WO2023286078A1 - Procédé amélioré pour préparer un intermédiaire de morboxavir morboxil - Google Patents

Procédé amélioré pour préparer un intermédiaire de morboxavir morboxil Download PDF

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Publication number
WO2023286078A1
WO2023286078A1 PCT/IN2022/050629 IN2022050629W WO2023286078A1 WO 2023286078 A1 WO2023286078 A1 WO 2023286078A1 IN 2022050629 W IN2022050629 W IN 2022050629W WO 2023286078 A1 WO2023286078 A1 WO 2023286078A1
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Prior art keywords
formula
compound
mixture
solvent
base
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PCT/IN2022/050629
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English (en)
Inventor
Shyam Sunder Reddy TALASANI
Shankar Reddy BUDIDETI
Rajashekar KOTTE
Venkata Reddy Satti
Nagendra MALA
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
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Natco Pharma Limited
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Publication of WO2023286078A1 publication Critical patent/WO2023286078A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for the preparation of
  • Baloxavir morboxil is chemically known as ( ⁇ (12aR)-12-[(llS)-7,8-Difluoro-6,ll- dihydrodibenzo[b,e]thiepinll-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-l//- [ 1 ,4] oxazino [3 ,4-c]pyrido [2,1-f] [1 ,2,4] triazin-7 -yl ⁇ oxy )methylmethyl carbonate of Formula (II).
  • Baloxavir morboxil is an antiviral drug developed by Shionogi Co. and Roche for the treatment of influenza A and influenza B infections. It is a prodrug that is converted (by hydrolysis) to Baloxavir, the active form that exerts anti -influenza virus activity.
  • WO 2017221869 A1 and CN 112079848 A1 also disclose a process for the preparation of ( 12aR)-3,4, 12, 12a-tetrahydro-7-(phenylmethoxy)- IH-[ 1 ,4] oxazino[3,4-c] pyrido[2,l-f][l,2,4]triazine-6,8-dione of Formula (I) by reacting 3,4,12,12a-tetrahydro-7-(phenylmethoxy) oxazino[3,4-c]pyrido [l,2,4]triazine-6,8-dione hemihydrate of Formula (Ilia) with (R)-2- tetrahydrofuroic acid of formula (IV) in the presence of propanephosphonic acid anhydride (T3P) and triethylamine in ethyl acetate and ethanol to produce (12aR)- 3,4,
  • the main objective of the present invention is to provide a simple and cost effective process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7- (phcnylmcthoxy)- oxazino[3,4-c]pyrido[2,l-f][l,2,4] triazine-6,8-dione of Formula (I) which is a key intermediate for the preparation of Baloxavir morboxil of Formula (II) with high purity and good yield on a commercial scale.
  • the present invention provides an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)- [2,1-f] [1,2,4] triazine-6,8-dione of Formula (I), comprising the steps of:
  • Formula (VI) c) separating the compound of Formula (V) from the mixture obtained in above step b); d) deprotecting the compound of Formula (V) in presence of a base in suitable solvent to produce compound of Formula (I).
  • Another present invention provides a process for the preparation of 3,4,12,12a- tetrahydro-7-(phenylmethoxy)- 1 H-[ 1 ,4]oxazino[3 ,4-c]pyrido triazine-6,8-dione compound of Formula (III), comprising the step of converting the compound of Formula (VI)
  • the present invention provides an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-l//-[l,4]oxazino[3,4-c]pyrido [2,1-f] [1,2,4] triazine-6,8-dione of Formula (I), comprising the steps of: a) reacting a compound of Formula (IV) with chlorinating agent in presence of a base in a solvent to produce acid chloride compound of Formula (IVa), b) reacting the compound of Formula (IVa) in situ with compound of Formula (III) in presence of a base in a solvent to produce to produce mixture of compound of Formula (V) and compound of Formula (VI), c) separating the compound of Formula (V) from the mixture obtained in above step b), d) deprotecting the compound of Formula (V) in presence of a base in suitable solvent to produce compound of Formula (I).
  • the chlorinating agent used in step a) is selected from thionyl Chloride Oxalyl chloride Cyanuric Chloride, Phosphorus oxychloride, Phosphorus trichloride, phosphorus pentachloride or mixtures thereof.
  • the solvent used in step a) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof; ketone solvent comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
  • the reaction may be performed usually from 0 ° C to a boiling point of used solvent for 30 min to 48hours and then compound of formula (IVa) can be obtained by a usual procedure. The obtained compound (IVa) can be used in the next reaction directly without isolation.
  • the base used in step b) is an organic or inorganic base.
  • the organic base is selected from diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine preferably triethylamine;
  • the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof or mixtures thereof.
  • the solvent used in step b) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof preferable dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
  • an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or
  • Step c) performs in a suitable solvent selected from dichloromethane and ethylacetetate or mixture thereof.
  • reaction may be performed from -30 C to 60 ° C for 30 min to 48hours and then compound of formula (V) can be obtained by a usual procedure.
  • the base used in step d) is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
  • the solvent used in step d) is organic solvent, for example alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2 -methoxy ethanol or mixture thereof preferable methanol; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof preferable ethyl acetate.
  • alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol,
  • reaction may be performed from -30 C to 60 ° C for 30 min to 48hours and then compound of formula (I) can be obtained by a usual procedure.
  • Another present invention provides a process for the preparation of 3,4,12,12a- ) triazine-6,8-dione compound of Formula (III), comprising the step of converting compound of Formula (VI) to compound of Formula (III) in presence of base and suitable solvent.
  • the base used in above step is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
  • the solvent used in above step is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, isoamylalcohol, 2- methoxy ethanol or mixture thereof preferable methanol.
  • reaction may be performed from -30 C to 60 ° C for 30 min to 48hours and then compound of formula (III) can be obtained by a usual procedure.
  • Example- 1 Preparation of (12a/?)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12- [l,2,4]triazine-6,8-dione of Formula (V).
  • reaction mixture was washed with water (2000 ml), separated the organic layer and concentrated at below 40°C, resulting residue was purified in mixture of dichloromethane and ethyl acetate to produce compound of Formula (V) (118 g, wet) as a solid. Also, the filtrate and the washing solutions were combined to obtain as ethyl acetate solution of compound of formula (V), which was used for isolation of compound of Formula (VI) and preparation of compound (III).
  • Example-2 Isolation of (12aS)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12- [[(2/?)-tetrahydro-2-furanyl]carbonyl]-lH-[l,4]oxazino[3,4-c]pyrido[2,l]
  • Example-4 Preparation of (12a5)-3, 4, 12,12a-tetrahydro-7-(phenylmethoxy)- -[l,4]oxazino [3,4-c]pyrido[2,l-/][l,2,4]triazine-6,8-dione of Formula (VII).
  • Example-6 Preparation of 7-(hexyloxy)-3, 4, 12, 12a-tetrahydro-(12aR)-
  • Example-7 Preparation of triazine-6,8-dione,12-[(llS)-7,8-difluoro-6,ll-dihydrodibenzo[b,e]thiepin-ll- yl]-7-(hexyloxy)-3,4,12,12a-tetrahydro-(12aR)-,methanesulfonate (X).
  • Example-8 Preparation of 12-[(llS)-7,8-difluoro-6,ll-dihydrodibenzo[b,e] thiepin-ll-yl]-3,4,12,12a-tetrahydro-7-hydroxy-(12aR)lH-[l,4]Oxazino[3,4- c]pyrido[2,l-f][l,2,4]triazine-6,8-dione (XI) (Baloxavir)
  • Example-9 Preparation ( ⁇ (12aR)-12-[(lls)-7,8-difluoro -dihydro dibenzo-[B,E]-thiepinll-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-lh-[l,4]- oxazino[3,4-c]pyrido[2,l-f][l,2,4]triazin-7-yl ⁇ oxy)methyl methyl carbonate of Formula (II) (Baloxavir morboxil):
  • Route of synthesis-I of Route of synthesis- II of (12aR)-3,4, 12,12a-tetrahydro-7-(phenylmethoxy)-l//- [1,4] oxazino from the compound of Formula (VI) in the present invention Route of synthesis-III of Baloxavir morboxil of Formula-(II) in the present invention.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne un procédé amélioré pour préparer du (12aR)-3,4,12,12a-tétrahydro-7-(phénylméthoxy)-1H-[1,4]oxazino[3,4-c] pyrido[2,1-f] [1,2,4]triazine-6,8-dione de formule (I). La formule I qui est un intermédiaire clé dans la synthèse de Baloxavir Morboxil de formule (II).
PCT/IN2022/050629 2021-07-13 2022-07-11 Procédé amélioré pour préparer un intermédiaire de morboxavir morboxil WO2023286078A1 (fr)

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IN202141031429 2021-07-13
IN202141031429 2021-07-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016175224A1 (fr) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci
WO2017221869A1 (fr) * 2016-06-20 2017-12-28 塩野義製薬株式会社 Méthodes de production de dérivés substitués de pyridone polycyclique et cristal correspondant
CN112679522A (zh) * 2020-12-29 2021-04-20 南京友杰医药科技有限公司 一种巴洛沙韦中间体的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016175224A1 (fr) * 2015-04-28 2016-11-03 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci
WO2017221869A1 (fr) * 2016-06-20 2017-12-28 塩野義製薬株式会社 Méthodes de production de dérivés substitués de pyridone polycyclique et cristal correspondant
CN112679522A (zh) * 2020-12-29 2021-04-20 南京友杰医药科技有限公司 一种巴洛沙韦中间体的制备方法

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