WO2022168106A1 - Procédé chimio-enzymatique pour la synthèse du molnupiravir - Google Patents

Procédé chimio-enzymatique pour la synthèse du molnupiravir Download PDF

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Publication number
WO2022168106A1
WO2022168106A1 PCT/IN2021/050456 IN2021050456W WO2022168106A1 WO 2022168106 A1 WO2022168106 A1 WO 2022168106A1 IN 2021050456 W IN2021050456 W IN 2021050456W WO 2022168106 A1 WO2022168106 A1 WO 2022168106A1
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Prior art keywords
formula
compound
cytidine
volumes
acetone
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PCT/IN2021/050456
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English (en)
Inventor
Anupama Datla
Prashant NAGRE
Jagdish TAMORE
Manojkumar Sadanand PRABHU
Sreenath TRIVIKRAM
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Fermenta Biotech Limited
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Publication of WO2022168106A1 publication Critical patent/WO2022168106A1/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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/38—Nucleosides
    • C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides

Definitions

  • the present invention is in the field of process for synthesis of Molnupiravir. More particularly, the present invention relates to a chemo-enzymatic process for synthesis of Molnupiravir from Cytidine.
  • Molnupiravir also known as MK-4482, EIDD-2801
  • MK-4482 EIDD-2801
  • the Drug was first disclosed in W02002032920 for treatment or prophylaxis of host exhibiting a Flaviviridae, Orthomyxoviridae or Paramyxoviridae viral infection or abnormal cellular proliferation.
  • Molnup iravir and its pharmaceutical compositions were claimed in Indian Patent Application Nos 201717025098 and 202017019418, corresponding to pending European Patent Application No EP3236972 and EP3706762, respectively.
  • Molnupiravir is effective in treatment of SARS CoV-2/COVID-19 virus, which has caused the current pandemic. It has been reported that Molnupiravir effectively inhibits viral replication in SARS CoV- 2/Covidl9 patients within 24hrs of administration. Hence, it has been repurposed to be used as a treatment of Coronavirus disease (COVID-19).
  • Molnupiravir is a prodrug of the synthetic nucleoside derivative N4- hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication.
  • Molnupiravir has, conventionally, been produced from uridine or cytidine through a multi-step chemical or enzymatic process.
  • the chemical process was discussed in Indian Patent Application 201717025098 and 202017019418.
  • the processes as discussed therein are chemical processes which uses uridine as starting material.
  • Uridine is a costly raw material which has a limited availability.
  • two more chemical routes for synthesis of Molnupiravir were discussed in article published by V. Gopalsamuthiram et al. (September, 2020) and in an article published by A. Steiner et al (October, 2020).
  • V. Gopalsamuthiram et al. reports a 5-step process for synthesis of Molnupiravir starting from cytidine.
  • the process as disclosed in A. Steiner et al is a six-step process for synthesis of Molnupiravir starting from uridine.
  • N. Vasudevan et al To reduce the cost of raw material, use of cytidine was proposed by N. Vasudevan et al in their article published in October 2020. This article describes the preparation of Molnupiravir consisting of an esterification and hydroxyamination of cytidine, in which Enzyme catalysed esterification of cytidine was carried out by using immobilized C ALB (Candida Antarctica Lipase B).
  • C ALB Candida Antarctica Lipase B
  • the disclosure of N. Vasudevan et al reports two alternative routes for converting cytidine to Molnupiravir via a two-step process. The process involves direct transformation of cytidine or N-hydroxycytidine to Molnupiravir without protecting the group. This might lead to more impurities, thereby increasing the expenses towards purification of final product.
  • the invention provides a chemo-enzymatic process for synthesis of Molnupiravir of formula I from cytidine of Formula II using a lipase for esterification reaction.
  • the process of the invention comprises of following steps:
  • the current invention provides an enzymatic process of obtaining 5’-isobutylester of formula IV using IMMOBILIZED CAL B lipase enzyme expressed in Pichia pastoris.
  • the present invention describes a novel process for synthesis of Molnupiravir, whereby the process uses a combination of chemical reactions and enzymatic transformation.
  • the chemo-enzymatic reactions used in the process of the invention effectively reduces the overall cost of the process for synthesis of the Molnupiravir. Furthermore, as the use of chemicals is significantly reduced, the process is greener as compared to the processes known in the art.
  • the process of the invention achieves an improved yield as compared to the pure chemical process, by about 4 times, thereby further improving the economic advantage achieved by the process.
  • the process of the invention comprises of following steps:
  • the first step of the process of invention involves treatment of Cytidine (Formula II) with Acetone only in presence of Concentrated Sulphuric acid to obtain Cytidine Acetonide sulphate of Formula III, which can be used in further steps.
  • one equivalent of Cytidine is treated with in procuring 20-120 volumes of Acetone preferably 40-100 volumes more preferably 60-90 volumes of Acetone and 1-5 volumes of concentrated sulphuric acid.
  • the reaction mass is stirred at 25-35°C for 6-30 hours preferably 12-24 hours till the analysis indicates completion of reaction.
  • the reaction mass is further filtered and purified to isolate Cytidine Acetonide sulphate.
  • Compound of Formula II can be treated with Acetone & 2,2- Dimethoxypropane in presence of Concentrated Sulphuric acid to get Cytidine Acetonide Sulphate (Formula III) and used in further step.
  • Cytidine is treated with either 5-20 volumes of Acetone preferably 6-15 volumes more preferably 8-13 volumes of Acetone, 1-10 volumes of 2,2-Dimethoxypropane preferably 1.5-6 volumes more preferably 2-4 volumes and 0.1-1 volume concentrated sulphuric acid.
  • the reaction mass is stirred at 25-35°C for 6-30 hours preferably 12-24 hours till the analysis indicates completion of reaction.
  • the reaction mass is further filtered and purified to isolate Cytidine Acetonide sulphate.
  • the isolated Cytidine Acetonide Sulphate of Formula III can also be neutralised with Ammonium Hydroxide and used as Cytidine Acetonide in subsequent steps.
  • the Cytidine Acetonide sulphate (Formula III) is treated with Acetone isobutryl oxime ester in presence of IMMOBILIZED enzyme CAL B 1000 -12000 u/gm, preferably 3000-10000 u/gm & more preferably 5000-10000u/gm & Tri ethylamine in a solvent selected from Tetrahydrofuran, Methyl tetrahydrofuran, 1,4-Dioxane, Methyl -tert-butyl ether, Diethyl ether, Toluene or a mixture of Toluene & n-heptane, for 6-50 hours at 15-100°C.
  • the biocatalyst used in this enzymatic step is Candida antarctica lipase-B (IMMOBILIZED CAL-B) expressed in Pichia pastoris.
  • the invention relates to a process for obtaining acetone isobutyryl oxime ester, which functions as acyl donor for enzymatic for conversion of compound of Formula III to compound of Formula IV.
  • the process comprises of reacting acetone (Formula IIIA) with hydroxylamine hydrochloride or hydroxylamine sulphate to obtain acetone oxime (Formula IIIB).
  • acetone oxime hence formed is then converted to acetone isobutryl oxime ester
  • the above reaction can be effected by reacting compound of Formula IIIB with isobutyric anhydride in presence of pyridine and 4-dimethylaminopyridine.
  • the compound of Formula IIIC can be obtained by reacting compound of Formula IIIB with isobutyric acid in presence of N-(3-
  • the compound of Formula IIIC is obtained by reacting compound of Formula IIIB with isobutanoyl chloride in presence of triethylamine at 0°C.
  • the compound of Formula IIIC is obtained by reacting compound of Formula IIIB with isobutyric acid in presence of N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine in Methylene dichloride solvent, as this process is economical and gives good yield.
  • Step 1 equivalent of Formula II is treated with either 5-20 volumes of
  • Formula IIIA preferably 6-15 volumes more preferably 8-13 volumes of Formula IIIA, 1-10 volumes of 2,2-Dimethoxypropane preferably 1.5-6 volumes more preferably 2-4 volumes and 0.1-1 volume concentrated sulphuric acid OR with 20- 120 volumes of Formula IIIA preferably 40-100 volumes more preferably 60-90 volumes of Formula IIIA and 1-5 volumes of concentrated sulphuric acid, Stirred at 25-35°C for 6-30 hours preferably 12-24 hours till the analysis indicates completion of reaction.
  • the reaction mass is filtered and purified to isolate compound of Formula III.
  • the isolated compound of Formula III can also be neutralised with Aqueous Ammonia and the isolated Cytidine Acetonide can be used as such in the enzymatic reaction.
  • Step 2 100 gms (0.2624M) of compound of Formula III is treated with 1.1 - 5 equivalents of compound of Formula IIIC preferably 2-5 equivalents more preferably 2.2- 3.3 equivalents in 1,4-Dioxane or tetrahydrofuran or Diethyl ether or methyl tert-butyl ether or Di -isopropyl ether or Toluene or a mixture of Toluene & n-hexane or n-Heptane with 10%-300% w/w of IMMOBILIZED enzyme CAL B 1000-12000 preferably with 50- 200% w/w of the substrate and more preferably with 100-200% w/w of the substrate.
  • a base preferably selected from Triethylamine or Diethyl amine or N, N-diisopropyl ethylamine is added to the reaction mass and the reaction is stirred between 15 °C - 100°C preferably at 25- 65°C & more preferably at 30-40°C for 6-50 hours. TLC analysis after 6-50 hours indicates completion of reaction. HPLC analysis indicated 90% formation of the desired product. The reaction mass is filtered, washed with the relevant solvent and the filtrate is evaporated. The residue after evaporation is purified by column chromatography to give 84 gms of compound of Formula IV. HPLC analysis indicated the purified sample to be 95%-98% pure.
  • Step 3 To 1 equivalent of compound of Formula IV in 20 volumes of Isopropanol water mixture (24% water content) is added 2-7 equivalents of Hydroxylamine sulphate preferably 2-5 equivalents more preferably 3-5 equivalents & the entire reaction mass was heated at 25-80°C preferably 35-80°C more preferably 40-78°C for 6-45 hours. After TLC analysis the reaction mass is worked up and the crude product is either treated with 5-25 volumes of Formic acid preferably 6-20 volumes more preferably 10-15 volumes at 0-40 °C preferably at 20-40°C more preferably at 23-35°C for 3-10 hours till the TLC indicates completion of the reaction. After the reaction mass is worked up and purified by column chromatography to isolate pure 98%+ compound of Formula I.
  • reaction mass is heated at 25-80°C preferably at 35-80°C more preferably at 40-60°C for 6-45 hours preferably for 20-35 hours.
  • TLC analysis the reaction mass is worked up and the crude product is either treated with 5-25 volumes of Formic acid preferably 6-20 volumes more preferably 10-15 volumes at 0-40°C preferably at 20-40°C more preferably at 23-35°C for 3- 10 hours till the TLC indicates completion of the reaction.
  • the reaction mass is worked up and purified by column chromatography to isolate pure 98%+ compound of Formula I.
  • the CAL B enzyme used in the process of invention is expressed in Pichia pastoris.
  • Enzymes used for biocatalysis are immobilized on solid polyacrylate supports.
  • the supports are in form of porous hydrophobic polymer beads which may or may not contain active functional groups being any of epoxy, aldehyde or ionic groups.
  • Biocatalyst resulting from immobilization on these polymer beads by either adsorption, ionic interaction or covalent binding exhibit varying degree of selectivity, reactivity, and recyclability in the enzymatic reactions under different reaction conditions.
  • a reference immobilized form is denoted as Biocatalyst CALB TA 10000 and variants represented with alphanumeric notation in bracket following it (Cl, C2. . .) wherein difference in polymer support represented by numericals and alphabet representing enzyme variant used. It has been found that heterologous expression of CAL B in P. pastoris host, shows increased activity of lipase up to 3 to 10 times as compared to the native expression.
  • Cytidine (100g, 0.41mol) is treated with 8 litres of anhydrous acetone under nitrogen atmosphere. Neat sulfuric acid (100 ml) was added to the above suspension with vigorous stirring for 7-15 hours. After TLC analysis the reaction mass was filtered and the solid obtained was washed multiple (3 to 4) times with acetone (250mL X 4) followed by ether(250mLX2).
  • Biocatalyst CAL B 10000 (300g, 200 wt%) (BIOCATALYST CAL B TA 10000, 10000 u/g, expressed in Pichia pastoris, (Fermenta Biotech ltd) and acetone oxime O-iso butyryl ester (169 g, 1.18 mol, 3 equiv.) was then added and the resultant reaction was left stirring at room temperature for 24h. The reaction mixture was then filtered to remove enzymes and the solvent was removed by rotary evaporation, yielding the crude product as a yellow oil.
  • the crude product was redissolved in Dichloromethane (L5L) and washed the organic layer thoroughly with water (250ml X 4) and then with brine solution (250ml X 2), dichloromethane layer separated and dried with anhydrous Sodium sulphate. The Solvent was evaporated under vacuum yielding the crude product as yellowish oil. The crude product was purified by column chromatography (2-5 % gradient of Methanol in di chloromethane).
  • Cytidine acetonide salt (15g, 0.039 mol) in a 1 litre three neck round bottom flask was added anhydrous Tetrahydrofuran (300ml). Triethylamine (2.89 ml, 0.039mol, 1 equiv.) was added to the above flask upon which the suspension became a clear solution after stirring at room temperature for 5 minutes.
  • Biocatalyst CAL B 10000 (15g, 100 wt%) (BIOCATALYST CAL B TA 10000, 10000 u/g, expressed in Pichia pastoris, and acetone oxime O-iso butyryl ester (16.7 g, 0.115 mol, 3 equiv.) was then added and the resultant reaction was left stirring at room temperature for 40 hours. The reaction mixture was then filtered to remove enzymes and the solvent was removed by rotary evaporation, yielding the crude product as a yellow oil.
  • the crude product was redissolved in Dichloromethane (500ml) and washed Di chloromethane layer thoroughly with water (50ml X 4) and then with brine solution (50ml X 2), dichloromethane layer separated and dried with anhydrous sodium sulphate. Solvent was removed by rotary evaporation yielding the crude product as yellowish oil.
  • the crude product was purified by column chromatography (2-5 % gradient of Methanol in di chloromethane).
  • Cytidine acetonide salt (15g, 0.039 mol) in a 1 litre three neck round bottom flask was added anhydrous 1,4-Dioxane (300ml). Triethylamine (2.89 ml, 0.039mol, 1 equiv.) was added to the above flask upon which the suspension became a clear solution after stirring at room temperature for 5 minutes.
  • Biocatalyst CAL B 10000 (30g, 200 wt%) (BIOCATALYST CAL B TA 10000, 10000 u/g, expressed in Pichia pastoris, Fermenta Biotech ltd.,) and acetone oxime O-iso butyryl ester (16.7 g, 0.115 mol, 3 equiv.) was then added and the resultant reaction was left stirring at room temperature for 45 hours. The reaction mixture was then filtered to remove enzymes and the solvent was removed by rotary evaporation, yielding the crude product as a yellow oil.
  • the crude product was redissolved in dichloromethane (500ml) and washed dichloromethane layer thoroughly with water (50ml X 4) and then with brine solution (50ml X 2), DICHLOROMETHANE layer separated and dried with anhydrous sodium sulphate. Solvent was removed by rotary evaporation yielding the crude product as yellowish oil.
  • the crude product was purified by column chromatography (2-5 % gradient of Methanol in di chloromethane).
  • Cytidine acetonide salt (15g, 0.039 mol) in a 1 litre three neck round bottom flask was added anhydrous 1,4-Dioxane (300ml). Triethylamine (2.89 ml, 0.039mol, 1 equiv.) was added to the above flask upon which the suspension became a clear solution after stirring at room temperature for 5 minutes.
  • Biocatalyst CAL B 10000 (30g, 200 wt%) (BIOCATALYST CAL B TA 10000, 10000 u/g, expressed in Pichia pastoris, (Fermenta Biotech ltd) and acetone oxime O-iso butyryl ester (16.7 g, 0.115 mol, 3 equiv.) was then added and the resultant reaction was left stirring at 50-55°C for 24-29 hours. The reaction mixture was then filtered to remove enzymes and the solvent was removed by rotary evaporation, yielding the crude product as a yellow oil.
  • the crude product was redissolved in dichloromethane (500ml) and washed dichloromethane layer thoroughly with water (50ml X 4) and then with brine solution (50ml X 2), dichloromethane layer separated and dried with anhydrous sodium sulphate. Solvent was removed by rotary evaporation yielding the crude product as yellowish oil.
  • the crude product was purified by column chromatography (2-5 % gradient of Methanol in di chloromethane).
  • the crude dry residue is treated with Formic acid and heated at 23-33 °C for 3-5 hours till the TLC analysis indicated the completion of the reaction.
  • the solvent is evaporated under vacuum and stripped with Methanol, isopropanol & methyl tert-butyl ether repeatedly and the crude residue is purified by column chromatography using Ethyl Acetate: Methanol (0-15% gradient respectively).
  • the crude dry residue is treated with Formic acid and heated at 23- 33 °C for 3-5 hours till the TLC analysis indicated the completion of the reaction.
  • the solvent is evaporated under vacuum and stripped with Methanol, isopropanol & methyl tert-butyl ether repeatedly and the crude residue is purified by column chromatography using Ethyl Acetate: Methanol (0-15% gradient respectively). After evaporation 5.5 gms of the white solid is isolated.
  • the HPLC analysis of the isolated compound MOLNUPIRAVIR indicates 98%+ purity.

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Abstract

Est divulgué ici un procédé pour la synthèse de Molnupiravir à partir de cytidine à l'aide d'une lipase pour une réaction d'estérification. Le procédé comprend la réaction d'un composé de formule II avec de l'acétone en présence d'acide sulfurique pour obtenir un composé de formule III; la conversion enzymatique d'un composé de formule III en un composé de formule IV, et l'hydroxyamination d'un composé de formule IV à l'aide d'un hydroxylamine sulfate ou d'un chlorhydrate suivie d'une déprotection pour obtenir un composé de formule I.
PCT/IN2021/050456 2021-02-06 2021-05-13 Procédé chimio-enzymatique pour la synthèse du molnupiravir WO2022168106A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019113462A1 (fr) * 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine et dérivés et leurs utilisations anti-virales

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019113462A1 (fr) * 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine et dérivés et leurs utilisations anti-virales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BENKOVICS TAMAS, MCINTOSH JOHN A, SILVERMAN STEVEN M, KONG JONGROCK, MALIGRES PETER, ITOH TETSUJI, YANG HAO, HUFFMAN MARK A, VERMA: "Evolving to an Ideal Synthesis of Molnupiravir, an Investigational Treatment for COVID19", CHEMRXIV, 23 December 2020 (2020-12-23), Cambridge, pages 1 - 5, XP055959886, DOI: 10.26434/chemrxiv.13472373.v1 *
N. VASUDEVAN ET AL.: "A concise route to MK -4482 (EIDD-2801) from cytidin e", CHEM. COMMUN., vol. 56, 2 October 2020 (2020-10-02), pages 13363 - 13364, XP055950766, DOI: https://doi.org/10.1039/DOCC05944G *

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