KR20020039951A - Process for preparing form ii crystals of clarithromycin and crystalline clarithromycin mesilate trihydrate used therein - Google Patents

Abstract

PURPOSE: Provided is a manufacturing method of clarithromycin of crystalline type II in high purity and yield. Also, provided is crystalline clarithromycin mesylate trihydrate used as an intermediate therefor. CONSTITUTION: The manufacturing method of clarithromycin of crystalline type II represented by the formula(1) comprises the steps of: treating clarithromycin with methanesulfonic acid in the mixed solvent of water mixable organic solvent and water to obtain crystalline clarithromycin mesylate trihydrate of the formula(2); and neutralizing the obtained salt with ammonia solution in the mixed solvent of water mixable organic solvent and water then crystallizing it.

Description

PROCESS FOR PREPARPARING FORM II CRYSTALS OF CLARITHROMYCIN AND CRYSTALLINE CLARITHROMYCIN MESILATE TRIHYDRATE USED THEREIN}

The present invention relates to a novel process for the preparation of high purity clarithromycin crystalline Form II in high yield and to the crystalline clarithromycin mesylate trihydrate used in the process.

Clarisomycin (6- O -methylerythromycin A) represented by the following Chemical Formula 1 is an oral semisynthetic macrolide antibiotic that shows a wide range of strong antibacterial activity against various bacteria and is very stable against gastric acid, and has an excellent therapeutic effect on various infectious diseases. In combination with ulcer medications, it is also effective in preventing recurrence of ulcers:

Formula 1

To date, clarithromycin is known to exist in at least three crystalline forms and, as specified in WO 98-4573 and 98-31699, they are usually represented by crystalline forms O, I and II. These crystalline forms are mainly distinguished by powder X-ray diffraction spectroscopy, infrared spectroscopy or differential scanning calorimetric thermogram, and in particular by powder X-ray diffraction spectroscopy. Among them, Form II is thermodynamically more stable than Form I and is currently used for commercially available purification.

Clarithromycin crystalline Form II is usually prepared according to three known methods.

The first method is the heating of Form O or I to a temperature of 70 to 110 ° C. under vacuum for a long time, as disclosed in WO 98-31699 and WO 98-4573. The second method is to recrystallize Form I in a mixed solvent of chloroform and isopropyl ether (see Merck Index, 12th edition, 395). A third method is disclosed in WO 98-4574, which recrystallizes Form I in an organic solvent or a mixed solvent of organic solvent and water.

However, these methods have a disadvantage in that the purification effect is insignificant, and in order to obtain crystalline form II of pharmaceutically acceptable purity, high purity form I should be used as a raw material. In particular, according to these methods, clathromycin crude product containing various by-products and impurities cannot be used as a raw material, and high purity crystalline form O or I is obtained from the crude product through several purification processes and then used as a raw material. do. However, this purification process inevitably results in large loss of clarithromycin and increased production time and cost.

In addition, the first method has a disadvantage of low productivity due to the use of high vacuum conditions, and the second and third methods also need to perform a hot-filtering process during the crystallization process to obtain high purity Form II. It is not suitable for production, the yield is low, and there is a possibility that organic solvents harmful to human body remain.

Accordingly, the present inventors have continued their research, and obtained crystalline clarithromycin mesylate trihydrate from clarithromycin, and then neutralizing the salt with ammonia water to prepare high purity clarithromycin crystalline Form II in high yield. Discovered to complete the present invention.

It is an object of the present invention to provide a novel process for preparing high purity clarithromycin crystalline Form II in high yield.

Another object of the present invention is to provide a crystalline clarithromycin mesylate trihydrate used in the above method.

1 shows an Infrared Spectrum of crystalline clarithromycin mesylate trihydrate prepared according to the method of the present invention,

FIG. 2 shows a Powder X-ray Diffraction Spectrum of crystalline clarithromycin mesylate trihydrate prepared according to the method of the present invention,

3 shows the infrared spectroscopy of clarithromycin crystalline Form II prepared according to the method of the present invention,

4 shows the powder X-ray diffraction spectroscopy of clarithromycin crystalline Form II prepared according to the method of the present invention.

According to the above object, in the present invention

(a) treating the clarithromycin with methanesulfonic acid in a mixed solvent of a water-miscible organic solvent and water to produce crystalline clarithromycin mesylate trihydrate of the following formula (2),

(b) neutralizing the crystalline clarithromycin mesylate trihydrate produced in step (a) with ammonia water in a mixed solvent of a water miscible organic solvent and water to crystallize

Provided is a process for preparing clarithromycin crystalline Form II of Formula 1, comprising the step:

Formula 1

Formula 2

The present invention also provides a crystalline clarithromycin mesylate trihydrate of formula (II) for use as an intermediate in the process.

Hereinafter, the present invention will be described in more detail.

As used herein, the term “clarisomycin” refers to a clarithromycin crude product, clarithromycin crystalline form O, I, II, or mixtures thereof, obtained by known or other methods, wherein The terms "crystalline Form O", "crystalline Form I" and "crystalline Form II" mean as defined in WO 98-31699, 98-4573 and 98-4574. Representative methods for preparing clarithromycin are described in European Patent Nos. 158,467, 195,960, 260,938 and 272,110, and in International Publication Nos. 97-36912 and 97-36913.

The two steps constituting the method of the present invention are described in detail as follows.

Step (a): Preparation of Crystalline Clarisomycin Mesylate Trihydrate

In step (a) of constructing the method of the present invention, the clarithromycin is treated with methanesulfonic acid in a mixed solvent of water-miscible organic solvent and water to produce crystalline clarithromycin mesylate trihydrate of formula (2).

Specifically, the clarithromycin is dissolved or suspended in a water miscible organic solvent containing at least 3 equivalents or more of water, preferably acetone, ethanol or isopropanol, and then 0.9 mole equivalents to clarithromycin at room temperature to 45 ° C. Methanesulfonic acid in a molar to 1.1 molar equivalent ratio is added. The amount of mixed solvent used is preferably 3 to 5 times the volume (mL) per gram (g) weight of clarithromycin. Methanesulfonic acid can be used as a neat (neat) or a solution dissolved in the same water-miscible organic solvent. Methanesulfonic acid is added and then stirred at room temperature to 45 ° C. for 30 minutes to 3 hours, then cooled to 0 ° C. to 5 ° C. and stirred for 1 hour to 5 hours. The precipitated crystals are filtered and washed with the same water miscible organic solvent, and then dried under vacuum or at atmospheric pressure at room temperature to 45 ° C. to obtain crystalline clarithromycin mesylate trihydrate.

In this step, in order to obtain crystalline clarithromycin mesylate trihydrate, the total content of water contained in the mixed solvent is preferably 3 molar equivalents, but preferably 3 molar to 15 molar equivalents.

In addition, if necessary, in order to increase the purity of clarithromycin mesylate trihydrate, clarithromycin mesylate trihydrate can be further recrystallized according to a conventional method of heating, dissolving and cooling in the same mixed solvent. For example, it may be heated to room temperature to the boiling point temperature of the solvent, then cooled to 0 ° C to room temperature, filtered and dried.

The resulting clarithromycin mesylate trihydrate is characterized by the Infrared Spectrum and Powder X-ray Diffraction Spectrum of FIGS. 1 and 2, and standard Karl Fischer The water content determined by the titration method is maintained at 6.0% to 6.5% (theoretical value 6.02%).

Step (b): Preparation of clarithromycin crystalline Form II

In step (b) constituting the method of the present invention, the crystallization of the clarithromycin mesylate trihydrate produced in step (a) by neutralization with ammonia water in a water-miscible organic solvent and a mixed solvent of water, crystallization Prepare Form Roman II.

Specifically, clarithromycin mesylate trihydrate is dissolved in a mixed solvent of water-miscible organic solvent such as ethanol and water at room temperature. This solution is then filtered to remove impurities and suspended solids, and ammonia water is added to the filtrate to neutralize the pH of the solution to maintain 9-12. After neutralizing with ammonia water and stirring for 30 minutes or more, the precipitated crystals are filtered and washed with a cold solvent or water mixed solvent or water. Drying in vacuo or at atmospheric pressure at room temperature to 60 ° C. affords clarithromycin crystalline Form II. At this time, the mixed solvent is preferably a mixture of ethanol and water in a volume ratio of 30:70 to 70:30.

Crystals prepared in this manner can be confirmed that the crystallinity is crystallis II by infrared spectroscopy and powder X-ray diffraction spectroscopy, as illustrated in Figures 3 and 4, the results are clearly distinguished from crystalline form O or I .

According to the method of the present invention, high purity clarithromycin crystalline Form II can be easily produced in high yield from crystalline clarithromycin mesylate trihydrate from clarithromycin, and in particular, to prepare crystalline Form II Unlike conventional methods that used raw materials, crude products of clarithromycin, which are difficult to purify by the known methods, can be used as raw materials because they contain a number of protecting group residues and by-products introduced in the production of clarithromycin. Since it has the advantage that can directly prepare a high-purity Form II without going through a separate Form I manufacturing process.

In addition, those skilled in the art can understand that the crystalline clarithromycin mesylate trihydrate provided in the present invention can be used not only as an intermediate for producing clarithromycin crystalline Form II, but also as an antibiotic as such. There will be. For example, clarithromycin mesylate trihydrate is a salt of stabilized clarithromycin, which has much better solubility in water than clarithromycin, so it has many pharmaceutical benefits that cannot be achieved by clarithromycin itself, such as injectables. Have

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited by the embodiment.

Reference Example: Preparation of clarithromycin crude product

The clarithromycin crude product was prepared by the following method as disclosed in Korean Patent Application No. 2000-13033.

(Step 1) Preparation of Erythromycin A 9-Oxime

After dissolving 31.9 g of erythromycin A in 50 ml of methanol, 15.1 g of hydroxylamine hydrochloride and 15.1 ml of triethylamine were added and refluxed for 24 hours, followed by cooling to 5 ° C or lower. After stirring for 2 hours at 5 ° C. or less, the resulting crystals were filtered, washed with cold methanol and dried to obtain 32.8 g (yield 96%) of erythromycin A 9-oxime hydrochloride.

This hydrochloride was suspended in 100 ml of methanol, 20 ml of concentrated ammonia water was added, stirred at room temperature for 30 minutes, and 125 ml of water was added thereto. After stirring for several hours at 0-5 ° C., the resulting solid was filtered, washed with water and dried to give 26.0 g (80% yield from erythromycin A) of erythromycin A 9-oxime.

(Step 2) Preparation of Erythromycin A 9- O -Trophyl Oxime

After dissolving 11.23 g of erythromycin A 9-oxime obtained in step 1 in 75 ml of N, N-dimethylformamide, 3.20 g of trophylium tetrafluoroborate and 3.14 ml of triethylamine were added thereto at 30 to 40 ° C. Stir for 4 hours. Subsequently, the reaction solution was cooled to room temperature, 200 ml of water was added thereto, and then extracted twice using 100 ml of ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to yield 12.6 g (yield 100%) of foamy erythromycin A 9- O -trophiloxime. The foamed crude product was crystallized with acetonitrile to give 10.95 g (yield 87%) of pure erythromycin A 9- O -tropiloxime as a white powder.

(Step 3) Preparation of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- O -trophiloxime

12.59 g of erythromycin A 9- O -trophiloxime obtained in step 2 was dissolved in 75 ml of N, N-dimethylformamide, where 1.20 g of ammonium chloride and 1,1,1,3,3,3-hexa 6.3 ml of methyldisilazane was added and then stirred at 35 to 40 ° C. for 4 hours. Then, the reaction solution was cooled to room temperature, 200 ml of water was added thereto, and extracted twice with 100 ml of ethyl acetate. The organic layer was washed twice with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 14.5 g (98% yield) of foamy 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- O -tropiloxime.

(Step 4) Preparation of 2 ', 4 "-O-bis (trimethylsilyl) -6- O -methylerythromycin A 9- O -trophiloxime

14.75 g of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- O -trophiloxime obtained in step 3 was dissolved in a mixed solvent of 60 ml of tetrahydrofuran and 60 ml of dimethyl sulfoxide, followed by 0 ° C. After cooling, the mixture was added with 1.21 ml of methane iodide and 1.09 g of 85% potassium hydroxide powder having a particle size of 600 µm or less, the mixture was stirred at 0-5 ° C. for 4 hours, 150 ml of water was added, and ethyl acetate 100 The extract was extracted twice using ㎖. The organic layer was washed twice with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give a foamy 2 ', 4 "-O-bis (trimethylsilyl) -6- O -methylerythromycin A. 14.21 g (95% yield) of 9- O -tropiloxime were obtained.

(Step 5) Preparation of clarithromycin crude product

13.3 g of 2 ', 4 " -O -bis (trimethylsilyl) -6- O -methylerythromycin A 9- O -trophiloxime obtained in step 4 was dissolved in 70 ml of ethanol, followed by 0.75 ml of formic acid and 70 ml of water. And 4.16 g of sodium hydrogen sulfite were added sequentially and refluxed for 2 hours The reaction solution was cooled to 10 DEG C or lower, 140 mL of water and 50 mL of hexane were added, and the pH of the reaction solution was adjusted to about 10 with 2N sodium hydroxide solution. Subsequently, the reaction solution was stirred at 10 ° C. or lower for 1 hour, and then the resulting solid was filtered, washed with water and dried at 50 ° C. or higher to obtain 7.46 g (yield 75%) of clarithromycin as a white powder.

Examples 1 to 3: Preparation of clarithromycin mesylate trihydrate from clarithromycin of various purity

11.2 g (15 mmol, purity 97.0%) of clarithromycin was dissolved in 32 ml of 95% acetone, and then 1.4 g of methanesulfonic acid was added dropwise at room temperature and stirred at room temperature for 1 hour. The resulting suspension was then cooled to 0 ° C. and stirred for 3 hours. The resulting crystals were filtered off, washed with cold acetone and dried at 45 ° C. to obtain 10.3 g (92% yield, 98.8% purity) of crystalline clarithromycin mesylate trihydrate (Example 1).

Melting Point: 160-161 ° C

Humidity: 6.2% (Karl Fischer, 6.02% theory)

IR (KBr, cm ⁻¹ ): 3428, 2978, 2939, 1734, 1686, 1459, 1378, 1347, 1170, 1110, 1077, 1051, 1010, 954, 908, 892, 780.

¹ H-NMR (CDCl ₃ , ppm): 5.07 (dd, 1H, 13-H), 4.91 (d, 1H, 1 "-H), 4.60 (d, 1H, 1'-H), 3.98 (dq, 1H, 5 "-H), 3.76 (ddq, 1H, 5'-H), 3.76 (d, 11H, 1-H), 3.72 (dd, 1H, 3-H), 3.70 (dd, 1H, 5- H), 3.55 (ddd, 1H, 3'-H), 3.47 (dq, 1H, 2'-H), 3.35 (s, 3H, 3 "-OCH ₃ ), 3.07 (dd, 1H, 4" -H ), 3.04 (s, 3H, 6-OCH ₃ ), 3.03 (s, 1H, 10-H), 2.93 (s, 6H, 3'-N (CH ₃ ) ₂ ), 2.87 (dq, 1H, 8- H), 2.78 (s, 3H , CH 3 SO 3 -), 2.58 (dq, 1H, 2-H), 2.37 (dd, 1H, 2 "-H eq), 2.08 (ddd, 1H, 4'-H _eq ), 1.94 (ddq, 1H, 4-H), 1.93 (dd, 1h, 7-H _ax ), 1.92 and 1.48 (ddq, 2H, 14-H), 1.72 (dd, 1H, 7-H _eq ) , 1.59 (ddq, 1H, 2 "-H _ax ), 1.41 (s, 3H, 18-H), 1.31 (d, 3H, 6" -H), 1.30 (ddd, 1H, 4'-H _ax ), 1.25 (s, 3H, 7 "-H), 1.23 (d, 3H, 6'-H), 1.21 (d, 3H, 16-H), 1.14 (d, 3H, 19-H), 1.13 (d, 3H, 20-H), 1.12 (s, 3H, 21-H), 1.09 (d, 3H, 17-H), 0.83 (t, 3H, 15-CH ₃ ).

¹³ C-NMR (CDCl ₃ , ppm): 221.3 (9-C), 176.4 (1-C), 102.4 (1'-C), 97.0 (1 "-C), 82.3 (5-C), 79.5 ( 3-C), 78.9 (6-C), 78.3 (4 "-C), 77.4 (13-C), 74.9 (12-C), 73.6 (3" -C), 70.6 (2'-C), 69.7 (11-C), 67.7 (5'-C), 66.7 (5'-C), 66.1 (3'-C), 51.1 (22-C), 49.9 (8 "-C), 45.7 (8- C), 45.6 (2-C), 39.8 (7'-C, 8'-C and 7-C), 39.7 (4-C), 38.0 (10-C), 35.7 (2 "-C), 31.6 (4'-C), 22.0 (6'-C), 21.6 (7 "-C and 14-C), 20.5 (18-C), 19.2 (6" -C), 18.5 (19-C), 16.7 (21-C), 16.5 (16-C), 12.8 (20-C), 11.2 (15-C), 9.9 (17-C).

The obtained crystals were analyzed by infrared spectroscopy and powder X-ray diffraction spectroscopy. The results are shown in FIGS. 1 and 2, respectively.

In addition, according to the composition shown in Table 1, using the clarithromycin crystalline raw materials of various purity and various organic solvents, the crystalline clarithromycin mesylate trihydrate was obtained in a similar manner to the above method and the results are shown in the following table 1 is shown.

Organic solvent water(%) Yield (g) yield(%) Humidity (%) ingredient Usage amount (ml) Clarithromycin Raw Material Prepared clarithromycin mesylate Example 1 95% acetone 32 97.0 98.8 12.4 92 6.2 94.4 97.2 11.7 87 6.1 90.2 96.0 11.0 82 6.3 Example 2 95% ethanol 40 97.0 98.1 11.8 88 6.0 94.4 97.5 11.3 84 6.1 90.2 96.5 10.8 80 6.4 Example 3 95% Isopropanol 40 97.0 98.0 12.0 89 6.1 94.4 97.3 11.6 86 6.3 90.2 96.3 11.2 83 6.3

Examples 4 and 5: Recrystallization of clarithromycin mesylate trihydrate

In order to increase the purity of 14.0 g (92% purity) of crystalline clarithromycin mesylate trihydrate obtained by carrying out analogous to the method of Examples 1 to 3 from 80% pure clarithromycin, it was recrystallized as follows. The clarithromycin mesylate trihydrate was suspended in 50 ml of 95% ethanol and refluxed. Once completely dissolved, the solution was slowly cooled to 0 ° C. and stirred for 4 hours. The resulting crystals were filtered, washed with 0 ° C. ethanol and dried at 45 ° C. in air to obtain 12.0 g (86% recovery, 97.5% purity, 6.2% moisture content) of crystalline clarithromycin mesylate trihydrate. (Example 4).

Further, Example 5 was carried out in the same manner as in Example 4 but using 95% isopropanol instead of 95% ethanol as a solvent to obtain more purified clarithromycin mesylate trihydrate, and the results are shown in Table 2 below. Shown in

Organic solvent Recovery amount (g) % Recovery water(%) Humidity (%) Example 4 95% ethanol 12.0 86 97.5 6.2 Example 5 95% isopropanol 12.2 84 97.1 6.3

Example 6: Preparation of clarithromycin crystalline Form II from clarithromycin mesylate trihydrate

14.0 g (purity 96%) of clarithromycin mesylate trihydrate obtained in the same manner as in Examples 1 to 5 was dissolved in a mixed solvent of 42 ml of ethanol and 84 ml of water, and the insolubles were filtered off. . About 4.8 ml of concentrated ammonia water was slowly added dropwise to the filtrate, and the mixture was stirred at room temperature for 3 hours. The resulting solid was filtered and dried overnight at 55 ° C. in air to give 11.3 g (97% yield, 97.2% purity) of clarithromycin crystalline Form II.

The obtained crystals were confirmed to be clarithromycin crystalline Form II by infrared spectroscopy and powder X-ray diffraction spectroscopy, and the results are shown in FIGS. 3 and 4, respectively.

Example 7: Preparation of clarithromycin mesylate trihydrate from clarithromycin crude product, recrystallization thereof and preparation of clarithromycin crystalline Form II

In a similar manner to the reference example, 91.3 g (0.124 mol) of clarithromycin crude product was dissolved in 260 ml of 95% acetone, filtered to remove insolubles, and 10 g (0.105 mol) of methanesulfonic acid was added dropwise to the filtrate. Stir for 1 hour. The resulting suspension was then cooled to 0 ° C. and stirred for 3 hours. The resulting crystals were filtered off, washed with cold acetone and dried at 45 ° C. in air to give 87.5 g of crystalline clarithromycin mesylate trihydrate (yield 78%, purity 93%, moisture content 6.4%).

87.5 g (0.097 mol) of this clarithromycin mesylate trihydrate was suspended in 306 ml of 95% ethanol, refluxed for 30 minutes, and completely dissolved, and then slowly cooled to 0 ° C. with slow stirring. After stirring at 0 ° C. for 4 hours, the resulting solid was filtered and washed with 50 mL of 0 ° C. ethanol. Drying in air at 45 ° C. yielded 74.4 g of purified clarythromycin mesylate trihydrate (yield 85%, purity 97.0%, moisture content 6.1%).

74.4 g (0.083 mol) of the obtained clarithromycin mesylate trihydrate was dissolved in a mixed solvent of 220 ml of ethanol and 440 ml of water, and the insoluble substance was removed by filtration. About 25 ml of concentrated ammonia water was slowly added dropwise to the filtrate and stirred at room temperature for 3 hours. The resulting solid was filtered and dried overnight in air at 55 ° C. to obtain 60.0 g of clarithromycin crystalline Form II (yield 97%, purity 98.0%).

Comparative example

First, clarithromycin crystalline Form I was prepared from clarithromycin crude product according to the method described in WO 98-4573.

That is, 93.1 g (0.124 mol) of clarithromycin crude product obtained in a similar manner to the reference example was crystallized in 600 ml of ethanol and dried to obtain 65.2 g of clarithromycin crystalline Form I (70% yield, 94% purity). .

65.2 g (0.087 mol) of this clarithromycin Form I was suspended in 510 ml of ethanol and refluxed for 1 hour to dissolve most of the crystals. After the solution was heat-filtered to remove insolubles, the filtrate was cooled to 10 ° C. and stirred for 2 hours. The resulting crystals were filtered and dried at 50 ° C. to obtain 54.1 g of purified clarythromycin crystalline Form I (83% recovery, 97.1% purity).

Subsequently, clarithromycin crystalline Form II was prepared according to the method of WO 98-4574 from clarithromycin crystalline Form I.

That is, 54.1 g (0.072 mol) of the purified clarithromycin crystalline Form I was suspended in 270 ml of ethyl acetate and refluxed for 1 hour. The solution was heat-filtered to remove insoluble matters, and 40 ml of ethyl acetate was added to the filtrate, followed by reflux again for dissolution. The solution was cooled to 50 ° C. and 270 ml of isopropyl ether was added thereto, followed by cooling to 5 ° C. The resulting crystals were filtered and dried to obtain 41.7 g of clarithromycin crystalline Form II (yield 77%, purity 97.2%).

According to the method of the present invention, high purity clarithromycin crystalline Form II can be easily produced from clarithromycin in high yield. In particular, by using crystalline clarithromycin mesylate trihydrate as an intermediate, high purity using clarithromycin crude product, which is difficult to purify, including a large number of protecting group residues and by-products introduced in the preparation of clarithromycin Form II can be prepared directly.

Claims (6)

(a) treating the clarithromycin with methanesulfonic acid in a mixed solvent of a water-miscible organic solvent and water to produce crystalline clarithromycin mesylate trihydrate of the following formula (2), (b) neutralizing the clarithromycin mesylate trihydrate produced in step (a) with ammonia water in a mixed solvent of a water miscible organic solvent and water to crystallize A process for preparing clarithromycin crystalline Form II of Formula 1, comprising the step: Formula 1 Formula 2 The method of claim 1, The mixed solvent of step (a) is a mixture of water-miscible organic solvent selected from the group consisting of acetone, ethanol and isopropanol and water, the total content of water in the mixed solvent ranges from 3 to 15 molar equivalents. The method of claim 1, Using methanesulfonic acid in a ratio of 0.9 to 1.1 molar equivalents relative to 1 molar equivalent of clarithromycin in step (a). The method of claim 1, The mixed solvent of step (b) is a mixture of ethanol and water in a volume ratio of 30:70 to 70:30. The method of claim 1, Neutralizing the solution to maintain a pH of 9-12. Clarisomycin mesylate trihydrate of formula Formula 2