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WO2025094187A1 - Procédé en une seule étape pour la préparation de tosylate d'omadacycline de formule (x) - Google Patents

Procédé en une seule étape pour la préparation de tosylate d'omadacycline de formule (x) Download PDF

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Publication number
WO2025094187A1
WO2025094187A1 PCT/IN2024/052023 IN2024052023W WO2025094187A1 WO 2025094187 A1 WO2025094187 A1 WO 2025094187A1 IN 2024052023 W IN2024052023 W IN 2024052023W WO 2025094187 A1 WO2025094187 A1 WO 2025094187A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
omadacycline
tosylate
preparation
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IN2024/052023
Other languages
English (en)
Inventor
Tarunkumar Akhaja
Naresh Ranaji Kiri
Dr. Rakesh Kumar AMETA
Akshaykumar Mukeshbhai Patel
Nileshkumar Balaji Thakor
Harshilkumar Shaileshbhai Patel
Sunny Nitinkumar Patel
Keyurkumar Arjanbhai Kamani
Jignesh Priyakant Raval
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumar Biotech LLP
Original Assignee
Sumar Biotech LLP
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumar Biotech LLP filed Critical Sumar Biotech LLP
Publication of WO2025094187A1 publication Critical patent/WO2025094187A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes

Definitions

  • 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.
  • 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.
  • Omadacycline tosylate may be represented with the chemical formula (X).
  • Minocycline has several reactive functional groups and the C2 primary amide is more reactive towards electrophiles than C9 or the CIO. Due to
  • the resulting intermediate is reacted with hydrogen under hydrogenation conditions to form a C9-substituted aminomethyl tetracycline intermediate.
  • the formed compound is reacted with pivaldehyde under hydrogenation conditions to afford omadacycline.
  • pH adjustment and precipitation the desired product is afforded as an amorphous, unstable solid.
  • 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.
  • 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
  • step b) SUBSTITUTE SHEET (RULE 26) intermediate formed in step b) and in the absence of a hydrogenation reaction prior to step c) or d).
  • 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
  • steps b) and d) of the method of the present invention may operate in a continuous manner.
  • 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).
  • 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.
  • step a to d 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.
  • 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.
  • 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) .
  • 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.
  • 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).
  • PTSA p-toluene sulphonic acid
  • platinum oxide (PtOa) is used as hydrogenating agent, platinum oxide is not reported in any of the prior art processes.
  • 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.
  • 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.
  • 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.
  • ethylenediamine used in the present invention is a liquid in nature having boiling point of 116°C that makes easy to maintain pH of
  • 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.
  • 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.
  • a single step process for the preparation of omadacycline tosylate of formula (X) 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.
  • 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).
  • 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.
  • 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.
  • step-ii 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.
  • 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.
  • 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).
  • step-ii 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.
  • step-iii 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • p-TSA p-toluene sulphonic acid
  • p-TSA p-toluene sulphonic acid
  • reaction mass 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) .
  • p-TSA p-toluene sulphonic acid
  • 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) .
  • solvent selected from water, methanol, ethanol or methyl t-butyl ether (MTBE)
  • MTBE methyl t-butyl ether
  • the reaction mass may also be taken further for purification as per the prior art processes to obtain pure omadacycline tosylate of formula (X).
  • the Omadacycline tosylate of formula (X) obtained with the said process is having HPLC purity between 98% to 99.8% including tautomer of it.
  • 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.
  • Step-ii Preparation of compound of formula (4):
  • Step-iii Preparation of omadacy cline free base (6):
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de tosylate d'omadacycline de formule (X). Plus particulièrement, la présente invention concerne un procédé en une seule étape pour la préparation de tosylate d'omadacycline de formule (X), le procédé en une seule étape commençant par l'utilisation du chlorhydrate de minocycline de formule (1) en tant que matériau de départ et donnant du tosylate d'omadacycline final de formule (X) sans isoler aucun intermédiaire du procédé. Formule (1) Formule (X)
PCT/IN2024/052023 2023-10-31 2024-10-09 Procédé en une seule étape pour la préparation de tosylate d'omadacycline de formule (x) Pending WO2025094187A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202321074089 2023-10-31
IN202321074089 2023-10-31

Publications (1)

Publication Number Publication Date
WO2025094187A1 true WO2025094187A1 (fr) 2025-05-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2024/052023 Pending WO2025094187A1 (fr) 2023-10-31 2024-10-09 Procédé en une seule étape pour la préparation de tosylate d'omadacycline de formule (x)

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WO (1) WO2025094187A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9434680B2 (en) * 2007-04-27 2016-09-06 Paratek Pharmaceuticals, Inc. Methods for synthesizing and purifying aminoalkyl tetracycline compounds
WO2022248865A1 (fr) * 2021-05-26 2022-12-01 Hovione Scientia Limited Procédé de synthèse de composés 9-aminométhyl tétracycline
WO2023047323A1 (fr) * 2021-09-24 2023-03-30 Glenmark Life Sciences Limited Procédé de préparation de tosylate d'omadacycline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9434680B2 (en) * 2007-04-27 2016-09-06 Paratek Pharmaceuticals, Inc. Methods for synthesizing and purifying aminoalkyl tetracycline compounds
WO2022248865A1 (fr) * 2021-05-26 2022-12-01 Hovione Scientia Limited Procédé de synthèse de composés 9-aminométhyl tétracycline
WO2023047323A1 (fr) * 2021-09-24 2023-03-30 Glenmark Life Sciences Limited Procédé de préparation de tosylate d'omadacycline

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