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WO2019097547A1 - Procédé amélioré pour la préparation de lifitegrast ou de sels de celui-ci - Google Patents

Procédé amélioré pour la préparation de lifitegrast ou de sels de celui-ci Download PDF

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Publication number
WO2019097547A1
WO2019097547A1 PCT/IN2018/050756 IN2018050756W WO2019097547A1 WO 2019097547 A1 WO2019097547 A1 WO 2019097547A1 IN 2018050756 W IN2018050756 W IN 2018050756W WO 2019097547 A1 WO2019097547 A1 WO 2019097547A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
benzofuran
process according
carboxylic acid
lifitegrast
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.)
Ceased
Application number
PCT/IN2018/050756
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English (en)
Inventor
Manjinder Singh Phull
Dharmaraj Ramachandra Rao
Geena Malhotra
Sanoj Jose THOPPIL
Sunil Akaram PAWAR
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.)
Cipla Ltd
Original Assignee
Cipla Ltd
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 Cipla Ltd filed Critical Cipla Ltd
Publication of WO2019097547A1 publication Critical patent/WO2019097547A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention relates to a novel process for synthesis of lifitegrast or salts thereof.
  • DED Dry eye disease
  • ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation that affects an estimated 20 million patients in the US alone.
  • DED is associated with localized inflammation of the ocular surface and periocular tissues leading to homing and activation of T cells, cytokine release, and development of hyperosmolar tears. This inflammatory milieu results in symptoms of eye dryness and discomfort.
  • Lifitegrast (trade name Xiidra) is an FDA approved drug indicated for the treatment of both signs and symptoms of dry eye. It is an ophthalmic solution applied in the form of eye drops two times a day. Lifitegrast , the compound of Formula I:
  • Lifitegrast inhibits T cell-mediated inflammation by blocking the binding of two important cell surface proteins (lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1), thus lessening overall inflammatory responses.
  • Most drugs administered to the ocular surface are rapidly cleared from the tear film within the first 30-60 minutes following topical administration due to the normal tear turnover.
  • Lifitegrast has excellent aqueous solubility (>100 mg/mL). The high solubility allows a relatively large concentration to be administered into the tear film and theoretically allows significant residual concentration despite the normal tear turnover.
  • One object of the present invention is to provide an improved process for preparing lifitegrast of Formula (I) or salts thereof, which is simple, economical and suitable for industrial scale up.
  • Another object of the present invention is to provide lifitegrast of Formula (I) or salts thereof with high purity without subjecting to further purification.
  • the present invention discloses an efficient process for the manufacture of enantiomerically pure lifitegrast of Formula (I) or salts thereof, which comprises;
  • the present invention provides a safe, high-yielding, high-purity and industrially-viable method than any method known in the art.
  • compositions may be combined with a suitable carrier to make a pharmaceutical composition.
  • a suitable carrier may be used to treat inflammatory eye disorder.
  • a pharmaceutical composition comprising lifitegrast prepared by the process described above together with one or more pharmaceutically-acceptable excipients.
  • lifitegrast prepared by the process described above for use in medicine.
  • the lifitegrast is for use in treating inflammatory eye disorder.
  • a method of treating inflammatory eye disorder in patients comprising administering to a patient in need thereof an effective amount of lifitegrast prepared by the process described above.
  • the present invention provides a process for the synthesis of lifitegrast (I) or a salt thereof, which comprises the following process steps.
  • benzofuran-6-carboxylic acid of Formula (VI) is treated with a suitable chlorinating agent, to yield benzofuran-6-carboxylic chloride of Formula (VII), which is further condensed with 5,7-dichloro-l,2,3,4- tetrahydroisoquinoline-6-carboxylic acid of Formula (V) or a salt thereof to yield 2-(benzofuran-6-carbonyl) -5,7-dichloro-l,2,3 ,4-tetrahydroisoquinoline-6- carboxylic acid of Formula (III).
  • Suitable chlorinating agents for the above reaction are selected from, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene and oxalyl chloride.
  • the chlorination is performed in a manner known to those skilled in the art of organic synthesis.
  • the benzofuran-6-carboxylic acid of Formula (VI) with the chlorinating agent, which will either be used neat or in solution with a suitable aprotic solvent such as, for example, toluene, methylenechloride (MDC), acetonitrile, tetrahydrofuran, diglyme, dimethylforamide (DMF) or dioxane or the like and the mixture thereof.
  • a suitable aprotic solvent such as, for example, toluene, methylenechloride (MDC), acetonitrile, tetrahydrofuran, diglyme, dimethylforamide (DMF) or dioxane or the like and the mixture thereof.
  • MDC methylenechloride
  • DMF dimethylforamide
  • the reaction mixture is preferably maintained at a temperature of about 0° C to about 80° C, preferably about 10° C to about 50° C, and most preferably about 20° C to about 40° C, preferably for about 1 hour to about 20 hours, more preferably about 2 hours to about 10 hours, and most preferably about 2hours to about 7 hours.
  • the process is carried out without isolating the intermediate benzofuran-6-carboxylic chloride of Formula (VII).
  • the term“without isolation” means that the product being referred to as not being isolated is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid.
  • “without isolation” may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.
  • benzofuran-6-carboxylic chloride of Formula (VII) and 5,7- dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of Formula (V) or a salt thereof are reacted by dissolution in a suitable anhydrous solvent such as, for example acetonitrile, tetrahydrofuran, diglyme, dimethylformamide, dioxane, methylene chloride, or toluene.
  • a suitable anhydrous solvent such as, for example acetonitrile, tetrahydrofuran, diglyme, dimethylformamide, dioxane, methylene chloride, or toluene.
  • a base either organic or inorganic, such as triethylamine diisopropylethylamine, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium hydroxide, potassium hydroxide or the like, may be added to the reaction mixture as an acid scavenger.
  • the reaction rate may be increased by heating up to the boiling point of the solvent.
  • the reaction is carried out at a temperature of about 0°C to about l50°C, preferably about 20° C to about l00°C, more preferably about 25°C to about 50°C; preferably, for about an hour to about 40 hours, more preferably about 2 hours to about 30 hours, most preferably about 2 hours to about 25 hours.
  • step II the coupling reaction of the 2-(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3 ,4-tetrahydroisoquinoline-6-carboxylic acid of Formula (III) with methyl (S)- 2-amino -3-(3-(methylsulfonyl) phenyl) propanoate of Formula (IV) is carried out in the presence of suitable coupling agent to yield LIF methyl ester of Formula ( II).
  • suitable coupling agent is selected from one or more of but not limited to for e.g. DCC or other dialkyl carbodiimides, l,r-carbonyldiimidazole (CDI), 1 ,2-oxazolinium compounds, e.g. 2-ethyl-5-phenyl-l,2-oxazolium-3'- suphonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g.
  • HATU hexafluorophosphate
  • HBTU 2-(l//-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate)
  • TBTU O-(Benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium tetrafluorob orate
  • DMAP Dimethylaminopyridine
  • a particularly suitable coupling reagent for use in the above process according to the present invention is HATU.
  • the reaction is preferably conducted in the presence of a base.
  • the reaction is preferably conducted in the presence of an organic solvent.
  • a suitable base either organic or inorganic, for use in a process according to the present invention can be selected from the group comprising of such as triethylamine, diisopropylethylamine, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like.
  • a particularly suitable base for use in the above process according to the present invention is triethylamine.
  • a suitable organic solvent for use in a process according to the present invention can be selected from the group comprising of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, sulfolane, diglyme; l,4-dioxane, tetrahydrofuran, acetonitrile, acetone and other inert organic solvents known in the art.
  • a particularly suitable inert organic solvent for use in the above process according to the present invention is dimethylformamide.
  • the coupling reaction is preferably carried out at a temperature of about 0°C to about the boiling point of the reaction mass, preferably about 0°C to about 80°C, more preferably about lO°C to about 50°C; for about an hour to about 20 hours, preferably about an hour to about 10 hours, most preferably about an hour to about 8 hours.
  • LIF methyl ester (II) thus obtained may be isolated by any method known in the art.
  • step III hydrolysis of LIF methyl ester of Formula (II) is carried out with a suitable base in one or more protic solvent(s) to yield lifitegrast of Formula (I) or a salt thereof .
  • a suitable protic solvent can be selected from the group comprising of water, Cl- C6 alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and isobutanol or the mixture thereof.
  • the protic solvent used is selected from water or aqueous alcohol.
  • the hydrolysis is preferably carried out using an aqueous mixture of a strong base, such as a hydroxide of an alkali metal or an alkaline earth metal.
  • a strong base such as a hydroxide of an alkali metal or an alkaline earth metal.
  • the hydroxide of an alkali metal or an alkaline earth metal to be used in the reaction of the present invention include potassium hydroxide, lithium hydroxide, sodium hydroxide, caesium hydroxide, calcium hydroxide, barium hydroxide and strontium hydroxide, as well as hydrates thereof.
  • More preferred bases are potassium hydroxide, lithium hydroxide, calcium hydroxide, and hydrates thereof, and even more preferred bases are potassium hydroxide, lithium hydroxide and hydrates thereof.
  • the hydrolysis is carried out using either water-KOH or aqueous methanol- lithium hydroxide and hydrates thereof.
  • the hydrolysis is preferably carried out at a temperature of about 0°C to about the boiling point of the reaction mass, preferably about 0°C to about 80°C, more preferably about lO°C to about 50°C; for about 30 minutes to about 10 hours, preferably about an hour to about 8 hours, most preferably about an hour to about 5 hours.
  • Lifitegrast is isolated from the reaction mixture as a free acid.
  • the product may be purified if desired by conventional methods such as recrystallization, purification by slurry or by conversion to suitable salt such as sodium, potassium, calcium, lithium, magnesium, zinc and the like of the free acid followed by regeneration of free acid. Recrystallization involves providing a solution of crude Lifitegrast or a salt thereof in a suitable solvent or mixture of solvents and then crystallizing the solid from the solution.
  • the present invention includes substantially pure lifitegrast or its salts.
  • substantially pure refers to chemical and optical purity of lifitegrast greater than 90 %, preferably 92 %, and more preferably 95 % by weight.
  • Lifitegrast and its pharmaceutically acceptable salts described herein and/or prepared in accordance with the processes described herein may contain less than about 0.5 %, or less than about 0.1 %, by weight of process, optical, or structural impurities as characterized by high performance liquid chromatography (HPLC) and chiral HPLC.
  • HPLC high performance liquid chromatography
  • the process of the present invention is advantages over prior art processes.
  • the hydrolysis reaction is carried out using water as a green solvent.
  • Water not only is a natural solvent but also the most inexpensive and environmentally benign solvent.
  • the hydrolysis reaction is greatly accelerated by using water as a solvent instead of organic solvents as reported in the prior art.
  • the use of water as a solvent also implies the elimination of tedious extraction, distillation/evaporation processes, simplifies work up procedure and thus contributes to the overall synthetic efficiency, chemical and optical purity of lifitegrast.
  • Benzofuran-6-carboxylic acid (VI) (7.5 gms , 0.046 moles) was suspended in 100 ml MDC and cooled to 0-5°C. 1 ml DMF was added at 0-5°C followed by thionyl Chloride ( 3.8 ml , 0.02moles). The temperature was raised to 25-30°C and the reaction mixture was further stirred for 4 hours. The solvent was removed under vacuum at 45 °C. The residue was stirred in 50 ml MDC and the solution was cooled to 5-l0°C.
  • reaction mixture was quenched in 50 ml of water and stirred for 15 mins. Ethyl acetate (25 ml) was added. The organic layer was separated, washed with 10 % sodium carbonate solution and evaporated to yield titled compound.
  • Benzofuran-6-carboxylic acid (VI) 50 gms , 0.3086 moles was suspended in 250 ml MDC and cooled to l5-20°C. 5 ml DMF was added at l5-20°C followed by thionyl Chloride ( 34 ml , 0.4629 moles). The temperature was raised to 35-40°C and the reaction mixture was further stirred for 2 hours. The solvent was removed under vacuum at 45°C. The residue was stirred in 250 ml MDC and the solution was cooled to 5-l0°C.
  • reaction mixture was filtered over hyflo and the clear filtrate evaporated under vacuum at 40-45°C.
  • the residue was stirred in 250 ml ethyl acetate and stirred for an hour at 25-30°C.
  • the solid was isolated by filtration and dried to yield titled compound.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé amélioré pour la synthèse de lifitegrast ou de sels de celui-ci avec des rendements élevés et une haute pureté, ainsi que son utilisation en thérapie.
PCT/IN2018/050756 2017-11-15 2018-11-15 Procédé amélioré pour la préparation de lifitegrast ou de sels de celui-ci Ceased WO2019097547A1 (fr)

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IN201721040720 2017-11-15
IN201721040720 2017-11-15

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111060629A (zh) * 2019-12-31 2020-04-24 成都惟邦药业有限公司 一种利非司特有关物质的检测方法
WO2020114202A1 (fr) * 2018-12-07 2020-06-11 苏州旺山旺水生物医药有限公司 Procédé de préparation de composé lifitegrast
CN111484467A (zh) * 2020-06-01 2020-08-04 雅本化学股份有限公司 一种立他司特中间体的制备方法
CN112300139A (zh) * 2020-12-29 2021-02-02 南京佰麦生物技术有限公司 立他司特水合物晶型及其制备方法
KR20210065720A (ko) * 2019-11-27 2021-06-04 연성정밀화학(주) 리피테그라스트의 제조방법
CN113880819A (zh) * 2021-09-18 2022-01-04 浙江大学医学院附属第一医院 立他司特的制备方法及其中间体化合物
CN115436532A (zh) * 2022-11-09 2022-12-06 山东金城柯瑞化学有限公司 立他司特中间体5,7-二氯-1,2,3,4-四氢异喹啉的检测方法

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020114202A1 (fr) * 2018-12-07 2020-06-11 苏州旺山旺水生物医药有限公司 Procédé de préparation de composé lifitegrast
KR20210065720A (ko) * 2019-11-27 2021-06-04 연성정밀화학(주) 리피테그라스트의 제조방법
WO2021107514A3 (fr) * 2019-11-27 2021-07-22 연성정밀화학(주) Procédé de préparation de lifitegrast
KR102362551B1 (ko) * 2019-11-27 2022-02-15 연성정밀화학(주) 리피테그라스트의 제조방법
CN111060629A (zh) * 2019-12-31 2020-04-24 成都惟邦药业有限公司 一种利非司特有关物质的检测方法
CN111060629B (zh) * 2019-12-31 2022-07-05 成都惟邦药业有限公司 一种利非司特有关物质的检测方法
CN111484467A (zh) * 2020-06-01 2020-08-04 雅本化学股份有限公司 一种立他司特中间体的制备方法
CN112300139A (zh) * 2020-12-29 2021-02-02 南京佰麦生物技术有限公司 立他司特水合物晶型及其制备方法
CN113880819A (zh) * 2021-09-18 2022-01-04 浙江大学医学院附属第一医院 立他司特的制备方法及其中间体化合物
WO2023040103A1 (fr) 2021-09-18 2023-03-23 浙江大学医学院附属第一医院 Procédé de préparation de lifitégrast et composé intermédiaire de lifitégrast
CN115436532A (zh) * 2022-11-09 2022-12-06 山东金城柯瑞化学有限公司 立他司特中间体5,7-二氯-1,2,3,4-四氢异喹啉的检测方法

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