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WO2025186604A1 - Procédé de préparation de lifitégrast par transestérification et composé associé - Google Patents

Procédé de préparation de lifitégrast par transestérification et composé associé

Info

Publication number
WO2025186604A1
WO2025186604A1 PCT/IB2024/058346 IB2024058346W WO2025186604A1 WO 2025186604 A1 WO2025186604 A1 WO 2025186604A1 IB 2024058346 W IB2024058346 W IB 2024058346W WO 2025186604 A1 WO2025186604 A1 WO 2025186604A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
phenyl
methylsulfonyl
dichloro
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/IB2024/058346
Other languages
English (en)
Other versions
WO2025186604A8 (fr
Inventor
Mohan Anand Chandavarkar
Kishor Ramdas MORE
Sudhir Shrirang Sawant
Prashant Bhaskarrao PATIL
Arvind Tukaram GIRKAR
Dujon Norbert NORONHA
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.)
FDC Ltd
Original Assignee
FDC 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 FDC Ltd filed Critical FDC Ltd
Publication of WO2025186604A1 publication Critical patent/WO2025186604A1/fr
Publication of WO2025186604A8 publication Critical patent/WO2025186604A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmaceuticals. More particularly, the present invention relates to the synthesis of Lifitegrast via transesterification and the compound thereof.
  • DED Dry eye disease
  • Lifitegrast is chemically known as (S)-2-(2-(benzofiiran-6-carbonyl)-5,7- dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3- methylsulfonyl) phenyljpropanoic acid and is known commercially as Xiidra and sanctioned by the FDA, emerges as an effective treatment for both the signs and symptoms of dry eye.
  • Lifitegrast Administered as an ophthalmic solution through twice-daily eye drops, Lifitegrast, is an immune-inhibiting medication represented by the compound of Formula I, has proven effective in inhibiting interactions between Lymphocyte Function-Associated Antigen- 1 (LFA-1) and the family of intercellular adhesion molecules (I CAM). Notably, Lifitegrast boasts desirable pharmacokinetic properties, featuring rapid systemic clearance.
  • LFA-1 Lymphocyte Function-Associated Antigen- 1
  • I CAM intercellular adhesion molecules
  • Lifitegrast, its salts and compositions containing Lifitegrast were first disclosed in the patent US8084047. Different processes for preparing Lifitegrast are disclosed in various patents and applications. US9085553 discloses the method of preparation of Lifitegrast and its salts wherein the ester precursor of Lifitegrast was hydrolysed with a base under biphasic conditions. Wherein, the precursor ester group is a carbon-containing moiety or a silyl containing moiety.
  • WO2019097547 discloses a process wherein enantiomerically pure Lifitegrast is prepared by the hydrolysis of Lifitegrast methyl ester with a base in the presence of protic solvents.
  • WO2019096996 discloses a transfer hydrogenolysis process for the preparation of Lifitegrast wherein benzyl (S)-2-[2-(benzofiiran-6-carbonyl)-5,7-dichloro-l ,2,3,4- tetrahydroisoquinoline-6-carboxamido]-3-[3-(methylsulfonyl)phenyl]propanoate is hydrogenated in a mixture comprising atleast one solvent selected from the group consisting of acetonitrile, a ketone solvent, an ester solvent and in the presence of a catalyst.
  • US20110092707 discloses process for the preparation of N-[[2-(6- benzofiiranylcarbonyl)-5 ,7-dichloro- 1 ,2,3 ,4-tetrahydro-6-isoquinolinyl]carbonyl] -3 - (methylsulfonyl)-L-phenylalanine in novel crystalline polymorphic forms A, B, C, D, and E.
  • 6-benzofurancarboxylic acid was treated with oxalyl chloride and then reacted with N-[(5,7-dichloro-l,2,3,4-tetrahydro-6-isoquinolinyl)carbonyl]-3-(methylsulfonyl)-L- phenylalanine phenylmethyl ester hydrochloride and methylene chloride in the presence of diisopropylethylamine to afford a condensation intermediate.
  • One objective 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 objective of the present invention is to provide a method of synthesizing alkyl (S)-2-(5,7-dichloro- 1,2,3, 4-tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoate a compound of Formula V by transesterification.
  • Another objective of the present invention is to provide a Lifitegrast compound with Formula I with high purity.
  • Another objective of the present invention is to provide a method which is cost effective and results into the high yield.
  • the present invention discloses a process for the preparation of Lifitegrast of Formula I from alkyl (S)-2-(5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3- (3-(methylsulfonyl)phenyl)propanoate a compound of Formula V via transesterification of Phenyl (S)-2-(5,7-dichloro- 1,2,3, 4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
  • Lifitegrast comprising step of a) tert-butyl (S)-6-((l-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-l-oxopropan-2- yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(lH)-carboxylate a compound of Formula IV is prepared by treatment of 2-(tert butoxy carbonyl)-5, 7- dichloro 1,2, 3, 4 tetrahydro isoquinoline-6-carboxylic acid a compound of Formula II with benzyl-(S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride a compound of Formula III in presence of triethylamine (TEA), coupling agent and dimethylformamide
  • TAA triethylamine
  • R is a straight chain or branched chain alkyl preferably -CH 3 , -C2H5, -C3H7, -C4H9, - CH(CH 3 ) 2 , -C(CH 3 ) 3 .
  • the present invention provides a high yielding, economical, simple and commercially viable method for the preparation of Lifitegrast and its salts thereof.
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising Lifitegrast of Formula I or its salts prepared by the process described above and a pharmaceutically acceptable carrier or excipient.
  • composition comprising Lifitegrast prepared by the process described above as a medicament for treating eye disorder.
  • FIG. 1 UPLC of compound of Formula IV prepared by example stage 1 intermediate I
  • FIG. 2 UPLC of methyl ester of compound of Formula V prepared by example stage I intermediate II
  • FIG. 3 UPLC of methyl ester of compound of Formula VI prepared by example stage II
  • FIG. 4 UPLC of benzylamine salt of compound of Formula I prepared by example stage III
  • FIG. 5 UPLC of compound of Formula I prepared by example stage IV
  • FIG. 6 UPLC of ethyl ester of compound of Formula V
  • FIG. 7 UPLC of isopropyl ester of compound of Formula V
  • FIG. 8 UPLC of butyl ester of compound of Formula V
  • FIG. 9 UPLC of propyl ester of compound of Formula V
  • the process of preparing Lifitegrast comprising step of a) tert-butyl (S)-6-((l-(benzyloxy)-3-(3-(methylsulfonyl)phenyl)-l-oxopropan-2- yl)carbamoyl)-5,7-dichloro-3,4-dihydroisoquinoline-2(lH)-carboxylate a compound of Formula IV is prepared by treatment of 2-(tert butoxy carbonyl)-5,7- dichloro 1,2, 3, 4 tetrahydro isoquinoline-6-carboxylic acid a compound of Formula II with benzyl-(S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride a compound of Formula III in presence of triethylamine (TEA), coupling agent and dimethylformamide
  • TAA triethylamine
  • Formula IV b) Transesterification of compound of Formula IV to alkyl (.S')-2-(5.7-dichloro- l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate hydrochloride a compound of Formula V using alkyl alcohol and oxalyl chloride
  • R is a straight chain or branched chain alkyl preferably -CH 3 , -C2H5, -C3H7, -C4H9, - CH(CH 3 ) 2 , -C(CH 3 ) 3 .
  • said process for the preparation of Lifitegrast of Formula I is performed from alkyl (S)-2-(5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)- 3-(3-(methylsulfonyl)phenyl)propanoate a compound of Formula V via transesterification of Phenyl (S)-2-(5,7-dichloro l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3 (methylsulfonyl)phenyl)propanoate of Formula IV
  • compound of Formula V or its salt thereof is prepared by transesterification and BOC deprotection of compound of Formula IV in the presence of oxalyl chloride and alcohol
  • R of Formula V is selected from straight chain or branched chain alkyl preferably -CH 3 , -C2H5, -C3H7, -C4H9, -CH(CH 3 ) 2 , -C(CH 3 ) 3 .
  • said alcohol is selected from, but not limited to the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and isobutanol.
  • said process is carried out in the presence of coupling agent selected from the group consisting HATU(Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), EDC.HC1 (l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide Hydrochloride), CDI (1,1 '-Carbonyldiimidazole), Ethyl 2-cyano-2-(hydroxylimino) acetate, HBTU(Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), EDC.HC1 (l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide Hydrochloride), CDI (1,1 '-Carbonyldiimidazole), Ethyl 2-cyano-2-(hydroxylimino) acetate, HBTU(Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), EDC.HC1 (l-Eth
  • HCTU O-(6- Chlorobenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate
  • the base is selected from the group consisting of potassium hydroxide, lithium hydroxide, sodium hydroxide, caesium hydroxide, calcium hydroxide, barium hydroxide and strontium hydroxide, as well as hydrates thereof.
  • said transesterification is performed under controlled temperature ranging from about 60°C to about 85°C.
  • the purity of the compound more than 98%.
  • the present invention describes the process for preparing compound of Lifitegrast of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising Lifitegrast of Formula I or its salts prepared by the process described above and a pharmaceutically acceptable carrier or excipient.
  • composition comprising Lifitegrast prepared by the process described above as a medicament for treating eye disorder.
  • the present invention describes the process for preparing compound of Formula 1 or a pharmaceutically expectable salt thereof.
  • the process of the present invention is outlined in Scheme 1 : [0049] Scheme 1: EXAMPLE

Landscapes

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

Abstract

La présente invention concerne un procédé de préparation d'un composé de lifitégrast de formule (I) ou d'un sel de celui-ci. Brièvement, la présente invention concerne un procédé de préparation de lifitégrast de formule I à partir de (S)-2-(5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3(méthylsulfonyl)phényl)propanoate d'alkyle, un composé de formule V par transestérification de (S)-2-(5,7-dichloro-1,2,3,4-tétrahydroisoquinoléine-6-carboxamido)-3-(3)(méthylsulfonyl)phényl)propanoate de phényle de formule IV.
PCT/IB2024/058346 2024-03-07 2024-08-28 Procédé de préparation de lifitégrast par transestérification et composé associé Pending WO2025186604A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202421016176 2024-03-07
IN202421016176 2024-03-07

Publications (2)

Publication Number Publication Date
WO2025186604A1 true WO2025186604A1 (fr) 2025-09-12
WO2025186604A8 WO2025186604A8 (fr) 2025-10-02

Family

ID=96990056

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/058346 Pending WO2025186604A1 (fr) 2024-03-07 2024-08-28 Procédé de préparation de lifitégrast par transestérification et composé associé

Country Status (1)

Country Link
WO (1) WO2025186604A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110092707A1 (en) * 2009-10-21 2011-04-21 Sarcode Corporation Crystalline Pharmaceutical and Methods of Preparation and Use Thereof
US8080562B2 (en) * 2008-04-15 2011-12-20 Sarcode Bioscience Inc. Crystalline pharmaceutical and methods of preparation and use thereof
US20200306242A1 (en) * 2017-10-10 2020-10-01 Mankind Pharma Ltd. Novel process for the preparation of lifitegrast

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8080562B2 (en) * 2008-04-15 2011-12-20 Sarcode Bioscience Inc. Crystalline pharmaceutical and methods of preparation and use thereof
US20110092707A1 (en) * 2009-10-21 2011-04-21 Sarcode Corporation Crystalline Pharmaceutical and Methods of Preparation and Use Thereof
US20200306242A1 (en) * 2017-10-10 2020-10-01 Mankind Pharma Ltd. Novel process for the preparation of lifitegrast

Also Published As

Publication number Publication date
WO2025186604A8 (fr) 2025-10-02

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