WO2022211680A1 - Procédé de production d'anticoagulant hydrochlorure de n-(5-chloropridine-2-yl)-2-({4-[éthane-imidoyl(méthl)amino]benzoyl}amino)-5-méthylbenzamide - Google Patents

Procédé de production d'anticoagulant hydrochlorure de n-(5-chloropridine-2-yl)-2-({4-[éthane-imidoyl(méthl)amino]benzoyl}amino)-5-méthylbenzamide Download PDF

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Publication number
WO2022211680A1
WO2022211680A1 PCT/RU2022/050098 RU2022050098W WO2022211680A1 WO 2022211680 A1 WO2022211680 A1 WO 2022211680A1 RU 2022050098 W RU2022050098 W RU 2022050098W WO 2022211680 A1 WO2022211680 A1 WO 2022211680A1
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Prior art keywords
chloride
amino
solvent
acid
independently selected
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PCT/RU2022/050098
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English (en)
Russian (ru)
Inventor
Дмитрий Николаевич ТАРАСОВ
Дмитрий Геннадьевич ТОВБИН
Олег Егорович БАЛАШОВ
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Общество С Ограниченной Ответственностью "Фармадиол"
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Priority claimed from EA202100120 external-priority patent/EA041945B1/ru
Application filed by Общество С Ограниченной Ответственностью "Фармадиол" filed Critical Общество С Ограниченной Ответственностью "Фармадиол"
Publication of WO2022211680A1 publication Critical patent/WO2022211680A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the invention relates to the field of organic chemistry, namely to a method for producing 1H-(5-chloropyridin-2-yl)-2-( ⁇ 4-[ethane-imidoyl(methyl)amino]benzoyl ⁇ amino)-5-methylbenzamide hydrochloride, which can be used as an inhibitor of factor Xa to control blood clotting in humans and other mammals, as well as to treat diseases associated with blood clotting.
  • Blood clotting can be controlled with anticoagulants, which are inhibitors of the protein (factor) Xa.
  • Factor Xa belongs to the family of serine proteases. Unlike thrombin, which acts on multiple substrate proteins and specific receptors, factor Xa appears to only act on a single substrate, namely prothrombin.
  • Direct factor Xa inhibitors such as inhibitors of thrombin formation, can be used to effectively control blood clotting. Therefore, it is clear that substances that inhibit factor Xa can be used as drugs for diseases associated with blood clotting.
  • Patent EA015918 describes the compound 1H-(5-chloropyridin-2-yl)-2-( ⁇ 4-[ethanimidoyl(methyl)amino]benzoyl ⁇ amino)-5-methylbenzamide which is highly active against factor Xa:
  • the disadvantages of the method disclosed in the patent EA 015918 include a large number of stages, the need to use tin (II) chloride to restore the nitro group, which leads to a long procedure for separating side tin compounds, the need to use hydrochloric acid to restore the nitro group, inefficient use of protective groups , as well as the need to isolate and purify the products by column chromatography after each step.
  • Another patent RU2698202C2 proposes a method for obtaining the compound N-(5-chloropyridin-2-yl)-2-( ⁇ 4-[ethane-imidoyl(methyl)amino]benzoyl ⁇ amino)-5-methylbenzamide hydrochloride, which includes the following steps : a) interaction of 5-methylanthranilic acid with thionyl chloride in toluene; reacting the product of the previous reaction with 2-amino-5-chloropyridine in tetrahydrofuran to give 2-amino-1H-(5-chloropyridin-2-yl)-5-methyl-benzamide;
  • the objective of the present invention is to develop and create a new method for producing anticoagulant 1H-(5-chloropyridin-2-yl)-2-( ⁇ 4-
  • the technical result of the present invention is to create a new and effective method for producing anticoagulant 1H-(5-xporpyridin-2-yl)-2-( ⁇ 4-[etanimidoyl(methyl)amino]benzoyl ⁇ amino)-5-methylbenzamide hydrochloride (compound of formula I), which makes it possible to obtain a product with a high degree of purity (>99%) and a high yield; the technical result of the present invention also lies in the simplification of the synthesis of the compound of formula I, the reduction of risks in industrial implementation and the scaling of the synthesis.
  • a method for obtaining a compound of formula I which includes the following steps: a) interaction of 5-methylanthranilic acid and 5-xporpyridine-2-amine to obtain 2-amino-1H-(5-xporpyridin-2-yl)-5-methylbenzamide II: b) interaction of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride to obtain 4-(1H-methylacetimidamido)benzoic acid hydrochloride III:
  • the interaction is the interaction of 5-methylanthranilic acid with thionyl chloride in an aromatic solvent, an organochlorine solvent, a solvent containing an ether moiety or without a solvent; reaction of the product of the previous reaction with 5-chloropyridine-2-amine in dialkyl ether of mono-, di- or polyethylene glycol or in another solvent containing a structural fragment of a simple ether in the presence of a base to obtain 2-amino-1H- (5-xporpyridine-2 -yl)-5-methyl-benzamide.
  • the aromatic solvent in step a) is benzene.
  • the organochlorine solvent is methylene chloride, chloroform, carbon tetrachloride, or dichloroethane.
  • the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether.
  • the diethylene glycol dialkyl ether is diethylene glycol dimethyl ether.
  • the base is independently selected and is pyridine, substituted pyridine, dialkylaniline, or trialkylamine.
  • the substituted pyridine is independently selected and is an alkyl pyridine or a dialkylamino pyridine.
  • step b) of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride is carried out with the participation of dry gaseous hydrogen chloride and / or its solution in an organic solvent and / or with the participation of reagents capable of generating hydrogen chloride directly in the reaction system.
  • the organic solvent is acetonitrile.
  • hydrogen chloride can be generated in the reaction system by reacting an acid chloride with an equivalent amount of water or alcohol, and the acid chloride can be an organic or inorganic acid chloride, the alcohol can be primary, secondary and tertiary aliphatic alcohols.
  • the acid chloride of an organic or inorganic acid is independently selected and is thionyl chloride, sulfuryl chloride, phosphorus oxychloride, boron chloride, oxalyl chloride, acetyl chloride, alkyl carboxylic acid chlorides, benzoyl chloride, benzoic acid chloride or cyanuric chloride.
  • the alcohol is independently selected and is methanol, ethanol, 2-propanol or mpem-butanol.
  • the interaction of 4-(1H-methylacetimidamido)benzoic acid hydrochloride III and acid chloride is carried out in an aromatic solvent, an organochlorine solvent, in a solvent containing a structural fragment of a simple ether or without a solvent in the presence of a catalyst to obtain hydrochloride 4 -(1H-methylacetimidamido) benzoyl chloride.
  • the acid chloride is independently selected and is thionyl chloride, oxalyl chloride, cyanuric chloride, phosgene, phosphorus trichloride, or phosphorus pentachloride.
  • the aromatic solvent is independently selected and is benzene or toluene.
  • the organochlorine solvent is independently selected and is methylene chloride, chloroform, carbon tetrachloride or dichloroethane.
  • the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di- or polyethylene glycol dialkyl ether.
  • the catalyst in step c), is independently selected and is dimethylformamide or N,N-disubstituted carboxylic acid amide.
  • the N,N-disubstituted carboxylic acid amide is dimethiacetamide, N-methylformanilide.
  • the reaction at stage d) of 4-(1H-methylacetimidamido)benzoyl chloride IV hydrochloride and 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide II is carried out in tetrahydrofuran or in another a solvent containing an ether moiety such as diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether, or an alkyl carboxylate.
  • an ether moiety such as diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether, or an alkyl carboxylate.
  • the alkyl carboxylate is ethyl acetate.
  • step e) of N-(5-chloropyridin-2-yl)-2-( ⁇ 4-[ethane-imidoyl(methyl)amino]-benzoyl ⁇ amino)-5-methylbenzamide dihydrochloride I with organic and an inorganic base is carried out in a solvent or water.
  • the organic or inorganic base is independently selected and is ammonia, mono-, di- or trialkylamine, pyridine, alkylpyridine, dialkylaminopyridine, alkali or alkaline earth metal hydroxide.
  • the solvent is selected independently and is a primary, secondary or tertiary aliphatic alcohol, an alkyl carboxylate, a solvent containing an ether structural fragment.
  • the aliphatic alcohol is methanol, ethanol, 2-propanol or mpem-butanol
  • the alkyl carboxylate is ethyl acetate
  • the solvent containing the ether moiety is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, dialkyl ether of mono-, di- or polyethylene glycol.
  • alkyl in this document means both straight and branched. In addition, “alkyl” may be either substituted or unsubstituted.
  • alkyl as used herein refers to groups typically having one to five carbon atoms. Brief description of the drawings.
  • Step 1 Reaction of 5-methylanthranilic acid with 2-amino-5-chloropyridine to give 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide (compound II).
  • hydrogen chloride can be produced directly in the reaction system by reacting an organic or inorganic acid chloride with an equivalent amount of water or alcohol. For example, if 17.9 g (0.15 mol) of thionyl chloride is added to 100 ml of dry acetonitrile, the mixture is cooled to +10 °C, and 2.7 g (0.15 mol) of distilled water is added, then a solution of HCI in acetonitrile with a concentration of ⁇ 3 mol/l will be obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention se rapporte au domaine de la chimie organique, et concerne notamment un nouveau procédé de production d'un composé de la formule I (où n = 1) consistant en de l'hydrochlorure de N-(5-chloropridine-2-yl)-2-({4-[éthane-imidoyl(méthl)amino]benzoyl}amino)-5-méthylbenzamide, lequel peut être utilisé en qualité d'inhibiteur de facteur Xa pour contrôler la coagulation du sang chez une personne et d'autres mammifères, ainsi que pour traiter des maladies liées à la coagulation du sang.
PCT/RU2022/050098 2021-03-30 2022-03-25 Procédé de production d'anticoagulant hydrochlorure de n-(5-chloropridine-2-yl)-2-({4-[éthane-imidoyl(méthl)amino]benzoyl}amino)-5-méthylbenzamide WO2022211680A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EA202100120 2021-03-30
EA202100120 EA041945B1 (ru) 2021-03-30 Способ получения антикоагулянта n-(5-хлорпиридин-2-ил)-2-({4-[этанимидоил(метил)амино]бензоил}амино)-5-метилбензамид гидрохлорида

Publications (1)

Publication Number Publication Date
WO2022211680A1 true WO2022211680A1 (fr) 2022-10-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064643A2 (fr) * 2000-02-29 2001-09-07 Cor Therapeutics, Inc. Benzamides et inhibiteurs associes du facteur xa
RU2440986C2 (ru) * 2005-11-08 2012-01-27 Милленниум Фамэсьютикэлс, Инк. СОЛЬ ИНГИБИТОРА ФАКТОРА Ха, СПОСОБ ЕЕ ПОЛУЧЕНИЯ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЕ ОСНОВЕ, СОСТОЯЩИЕ ИЗ НАЗВАННОЙ КОМПОЗИЦИИ ТАБЛЕТКА, КАПСУЛА И ЛЕПЕШКА, СПОСОБ ЛЕЧЕНИЯ ТРОМБОЗА И СПОСОБ ИНГИБИРОВАНИЯ КОАГУЛЯЦИИ ОБРАЗЦОВ КРОВИ
EA030138B1 (ru) * 2016-06-15 2018-06-29 Общество С Ограниченной Ответственностью "Фармадиол" Фармацевтические композиции, включающие антикоагулянт n-(5-хлорпиридин-2-ил)-2-({4-[этанимидоил(метил)амино]бензоил}амино)-5-метилбензамид
RU2698202C2 (ru) * 2016-06-01 2019-08-23 Закрытое акционерное общество "ФАРМА ВАМ" СПОСОБ ПОЛУЧЕНИЯ ПРЯМОГО ИНГИБИТОРА ФАКТОРА Ха

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064643A2 (fr) * 2000-02-29 2001-09-07 Cor Therapeutics, Inc. Benzamides et inhibiteurs associes du facteur xa
RU2440986C2 (ru) * 2005-11-08 2012-01-27 Милленниум Фамэсьютикэлс, Инк. СОЛЬ ИНГИБИТОРА ФАКТОРА Ха, СПОСОБ ЕЕ ПОЛУЧЕНИЯ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЕ ОСНОВЕ, СОСТОЯЩИЕ ИЗ НАЗВАННОЙ КОМПОЗИЦИИ ТАБЛЕТКА, КАПСУЛА И ЛЕПЕШКА, СПОСОБ ЛЕЧЕНИЯ ТРОМБОЗА И СПОСОБ ИНГИБИРОВАНИЯ КОАГУЛЯЦИИ ОБРАЗЦОВ КРОВИ
RU2698202C2 (ru) * 2016-06-01 2019-08-23 Закрытое акционерное общество "ФАРМА ВАМ" СПОСОБ ПОЛУЧЕНИЯ ПРЯМОГО ИНГИБИТОРА ФАКТОРА Ха
EA030138B1 (ru) * 2016-06-15 2018-06-29 Общество С Ограниченной Ответственностью "Фармадиол" Фармацевтические композиции, включающие антикоагулянт n-(5-хлорпиридин-2-ил)-2-({4-[этанимидоил(метил)амино]бензоил}амино)-5-метилбензамид

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