A single step process for the preparation of omadacycline tosylate of formula (x)

Abstract

The present invention relates to a process for the preparation of Omadacycline tosylate of formula (X). More particularly, the present invention relates to a single step process for the preparation of omadacycline tosylate of formula (X) in which the single step process starts with using minocycline hydrochloride of formula (1) as starting material and give final omadacycline tosylate of formula (X) without isolating any intermediate of the process.

Description

[0001] TITLE OF THE INVENTION

[0002] “A single step process for the preparation of omadacycline tosylate of formula (X)”

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to a process for the preparation of Omadacycline tosylate of formula (X). More particularly, the present invention relates to a single step process for the preparation of omadacycline tosylate of formula (X) in which the single step process starts with using minocycline hydrochloride of formula (1) as starting material and give final omadacycline tosylate of formula (X) without isolating any intermediate of the process.

[0005] Formula (1) Formula (X)

[0006] BACKGROUND OF THE INVENTION

[0007] Omadacycline tosylate of formula (X) is a compound selected from group of 9-aminomethyl substituted minocycline compounds, a class of tetracycline antibiotic compounds. Omadacycline tosylate of formula (X) is used for the treatment of community acquired bacterial pneumonia infections and acute bacterial skin infections caused by susceptible microorganisms.

[0008] Formula (X)

[0009] It is also known by its IUPAC name (4S,4aS,5aR, 12aR)-4,7- bis(dimethylamino)-9-[(2,2-dimethylpropyl amino) methyl]- 1, 10, 11, 12a- tetrahydroxy-3, 12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2- carboxamide;4-methylbenzene sulfonic acid.

[0010] Omadacycline tosylate may be represented with the chemical formula (X).

[0011] The current synthesis of omadacycline, depicted in Scheme- 1, has been used for multi-kilogram preparations and is described in US 9434680 B2.

[0012] Minocycline has several reactive functional groups and the C2 primary amide is more reactive towards electrophiles than C9 or the CIO. Due to

[0013] 1

[0014] SUBSTITUTE SHEET (RULE 26) this fact, the first step of Scheme- 1 requires nearly three equivalents of the N’-(hydroxymethyl)-phthalimide in triflic acid yielding a bissubstituted aminomethyl phtalimide tetracycline compound. In the second step of Scheme- 1 , the phthalimides are de-protected with a large excess of methylamine in alcoholic solution to afford a bis-substituted aminomethyl tetracycline intermediate.

[0015] Scheme- 1: Synthesis of omadacycline using minocycline as substrate and N’-(hydroxymethyl) phtalimide as reagent:

[0016] In the third step of Scheme- 1 , the resulting intermediate is reacted with hydrogen under hydrogenation conditions to form a C9-substituted aminomethyl tetracycline intermediate. In the fourth step of Scheme- 1, the formed compound is reacted with pivaldehyde under hydrogenation conditions to afford omadacycline. After reverse-phase chromatographic purification, pH adjustment and precipitation the desired product is afforded as an amorphous, unstable solid. For a long-term manufacturing route, the challenges of the instability of the aminomethyl intermediate and chromatographic column purification step must be overcome.

[0017] WO2022248865A1 has disclosed a process for the preparation of 9- aminomethyl tetracycline compounds including omadacycline and its salt wherein semicontinuous and continuous flow processes have been disclosed.

[0018] In a continuous flow process as disclosed in the said patent, the whole synthetic sequence of the method of the present invention may be carried out from the minocycline reacted in step a) to the 9-aminomethyl tetracycline compound formed in step d) without the use of batch reactors, without the need to isolate the 9-aminomethyl tetracycline

[0019] 2

[0020] SUBSTITUTE SHEET (RULE 26) intermediate formed in step b) and in the absence of a hydrogenation reaction prior to step c) or d). Alternatively, in a semi continuous flow process, two of steps a), b) and c) or d) may be carried without the use of batch reactors, without the need to isolate intermediate products between the reaction steps. The steps a) and b) of the method of the present invention may operate in a continuous manner, steps b) and c) of the method of the present invention may operate in a continuous manner, or steps b) and d) of the method of the present invention may operate in a continuous manner. Where steps b) and c) or steps b) and d) operate in a continuous manner, the 9-aminomethyl tetracycline intermediate formed in step b) may be used directly in step c) or d).

[0021] According to the said patent, continuous flow technologies use process intensification (e.g. high temperatures and pressure) and improved mass and heat transfer to increase selectivity and overcome the challenges of purification, low yields and the isolation of an unstable intermediate. It has been found that it is possible to synthesize a 9- aminomethyl tetracycline intermediate directly from 2,9-(methylamide- substituted) minocycline compound by using higher temperatures that are only feasible by using flow chemistry technologies at low residence time.

[0022] In the above patent, the process of all steps including step a to d, is carried out at a higher temperature up to 300°C and a pressure up to 500 psi, the higher temperature and higher pressure may cause major industrial accidents and damages to human beings, properties and hence is not a commercially viable process.

[0023] Scheme-2: Impurities formed in the first step (Reaction between Minocycline HC1 and N-hydroxy methyl phthalimide):

[0024] SUBSTITUTE SHEET (RULE 26) As shown in scheme-2 and as disclosed in the prior art methods, in the reaction between minocycline Hcl and N-hydroxymethyl phthalimide, 2- substituted, 9-substituted, and tri-substituted compounds are also formed as impurities along with bis-substituted compound of formula (3) and the proportion of those compounds / impurities are not small. Among above all, only bis-substituted compound of formula (3) is useful in preparation of omadacyline tosylate.

[0025] The 2 -position substitution impurity cannot be changed into a next product through a subsequent process, but becomes a starting material and cannot be recycled, so that the raw material is wasted, and the 9- position substitution and the tri-position substitution can be converted into a product in the next process, but the reaction time is prolonged, and the production cost is also increased.

[0026] Hence, there is a demand of providing a simple, easy to operate, industry & economically viable and environment friendly, single step process for the preparation of omadacycline tosylate of formula (X) from minocycline hydrochloride of formula (1). Applicant has found that the proposed processes for the preparation of omadacycline tosylate of formula (X) provide increased yield of omadacycline tosylate of formula (X) with improved quality having lesser amounts of impurities in the final product.

[0027] OBJECTS OF THE INVENTION

[0028] Accordingly, the main object of the present invention is to overcome the problems faced by the prior art processes in the preparation of omadacycline tosylate of formula (X) .

[0029] There is an object of the present invention to provide a simple, environment friendly, robust, easy to operate, industry & economically viable and single step environment friendly process for the preparation of omadacycline tosylate of formula (X) from minocycline hydrochloride of formula (1).

[0030] It is also an object to provide a process for the preparation of omadacycline tosylate of formula (X) from minocycline hydrochloride of formula (1) that provides increased yield of omadacycline tosylate of formula (X) with improved quality having lesser amounts of impurities in the final product.

[0031] 4

[0032] SUBSTITUTE SHEET (RULE 26) DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention relates to a single step process for the preparation of omadacycline tosylate of formula (X) in which the single step process starts with using minocycline hydrochloride of formula (1) as starting material and give final omadacycline tosylate of formula (X) without isolating the intermediate in any of the steps of the process.

[0034] Formula (1) Formula (X)

[0035] Proposed Route of synthesis along with the brief process for the preparation of omadacycline tosylate of formula (X) is shown as follows:

[0036] Scheme-3: Route of Synthesis for Preparation of omadacycline tosylate of formula (X): hydrochloride

[0037] X6omadacycline omadacyC|jne tosyiate freebase

[0038] The present invention provides a simple, environment friendly, robust, easy to operate, industry & economically viable and single step process for the preparation of omadacycline tosylate of formula (X) from minocycline hydrochloride of formula (1).

[0039] 5

[0040] SUBSTITUTE SHEET (RULE 26) The present innovators have comprehensively and successfully investigated the possibility of developing a single step process for the preparation of omadacycline tosylate of formula (X) .

[0041] The major differences between the Route of synthesis and process of the present invention as per the scheme-3 and in the prior art methods are as follows:

[0042] (i) In the present invention, the whole process is carried out as a single step process and no intermediates of any step is isolated and carried forward directly for the next step until the final omadacycline tosylate of formula (X) is obtained.

[0043] (ii) p-toluene sulphonic acid (PTSA) is used in the present invention in place of methane sulphonic acid, triflic acid or sulfuric acid in the first step, p-toluene sulphonic acid is not reported in any of the prior art processes.

[0044] (iii) Ethylenediamine is used in place of methyl amine in the second step, ethylenediamine is not reported in any of the prior art processes.

[0045] (iv) ethylenediamine is used in place of triethyl amine in the third step, Ethylenediamine is not reported in any of the prior art processes.

[0046] (v) platinum oxide (PtOa) is used as hydrogenating agent, platinum oxide is not reported in any of the prior art processes.

[0047] Methyl amine which is reported in the prior art processes, is included in List 1 precursor due to its use in methamphetamine narcotic drug hence the use of methylamine should be done under strict observation. Methyl amine is gaseous in nature and is available in gaseous form or as % molar solution in methanol, ethanol, water or Tetrahydro furan. Use of molar solution of methyl amine in the reaction may increase the complexity due to its solution in any of the above listed solvents which actually, may not a part of the reaction and additional activity like distillation, filtration, washing etc. is required to be carried out after completion of the reaction that makes the process lengthy and tedious. Further, due to its gaseous nature, methylamine may escape from the reaction easily hence either more quantity of methyl amine is required or reaction has to carried out at a temperature near to 0°C to maintain the pH of the reaction mass to complete the reaction. Also, due to escape of methyl amine from the reaction, pH of reaction mass differs which lead to incomplete reaction or it may lead to impurities as described above.

[0048] Also, methyl amine in the reaction is not recyclable and for every reaction process, fresh methyl amine has to be used which may create environmental issues.

[0049] While ethylenediamine used in the present invention, is a liquid in nature having boiling point of 116°C that makes easy to maintain pH of

[0050] 6

[0051] SUBSTITUTE SHEET (RULE 26) the reaction mass throughout the reaction even at a temperature between 20°C to 80°C and thus ethylenediamine plays an important role in completion of the reaction. It is also possible that ethylene diamine can be recovered and may be used in the reaction again. Thus, recycling of ethylenediamine may reduce the environmental issues.

[0052] Methane sulphonic acid, triflic acid and sulfuric acid are strong acids have been used in the prior art processes, all are liquid in nature hence utmost care has to be taken while using either of two in the reaction process or handling it or storing it as chemical. While p-toluene sulphonic acid (PTSA) used in the present invention is also a strong acid but solid in nature hence the weighing it for reaction purpose or storing it as chemical is much easier than methane sulphonic acid, triflic acid or sulfuric acid.

[0053] According to the present invention, a single step process for the preparation of omadacycline tosylate of formula (X) is provided, the said process comprises: i. Reacting minocycline hydrochloride of formula (1) with N- hydroxymethyl phthalimide of formula (2) in presence of p- toluene sulphonic acid in alcoholic solvent at a temperature between 25°C to 80°C to give tris protected minocycline of formula (3) in alcoholic solvent; ii. Adding ethylene diamine at a temperature between 0°C to 10°C to get pH between 8.5 to 9.5 followed by removal of solid mass through filtration and distilling alcoholic solvent to get oily mass of compound of formula (4); iii. Adding ethyl acetate, pilvadehyde of formula (5), and 5% platinum oxide (PtOa) into oily mass of compound of formula (4) and stirring the reaction mass at a temperature between 20°C to 40°C under continuous passing of hydrogen gas at a pressure between 0.5 to 0.8 psi for 5 to 7 hours followed by removal of Platinum oxide (PtOa) from the reaction mass and adjusting pH between 8-9 using ehthylenediamine to give omadacycline free base of formula (6) in ethyl acetate solvent; iv. Adding p-toluene sulphonic acid to adjust pH between 3.5 to 4.5 and stirring it at a temperature between 0°C to 10°C followed by filtration to give Omadacycline tosylate of formula (X) .

[0054] Now, each step of a single step is explained as follows:

[0055] Step-i:

[0056] The role of temperature, addition of p-toluene sulphonic acid, N- hydorxymethyl phthalimide is important to increase the percentage (%)

[0057] 7

[0058] SUBSTITUTE SHEET (RULE 26) formation of tris protected minocycline of formula (3) and to eliminate or to reduce the percentage (%) formation of mono and bis protected minocycline hence the reaction is carried out at a temperature between 25°C to 80°C.

[0059] Minocycline HC1 of formula (1): N-hydroxymethyl phthalimide (2): p- toluene sulphonic acid is taken in a mole ratio between 1:2-4:0.03-0.1. Alcoholic solvent is added in a volume between 5 to 20 volumes for proper mixing of the reaction mass. Alcoholic solvent is selected from but not limited to methyl alcohol (MeOH), ethyl alchol (EtOH) or isopropyl alchohol (IPA).

[0060] During the reaction of step-i, online HPLC analysis is carried out, it confirms that in step-i, tris protected minocycline of formula (3) is obtained as a major product while mono and bis protected minocycline is obtained in about 2-5% after completion of the reaction.

[0061] After completion of the reaction of step-i, tris protected minocycline of formula (3) which is in the alcoholic solvent is further taken for step-ii. It is to be noted here that the tris protected minocycline of formula (3) may be taken for step-ii with or without isolation of it. More preferably, tris protected minocycline of formula (3) may be taken for step-ii without isolation as it will save time, men power and resources.

[0062] While conducting step-ii, there is no need to transfer the reaction mass and the same vessel or apparatus may be used for carrying out step-ii.

[0063] Step-ii:

[0064] In the reaction, ethylene diamine is added in excess volume to the alcoholic reaction mass containing tris protected minocycline of formula (3).

[0065] The volume of ethylene diamine is kept between 10 to 15 volumes by adjusting pH between 8.5 to 9.5. The selection of ethylene diamine replaces methyl amine use in the reaction. The whole reaction is carried out at a temperature between 0°C to 10°C.

[0066] Use of ethylene diamine, volume of ethylene diamine, pH and temperature play an important role in step-ii. If volume of ethylene diamine or temperature range or pH range is higher or lower than the decided range, it will give undesired products or impurities that will ultimately decrease the quality and quantity of the obtained compound of formula (4).

[0067] After completion of the reaction of step-ii, solid mass is removed through filtration and filtrate containing alcoholic solvent is removed using vacuum distillation at a temperature between 30-45°C. During

[0068] 8

[0069] SUBSTITUTE SHEET (RULE 26) vacuum distillation, excess of ethylene diamine is also removed along with alcohol.

[0070] After distilling out alcoholic solvent completely from step-ii, oily mass containing compound of formula (4) is further taken for hydrogenation reaction i.e. step-iii.

[0071] Step-iii:

[0072] Step-iii is carried out in the pressure reaction vessel. The reaction vessel is degassed by passing nitrogen gas and ensures the absence of oxygen gas in the reaction vessel. The oily mass containing compound of formula (4) is transferred to the pressure reaction vessel. Ethyl acetate, pilvadehyde of formula (5), and 5% platinum oxide (PtOa) is added into oily mass of compound of formula (4) and stirred the reaction mass at a temperature between 20°C to 40°C under continuous passing of hydrogen gas at a pressure between 0.5 to 0.8 psi for 5 to 7 hours.

[0073] After completion of the reaction, Platinum oxide (PtOa) is removed from the reaction mass through filtration. Ethylene diamine is added to the filtrate to adjust pH between 8 to 9 which will give omadacycline free base of formula (6) in ethyl acetate solvent.

[0074] In the above step-iii, ethyl acetate is used in a volume between 5 to 15 volumes and pivaldehyde of formula (5) is added in 0.5 to 1 volume.

[0075] The said ethyl acetate filtrate containing omadacycline free base of formula (6) is washed with water several times. Charcoal treatment at a temperature between 40 to 50°C is given to the ethyl acetate filtrate to remove undesired impurities, unreacted pivaldehyde and ethylene diamine from ethyl acetate filtrate. The treated ethyl acetate filtrate containing omadacycline free base of formula (6) is taken for next step- iv.

[0076] Step-iv:

[0077] The reaction is carried out in same solvent and tosylate salt of omadacycline is prepared using p-toluene sulphonic acid (p-TSA) at a pH between 3.5 to 4.5.

[0078] The addition of p-toluene sulphonic acid (p-TSA) is crucial and it should be added in a quantity to adjust the pH of the reaction mass between 3.5 to 4.5. pH and temperature play an important role in formation and isolation of the final Omadacycline tosylate of formula (X) .

[0079] After addition of 0.5 to 1 mole ratio of p-toluene sulphonic acid (p-TSA), the reaction mass is stirred at a temperature between 0°C to 10°C and filtered it to give Omadacycline tosylate of formula (X) .

[0080] 9

[0081] SUBSTITUTE SHEET (RULE 26) After completion of the reaction, the reaction mass is filtered and washed with solvent selected from water, methanol, ethanol or methyl t-butyl ether (MTBE) to give pure omadacycline tosylate of formula (X) . Optionally, the reaction mass may also be taken further for purification as per the prior art processes to obtain pure omadacycline tosylate of formula (X).

[0082] The Omadacycline tosylate of formula (X) obtained with the said process is having HPLC purity between 98% to 99.8% including tautomer of it.

[0083] EXAMPLES:

[0084] A single step process for the preparation of Omadacycline tosylate of formula (X) as per Scheme-3:

[0085] Minocycline hydrochloride of formula (1) is added to the alcoholic solvent followed by addition of p-toluene sulphonic acid (PTSA) and N- hydroxymethyl phthalimide of formula (2) at a temperature between 25- 30°C, heated to 60-80°C and stirred for 10 to 12 hrs at the same temperature to get mixture of mono, bis and tris protected minocycline of formula (3). The said mixture is cooled to 0-5°C and adjusted pH between 8.5 to 9.5 with the addition of ethylenediamine. The reaction mass is stirred at 0-10°C for half an hour and filtered to remove the solid mass for the reaction mass. Reaction mass then taken for distillation to remove alcoholic solvent to get compound of formula (4) as an oily mass. Ethyl acetate is added in the said oily mass, and dried it over drying agent to remove moisture from the reaction mass. Transfer the reaction mixture to the pressure vessel and remove the oxygen completely from the pressure vessel by purging nitrogen gas into the vessel. Pivaldehyde of formula (5) is added in the said mass followed by addition of hydrogenation catalyst 5% PtC>2, the said mass is then carried forward for hydrogenation through passing of hydrogen gas at a pressure between 0.5 to 0.8 psi at a temperature between 20 to 30°C and stirred the mass for 5 to 7 hours along with continuous passing of hydrogen gas at the same temperature. After completion of the reaction, filtered the reaction mass to get clear reaction mass followed by adjusting pH of the mass between 8 to 9 using ethylenediamine to give omadacycline free base of formula (6) in ethyl acetate solvent. Water wash is given to the said mass followed by giving the charcoal treatment to the said mass at a temperature between 40°C to 50°C to remove the impurities, unreacted pivaldehyde and / or ethylenediamine. Omadacycline free base of formula (6) remained in ethyl acetate is further reacted with p-toluene sulphonic acid at a pH between 3.5 to 4.5 and at a temperature between 0- 10°C

[0086] 10

[0087] SUBSTITUTE SHEET (RULE 26) followed by filtration and washing it with solvent to give omadacycline tosylate of formula (X) .

[0088] Following are the examples provided with comparative examples as per the prior art processes for each step. Step-i: Preparation of compound of formula (3):

[0089] Examples with different parameters are provided as follows:

[0090] Step-ii: Preparation of compound of formula (4):

[0091] Examples with different parameters are provided as follows:

[0092] 11

[0093] SUBSTITUTE SHEET (RULE 26)

[0094]

[0095] Step-iii: Preparation of omadacy cline free base (6):

[0096] Examples with different parameters are provided as follows:

[0097] 12

[0098] SUBSTITUTE SHEET (RULE 26)

[0099]

[0100] Step-iv: Preparation of omadacy cline tosylate (X):

[0101] Examples with different parameters are provided as follows: (As per present invention):

[0102] 13

[0103] SUBSTITUTE SHEET (RULE 26)

[0104] ADVANTAGES OF THE PRESENT INVENTION . The process for the preparation of omadacycline tosylate of formula (X) is a single step process. . The process of the present invention is a simple, environment friendly, robust, easy to operate, industry & economically viable process. . The said process provides increased yield of omadacycline tosylate of formula (X) with improved quality having lesser amounts of impurities in the final product.

[0105] Dated this the 10thday of October, 2024

[0106] On Behalf of the Applicant,

[0107] Signature: Vinay V. Pandya

[0108] Name: [Vinaykumar V. Pandya]

[0109] (Registered Patent Agent: IN / PA- 1674)

[0110] SUBSTITUTE SHEET (RULE 26)

Claims

We claim:

1. A single step process for the preparation of omadacycline tosylate of formula (X) comprises the steps: i. Reacting minocycline hydrochloride of formula (1) with N- hydroxymethyl phthalimide of formula (2) in presence of p- toluene sulphonic acid in 5-20 volumes of alcoholic solvent at a temperature between 25°C to 80°C to give tris protected minocycline of formula (3) in alcoholic solvent; ii. Adding 10 to 15 volumes of ethylene diamine at a temperature between 0°C to 10°C to get pH between 8.5 to 9.5 followed by removal of solid mass through filtration and distilling alcoholic solvent to get oily mass of compound of formula (4); iii. Adding 5 to 15 volumes of ethyl acetate, 0.5 to 1 volume of pilvadehyde of formula (5), and 5% platinum oxide (PtCh) into oily mass of compound of formula (4) and stirring the reaction mass at a temperature between 20°C to 40°C under continuous passing of hydrogen gas at a pressure between 0.5 to 0.8 psi for 5 to 7 hours followed by removal of Platinum oxide (PtOa) from the reaction mass and adjusting pH between 8-9 using ehthylenediamine to give omadacycline free base of formula (6) in ethyl acetate solvent; iv. Adding 0.5 to 1 mole ratio of p-toluene sulphonic acid (pTSA) to adjust pH between 3.5 to 4.5 and stirring it at a temperature between 0°C to 10°C followed by filtration to give Omadacycline tosylate of formula (X) .

2. The process for the preparation of omadacycline tosylate of formula (X) as claimed in claim- 1 wherein in step-i, alcoholic solvent is selected from methanol, ethanol or Isopropyl alcohol (IPA).

3. The process for the preparation of omadacycline tosylate of formula (X) as claimed in claim- 1 wherein in step-i, minocycline HC1 of formula (1): N-hydroxymethyl phthalimide (2): p-toluene15SUBSTITUTE SHEET (RULE 26)sulphonic acid (pTSA) is taken in a mole ratio between 1:2-4:0.03-0.1.

4. The process for the preparation of omadacycline tosylate of formula (X) as claimed in claim- 1 wherein after completion of step-iii, water wash and charcoal treatment is given to the ethyl acetate filtrate.16SUBSTITUTE SHEET (RULE 26)

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