[go: up one dir, main page]

WO2023200364A1 - Procédé de production de (1r,2s,5s)-n-[(1s)-1-cyano-2-[(3s)-2-oxopyrrolidine-3-l]éthyl-3-[(2s)-3,3-diméthyl-2-[(2,2,2-trifluoroacétyl)amino]butanoyl]-6,6-diméthyl-3-azabicclo[3.1.0]hexan-2-carboxamide - Google Patents

Procédé de production de (1r,2s,5s)-n-[(1s)-1-cyano-2-[(3s)-2-oxopyrrolidine-3-l]éthyl-3-[(2s)-3,3-diméthyl-2-[(2,2,2-trifluoroacétyl)amino]butanoyl]-6,6-diméthyl-3-azabicclo[3.1.0]hexan-2-carboxamide Download PDF

Info

Publication number
WO2023200364A1
WO2023200364A1 PCT/RU2023/000117 RU2023000117W WO2023200364A1 WO 2023200364 A1 WO2023200364 A1 WO 2023200364A1 RU 2023000117 W RU2023000117 W RU 2023000117W WO 2023200364 A1 WO2023200364 A1 WO 2023200364A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
temperature
product
reaction
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/RU2023/000117
Other languages
English (en)
Russian (ru)
Inventor
Петр Александрович Белый
Эдуард Юрьевич Лопатухин
Владимир Львович КОРОЛЕВ
Кира Яковлевна ЗАСЛАВСКАЯ
Евгений Юрьевич БЕЛОВ
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.)
"promomed Rus" LLC
Original Assignee
"promomed Rus" LLC
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
Priority claimed from RU2022110275A external-priority patent/RU2794748C1/ru
Application filed by "promomed Rus" LLC filed Critical "promomed Rus" LLC
Publication of WO2023200364A1 publication Critical patent/WO2023200364A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • RNA viruses notable examples of which over the past 20 years are: severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002-2003, influenza (swine flu) A/H1N1 in 2009 ., the Middle East respiratory syndrome (MERS) coronavirus in 2012, the Ebola virus disease epidemic in 2013-2015, the Zika virus pandemic in 2016-2017, and now the COVID-19 pandemic.
  • IP A isopropanol
  • the last stage of the synthesis involves the addition of methanesulfonic acid to the product obtained in the previous stage, in 1,1,1,3,3,3-hexafluoropropan-2-ol, with further concentration in a mixture of solvents acetonitrile/ethyl acetate and ethyl acetate/heptane, followed by dissolution in dichloromethane and treatment with 4-methylmopholine and trifluoroacetic anhydride.
  • stereoisomers in the context of the present invention defines all possible isomers that the compounds of the present invention may have, formed from identical sets of atoms connected by the same sequence of bonds, but having different spatial arrangements of atoms or groups of atoms relative to the bonds, while isomeric compounds are not are interchangeable.
  • the chemical designation of a compound includes a mixture of all possible stereochemically isomeric forms that the specified compound may have. Said mixture may contain all diastereomers and/or enantiomers of the molecular structure of said compound.
  • all stereoisomeric forms of the compounds used herein are intended to be invention, both in pure (individual) form and in mixture with each other, are included within the scope of the present invention.
  • One embodiment of the present invention is a method for preparing a compound of formula (I), which includes dehydrating a compound of formula (II) to form a compound of formula (I) using 2,4,6-trichloro-1,3,5-triazine in a solvent environment , carried out according to the following scheme:
  • the stated problem is solved, and the stated technical results are achieved by means of a new method for producing a compound of formula (I), which includes dehydration of a compound of formula (II) obtained by any of the methods of the present invention, with the formation of a compound of formula (I) using 2, 4, 6-trichloro-1, 3,5-triazine in a solvent environment, according to the following scheme:
  • One embodiment of the invention is a method for producing a compound of formula (I), in which N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone is used as a solvent.
  • One embodiment of the invention is a method for preparing a compound of formula (I), in which the dehydration of a compound of formula (II) is carried out at a temperature in the range from 0°C to 100°C, more preferably from 15°C to 25°C.
  • One embodiment of the invention is a method for producing a compound of formula (I) (target product), in which the stage of dehydration of a compound of formula (II) additionally includes the following stages: a) isolating the target product and/or b) washing the isolated target product and/or; c) drying the target product, where the step of washing the isolated target product further includes a step of recrystallizing the target product by suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained and then cooling naturally at room temperature.
  • an aprotic solvent is used as an organic solvent in the reaction to produce a compound of formula (IV) by reacting a compound of formula (P”) with a compound of formula (PG).
  • the tertiary amine of the present invention is, but is not limited to, a compound of the formula R2R3R4N, wherein R2, R3, R4 independently represent a C-C5 alkyl group or, when R2 and R3 together with a nitrogen atom form a C4-C8 cycloalkyl group or a C -Cya heterocyclic group, where the heteroatom is oxygen and R4 is C1-C5 alkyl.
  • One embodiment of the invention is a method for preparing a compound of formula (IV), wherein, provided that when Rf is hydrogen, R2' is tert-butyl, the compound of formula (PG) is used in the form of a hydrochloride salt.
  • One embodiment of the invention is a method for preparing a compound of formula (IV), in which the additional step of deprotection is carried out at a temperature from -10°C to 50°C, more preferably from -5°C to 40°C, more preferably from - 5°C to 30°C, more preferably -5°C to 20°C, more preferably -5°C to 10°C, more preferably 0°C to 10°C.
  • One embodiment of the present invention is a method for preparing a compound of formula (IV'), in which the reaction of a compound of formula (1D") with a compound of formula (III") takes place in an organic solvent.
  • the tertiary amine in the reaction to produce the compound of formula (IV') of the present invention is a compound of formula R2R3R4N as defined above.
  • the alkali hydroxide that is used in step a) of the present invention is sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • step b) of the present invention is carried out using anhydrous strong acid.
  • hydrochloric acid hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid is used as the inorganic acid in step b) of the present invention.
  • One embodiment of the invention is a method for producing a compound of formula (I), in which steps a)”, b)”, c)”, d)” and/or e)” additionally include the following stages: f) isolation of the product; j) washing the isolated product; h) drying the product, where step j) washing the isolated product further includes the step of recrystallizing the product from an organic solvent.
  • One embodiment of the invention is a method for producing a compound of formula (I) (target product), in which stages a)”, b)”, c)”, d)” and/or e)” additionally include the following stages: f) isolation product and/or j) washing the isolated product and/or; h) drying the product, where the step of washing the isolated product further includes the step of recrystallizing the product by suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained and then cooling naturally at room temperature.
  • Monitoring of the stereoisomeric purity of the compounds of the present invention can be carried out, including, but not limited to, using analytical HPLC.
  • the proposed method for obtaining a compound of formula (I) according to one of the embodiments of the present invention involves obtaining a compound of formula (I) according to the following synthesis scheme:
  • a compound of formula (II) is prepared by reacting a commercially available compound of formula (V) or a salt thereof, including, but not limited to, the hydrochloride, and a compound of formula (IV) obtained in the previous step in a suitable solvent, including an aprotic one, selected from the group, not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence a compound of the formula RiO-CO-Cl described above, and a base, including, but not limited to, pyridine, pyridine substituted with a C1-C5 alkyl, quinoline or quinoline substituted with a C1-C5 alkyl, tertiary amine, including , a tertiary amine of the formula R2R3R4N, as described above, at a temperature of -50°C
  • Compound (P”) is prepared by reacting compound (VII') with a reagent of formula CF3COOR1', provided that Ri' is pentafluorophenyl, in a suitable aprotic solvent selected from the group, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., and bases such as, but not limited to, pyridine, C1-C5 alkyl substituted pyridine, quinoline or C1-C5 alkyl substituted quinoline, tertiary amine, including , a tertiary amine of the formula R2R3R4N, described above in the text, at a temperature of -50°C to 50°C. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound formula (P”) is extracted with a suitable organic solvent that is immiscible with water
  • a base such as, but not limited to, pyridine, C1-C5 alkyl-substituted pyridine, quinoline or C1-C5 alkyl-substituted quinoline, a tertiary amine, including the tertiary amine of the formula R2R3R4N described above, at a temperature from -50° ⁇ to 50° ⁇ .
  • the reaction mass is evaporated or diluted with water, the compound of formula (P”) is extracted with a suitable organic solvent that is immiscible with water.
  • the resulting extract is washed, if necessary, with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with dewatering agents such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent, either purified by liquid chromatography or used in the next step without further purification.
  • recrystallization of the product may include suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and subsequent cooling (including naturally at room temperature).
  • the compound of formula (P”) of the present invention can also be isolated by precipitation by filtration.
  • a suitable solvent is added to the reaction mass, including, but not limited to, ethyl alcohol, methyl alcohol, isopropyl alcohol, THF, dioxane, ethyl acetate, etc., as well as an anhydrous strong acid selected from group, including, but not limited to: hydrochloric, hydrobromic, hydroiodic, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid, etc. at temperatures from -10°C to 50°C.
  • a compound of formula (V) or a salt thereof and the specified base for example, a tertiary amine as described above, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from 10°C to 50 °C until the reaction is completed.
  • the reaction mass is evaporated or diluted with water, the compound of formula (II) is extracted with a suitable organic solvent that is immiscible with water.
  • the resulting extracts at each stage of the synthesis are, if necessary, washed with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent, either purified by liquid chromatography, or used in the next step without further purification.
  • recrystallization of the product may include suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and subsequent cooling (including naturally at room temperature).
  • the intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.
  • Rf is succinimidyl
  • R > is hydrogen
  • the compound of formula (IV) can be prepared according to the present invention by reacting a compound of formula (II) obtained by a known synthesis or a new synthesis according to the present invention and a commercially available compound of formula (PG) or a salt thereof, in particular an alkali or alkaline earth metal salt of the compound formula (PG), in a solvent selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or a mixture thereof, at a temperature from 0°C to 100°C.
  • a solvent selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or a mixture thereof, at a temperature from 0°C to 100°C.
  • a base is added to the reaction mixture, in particular selected from the group, but not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, including a tertiary amine of the formula R2R3R4N, as described above.
  • the reaction mass is evaporated or diluted with water, acidified, if necessary, with inorganic or organic acid to pH from 0 to 6.9, the compound of formula (IV) is extracted with a suitable organic solvent that is immiscible with water.
  • a compound of formula (V) or its salt, including the hydrochloride, and the specified base, for example, a tertiary amine are added to the reaction mass, described above, at a temperature from -50°C to 10°C and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction.
  • the reaction mass is evaporated or diluted with water, the compound of formula (II) is extracted with a suitable organic solvent that is immiscible with water.
  • reaction mass is evaporated or diluted with water, the compound of formula (IV’) is extracted with a suitable organic solvent that is immiscible with water.
  • the compound of formula (VII”) (provided that Rj” is pentafluorophenyl) is prepared by reacting the compound of formula (VI) obtained in the previous step in a suitable solvent selected from the group not limited to the above: ethyl alcohol, methyl alcohol, isopropyl alcohol, THF, dioxane, ethyl acetate, etc.
  • a compound of formula CF COOR' (where R' is pentafluorophenyl) in the presence of a base selected from the group, but not limited to, pyridine, pyridine substituted with Ci-C5 alkyl, quinoline or quinoline substituted with C1- C5 alkyl, tertiary amine, including the tertiary amine of the formula R2R3R4N, described above, at a temperature of from 0°C to 100°C.
  • the reaction mass is evaporated or diluted with water, acidified with inorganic or organic acid to pH from 0 to 6.9, the compound of formula (VII”) is extracted with a suitable organic solvent that is immiscible with water.
  • a compound of formula (VII”) and the specified base for example a tertiary amine
  • a suitable solvent for example an aprotic solvent
  • a compound of the formula RiO-CO-Cl described above
  • a compound of formula (V) or a salt thereof, for example a hydrochloride and said base, for example a tertiary amine, are added to the reaction mixture.
  • a temperature from -50°C to 10°C and then maintain the resulting reaction mass at a temperature from -10°C to 50°C until the end of the reaction.
  • the resulting extracts at each stage of the synthesis are, if necessary, washed with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent and/or purified by liquid chromatography, or used in the next step without further purification.
  • recrystallization of the product may include suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and subsequent cooling (including naturally at room temperature).
  • the compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2, 4, 6-trichloro-1, 3,5-triazine in a suitable solvent, for example protic, selected from the group consisting of limited to the specified: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at a temperature of 0°C to 100°C for 1.5-3.0 hours.
  • a suitable solvent for example protic, selected from the group consisting of limited to the specified: dimethylformamide, dimethylacetamide, N-methylpyrrolidone
  • the resulting extract was washed with a solution of sodium bicarbonate, evaporated to constant weight and recrystallized from heptane, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the target product compound of formula (I) was obtained in the form of a powder with a yield of 96%.
  • compounds of formula (P”) were prepared by the following method. To 400.00 ml of tetrahydrofuran, 13.10 g of the compound of formula (VII'), 56.00 g of trifluoroacetic acid pentafluorobenzoate (2.00 equivalents) and 15.60 g of pyridine (2.00 equivalents) were added at a temperature of 25°C.
  • compounds of formula (P”) were prepared by the following method. To 300.00 ml of ethyl acetate were added 22.70 g of the compound of formula (VIF) and 11.50 g of N-hydroxysuccinimide, in the presence of 20.60 g of dicyclohexylcarbodiimide at a temperature of -10°C. The reaction mixture was heated to room temperature and kept at 25°C for 8 hours. Next, the reaction mass was filtered from the precipitated urea and evaporated to constant weight, the residue was recrystallized from heptane. The output was 98% of the compound of formula (P”).
  • a special case of the present invention is also a method for preparing a compound of formula (I) according to the following synthesis scheme: 20.60 g of a compound of formula (1D"), 23.10 g of a compound of formula (III") were dissolved in 210.00 ml of dimethylacetamide and 22.20 g (2.20 equivalents) of N-methylmorpholine were added. The reaction mass was stirred until dissolved and then 15.00 g (1.10 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0 ° C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25 ° C for 12-18 hours.
  • the resulting compound of formula (VII”) was extracted with ethyl acetate, the extract was washed with a solution of citric acid, water and a solution of sodium chloride, and evaporated. The resulting substance was used in the next step without purification.
  • reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at bath temperature of 45°C and a residual pressure of 30 mbar, the resulting compound of formula (II) was extracted with ethyl acetate, the extract was washed with water and a solution of citric acid, and then evaporated to constant weight.
  • the resulting substance of formula (II) was used in the next step without purification.
  • the resulting extract was washed with a solution of sodium bicarbonate, evaporated and recrystallized from heptane, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the target product compound of formula (I) was obtained in the form of a powder with a yield of 96%.
  • Burgess' reagent, trifluoroacetic anhydride, phosphorus trichloroxide and 2, 4,6-tripropyl-1,3, 5,2 are also known from the prior art as reagents for dehydration of the amide group of a compound of formula (II) ,4,6-trioxatriphosphinane 2,4,6-trioxide.
  • the authors of the present invention have carried out a number of experiments to study this reaction using various reagents.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Ce groupe d'inventions se rapporte au domaine de la médecine, de la pharmacologie et de l'industrie chimique et pharmaceutique, et concerne notamment de nouveaux procédés améliorés de production de (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-l]éthyl-3-[(2S)-3,3-diméthyl-2-[(2,2,2-trifluoroacétyl)amino]butanoyl]-6,6-diméthyl-3-azabicclo[3.1.0]hexan-2-carboxamide (composé de la formule (I)), ainsi que des procédés de production de produits intermédiaires que l'on utilise dans un procédé de production du composé de la formule (I).
PCT/RU2023/000117 2022-04-15 2023-04-14 Procédé de production de (1r,2s,5s)-n-[(1s)-1-cyano-2-[(3s)-2-oxopyrrolidine-3-l]éthyl-3-[(2s)-3,3-diméthyl-2-[(2,2,2-trifluoroacétyl)amino]butanoyl]-6,6-diméthyl-3-azabicclo[3.1.0]hexan-2-carboxamide Ceased WO2023200364A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
RU2022110275A RU2794748C1 (ru) 2022-04-15 Синтез (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
RU2022110273A RU2794755C1 (ru) 2022-04-15 Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
RU2022110272A RU2794754C1 (ru) 2022-04-15 Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
RU2022110276 2022-04-15
RU2022110273 2022-04-15
RU2022110274A RU2794746C1 (ru) 2022-04-15 Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
RU2022110272 2022-04-15
RU2022110274 2022-04-15
RU2022110275 2022-04-15
RU2022110276A RU2794750C1 (ru) 2022-04-15 Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида

Publications (1)

Publication Number Publication Date
WO2023200364A1 true WO2023200364A1 (fr) 2023-10-19

Family

ID=88330111

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2023/000117 Ceased WO2023200364A1 (fr) 2022-04-15 2023-04-14 Procédé de production de (1r,2s,5s)-n-[(1s)-1-cyano-2-[(3s)-2-oxopyrrolidine-3-l]éthyl-3-[(2s)-3,3-diméthyl-2-[(2,2,2-trifluoroacétyl)amino]butanoyl]-6,6-diméthyl-3-azabicclo[3.1.0]hexan-2-carboxamide

Country Status (1)

Country Link
WO (1) WO2023200364A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA023259B1 (ru) * 2011-01-04 2016-05-31 Новартис Аг Индольные соединения или их аналоги, полезные для лечения возрастной макулярной дегенерации (amd)
WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
CN114213275A (zh) * 2021-12-31 2022-03-22 戊言医药科技（上海）有限公司 用于合成帕罗韦德的中间产物及制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA023259B1 (ru) * 2011-01-04 2016-05-31 Новартис Аг Индольные соединения или их аналоги, полезные для лечения возрастной макулярной дегенерации (amd)
WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
CN114213275A (zh) * 2021-12-31 2022-03-22 戊言医药科技（上海）有限公司 用于合成帕罗韦德的中间产物及制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAFYDD R. OWEN ET AL.: "An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19", SCIENCE, vol. 374, no. 6575, 24 December 2021 (2021-12-24), pages 1586 - 1593, XP093017184, DOI: 10.1126/science.abl4784 *

Similar Documents

Publication Publication Date Title
CN104936961A (zh) (1s,4s,5s)-4-溴-6-氧杂二环[3.2.1]辛-7-酮的制备方法
JP7242924B2 (ja) 銅およびニッケル触媒による脱炭酸ホウ素化反応
JP6792069B2 (ja) ５ｒ−ベンジルオキシアミノピペリジン−２ｓ−ギ酸又はその誘導体の調製方法
EP0751145A2 (fr) Inhibiteurs de la protéase HIV
CN107474107B (zh) Glyx-13的制备方法及用于制备glyx-13的化合物
US9994526B2 (en) Process intermediates and methods for the preparation of process intermediates for the synthesis of argatroban monohydrate
RU2715233C2 (ru) Способ получения производных азотистого иприта
CN111606970B (zh) 一种1，5-二氮杂双环[5,3,0]十烷酮氨基酸衍生物及其制备方法和应用
RU2794754C1 (ru) Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
CN103641761A (zh) 一种维格利汀的制备方法
RU2794746C1 (ru) Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
RU2794755C1 (ru) Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
RU2794750C1 (ru) Способ получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
WO2023200364A1 (fr) Procédé de production de (1r,2s,5s)-n-[(1s)-1-cyano-2-[(3s)-2-oxopyrrolidine-3-l]éthyl-3-[(2s)-3,3-diméthyl-2-[(2,2,2-trifluoroacétyl)amino]butanoyl]-6,6-diméthyl-3-azabicclo[3.1.0]hexan-2-carboxamide
CN112272665A (zh) 制备立他司特的方法
RU2794748C1 (ru) Синтез (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
CN111072660A (zh) 一种瑞来巴坦的简便制备方法
EA048436B1 (ru) Способы получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
EA050370B1 (ru) Способы получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида
CN116410128A (zh) 一锅法制备甲苯磺酸艾多沙班中间体的方法
CN110903249B (zh) 一锅法制备洛匹那伟
de Meijere et al. Synthesis and biological activity of simplified belactosin C analogues
HRP980291A2 (en) Crystalline roxifiban
JP3408379B2 (ja) 新規なジペプチド化合物又はその薬理的に許容される塩及びその医薬用途
CN113372368A (zh) 一种弹性蛋白酶抑制剂前药及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23788676

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202491656

Country of ref document: EA

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23788676

Country of ref document: EP

Kind code of ref document: A1