of the present invention includes using a detector set at about 220 nm to about 230 nm.

[0053] In certain embodiments of the method of the present invention, the purity of the compounds of the present invention is at least about 98%, and the compounds of the present invention contain no more than about 2% impurities, as determined by gas chromatography (GC). In certain embodiments, the purity of the compounds of the present invention is from about 95.0% to 100%, and the compounds of the present invention contain from 0% to about 5.0% impurities, as determined by GC. In certain embodiments, the purity of the compounds of the present invention is from about 98% to 100%, and the compounds of the present invention contain from 0% to about 2% impurities, as determined by GC. In certain embodiments, the GC method used in determining the purity of the compounds of the present invention comprises the United States Pharmacopeia (USP) method <467>. In certain embodiments, the compounds of the present invention obtained by the method of the present invention contain less than about 0.5% solvent, as determined by GC. In certain embodiments, the compounds of the present invention contain less than about 0.3% solvent, as determined by GC. In certain embodiments, the compounds of the present invention obtained by the method of the present invention contain less than about 0.5% or less than about 0.3% solvent after drying, as determined by GC. In certain embodiments, the compounds of the present invention obtained by the method of the present invention contain less than about 0.5% or less than about 0.3% solvent after lyophilization, as determined by GC.

[0054] In certain embodiments of the method of the present invention, the compounds of the present invention contain less than 1.5% by weight of impurities. In certain embodiments, the compounds of the present invention contain less than 1% by weight of impurities. In certain embodiments, the compounds of the present invention contain less than 0.5% by weight of impurities. In certain embodiments, the impurity is Compound 1. In certain embodiments, the impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0055] In certain embodiments of the method of the present invention, the method is carried out in the absence of an alkyl mesylate. In certain embodiments, the method does not produce an alkyl mesylate, for example, as a by-product or degradation product. In certain embodiments, the compounds of the present invention do not contain an alkyl mesylate. In certain embodiments, the compounds of the present invention do not contain a detectable amount of an alkyl mesylate. In certain embodiments, the method does not produce a detectable amount of an alkyl mesylate, for example, as a by-product or degradation product. In certain embodiments, the detectable amount is detectable by GC, HPLC, or titration.

[0056] In certain embodiments of the method of the present invention, the alkyl mesylate is methyl mesylate, ethyl mesylate, n-propyl mesylate, or isopropyl mesylate.

[0057] In certain embodiments of the method of the present invention, the compounds of the present invention contain less than about 8% by weight of water, as determined by Karl Fischer titration. In certain embodiments, the compounds of the present invention contain less than about 6% by weight of water, as determined by Karl Fischer titration. In certain embodiments of the method of the present invention, the compounds of the present invention contain less than about 2% by weight of water, as determined by Karl Fischer titration. In certain embodiments, the compounds of the present invention contain less than about 1% by weight of water, as determined by Karl Fischer titration. In certain embodiments of the method of the present invention, the compounds of the present invention contain less than about 0.5% by weight of water, as determined by Karl Fischer titration. In certain embodiments, the compounds of the present invention contain less than about 8% by weight, less than about 7.5% by weight, less than about 7% by weight, less than about 6.5% by weight, less than about 6% by weight, less than about 5.5% by weight, less than about 5% by weight, less than about 4.5% by weight, less than about 4% by weight, less than about 3.5% by weight, less than about 3% by weight, less than about 2.5% by weight, less than about 2% by weight, less than about 1.5% by weight, less than about 1% by weight, or less than about 0.5% by weight of water, as determined by Karl Fischer titration.

[0058] In certain embodiments of the method of the present invention, the compounds of the present invention contain less than about 8% by weight or less than about 6% by weight of water after drying, as determined by Karl Fischer titration. In certain embodiments, the compounds of the present invention contain less than about 8% by weight or less than about 6% by weight of water after drying by rotary evaporator, as determined by Karl Fischer titration.

[0059] In certain embodiments of the method of the present invention, the compounds of the present invention contain less than about 2% by weight or less than about 1% by weight of water after drying, as determined by Karl Fischer titration. In certain embodiments, the compounds of the present invention contain less than about 2% by weight or less than about 1% by weight of water after lyophilization, as determined by Karl Fischer titration.

[0060] In certain embodiments, the purity of the methanesulfonic acid is at least about 95% (by weight) and the methanesulfonic acid contains no more than about 5% impurities (by weight). In certain embodiments, the purity of the methanesulfonic acid is at least about 97% (by weight) and the methanesulfonic acid contains no more than about 3% impurities (by weight). In certain embodiments, the purity of the methanesulfonic acid is at least about 98% (by weight) and the methanesulfonic acid contains no more than about 2% impurities (by weight). In certain embodiments, the purity of the methanesulfonic acid is at least about 99% (by weight) and the methanesulfonic acid contains no more than about 1% impurities (by weight). In certain embodiments, the methanesulfonic acid does not contain a detectable amount of alkyl methanesulfonate. In certain embodiments, impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, impurities are determined by gas chromatography (GC).

[0061] In certain embodiments, the purity of the acetone is at least about 95% (by weight) and the acetone contains no more than about 5% impurities (by weight). In certain embodiments, the purity of the acetone is at least about 97% (by weight) and the acetone contains no more than about 3% impurities (by weight). In certain embodiments, the purity of the acetone is at least about 98% (by weight) and the acetone contains no more than about 2% impurities (by weight). In certain embodiments, the purity of the acetone is at least about 99% (by weight) and the acetone contains no more than about 1% impurities (by weight). In certain embodiments, the acetone does not contain a detectable amount of alkyl methanesulfonate. In certain embodiments, impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, impurities are determined by gas chromatography (GC).

[0062] In certain embodiments, the purity of the water is at least about 95% (wt%) and the water contains no more than about 5% impurities (wt%). In certain embodiments, the purity of the water is at least about 97% (wt%) and the water contains no more than about 3% impurities (wt%). In certain embodiments, the purity of the water is at least about 98% (wt%) and the water contains no more than about 2% impurities (wt%). In certain embodiments, the purity of the water is at least about 99% (wt%) and the water contains no more than about 1% impurities (wt%). In certain embodiments, the water contains no detectable amount of alkyl mesylate. In certain embodiments, impurities are determined by high performance liquid chromatography (HPLC).

[0063] In certain embodiments, the purity of the methyl tert-butyl ether is at least about 95% (wt%) and the methyl tert-butyl ether contains no more than about 5% impurities (wt%). In certain embodiments, the purity of the methyl tert-butyl ether is at least about 97% (wt%) and the methyl tert-butyl ether contains no more than about 3% impurities (wt%). In certain embodiments, the purity of the methyl tert-butyl ether is at least about 98% (wt%) and the methyl tert-butyl ether contains no more than about 2% impurities (wt%). In certain embodiments, the purity of the methyl tert-butyl ether is at least about 99% (wt%) and the methyl tert-butyl ether contains no more than about 1% impurities (wt%). In certain embodiments, the methyl tert-butyl ether contains no detectable amount of alkyl mesylate. In certain embodiments, impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, impurities are determined by gas chromatography (GC).

[0064] The compound of the present invention

[0065] The present invention further provides phentolamine mesylate prepared by the method of the present invention, isolated phentolamine mesylate, filtered phentolamine mesylate, and dried phentolamine mesylate. In certain embodiments, the compound of the present invention is isolated phentolamine mesylate, filtered phentolamine mesylate, or dried phentolamine mesylate.

[0066] In certain embodiments, the compound of the present invention is hygroscopic.

[0067] In certain embodiments, the compound of the present invention is stored under an inert gas. In certain embodiments, the inert gas is argon. In certain embodiments, the inert gas is nitrogen.

[0068] In certain embodiments, the compound of the present invention is hygroscopic and stored under an inert gas (e.g., nitrogen or argon).

[0069] The present invention further provides a compound of the present invention that does not contain impurities. In certain embodiments, the isolated phetolamine mesylate, filtered phetolamine mesylate, or dried phetolamine mesylate contains impurities.

[0070] In certain embodiments, the impurity is Compound 1.

[0071] In certain embodiments, the impurity is an alkyl mesylate. In certain embodiments of the compound of the present invention, the alkyl mesylate is methyl mesylate, ethyl mesylate, n-propyl mesylate, or isopropyl mesylate.

[0072] In certain embodiments, the impurity is a process by-product or a degradation product.

[0073] In certain embodiments, the impurity is Impurity A ( N -(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide):

[0074] Impurity A.

[0075] In certain embodiments, the impurity is a salt of Impurity A. In certain embodiments, the impurity is the mesylate salt of Impurity A.

[0076] In certain embodiments, Impurity A is a process by-product or a degradation product.

[0077] In certain embodiments, the impurity is Impurity B (2-chloromethyl-4,5-dihydro-1 H -imidazole):

[0078] Impurity B.

[0079] In certain embodiments, the impurity is a salt of Impurity B. In certain embodiments, the impurity is the mesylate salt of Impurity B.

[0080] In certain embodiments, Impurity B is a process by-product or a degradation product.

[0081] In certain embodiments, the impurity is Impurity C (3-hydroxy-4'-methyldiphenylamine):

[0082] Impurity C.

[0083] In certain embodiments, the impurity is a salt of Impurity C. In certain embodiments, the impurity is the mesylate salt of Impurity C.

[0084] In certain embodiments, Impurity C is a process by-product. In certain embodiments, Impurity C is a degradation product.

[0085] In certain embodiments, the impurity is one or more of impurity A, impurity B, and impurity C or a salt thereof. In certain embodiments, the salt is a mesylate.

[0086] In certain embodiments of the compounds of the present invention, the impurity is an alcohol solvent. In certain embodiments of the compounds of the present invention, the alcohol solvent is methanol, ethanol, n-propanol, or isopropanol.

[0087] In certain embodiments of the compounds of the present invention, the impurity is toluene.

[0088] In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains less than 890 ppm of toluene, as determined by GC. In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm of toluene, as determined by GC. In certain embodiments, the isolated, filtered, or dried phentolamine mesylate does not contain toluene.

[0089] In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains less than 5000 ppm of acetone, as determined by GC. In certain embodiments, the isolated, filtered, or dried phentolamine mesylate contains less than 1000 ppm, less than 900 ppm, less than 800 ppm, or less than 700 ppm of acetone, as determined by GC.

[0090] In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains less than 5000 ppm of ethyl acetate, as determined by GC. In certain embodiments, the isolated, filtered, or dried phentolamine mesylate contains less than 100 ppm, less than 90 ppm, less than 80 ppm, less than 70 ppm, less than 60 ppm, less than 50 ppm, less than 40 ppm, or less than 30 ppm of ethyl acetate, as determined by GC.

[0091] In certain embodiments of the compounds of the present invention, the isolated, filtered or dried phentolamine mesylate contains less than 5000 ppm of methyl tert-butyl ether, as determined by GC. In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains less than 200 ppm, less than 180 ppm, less than 160 ppm, less than 140 ppm, less than 120 ppm or less than 110 ppm of methyl tert-butyl ether, as determined by GC.

[0092] In certain embodiments of the compounds of the present invention, the impurity is water.

[0093] In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains no more than 5 wt% of impurities.

[0094] In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains no more than 4.5 wt%, no more than 4 wt%, no more than 3.5 wt%, no more than 3 wt%, no more than 2.5 wt%, no more than 2 wt%, no more than 1.5 wt% or no more than 1 wt% of impurities.

[0095] In certain embodiments, the impurity is Compound 1.

[0096] In certain embodiments, the impurity is an alkyl mesylate. In certain embodiments of the compounds of the present invention, the alkyl mesylate is methyl mesylate, ethyl mesylate, n-propyl mesylate or isopropyl mesylate.

[0097] In certain embodiments, the impurity is a process by-product or degradation product.

[0098] In certain embodiments, the impurity is Impurity A ( N -(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide). In certain embodiments, the impurity is an Impurity A salt. In certain embodiments, the impurity is Impurity A mesylate.

[0099] In certain embodiments, Impurity A is a process by-product or degradation product.

[0100] In certain embodiments, the impurity is Impurity B (2-chloromethyl-4,5-dihydro-1 H-imidazole). In certain embodiments, the impurity is an impurity B salt. In certain embodiments, the impurity is an impurity B mesylate. In certain embodiments, impurity B is a process by-product or a degradation product.

[0101] In certain embodiments, the impurity is impurity C (3-hydroxy-4'-methyldiphenylamine). In certain embodiments, the impurity is an impurity C salt. In certain embodiments, the impurity is an impurity C mesylate. In certain embodiments, impurity C is a process by-product. In certain embodiments, impurity C is a degradation product.

[0102] In certain embodiments, the impurity is one or more of impurity A, impurity B, and impurity C or their salts. In certain embodiments, the salt is a mesylate.

[0103] In certain embodiments of the compounds of the present invention, the impurity is an alcohol solvent. In certain embodiments of the compounds of the present invention, the alcohol solvent is methanol, ethanol, n-propanol, or isopropanol.

[0104] In certain embodiments of the compounds of the present invention, the impurity is toluene.

[0105] In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains no more than 890 ppm of toluene, as determined by GC. In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains no more than 5 ppm, no more than 4 ppm, no more than 3 ppm, no more than 2 ppm, or no more than 1 ppm of toluene, as determined by GC.

[0106] In certain embodiments of the compounds of the present invention, the isolated, filtered, or dried phentolamine mesylate contains no more than 5000 ppm of acetone, as determined by GC. In certain embodiments, the isolated, filtered, or dried phentolamine mesylate contains no more than 1000 ppm, no more than 900 ppm, no more than 800 ppm, or no more than 700 ppm of acetone, as determined by GC.

[0107] In certain embodiments of the compounds of the present invention, the isolated, filtered or dried phetolamine mesylate contains an amount of ethyl acetate not exceeding 5000 ppm, as determined by GC. In certain embodiments, the isolated, filtered or dried phetolamine mesylate contains an amount of ethyl acetate not exceeding 100 ppm, not exceeding 90 ppm, not exceeding 80 ppm, not exceeding 70 ppm, not exceeding 60 ppm, not exceeding 50 ppm, not exceeding 40 ppm or not exceeding 30 ppm, as determined by GC.

[0108] In certain embodiments of the compounds of the present invention, the isolated, filtered or dried phetolamine mesylate contains an amount of methyl tert-butyl ether not exceeding 5000 ppm, as determined by GC. In certain embodiments, the isolated, filtered or dried phetolamine mesylate contains an amount of methyl tert-butyl ether not exceeding 200 ppm, not exceeding 180 ppm, not exceeding 160 ppm, not exceeding 140 ppm, not exceeding 120 ppm or not exceeding 110 ppm, as determined by GC.

[0109] In certain embodiments, the purity of the isolated, filtered or dried phetolamine mesylate is at least about 98% (by weight) and contains no more than about 2% (by weight) of impurities. In certain embodiments, purity or impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, impurities are determined by titration.

[0110] In certain embodiments, the purity of the isolated, filtered, or dried phentolamine mesylate is from about 95.0 wt% to 100 wt%, and the isolated, filtered, or dried phentolamine mesylate contains from 0 wt% to about 5.0 wt% impurities. In certain embodiments, the purity of the isolated, filtered, or dried phentolamine mesylate is from about 98 wt% to 100 wt%, and the isolated, filtered, or dried phentolamine mesylate contains from 0 wt% to about 2 wt% impurities. In certain embodiments, the purity of the isolated, filtered, or dried phentolamine mesylate is about 98 wt%, about 98.5 wt%, about 99 wt%, about 99.5 wt%, or 100 wt%, and the isolated, filtered, or dried phentolamine mesylate contains about 2 wt%, about 1.5 wt%, about 1 wt%, about 0.5 wt%, or 0 wt% impurities, respectively. In certain embodiments, the purity or impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0111] In certain embodiments of the compounds of the present invention, the isolated, filtered or dried phentolamine mesylate has a purity of at least about 98% and the isolated, filtered or dried phentolamine mesylate contains no more than about 2% impurities, as determined by GC. In certain embodiments, the isolated, filtered or dried phentolamine mesylate has a purity of about 95.0% to 100% and contains from 0% to about 5.0% impurities, as determined by GC. In certain embodiments, the isolated, filtered or dried phentolamine mesylate has a purity of about 98% to 100% and the isolated, filtered or dried phentolamine mesylate contains from 0% to about 2% impurities, as determined by GC. In certain embodiments, the isolated, filtered or dried phentolamine mesylate has a purity of about 98%, about 98.5%, about 99%, about 99.5% or 100% and the isolated, filtered or dried phentolamine mesylate contains about 2%, about 1.5%, about 1%, about 0.5% or 0% impurities, respectively, as determined by GC. In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains less than about 0.5% solvent, as determined by GC. In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains less than about 0.3% solvent, as determined by GC.

[0112] In certain embodiments of the compounds of the present invention, the isolated, filtered or dried phentolamine mesylate contains less than 1.5% by weight of impurities. In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains less than 1% by weight of impurities. In certain embodiments, the isolated, filtered or dried phentolamine mesylate contains less than 0.5% by weight of impurities. In certain embodiments, the impurity is Compound 1. In certain embodiments, the impurity is one or more of Impurity A, Impurity B and Impurity C or salts thereof. In certain embodiments, the salt is a mesylate salt. In certain embodiments, the impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0113] In certain embodiments of the compounds of the present invention, the isolated phentolamine mesylate, filtered phentolamine mesylate, or dried phentolamine mesylate contains less than about 8% by weight of water, as determined by Karl Fischer titration. In certain embodiments, the isolated phentolamine mesylate, filtered phentolamine mesylate, or dried phentolamine mesylate contains less than about 6% by weight of water, as determined by Karl Fischer titration. In certain embodiments, the isolated phentolamine mesylate, filtered phentolamine mesylate, or dried phentolamine mesylate contains less than about 1% by weight of water, as determined by Karl Fischer titration. In certain embodiments, the isolated phentolamine mesylate, filtered phentolamine mesylate, or dried phentolamine mesylate contains less than about 8% by weight, less than about 7.5% by weight, less than about 7% by weight, less than about 6.5% by weight, less than about 6% by weight, less than about 5.5% by weight, less than about 5% by weight, less than about 4.5% by weight, less than about 4% by weight, less than about 3.5% by weight, less than about 3% by weight, less than about 2.5% by weight, less than about 2% by weight, less than about 1.5% by weight, less than about 1% by weight, or less than about 0.5% by weight of water, as determined by Karl Fischer titration.

[0114] In certain embodiments, the compounds of the present invention are provided as a mixture comprising the compounds of the present invention and impurities, wherein the impurities are present at no more than 0.5% of the mixture by weight, mole, or volume. In certain embodiments, the compounds of the present invention are provided as a mixture comprising the compounds of the present invention and impurities, wherein the impurities are present at no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% of the mixture by weight, mole, or volume.

[0115] In certain embodiments, the impurity is Compound 1.

[0116] In certain embodiments, the impurity is an alkyl mesylate. In certain embodiments of the compounds of the present invention, the alkyl mesylate is methyl mesylate, ethyl mesylate, n-propyl mesylate, or isopropyl mesylate.

[0117] In certain embodiments, the impurity is a process by-product or degradation product.

[0118] In certain embodiments, the impurity is Impurity A ( N -(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide). In certain embodiments, the impurity is a salt of Impurity A. In certain embodiments, the impurity is the mesylate salt of Impurity A.

[0119] In certain embodiments, impurity A is a by-product or a degradation product.

[0120] In certain embodiments, the impurity is impurity B (2-chloromethyl-4,5-dihydro-1 H -imidazole). In certain embodiments, impurity B is a process by-product. In certain embodiments, the impurity is an impurity B salt. In certain embodiments, the impurity is an impurity B mesylate.

[0121] In certain embodiments, the impurity is impurity C (3-hydroxy-4'-methyldiphenylamine). In certain embodiments, impurity C is a process by-product or a degradation product. In certain embodiments, impurity C is a degradation product. In certain embodiments, the impurity is an impurity C salt. In certain embodiments, the impurity is an impurity C mesylate.

[0122] In certain embodiments, the impurity is one or more of impurity A, impurity B, and impurity C or their salts. In certain embodiments, the salt is a mesylate.

[0123] In certain embodiments of the compounds of the present invention, the impurity is an alcohol solvent. In certain embodiments of the compounds of the present invention, the alcohol solvent is methanol, ethanol, n-propanol, or isopropanol.

[0124] In certain embodiments of the compounds of the present invention, the impurity is toluene.

[0125] In certain embodiments of the compounds of the present invention, the impurity is acetone, ethyl acetate, or methyl tert-butyl ether. In certain embodiments, the impurity is water. In certain embodiments of the compounds of the present invention, the impurity is a solvent.

[0126] In certain embodiments, compound 1 does not contain impurities. In certain embodiments, compound 1 contains impurities. In certain embodiments, the impurity is an alkyl mesylate. In certain embodiments of the compounds of the present invention, the alkyl mesylate is methyl mesylate, ethyl mesylate, n-propyl mesylate, or isopropyl mesylate. In certain embodiments, the impurity is a process by-product or a degradation product. In certain embodiments, the impurity is impurity A ( N -(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide). In certain embodiments, the impurity is an impurity A salt. In certain embodiments, the impurity is an impurity A mesylate. In certain embodiments, impurity A is a by-product or a degradation product. In certain embodiments, the impurity is impurity B (2-chloromethyl-4,5-dihydro-1 H-imidazole). In certain embodiments, Impurity B is a process by-product. In certain embodiments, the impurity is an Impurity B salt. In certain embodiments, the impurity is Impurity B mesylate. In certain embodiments, the impurity is Impurity C (3-hydroxy-4'-methyldiphenylamine). In certain embodiments, Impurity C is a process by-product or a degradation product. In certain embodiments, Impurity C is a degradation product. In certain embodiments, the impurity is an Impurity C salt. In certain embodiments, the impurity is Impurity C mesylate. In certain embodiments, the impurity is one or more of Impurity A, Impurity B, and Impurity C or their salts. In certain embodiments, the salt is mesylate.

[0127] In certain embodiments, the purity of Compound 1 is from about 95.0% by weight to 100% by weight, and Compound 1 contains from 0% by weight to about 5.0% by weight of impurities. In certain embodiments, the purity of Compound 1 is from about 98% by weight to 100% by weight, and Compound 1 contains from 0% by weight to about 2% by weight of impurities. In certain embodiments, the purity of Compound 1 is about 98% by weight, about 98.5% by weight, about 99% by weight, about 99.5% by weight, or 100% by weight, and Compound 1 contains about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, or 0% by weight of impurities, respectively. In certain embodiments, the purity or impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0128] In certain embodiments, the purity of Compound 1 is at least about 98% by weight, and Compound 1 contains no more than about 2% by weight of impurities, as determined by GC. In certain embodiments, the purity of Compound 1 is from about 95.0% by weight to 100% by weight, and contains from 0% by weight to about 5.0% by weight of impurities, as determined by GC. In certain embodiments, the purity of Compound 1 is from about 98% by weight to 100% by weight, and Compound 1 contains from 0% by weight to about 2% by weight of impurities, as determined by GC. In certain embodiments, the purity of Compound 1 is about 98% by weight, about 98.5% by weight, about 99% by weight, about 99.5% by weight, or 100% by weight, and Compound 1 contains about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, or 0% by weight of impurities, respectively, as determined by GC. In certain embodiments, Compound 1 contains less than about 0.5% solvent, as determined by GC. In certain embodiments, Compound 1 contains less than about 0.3% solvent, as determined by GC.

[0129] In certain embodiments, Compound 1 contains less than 0.5% by weight of impurities. In certain embodiments, Compound 1 contains less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight. In certain embodiments, Compound 1 contains no more than 0.5% by weight. In certain embodiments, Compound 1 contains no more than 0.5% by weight, no more than 0.4% by weight, no more than 0.3% by weight, no more than 0.2% by weight, or no more than 0.1% by weight. In certain embodiments, the impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0130] In certain embodiments, the impurity in Compound 1 is an alkyl methanesulfonate. In certain embodiments of the compounds of the present invention, the alkyl methanesulfonate is methyl methanesulfonate, ethyl methanesulfonate, n-propyl methanesulfonate, or isopropyl methanesulfonate.

[0131] In certain embodiments, the impurity in Compound 1 is a process by-product or a degradation product.

[0132] In certain embodiments, the impurity in Compound 1 is Impurity A ( N -(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide). In certain embodiments, the impurity is a salt of Impurity A. In certain embodiments, the impurity is the methanesulfonate salt of Impurity A.

[0133] In certain embodiments, Impurity A is a by-product or a degradation product.

[0134] In certain embodiments, the impurity in Compound 1 is Impurity B (2-chloromethyl-4,5-dihydro-1 H -imidazole). In certain embodiments, Impurity B is a process by-product. In certain embodiments, the impurity is a salt of Impurity B. In certain embodiments, the impurity is the methanesulfonate salt of Impurity B.

[0135] In certain embodiments, the impurity in Compound 1 is Impurity C (3-hydroxy-4'-methyldiphenylamine). In certain embodiments, Impurity C is a process by-product or a degradation product. In certain embodiments, Impurity C is a degradation product. In certain embodiments, the impurity is a salt of Impurity C. In certain embodiments, the impurity is the methanesulfonate salt of Impurity C.

[0136] In certain embodiments, the impurity in Compound 1 is one or more of Impurity A, Impurity B, and Impurity C or their salts. In certain embodiments, the salt is a methanesulfonate salt.

[0137] In certain embodiments, the impurity in Compound 1 is an alcohol solvent. In certain embodiments, the alcohol solvent is methanol, ethanol, n-propanol, or isopropanol.

[0138] In certain embodiments, the impurity in Compound 1 is toluene.

[0139] In certain embodiments, the impurity in Compound 1 is acetone, ethyl acetate, or methyl tert-butyl ether. In certain embodiments, the impurity is water. In certain embodiments of the compounds of the present invention, the impurity is a solvent.

[0140] In certain embodiments, the purity of the methanesulfonic acid is at least about 99% by weight, and the methanesulfonic acid contains no more than about 1% by weight of impurities. In certain embodiments, the purity of the methanesulfonic acid is from about 95.0% to 100% by weight, and the methanesulfonic acid contains from 0% to about 5.0% by weight of impurities. In certain embodiments, the purity of the methanesulfonic acid is from about 98% to 100% by weight, and the methanesulfonic acid contains from 0% to about 2% by weight of impurities. In certain embodiments, the purity of the methanesulfonic acid is about 98%, about 98.5%, about 99%, about 99.5%, or 100% by weight, and the methanesulfonic acid contains about 2%, about 1.5%, about 1%, about 0.5%, or 0% by weight of impurities, respectively. In certain embodiments, the purity or impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0141] In certain embodiments, the purity of the methanesulfonic acid is at least about 99%, and the methanesulfonic acid contains no more than about 1% of impurities, as determined by GC. In certain embodiments, the purity of the methanesulfonic acid is from about 95.0% to 100%, and contains from 0% to about 5.0% of impurities, as determined by GC. In certain embodiments, the purity of the methanesulfonic acid is from about 98% to 100%, and the methanesulfonic acid contains from 0% to about 2% of impurities, as determined by GC. In certain embodiments, the purity of Compound 1 is about 98%, about 98.5%, about 99%, about 99.5%, or 100%, and the methanesulfonic acid contains about 2%, about 1.5%, about 1%, about 0.5%, or 0% of impurities, respectively, as determined by GC. In certain embodiments, the methanesulfonic acid contains less than about 0.5% solvent, as determined by GC. In certain embodiments, the methanesulfonic acid contains less than about 0.3% solvent, as determined by GC.

[0142] In certain embodiments, the methanesulfonic acid contains less than 1 wt% or less than 0.5 wt% of impurities. In certain embodiments, the methanesulfonic acid contains less than 1 wt%, less than 0.9 wt%, less than 0.8 wt%, less than 0.7 wt%, less than 0.6 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt% or less than 0.1 wt% of impurities. In certain embodiments, the methanesulfonic acid contains no more than 1 wt% or no more than 0.5 wt% of impurities. In certain embodiments, the methanesulfonic acid contains no more than 1 wt%, no more than 0.9 wt%, no more than 0.8 wt%, no more than 0.7 wt%, no more than 0.6 wt%, no more than 0.5 wt%, no more than 0.4 wt%, no more than 0.3 wt%, no more than 0.2 wt% or no more than 0.1 wt%. In certain embodiments, the impurities are determined by high performance liquid chromatography (HPLC). In certain embodiments, the impurities are determined by titration.

[0143] In certain embodiments, the impurity in the methanesulfonic acid is an alkyl methanesulfonate. In certain embodiments of the compounds of the present invention, the alkyl methanesulfonate is methyl methanesulfonate, ethyl methanesulfonate, n-propyl methanesulfonate or isopropyl methanesulfonate.

[0144] In certain embodiments, the impurity in the methanesulfonic acid is an alcohol solvent. In certain embodiments, the alcohol solvent is methanol, ethanol, n-propanol or isopropanol.

[0145] In certain embodiments, the impurity in the methanesulfonic acid is toluene.

[0146] In certain embodiments, the impurities in the methanesulfonic acid are acetone, ethyl acetate or methyl tert-butyl ether. In certain embodiments, the impurity is water. In certain embodiments of the compounds of the present invention, the impurity is a solvent.

[0147] The present invention further provides a sealed container containing the compound of the present invention and an inert gas. In certain embodiments, the inert gas is argon or nitrogen.

[0148] The present invention further provides a sealed container containing separated phentolamine methanesulfonate and an inert gas. In certain embodiments, the inert gas is argon or nitrogen.

[0149] The present invention further provides a sealed container containing filtered phentolamine methanesulfonate and an inert gas. In certain embodiments, the inert gas is argon or nitrogen.

[0150] The present invention further provides a sealed container containing dried phentolamine methanesulfonate and an inert gas. In certain embodiments, the inert gas is argon or nitrogen.

[0151] Therapeutic use

[0152] In certain embodiments, the compounds of the present invention can be used to inhibit the contraction of iris smooth muscle. Accordingly, the present invention further provides a method for inhibiting the contraction of iris smooth muscle, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0153] In certain embodiments, the effective amount of the compound of the present invention is from about 0.01 mg to about 100 mg. In certain embodiments, the effective amount of the compound of the present invention is from about 0.05 mg to about 50 mg. In certain embodiments, the effective amount of the compound of the present invention is from about 0.1 mg to about 100 mg. In certain embodiments, the effective amount of the compound of the present invention is from about 1 mg to about 25 mg. In certain embodiments, the effective amount of the compound of the present invention is from about 5 mg to about 10 mg.

[0154] In certain embodiments, the effective amount of the compound of the present invention is from about 0.1 mg to about 2.0 mg, from about 0.2 mg to about 0.7 mg, from about 0.4 mg to about 0.6 mg, or from about 0.8 mg to about 1.2 mg. In certain embodiments, the effective amount of the compound of the present invention is about 0.5 mg or about 1 mg.

[0155] In certain embodiments, the compounds of the present invention can be used to reduce pupil diameter. Accordingly, the present invention further provides a method for reducing pupil diameter, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0156] In certain embodiments, the compounds of the present invention can be used to improve contrast sensitivity or visual acuity. Accordingly, the present invention further provides a method for improving contrast sensitivity or visual acuity, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0157] In certain embodiments, the compounds of the present invention can be used to treat blurred or night vision impairment. Accordingly, the present invention further provides a method for treating blurred or night vision impairment, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0158] In certain embodiments, the compounds of the present invention can be used to treat or reverse pharmacologically induced mydriasis. Accordingly, the present invention further provides a method for treating or reversing pharmacologically induced mydriasis, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0159] In certain embodiments, the compounds of the invention can be used to treat presbyopia. Accordingly, the invention further provides a method for treating presbyopia, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[0160] Pharmaceutical composition

[0161] In certain embodiments, the compounds of the invention are present in a composition. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the composition comprises a compound of the invention and a pharmaceutically acceptable carrier or excipient.

[0162] In certain embodiments, the composition is formulated for administration by a variety of routes, including orally, parenterally, by inhalation spray, topically or rectally. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular and intraarterial injection by a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through a catheter.

[0163] In certain embodiments, the composition is a solution, suspension, emulsion, tablet, pill, capsule, powder, cream or gel. In certain embodiments, the pharmaceutical composition is an ophthalmic solution. In certain embodiments, the ophthalmic solution comprises from about 0.5% to about 2% by weight of a compound of the invention. In certain embodiments, the ophthalmic solution comprises a compound of the invention in an amount of from about 0.5% to about 5% by weight of the molar equivalent of Compound 1. In certain embodiments, the ophthalmic solution comprises a compound of the invention in an amount of about 0.35% or about 1% by weight of the molar equivalent of Compound 1. In certain embodiments, the ophthalmic solution comprises a compound of the invention in an amount of about 0.35% or about 0.75% by weight of the ophthalmic composition.

[0164] In certain embodiments, the ophthalmic solution is suitable for ocular administration or application. In certain embodiments, the ophthalmic solution is suitable for topical, subconjunctival, intravitreal, retrobulbar, intracameral or systemic administration.

[0165] In certain embodiments, the pharmaceutically acceptable carrier or vehicle is a stabilizer, binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, colorant, dye migration inhibitor, sweetening agent, flavoring agent, viscosity modifier, pH modifier, buffer, permeation enhancer, chelating agent, surfactant or cosolvent.

[0166] In certain embodiments, the viscosity modifier is polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer and polysaccharides, i.e., cellulose derivatives, gellan gum or xanthan gum.

[0167] In certain embodiments, the pharmaceutically acceptable carrier or vehicle is sterile water, a sterile buffer solution, or sterile saline.

[0168] In certain embodiments, the pharmaceutically acceptable carrier or vehicle comprises or is mannitol or sodium acetate.

[0169] In certain embodiments, the composition comprises a preservative. In certain embodiments, the preservative is benzalkonium chloride, cetrimide, polyquaternium-1, thimerosal, sodium perborate, a stabilized oxychloro complex, a stabilized chlorite peroxide, chlorhexidine, chlorobutanol, phenylethyl alcohol, or methylparaben.

[0170] In certain embodiments, the composition is contained in a sealed container. In certain embodiments, the sealed container further contains an inert gas. In certain embodiments, the inert gas is argon or nitrogen.

[0171] In certain embodiments, the composition can be used to inhibit iris smooth muscle contraction. Accordingly, the present invention further provides a method for inhibiting iris smooth muscle contraction, the method comprising administering an effective amount of the composition to a subject in need thereof.

[0172] In certain embodiments, the composition can be used to reduce pupil diameter. Accordingly, the present invention further provides a method for reducing pupil diameter, the method comprising administering an effective amount of the composition to a subject in need thereof.

[0173] In certain embodiments, the composition can be used to improve contrast sensitivity or visual acuity. Accordingly, the present invention further provides a method for improving contrast sensitivity or visual acuity, the method comprising administering an effective amount of the composition to a subject in need thereof.

[0174] In certain embodiments, the composition can be used to treat blurred or night vision impairment. Accordingly, the present invention further provides a method for treating blurred or night vision impairment, the method comprising administering an effective amount of the composition to a subject in need thereof.

[0175] In certain embodiments, the composition can be used to treat or reverse pharmacologically induced mydriasis. Accordingly, the present invention further provides a method for treating or reversing pharmacologically induced mydriasis, the method comprising administering an effective amount of the composition to a subject in need thereof.

[0176] In certain embodiments, the composition can be used to treat presbyopia. Accordingly, the present invention further provides a method for treating presbyopia, the method comprising administering to a subject in need thereof an effective amount of the composition. Example

[0177] Example 1. Synthesis of Phentolamine Mesylate from Compound 1

[0178]

[0179] Under an argon atmosphere, methanesulfonic acid (54.5 g, 567 mmol, 1.1 eq) was added to a suspension of 3-[[(4,5-dihydro-1 H -imidazol-2-yl)methyl](4-methylphenyl)amino]phenol (Compound 1; 145 g, 515.35 mmol) in a mixture of acetone (1560 mL) and water (134 mL) over 20 min. The temperature of the reaction mixture increased from 20 °C to 29.4 °C. The reaction mixture became a clear solution, and the reaction mixture was further stirred at room temperature for 0.5 h. Methyl tert-butyl ether (MTBE; 1450 mL) was added to the reaction mixture. The resulting mixture was cooled to 0 ± 3 °C at a rate of about 1.33 °C / min for about 15 min. When it reached a temperature of about 11 °C, phentolamine mesylate began to precipitate from the mixture. After reaching 0 ± 3 °C, the mixture was maintained at this temperature for 1 h, further cooled to -20 ± 3 °C at a rate of about 1 °C / min for about 20 min, and maintained at -20 ± 3 °C with stirring for 3 h. The precipitate was collected by vacuum filtration and washed with MTBE (435 mL). The resulting filtered solid was dried using a 1-L rotary evaporator at 43 °C under reduced pressure to give 3-[[(4,5-dihydro-1 H -imidazol-2-yl)methyl](4-methylphenyl)amino]phenol methanesulfonate (phentolamine mesylate; 181 g, containing acetone), which was lyophilized to give phentolamine mesylate as a white solid (171 g, yield: 87.9%). HPLC: 99.95%. 1 1H NMR (300 MHz, DMSO-d6 / TMS): δ 9.99 (s, 2H), 9.31 (s,1H), 7.18 (d, J J = 8.1 Hz, 2H), 7.08 (d, J J = 8.1 Hz, 2H), 7.02 (t, J J = 8.1 Hz,1H), 6.33 (dd, J= 7.2 Hz, J = 1.8 Hz, 1H), 6.24 (dd, J = 7.2 Hz, J = 1.8 Hz,1H), 6.20 (s, 1H), 4.73 (s, 2H), 3.81 (s, 4H), 2.30 (s, 3H), 2.27 (s, 3H). 13 C NMR (75 MHz, DMSO-d6 / TMS): δ 170.2, 158.6, 149.2, 144.5, 133.9, 130.5, 130.3, 124.3, 108.7, 108.6, 105.4, 49.3, 44.9, 20.8.

[0180] Example 2. Synthesis of Phentolamine Mesylate from Compound 1

[0181] Under an argon atmosphere, methanesulfonic acid (311 g, 3.21 mol, 1.1 eq) was added to a suspension of 3-[[(4,5-dihydro-1 H -imidazol-2-yl)methyl](4-methylphenyl)amino]phenol (Compound 1; 828 g, 2.91 mmol) in a mixture of acetone (8900 mL) and water (765 mL) over 30 minutes. The temperature of the reaction mixture increased from 15.7 °C to 26 °C. The reaction mixture became clear, and the reaction mixture was further stirred at room temperature for 0.5 h. MTBE (8280 mL) was added to the above reaction mixture. The resulting mixture was cooled to 0 ± 3 °C at a rate of about 1.33 °C per minute for about 15 minutes. When it reached a temperature of about 11 °C, phentolamine mesylate began to precipitate from the mixture. After reaching 0 ± 3 °C, the mixture was maintained at this temperature for 1 h, further cooled to -20 ± 3 °C at a rate of about 1 °C per minute for about 20 minutes and maintained at -20 ± 3 °C with stirring for 3 h. The precipitate was collected by vacuum filtration and washed with MTBE (1240 mL × 2). The resulting filtered solid was dried using a 10-L rotary evaporator at 43 °C under reduced pressure (40 mbar) for 5 h and at 6 mbar for 5 h to give 3-[[(4,5-dihydro-1 H -imidazol-2-yl)methyl](4-methylphenyl)amino]phenol methanesulfonate (phentolamine mesylate; 956.2 g, yield: 86.6%). HPLC: 99%. 1 H NMR (300 MHz, DMSO- d 6 / TMS): δ9.99 (s, 2H), 9.31 (s, 1H), 7.18 (d, J= 8.1 Hz, 2H), 7.08 (d, J = 8.1 Hz,2H), 7.02 (t, J = 8.1 Hz, 1H), 6.33(dd, J = 7.2 Hz, J = 1.8 Hz, 1H), 6.24(dd, J = 7.2 Hz, J = 1.8 Hz, 1H), 6.20 (s, 1H), 4.73 (s, 2H), 3.81 (s, 4H),2.30 (s, 3H), 2.27 (s, 3H). 13C NMR (75 MHz, DMSO- d 6 / TMS): δ 170.2, 158.6,149.2, 144.5, 133.9, 130.5, 130.3, 124.3, 108.7, 108.6, 105.4, 49.3, 44.9,20.8.

Claims

1. A method for preparing phentolamine mesylate, the method comprising: (a) Reacting compound 1 with methanesulfonic acid in the presence of acetone and water to effectively prepare a first mixture; (b) Mixing the first mixture and methyl tert-butyl ether to prepare a second mixture; (c) Precipitating phentolamine mesylate from the second mixture; (d) Separating phentolamine mesylate from the second mixture; (e) Drying the separated phentolamine mesylate to provide dried phentolamine mesylate having a purity of more than 99% by weight; and wherein the method is carried out in the absence of an alcohol solvent.

2. The method according to claim 1, wherein precipitating phentolamine mesylate from the second mixture comprises cooling the second mixture to a temperature of 15°C to -25°C.

3. The method according to claim 1, wherein precipitating phentolamine mesylate from the second mixture comprises cooling the second mixture to a temperature of 0°C.

4. The method according to claim 1, wherein the separation is filtration, and the separated phentolamine mesylate is the filtered phentolamine mesylate.

5. The method according to claim 1, wherein the ratio of acetone to water in the first mixture of step (a) is about 10:1 to about 12:1 by volume, where about means ± up to 20%.

6. The method according to claim 1, wherein compound 1 is present in the first mixture of step (a) at a concentration of about 0.2 mol / L of acetone and water to about 0.4 mol / L of acetone and water, where about means ± up to 20%.

7. The method according to claim 1, the method comprising reacting 1 molar equivalent of compound 1 with about 1.1 molar equivalents of methanesulfonic acid, where about means ± up to 20%.

8. The method according to claim 1, wherein when mixing the first mixture and methyl tert-butyl ether, the temperature of the first mixture or methyl tert-butyl ether is about 15°C to about 25°C, where about means ± up to 20%.

9. The method according to claim 2, wherein precipitating phentolamine mesylate from the second mixture comprises further cooling the second mixture to a temperature of about -20°C, where about means ± up to 20%.

10. The method according to claim 9, wherein the further cooling lasts for about 10 minutes to about 30 minutes, where about means ± up to 20%.

11. The method according to claim 6, wherein the dried phentolamine mesylate contains less than 0.5% by weight of impurities based on the weight of the dried phentolamine mesylate.

12. The method according to claim 6, wherein the dried phentolamine mesylate contains less than 0.1% by weight of impurities based on the weight of the dried phentolamine mesylate.

13. The method according to claim 11 or 12, wherein the impurity is compound 1.

14. The method according to claim 11 or 12, wherein the impurity is an alkyl methanesulfonate.

15. The method according to claim 11 or 12, wherein the impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole or 3-hydroxy-4'-methyldiphenylamine or a salt thereof.

16. The method according to claim 1, wherein the mixing in step (b) comprises adding methyl tert-butyl ether to the first mixture.

17. The method according to claim 1, wherein the mixing in step (b) comprises adding the first mixture to methyl tert-butyl ether.

18. The method according to any one of claims 1-12, wherein the method is carried out in the absence of toluene.

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