WO2022018625A1 - Procédé de préparation d'un intermédiaire utilisé dans la synthèse du létermovir - Google Patents

Procédé de préparation d'un intermédiaire utilisé dans la synthèse du létermovir Download PDF

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Publication number
WO2022018625A1
WO2022018625A1 PCT/IB2021/056528 IB2021056528W WO2022018625A1 WO 2022018625 A1 WO2022018625 A1 WO 2022018625A1 IB 2021056528 W IB2021056528 W IB 2021056528W WO 2022018625 A1 WO2022018625 A1 WO 2022018625A1
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process according
carried out
formula
benzyl
methoxy
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PCT/IB2021/056528
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English (en)
Inventor
Stefania BERTUOLO
Mara Sada
Alberto Mazza
Aldo Bianchi
Lazzaro Feliciani
Giorgio Bertolini
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Olon S.P.A.
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Publication of WO2022018625A1 publication Critical patent/WO2022018625A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms

Definitions

  • the present invention relates to an enantioselective process for the preparation of letermovir.
  • Letermovir ((4S)-2- ⁇ 8-fluoro-2 - [4-( 3 -methoxypheny l)piperazin- 1 -y 1] - 3 - [2- methoxy-5-(trifluoromethyl)phenyl]-3 ,4-dihydroquinazolin-4-yl ⁇ acetic acid), of formula
  • CMV cytomegalovirus
  • HSCT allogeneic haematopoietic stem cell transplant
  • the medicament (tradename Prevymis®) has a novel action mechanism: it inhibits the CMV enzyme known as “terminase” involved in DNA packaging in the protein coatings of the virus. In this way the virus is prevented from developing correctly and infecting other cells.
  • Letermovir exhibits stereoisomerism due to the presence of a chiral centre with the S configuration on the C4 carbon atom of the dihydroquinazoline ring.
  • the penultimate step in the synthesis method disclosed in WO2006133822, WO2013127971 and WO2013127968 is resolution with chiral salts of (4R/S)-2- ⁇ 8- fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]- 3 ,4-dihy droquinazolin-4-yl ⁇ acetic acid in racemic form to give letermovir, leading to a reduction in the global yield of the process, and loss of the undesirable enantiomer.
  • Guy R Humphrey et al. described in Org. Process. Res. Dev. 2016, 20, 1097- 1103 an enantioselective aza-Michael reaction catalysed by chiral quaternary bisammonium salts. Said salts are unstable in a basic medium and are used in phase- transfer conditions, giving rise to a product with moderate enantioselectivity and not very high yields.
  • the synthesis comprises the formation of guanidine salicylate (intermediate A), obtained after 5 steps, followed by enantioselective closure of the heterocyclic ring (intermediate B) by means of the aza-Michael reaction.
  • the purpose of the invention is to find a novel enantiose!ective synthesis method that produces letermovir with high enantiomeric excesses and a higher yield, using cheaper intermediates.
  • Letermovir is obtained from intermediate VII, via a series of reactions, with good yields (57%) and a high degree of enantioselection, with no need for enrichments with chiral salts or particular purifications of the intermediates using chromatography columns.
  • Figure 1 chromatogram relating to the compound of formula VII for determination of the enantiomeric ratio.
  • Figure 4 chromatogram relating to letermovir (I) for determination of the enantiomeric ratio.
  • the present invention relates to an enantioselective process for the preparation of letermovir of formula (I) which comprises: a) Reaction of compound of formula III, wherein R is a straight or branched C1- C4 alkyl, with (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone (IV), in the presence of TiCl 4 and an aliphatic amine; b) Hydrolysis of compounds of formula V obtained in a) in the presence of bases to give compounds of formula VI; c) Cyclisation of compounds of formula VI in the presence of organic bases d) Esterification of compound of formula VII e) Reaction of ester of formula VIII with N-(3-methoxyphenyl)piperazine or a salt thereof to give compound of formula IX in the presence of a chlorinating agent and an organic base f) Hydrolysis of compound of fonnula IX to give letermovir I
  • R represents
  • organic base refers to aliphatic or aromatic amines, alcoholates and carboxylates.
  • base refers to any basic organic or inorganic compound that has basicity according to Bransted definition.
  • DMF dimethylfonnamide
  • DBU 1,8-diazabicyclo[5,4,0]undec-7-ene.
  • GDI carbonyldiimidazole
  • DCC dicyclohexylcarbodiimide
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide.
  • Step a) is conducted in an aprotic solvent selected from toluene, methylene chloride, chlorobenzene, dichlorobenzene, 1,2-dichloroethane, chloroform or mixtures thereof, preferably methylene chloride at a temperature ranging between -90°C and 0°C, and advantageously at -60°C.
  • an aprotic solvent selected from toluene, methylene chloride, chlorobenzene, dichlorobenzene, 1,2-dichloroethane, chloroform or mixtures thereof, preferably methylene chloride at a temperature ranging between -90°C and 0°C, and advantageously at -60°C.
  • the amine used in step a) is selected from triethylamine, diisopropylamine and tetramethylenediamine, sparteine, preferably triethylamine or diisopropylamine, and more preferably diisopropylamine.
  • Crude (2-((S)-3-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-1-((2-methoxy-5- (trifluoromethyl)phenyl)amino)-3-oxopropyl)-6-fluorophenyl)carbamate (V) is obtained at the end of the reaction, and used in the next step without any purification.
  • step b) (2-((S)-3-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-1-((2-methoxy-5- (trifluoromethyl)phenyl)ammo)-3-oxopropyl)-6-fluorophenyl)carbamate (V) IS hydrolysed in a mixture of solvents selected from tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane and 1,2-dicycloethane in combination with water in tiie presence of bases selected from alkali hydroxides, potassium tert-butylate, sodium methylate, sodium ethylate, sodium and potassium carbonates and bicarbonates, and DMAP; the preferred conditions are tetrahydrofuran/ water with the addition of sodium hydroxide.
  • solvents selected from tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane and 1,2-dicy
  • step c) to give (5)-2-(8-fluoro-3-(2- methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetic acid (VII) is conducted in a polar solvent selected from acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, dimethoxy ethane, ethanol and methanol, preferably acetonitrile in the presence of an organic base, preferably selected from DBU, DMAP, triethylamine, pyridine, potassium tert-butylate, sodium methylate and sodium ethylate, advantageously DBU.
  • a polar solvent selected from acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydro
  • Esterification step d) can be conducted in various ways. Acid VII is reacted with alcohols selected from straight C1-C3 alcohols, benzyl alcohol in the presence of a condensing agent selected from DCC, EDC and GDI, preferably GDI, and an organic base selected from DBU, triethylamine and DMAP, advantageously DBU.
  • a condensing agent selected from DCC, EDC and GDI, preferably GDI
  • an organic base selected from DBU, triethylamine and DMAP, advantageously DBU.
  • step d) is conducted in the presence of methyl bromide, ethyl bromide, benzyl bromide or chloride, preferably benzyl bromide, in a polar aprotic solvent selected from acetone, methyl ethyl ketone and acetonitrile, under reflux.
  • a polar aprotic solvent selected from acetone, methyl ethyl ketone and acetonitrile
  • Step e) which gives rise to synthesis of compound IX, is conducted in the presence of a chlorinating agent selected from POCl 3 and PCl 5 , preferably PCl 5 , and N-(3- methoxyphenyI)piperazine or a salt thereof, with the addition of organic bases selected from DBU, DMAP and TEA, advantageously DBU.
  • the reaction is conducted in a mixture of solvents selected from toluene, chlorobenzene, dioxane, DMF and TFE, preferably DMF and TFE, advantageously DMF.
  • Step f) when R* is benzyl, is conducted in the presence of gaseous hydrogen and a metal catalyst, preferably palladium on carbon, to give letermovir with an enantiomeric ratio of 99.97: 0.03, calculated by chiral HPLC.
  • a metal catalyst preferably palladium on carbon
  • the benzyl can be removed by using as hydrogen source formic acid or ammonium formate in water in the presence of a metal catalyst, preferably palladium on carbon.
  • step f) is conducted in the presence of alkali hydroxides, preferably sodium hydroxide.
  • the mixture is extracted with 0.5N NaOH (aq) (60 mL), dichloromethane (80 mL) is added to the aqueous phase, the mixture is acidified with HCl (aq) concentrated to an acid pH, and the organic phase is concentrated to residue.
  • a solution of benzyl alcohol (112 g) and DBU (7.7 g) in DMF (11.2 mL) is then dripped in, and the mixture is maintained under stirring for 18 hours at room temperature.
  • the mixture is diluted with toluene, and water is dripped in.
  • Solid potassium carbonate (0.75 g) is added to a suspension of (S)-2-(8-fluoro-3- (2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo- 1 ,2,3,4-tetrahydroquinazolin-4-yl)acetic acid (2.0 g) in acetone (40 mL), and stirred at room temperature for 5 min. A solution of acetone containing methyl bromide (0.5 g) is added, and the mixture is heated to reflux and stirred for 2-3 h. The mixture is cooled to room temperature, ethyl acetate (40 mL) and water (40 mL) are added, and the aqueous phase is removed.
  • the mixture is cooled to room temperature and the reaction mixture is dripped into water (240 mL), maintaining the temperature at between 40 and 50°C.
  • the mixture is cooled to room temperature and diluted with dichloromethane (240 mL), and the organic phase is separated, then washed once with water and once with a saturated solution of NaCl(iq).
  • the dichloromethane is distilled under atmospheric pressure.
  • 1-(3-methoxyphenyl)piperazine hydrochloride (18.1 g) and 1,4-dioxane (80 mL) are added, and DBU (23.5 g) is then dripped in.
  • the mixture is then heated under reflux for 2 h.
  • the mixture is cooled to room temperature, diluted with dichloromethane (250 mL) and washed with water, a 5% solution of NaHCO 3(aq) and a saturated solution of NaCl (aq) .
  • the solvent is distilled under vacuum to a small volume, after which isopropanol (300 mL) is added, and the mixture is heated until dissolution and left to stand at room temperature.
  • Phosphorus pentachloride (17 g) is added to a solution of crude (S)-benzyl 2-(8- fluoro-3 -(2-methoxy-5 - ⁇ trifluoromethy l)pheny l)-2-oxo-1,2,3,4 -tetrahydroquinazolin-4- yl)acetate (8.0 g) in dichloromethane (100 mL), heated to reflux and stirred for 2 hours. The mixture is left to cool at room temperature, water (50 mL) is added, the reflux reached is maintained for 15 min, the mixture is cooled to room temperature, and the aqueous phase is removed.
  • the organic phase is washed with a saturated solution of NaHCO 3(aq) and NaCl (aq) , then concentrated to residue.
  • the residue is taken up with DMF (50 mL), and a solution of 1 -(3 -methoxyphenyl)piperazme (15 g) in DMF (50 mL) is added.
  • the solution is heated to 120-130°C and stirred for 3 h.
  • the solution is cooled to room temperature, toluene is added, and the organic phase is washed with water and distilled to a small volume.
  • the organic phase is eliminated and acidified with an aqueous solution of 0.5 M HC1 until pH 5-6 is reached.
  • the aqueous phase is extracted with Et 2 O (5 mLx3).
  • the combined organic phases are washed with a saturated aqueous solution of NaCl and dried with Na 2 SO 4 .
  • the drying agent is filtered and evaporated to residue to obtain 22 mg of

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé énantiosélectif pour la préparation de létermovir de formule (I), qui comprend l'addition énantiosélective de (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)éthanone (IV), catalysé par TiCl4 sur l'imine de formule III, pour donner un intermédiaire V, qui est hydrolysé à l'acide de formule VI et ensuite cyclisé en présence de bases organiques pour donner un intermédiaire VII, à partir duquel le létermovir est obtenu avec de bons rendements et un degré élevé d'énantiosélection.
PCT/IB2021/056528 2020-07-21 2021-07-20 Procédé de préparation d'un intermédiaire utilisé dans la synthèse du létermovir WO2022018625A1 (fr)

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IT102020000017617 2020-07-21
IT102020000017617A IT202000017617A1 (it) 2020-07-21 2020-07-21 Procedimento per la preparazione di un intermedio utilizzato nella sintesi del letermovir

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114942278A (zh) * 2022-04-12 2022-08-26 山东诚创蓝海医药科技有限公司 来特莫韦中间体二d-(+)-二对甲基苯甲酰酒石酸乙酸乙酯络合物有关物质的分析方法
CN115010670A (zh) * 2022-07-07 2022-09-06 山东诚创蓝海医药科技有限公司 一种莱特莫韦中间体的氯代方法
WO2023185597A1 (fr) * 2022-04-01 2023-10-05 上海迪赛诺化学制药有限公司 Intermédiaire de letermovir et son procédé de préparation

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WO2006133822A1 (fr) * 2005-06-15 2006-12-21 Bayer Healthcare Ag Procede pour produire des dihydroquinazolines
WO2015088931A1 (fr) * 2013-12-12 2015-06-18 Merck Sharp & Dohme Corp. Procédé de préparation de composés quinazoline substitués

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DE102012101659A1 (de) 2012-02-29 2013-08-29 Aicuris Gmbh & Co. Kg Salze eines Dihydrochinazolinderivats
DE102012101673A1 (de) 2012-02-29 2013-08-29 Aicuris Gmbh & Co. Kg Salze eines Dihydrochinazolinderivats

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WO2006133822A1 (fr) * 2005-06-15 2006-12-21 Bayer Healthcare Ag Procede pour produire des dihydroquinazolines
WO2015088931A1 (fr) * 2013-12-12 2015-06-18 Merck Sharp & Dohme Corp. Procédé de préparation de composés quinazoline substitués

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FRANCISCO VELAZQUEZ ET AL: "The Application of Chiral Oxazolidinethiones and Thiazolidinethiones in Asymmetric Synthesis", CURRENT ORGANIC CHEMISTRY, vol. 6, no. 4, 1 April 2002 (2002-04-01), NL, pages 303 - 340, XP055751653, ISSN: 1385-2728, DOI: 10.2174/1385272024605023 *
PU-SHENG WANG ET AL: "Access to Chiral Hydropyrimidines through Palladium-Catalyzed Asymmetric Allylic C-H Amination", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 56, no. 50, 24 October 2017 (2017-10-24), pages 16032 - 16036, XP055730309, ISSN: 1433-7851, DOI: 10.1002/anie.201709681 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023185597A1 (fr) * 2022-04-01 2023-10-05 上海迪赛诺化学制药有限公司 Intermédiaire de letermovir et son procédé de préparation
CN114942278A (zh) * 2022-04-12 2022-08-26 山东诚创蓝海医药科技有限公司 来特莫韦中间体二d-(+)-二对甲基苯甲酰酒石酸乙酸乙酯络合物有关物质的分析方法
CN114942278B (zh) * 2022-04-12 2023-09-08 山东诚创蓝海医药科技有限公司 来特莫韦中间体二d-(+)-二对甲基苯甲酰酒石酸乙酸乙酯络合物有关物质的分析方法
CN115010670A (zh) * 2022-07-07 2022-09-06 山东诚创蓝海医药科技有限公司 一种莱特莫韦中间体的氯代方法

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