WO2023047323A1

WO2023047323A1 - Process for the preparation of omadacycline tosylate

Info

Publication number: WO2023047323A1
Application number: PCT/IB2022/058958
Authority: WO
Inventors: Venkata Raghavendra Acharyulu Palle; Pratik Patel; Nasir Ali Shafakat Ali; Shekhar DESHMUKH; Dipak PATIL; Sumit GAMPAWAR; Amol KADAM; Sachin VEER; Vijay GODASE
Original assignee: Glenmark Life Sciences Ltd
Current assignee: Alivus Life Sciences Ltd
Priority date: 2021-09-24
Filing date: 2022-09-22
Publication date: 2023-03-30
Anticipated expiration: 2024-03-24

Abstract

The present invention relates to a process for the preparation of omadacycline tosylate. The present invention also relates to an amorphous form of omadacycline tosylate, and a process for its preparation. Further, the process for amorphous omadacycline tosylate comprises a solvent mixture. The present invention further provides process for amorphous omadacycline tosylate characterised by XRPD.

Description

PROCESS FOR THE PREPARATION OF OMADACYCLINE TOSYLATE

PRIORITY

[0001] This application claims the benefit of Indian Provisional Application No. 202121043511 filed on September 24, 2021, entitled “process for the preparation of omadacycline tosylate”, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical field

Description of the related art

[0002] Omadacycline tosylate, which is chemically known as (4S,4aS,5aR,12aS)-4,7- bis(dimethylamino)-9-(2,2dimethylpropylaminomethyl)-3, 10, 12, 12a- tetrahydroxy- 1,11- dioxo-l,4,4a,5,5a,6,l l,12aoctahydrotetracene-2-carboxamide, 4- methylbenzenesulfonate, is represented by a compound of formula I,

I

[0003] Omadacycline tosylate is indicated for the treatment of adult patients with the community-acquired bacterial pneumonia infections or acute bacterial skin and skin structure infections caused by susceptible microorganisms.

[0004] Omadacycline tosylate is reported to exist in various polymorphic forms for example form I, form II, form III.

[0005] United States Patent No 8383610 (US’610 patent) discloses polymorphic form I, form II and form III of omadacycline tosylate.

SUMMARY OF THE INVENTION [0006] The present invention provides a process for the preparation of an amorphous omadacycline tosylate, a compound of formula I comprising:

a) contacting omadacycline, a compound of formula II, with a solvent mixture of an alcohol and an ether to obtain a reaction mixture;

b) treating the reaction mixture of step a) with p-toluene sulphonic acid monohydrate in ether; c) optionally adding an antisolvent to the reaction mixture of step b); and d) isolating amorphous omadacycline tosylate from the above steps (b) or (c).

[0007] The present invention provides a process for the preparation of an amorphous omadacycline tosylate, a compound of formula I, comprising:

a) reacting a compound of formula III,

wherein Ri is H or CH2NH2; with 2,2-dimethyl propanal in the presence of an antioxidant to obtain omadacycline, a compound of formula II,

b) contacting omadacycline, the compound of formula II, with a solvent mixture of an alcohol and an ether to obtain a reaction mixture; c) treating the reaction mixture of step b) with p-toluene sulphonic acid monohydrate in ether; and d) isolating amorphous omadacycline tosylate.

BRIEF DESCRIPTION OF DRAWING

[0008] Figure 1 is a characteristic XRPD of omadacycline as obtained in example 3. [0009] Figure 2 is a characteristic XRPD of omadacycline tosylate as obtained in example 6.

DETAILED DESCRIPTION OF THE INVENTION

[0010] In one embodiment, the present invention provides a process for the preparation of amorphous omadacycline tosylate, a compound of formula I comprising:

I a) contacting omadacycline, a compound of formula II, with a solvent mixture of an alcohol and an ether to obtain a reaction mixture; b) treating the reaction mixture of step a) with p-toluene sulphonic acid monohydrate in ether; c) optionally adding an antisolvent to the reaction mixture of step b); and d) isolating amorphous omadacycline tosylate from the above steps (b) or (c).

[0011] In one embodiment, in the context of the present invention, the term “contacting” refers to treating, suspending or slurrying.

[0012] In one embodiment, in step a), omadacycline, the compound of formula II is amorphous omadacycline. [0013] In one embodiment, in step a), amorphous omadacycline is treated with a solvent mixture of an alcohol and an ether wherein the alcohol and ether in the solvent mixture is in a ratio of 1 : 1.

[0014] In one embodiment, in step b), p-toluene sulphonic acid monohydrate in ether is added to a mixture of omadacycline in a solvent mixture of an alcohol and an ether at a temperature ranging from -5°C to 30°C to obtain omadacycline tosylate.

[0015] In one embodiment, the alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, 2-ethoxy ethanol, methyl glycol and ethylene glycol.

[0016] In one embodiment, the ether may be selected from the group consisting of diethyl ether, di isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,3-dioxane and 1,2-dioxane.

[0017] In one embodiment, in above step a) the solvent is a mixture of methanol and 2- methyl tetrahydrofuran.

[0018] In one embodiment, in above step b) the solvent is 2-methyl tetrahydrofuran.

[0019] In one embodiment, in step a) omadacycline is crystalline omadacycline.

[0020] In one embodiment, in step a) omadacycline is crystalline omadacycline and is converted to amorphous omadacycline tosylate.

[0021] In one embodiment, in step d) the isolation may be carried out by any of the method such as filtration, centrifugation or distillation.

[0022] In one embodiment, crystalline omadacycline is converted to amorphous omadacycline tosylate.

[0023] In one embodiment, the obtained amorphous omadacycline tosylate may be optionally purified in a suitable solvent.

[0024] In one embodiment, the isolated amorphous omadacycline tosylate, the compound of formula I, has a purity of at least 98% as measured by chiral HPLC (high performance liquid chromatography).

[0025] In one embodiment, the isolated amorphous omadacycline tosylate, the compound of formula I, has a purity of at least 99.2% as measured by chiral HPLC.

[0026] In one embodiment, the isolated amorphous omadacycline tosylate, the compound of formula I, has a purity of at least 99.9% as measured by chiral HPLC. [0027] In one embodiment, the isolated amorphous omadacycline tosylate, the compound of formula I, has a purity of at least 99.9% as measured by chiral HPLC and wherein the content of epimer impurity is less than l%w/w.

[0028] In one embodiment, the isolated amorphous omadacycline tosylate, the compound of formula I, has a purity of at least 99.9% as measured by chemical HPLC and wherein the content of epimer impurity, A is less than 5% w/w.

A

[0029] In one embodiment, the isolated amorphous omadacycline tosylate, the compound of formula I, has a purity of at least 99.9% as measured by chemical HPLC and wherein the content of epimer impurity, A is less than 1% w/w.

[0030] In one embodiment, the present invention provides omadacycline tosylate having a content of epimer impurity in an amount from about 0.80% w/w to about 0.03% w/w as determined by chemical HPLC.

[0031] In one embodiment, the process of the present invention provides amorphous omadacycline tosylate having XRPD pattern, which is substantially in accordance with figure 2.

[0032] In one embodiment, the present invention provides a solvate of omadacycline tosylate.

[0033] In one embodiment, the solvate of omadacycline tosylate may be selected from the group consisting of alcohol solvate such as methanol, ethanol, propanol, isopropanol, n- butanol, isobutanol, and the like; esters such as ethyl acetate, ether such as tetrahydrofuran, dioxane, diisopropyl ether, methyl tert-butyl ether, amide such as dimethyl formamide, acid such as formic acid, propionic acid, hexanoic acid, octanoic acid and the like.

[0034] In one embodiment, the present invention provides a hydrate of omadacycline tosylate.

[0035] In one embodiment, the present invention provides a hydrate of amorphous omadacycline tosylate. [0036] In one embodiment, the present invention provides a process for the preparation of amorphous omadacycline tosylate, a compound of formula I,

comprising: a) reacting a compound of formula III,

II b) contacting omadacycline, the compound of formula II, with a solvent mixture of an alcohol and an ether to obtain a reaction mixture; c) treating the reaction mixture of step b) with p-toluene sulphonic acid monohydrate in ether; and d) isolating amorphous omadacycline tosylate.

[0037] In one embodiment, in above step a) the reaction mixture comprising the compound of formula III and 2,2-dimethyl propanal is hydrogenated in the presence of an antioxidant to obtain omadacycline, the compound of formula II.

[0038] In one embodiment, it was surprisingly found that the purity of compound of formula II increased when the compound of formula III was hydrogenated in presence of an antioxidant. [0039] In one embodiment, the reaction mixture comprising the compound of formula III, 2, 2-dimethyl propanal is hydrogenated in the presence of an antioxidant and a base. [0040] In one embodiment, the antioxidant may be selected from the group consisting of ascorbic acid, gallic acid, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT).

[0041] Suitable base may be selected from the group consisting of organic bases or inorganic bases. Inorganic bases may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; carbonate such as of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxides such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like. Organic bases may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, 4- dimethylaminopyridine, N- methylmorpholine.

[0042] In one embodiment, a reaction mixture comprising the compound of formula III, 2, 2-dimethyl propanal is hydrogenated in the presence of an antioxidant, a base and a solvent.

[0043] The solvent used in hydrogenation step is selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, /c/7-butyl acetate and the like; hydrocarbons such as toluene, xylene, cyclohexane, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, /e/7-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0044] In one embodiment, the omadacycline as obtained in step a) is amorphous omadacycline.

[0045] In one embodiment, the steps b), c) and d) may be carried as discussed supra.

[0046] In one embodiment, the isolated omadacycline, the compound of formula II, has a purity of at least 90% as measured by chiral HPLC. [0047] In one embodiment, the isolated omadacycline, the compound of formula II, has a purity of at least 95% as measured by chiral HPLC.

[0048] In one embodiment, the isolated omadacycline, the compound of formula II, has a purity of at least 90% as measured by chemical HPLC.

[0049] In one embodiment, the isolated omadacycline, the compound of formula II, has a purity of at least 95% as measured by chemical HPLC.

[0050] In one embodiment, the present invention provides amorphous omadacycline having XRPD pattern, which is substantially in accordance with figure 1.

[0051] In one embodiment, the present invention provides omadacycline tosylate free of any of the below listed impurities:

E F

[0052] In one embodiment, the present invention provides substantially stable amorphous omadacycline tosylate.

[0053] As used herein, the term “stable” refers to amorphous omadacycline tosylate, which retains its original polymorphic form without undergoing polymorphic conversion over time.

[0054] In one embodiment, the present invention provides amorphous omadacycline tosylate which is stable at a temperature below 8°C.

[0055] In one embodiment, the present invention provides process for preparation of omadacycline tosylate, compound of formula I, comprising: a) reacting minocycline hydrochloride with N-hydroxy phthalimide in the presence of an acid;

b) Minocycline HC1 N-hydroxy phthalimide to obtain a compound of formula IV,

b) reacting the compound of formula IV with methyl amine to obtain a compound of formula III;

III wherein Ri is H or CH2NH2; c) reacting a compound of formula III with 2,2-dimethyl propanal in the presence of an antioxidant to obtain omadacycline, the compound of formula II; d) contacting omadacycline, the compound of formula II, with a solvent mixture of alcohol and ether; e) treating the reaction mixture of step b) with p-toluene sulphonic acid monohydrate in ether; and f) isolating omadacycline tosylate. [0056] In one embodiment, in the above step a), the reaction of minocycline hydrochloride with N-hydroxy phthalimide in the presence of an acid may be carried out in presence or absence of a solvent.

[0057] In one embodiment, the compound of formula IV, obtained in step a) may be further purified in a solvent or mixture of solvents.

[0058] The solvents may be as discussed supra.

[0059] In one embodiment, in above step b) the compound of formula IV is reacted with methyl amine in a solvent to obtain the compound of formula III.

[0060] In one embodiment, in step b) the reaction of compound of formula IV with methylamine may be carried out at a temperature ranging from about 0°C to reflux temperature of solvent/s to obtain the compound of formula III.

[0061] In one embodiment, the compound of formula III, obtained in step b) may be further purified in a solvent or a mixture of solvents.

[0062] In one embodiment, the compound of formula III, obtained in step b) may be further purified with an acid.

[0063] The acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, triflic acid and the like. The acid used may be in aqueous or organic solvent.

[0064] Solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, /c/ -butyl acetate and the like; hydrocarbons such as toluene, xylene, cyclohexane, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, /e/ -butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0065] In embodiment, the steps c), d), e) and f) are carried out by process described above.

[0066] In one embodiment, the minocycline hydrochloride may be prepared by a process represented in the below scheme:

Sancycline halo sancycline minocycline

[0067] In one embodiment, the sancycline is halogenated to obtain compound 2 (halo sancycline). Preferably sancycline is converted to iodo sancycline. The halo sancycline is reacted with dimethylamine and converted to minocycline or its salt.

[0068] In one embodiment, minocycline or its salt may be prepared by fermentation process.

Instrumental settings for XRPD of amorphous omadacycline tosylate:

[0069] Instrumental settings for XRPD: The measurements were performed on Philips X- Ray Diffractometer model XPERT-PRO (PANalytical) Detector: X’celerator [1] using Cu lamp with type and wavelength of the X-ray radiation: K-Alphal [A] and 1.54060 under the following conditions: Generator settings: 40mA/45kV, Time per step: 50, Step size: 0.0170, Peak width 2.00 and start angle (°) 2.0 and End angle: 50.0, Scan type: continuous; measurement performed at 25°C. The XRPD instrument is calibrated using NIST SRM 6-40C silicon standard and NIST SRM 1976 Alumina.

Instrumental settings for HPLC

[0070] High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:

[0071] Reagents, Solvents and Standards: Water (Milli Q or equivalent), Ammonium acetate (HPLC Grade), triethylamine (HPLC Grade), EDTA, Acetic acid (HPLC Grade). [0072] Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software; Column: X Bridge Cl 8, 250 x 4.6mm, 5pm; Column temperature: 40°C; Mobile Phase: Mobile phase A = Buffer: Acetonitrile (95:5, v/v), Buffer: Add 0.5 ml triethylamine and 0.77 gm Ammonium acetate in 1000 ml water. Add 0.250 gm of EDTA in it, mix well and sonicate to dissolve and filter through 0.45 p Filter paper. Adjust the pH of buffer to 9.20 ± 0.05 with diluted Triethylamine, Mobile phase B = Acetonitrile.

Diluent: Water: Acetonitrile (10:90, v/v); Flow Rate: 1.0 mL/minute; Detection: UV 250 nm; Injection Volume: 10 LIL. Run time: 49 minutes.

[0073] In one embodiment, the present invention provides omadacycline tosylate premix, which comprises of an amorphous or crystalline omadacycline tosylate in combination with a suitable premixing agent.

[0074] As used herein, the term “premix” refers to a combination of omadacycline tosylate and at least one premixing agent.

[0075] As used herein, the term "premixing agent" means a pharmaceutically acceptable excipient, which is used to form a premix with omadacycline tosylate and at least one premixing agent.

[0076] In an embodiment, more than one premixing agent may be used to form a premix with omadacycline tosylate.

[0077] The premixing agent is a pharmaceutical excipient the premixing agents is selected from group of cellulose derivatives but not limited to croscarmellose sodium, micro crystalline cellulose (MCC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone, polyvinylpyrrolidone, mannitol, polyvinyl acetate phthalate, polyethylene glycol, copovidone and the like.

[0078] In one embodiment, the present invention provides pharmaceutical compositions comprising omadacycline tosylate obtained by processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.

[0079] In one embodiment, the present invention provides pharmaceutical compositions comprising omadacycline tosylate obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.

[0080] In one embodiment, the present invention provides pharmaceutical compositions comprising omadacycline tosylate obtained by the processes herein described, having D90 particle size less than 150 microns, D50 particle size of less than 75 microns and Dio particle size less than 35 microns.

[0081] The particle size disclosed herein can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state omadacycline tosylate into any of the foregoing desired particle size range.

[0082] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES:

[0084] Example 1: Preparation of (4S,4aS,5aR,12aS)-N,9-bis[(l,3-dihydro-l,3-dioxo- 2H-isoindol-2-yl)methyl]-4,7-bis(dimethylamino-l,4,4a,5,5a,6,ll,12a-octahydro- 3,10,12,12a-tetrahydroxy-l,ll-dioxo-2-napthacenecarboxamide [IV]

Minocycline HC1 (100g) was added to triflic acid (400ml) at a temperature of about 0- 5°C. The reaction mixture was warmed to a temperature of about 20-30°C and stirred for about 30 min. The reaction mixture was cooled and N-(hydroxymethyl)-phthalimide was added to it. The reaction mass was stirred at a temperature of about 20-30°C. On completion, the reaction mass was quenched with water and stirred for about Ih at a temperature of about 20-30°C. The product was filtered and obtained solid was purified by mixture of acetone and water followed by mixture of methanol-methyl tert-butyl ether (MTBE). The solid obtained was dried in vacuum tray drier (VTD).

Yield: 160g; Chemical HPLC purity: 90%.

[0085] Example 2: Preparation of (4S,4aS,5aR,12aS)-N,9-bis(aminomethyl)-4,7- bis( dimet hylamino)-3.10,12,12a- tetrahydroxy- 1,1 l-dioxo-l,4,4a.5,5a, 6,11,12a- octahydrotetracene-2-carboxamide [III]

(4S, 4aS, 5aR, 12aS)-N,9-bis[(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)methyl]-4,7-bis (dimethylamino- 1,4, 4a, 5, 5a, 6, l l,12a-octahydro-3, 10, 12, 12a-tetrahydroxy-l,l l-dioxo- 2-napthacenecarboxamide (100g) was added to a solution of methylamine in methanol (33%, 450ml). The reaction mixture was stirred at a temperature of about 20-30°C for about 1.5 h. The reaction mixture was filtered and the filtrate was purified by a mixture of methanol-MTBE. The obtained solid was purified by methanol and IPA.HC1 at a temperature of about 20-30°C, dried in vacuum tray drier (VTD).

Yield: 40g; Chemical HPLC purity: 85%.

[0086] Example 3: Preparation of (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9- {[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-l,ll-dioxo- 1,4, 4a, 5, 5a, 6, 11, 12a-octahydrotetracene-2-carboxamide [II]

To a hydrogenation vessel, methanol (2100 ml) was charged, followed by butylated hydroxytoluene (30 gm), 10% Pd/C (50% wet, 90 gm) catalyst, (4S,4aS,5aR,12aS)-N,9- bis(aminomethyl)-4,7 -bis(dimethylamino)-3 , 10, 12, 12a-tetrahydroxy- 1,11 -dioxo- 1,4, 4a, 5, 5a, 6,1 l,12a-octahydrotetracene-2-carboxamide (300 gm), triethyl amine (186.78 gm), 2,2-dimethyl propanal (132.76 gm) were charged and methanol was flushed, followed by vessel pressurized with hydrogen gas. The reaction mixture was hydrogenated under hydrogen pressure around 50-70 psi for about 8-12 hrs at a temperature of about 18-23 °C. On completion of conversion reaction mass was filtered through celite pad. The filtrate was charged into water and the product was extracted with dichloromethane. The dichloromethane layer was added in to water and pH of the solution was adjusted to about 4.5-5 with 6N HC1 at a temperature of about 20-25°C. The aqueous layer was extracted with dichloromethane and adjust pH about 7.5 to 8 with triethylamine. The dichloromethane layer was partially concentrated under reduced pressure. To this dichloromethane solution was added n-heptane (1800 ml) at a temperature of about 20- 25°C. The reaction mass was stirred for 60-90 min, filtered. The solid obtained was dried in VTD (vacuum tray dryer) at a temperature of about 30-35°C.

Yield: 158 g (46.2%); Chemical HPLC purity: 92.41%; beta C-4 epimer: 2.76%.

[0087] Example 4: Preparation of Omadacycline Tosylate

(4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl }- 3,10,12,12a-tetrahydroxy-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro tetracene-2- carboxamide (100 gm) was charged in to mixture of 2-methyl tetrahydrofuran (200 ml) and methanol (200 ml) at a temperature of about 20-25°C stirred to get clear solution. The clear solution was micron filtered. The filtered solution was cooled to a temperature of about 5-10°C. A solution of p-toluene sulfonic acid monohydrate (29.1gm) in 2-methyl tetrahydrofuran (100 ml) was added drop wise in to reaction mass at a temperature of about 5-10°C. The reaction mixture was stirred for about l-2h at a temperature of about 5-10°C, filtered and washed with ether. The solid obtained was dried in vacuum tray drier (VTD) to get 72.0 gm omadacycline tosylate.

Yield: 55.38%; Chemical HPLC Purity: 98.83% beta C-4 epimer 0.58%.

[0088] Example 5: Purification of omadacycline tosylate

Crude omadacycline tosylate (22 gm) was charged in to mixture of 2-methyl tetrahydrofuran (87.5 ml) and methanol (62.5 ml) at a temperature of about of 5-10°C. The reaction mixture was stirred for about 1-2 h at a temperature of about 20-25°C, filtered and washed with ether. The solid obtained was dried in vacuum tray drier (VTD) to get product omadacycline tosylate (14.2 gm).

Chemical HPLC purity: 98.86%; beta C-4 epimer: 0.6%.

[0089] Example 6: Purification of omadacycline tosylate

Crude omadacycline tosylate (107 gm) was charged in to mixture of 2-methyl tetrahydrofuran (420 ml) and methanol (300 ml) at a temperature of about 5-10°C. The reaction mixture was stirred for about 1-2 h at about 5-10°C, filtered and washed with ether. The solid obtained was dried in vacuum tray drier (VTD) to get pure product omadacycline tosylate (70.0 gm).

Chemical HPLC purity: 99.36%; beta C-4 epimer: 0.26%.

[0090] Example 7: Preparation of omadacycline tosylate

4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl}- 3,10,12,12a-tetrahydroxy-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydrotetracene -2- carboxamide (1 gm) was charged in to mixture of IPA (5 ml) and 1,4 dioxane (3 ml) at a temperature of about 20-30°C stirred to get clear solution. Solution of p-toluene sulfonic acid monohydrate (0.27 gm) in 1,4 dioxane (2 ml) was added drop wise to reaction mass at a temperature of about 5-10°C. The reaction mixture was stirred for about 1-2 h at a temperature of about 5-10°C, filtered and washed with IPA. The solid obtained was dried in vacuum tray drier (VTD) to get 0.80 gm dry omadacycline tosylate.

Yield: 61.54%; HPLC Purity: 94.75%; beta C-4 epimer: 1.47%.

[0091] Example 8: Preparation of omadacycline tosylate

4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl] - 3,10,12,12a-tetrahydroxy-l,l 1 -dioxo- 1,4, 4a, 5, 5a, 6,1 l,12a-octahydrotetracene -2- carboxamide (9 gm) was charged in to mixture of IPA (81 ml) and methanol (9 ml) at a temperature of about 20-30°C, stirred to get clear solution. Solution of p-toluene sulfonic acid monohydrate (2.5 gm) in IPA (18 ml) was added drop wise to reaction mass at temp 20-30°C. The reaction mixture was stirred for about 1-2 h at about 20-30°C, filtered and washed with IPA. The solid obtained was dried in vacuum tray drier (VTD) to get 6.5 gm dry omadacycline tosylate. Yield: 55.55%; HPLC Purity: 88.72%; beta C-4 epimer: 1.03%.

[0092] Example 9: Preparation of omadacy cline tosylate

4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl] - 3,10,12,12a-tetrahydroxy-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydrotetracene -2- carboxamide (2 gm) was charged in to mixture of methanol (5 ml) and MTBE (5 ml) at a temperature of about 20-25°C stirred but observed hazy solution. Solution of p-toluene sulfonic acid monohydrate (0.51 gm) in 15 ml methanol was added drop wise to reaction mass at a temperature of about 20.25°C. The reaction mixture was observed clear solution, added MTBE (15 ml) at 0-5°C, stirred for about 1-2 h at a temperature of about 0-5°C, filtered and washed with MTBE. The solid obtained was dried in vacuum tray drier (VTD) to get 6.5 gm dry omadacycline tosylate.

Yield: 38.46%; HPLC Purity: 90.72%; beta C-4 epimer: 3.57%.

[0093] Example 10: Preparation of omadacycline tosylate

4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl] - 3,10,12,12a-tetrahydroxy-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydrotetracene -2- carboxamide (1 gm) was charged in to mixture of methanol (1.25 ml) and MEK (3.75 ml) at a temperature of about 20-25°C stirred to get clear solution. Solution of p-toluene sulfonic acid monohydrate (0.27 gm) in MEK (02 ml) added drop wise in to reaction mass at a temperature of about 5-10°C. The reaction mixture was stirred for about 1-2 h at a temperature of about 5-10°C, filtered and washed with MEK. The solid obtained was dried in vacuum tray drier (VTD) to get 6.5 gm dry omadacycline tosylate.

Yield: 34.62%; HPLC Purity: 78.92%; beta C-4 epimer: 14.00%.

[0094] Example 11: Preparation of omadacycline tosylate

4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl] - 3,10,12,12a-tetrahydroxy-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydrotetracene -2- carboxamide (1 gm) was charged to n-butanol (10 ml) at a temperature of about 20-30°C stirred to get clear solution. Solution of p-toluene sulfonic acid monohydrate (0.27 gm) in n-butanol (5 ml) was added drop wise to reaction mass at a temperature of about 20- 30°C. The reaction mixture was stirred for about 0.5-1 h at a temperature of about 20- 30°C. The reaction mixture was added dropwise into DIPE (15 ml) to get solid precipitate, reaction mixture was stirred for 0.5-01 hrs, filtered and washed with DIPE. The solid obtained was dried in vacuum tray drier (VTD) to get 6.5 gm dry omadacycline tosylate. Yield: 57.25%; HPLC Purity: 86.57%; beta C-4 epimer: 1.42%.

[0095] Example 12: Preparation of omadacycline tosylate

4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-{ [(2,2-dimethylpropyl) amino] methyl] - 3,10,12,12a-tetrahydroxy-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydrotetracene -2- carboxamide (1 gm) was charged in to acetone (15 ml) at a temperature of about 20-30°C stirred to get clear solution. Solution of p-toluene sulfonic acid monohydrate (0.27gm) in acetone (2 ml) was added drop wise to reaction mass at a temperature of about 10-15°C. The reaction mixture was stirred for about 1-2 h at a temperature of about 10-15°C, filtered and washed with acetone. The solid obtained was dried in vacuum tray drier (VTD) to get 6.5 gm dry omadacycline tosylate. Yield: 30.76%; HPLC Purity: 93.77%; beta C-4 epimer: 1.7%.

Claims

1] A process for the preparation of amorphous omadacycline tosylate, a compound of formula I,

I comprising: a) contacting omadacycline, a compound of formula II, with a solvent mixture of an alcohol and an ether to obtain a reaction mixture; b) treating the reaction mixture of step a) with p-toluene sulphonic acid monohydrate in an ether; c) optionally adding an antisolvent to the reaction mixture of step b); and d) isolating amorphous omadacycline tosylate from the above step of (b) or (c).

2] The process as claimed in claim 1, wherein omadacycline used in step a) is amorphous.

3] The process as claimed in claim 1, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, 2-ethoxy ethanol, methyl glycol and ethylene glycol.

4] The process as claimed in claim 1, wherein the ether is selected from the group consisting of diethyl ether, di isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2- methyl tetrahydrofuran, 1,4-dioxane, 1,3 -dioxane and 1,2-dioxane.

5] The process as claimed in claim 1, wherein in step (a) the ratio of alcohol and ether in the solvent mixture is 1:1.

6] A process for the preparation of amorphous omadacycline tosylate, compound of formula I,

I comprising: a) reacting a compound of formula III,

b) contacting omadacycline, the compound of formula II, with a solvent mixture of alcohol and ether to obtain a reaction mixture; c) treating the reaction mixture of step b) with p-toluene sulphonic acid monohydrate in ether; and d) isolating amorphous omadacycline tosylate.

7] The process as claimed in claim 6, wherein the antioxidant is selected from the group consisting of ascorbic acid, gallic acid, butylated hydroxy anisole (BHA) and butylated hydroxy toluene (BHT).