WO2016185492A1 - Procédé de préparation de nébivolol et de son sel - Google Patents

Procédé de préparation de nébivolol et de son sel Download PDF

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Publication number
WO2016185492A1
WO2016185492A1 PCT/IN2016/050144 IN2016050144W WO2016185492A1 WO 2016185492 A1 WO2016185492 A1 WO 2016185492A1 IN 2016050144 W IN2016050144 W IN 2016050144W WO 2016185492 A1 WO2016185492 A1 WO 2016185492A1
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Prior art keywords
fluoro
dihydro
formula
benzopyran
oxiran
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Ceased
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PCT/IN2016/050144
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English (en)
Inventor
Ashok Kumar
Reddy Reguri Buchi
Kishor Ramdas MORE
Rajashekhar CHIDURALA
Sanjay Pandurang Gawade
Navanath Maruti CHAVAN
Shailesh Mallikarjun CHOUDHARI
Jeevan Bharat SADAKAL
Sachin MALEKAR
Yuvaraj PATIL
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Ipca Laboratories Ltd
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Ipca Laboratories Ltd
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Publication of WO2016185492A1 publication Critical patent/WO2016185492A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin

Definitions

  • the present invention relates to a new process for preparation of Nebivolol or it's pharmaceutically acceptable salt. More particularly, the invention relates to an improved economical process for the preparation of intermediate, 6-fluoro-3,4- dihydro-2H-l-benzopyran-2-carboxaldehyde of Formula - II, converting the 6- fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde of Formula - II into mixture of [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-l-benzopyran and [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-l-benzopyran of Formula-V and separation of diastereomers of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)- 2H-benzopran by forming
  • Nebivolol is chemically known as ( ⁇ )(aR*,a'R*,2R*,2'S*)-a,a'- [iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanol] having Formul
  • Nebivolol structure has four stereogenic centers, which are indicated as 1, 2, 3 and 4.
  • Nebivolol is a mixture of equal amounts of two enantiomers having (S,R,R,R) and (R,S,S,S) configuration.
  • Nebivolol is useful in the treatment and prevention of coronary vascular disorders. Nebivolol is first disclosed in U.S Patent no. 4,654,362. This patent discloses a process for preparing Nebivolol using a key intermediate, 6-fluoro-3,4-dihydro- 2H-l-benzopyran-2-carboxaldehyde of Formula - II.
  • 6-Fluoro-4-oxo-4H-chromene-2-carboxylic acid is reduced with hydrogen in presence of 10% Pd/C catalyst to obtain 6-fluoro-3,4-dihydro- 2H-chromene-2-carboxylic acid.
  • the 6- fluoro-3,4-dihydro-2H-chromene-2- carboxylic acid is esterified with ethanolicHCl to obtain corresponding ethyl ester of 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid which is reduced with sodium dihydro-bis(2-methoxyethoxy)aluminate (also known as vitride) in benzene at reflux conditions to obtain (6-fluoro-3,4-dihydro-2H-chromen-2- yl)methanol, which is further reacted with oxalyl chloride in a mixture of dichlorom ethane and dimethyl sulfoxide at -60°C to obtain6-fluoro-3,4-dihydro- 2H-l-benzopyran-2-carboxaldehyde.This carboxaldehyde is further reacted with trimethylsulfoxonium iodide to obtain mixture of RS/SR & RR/
  • the stereoisomers are separated by chromatorgraphy into two racemic mixtures (R,S)-, (S,R)-epoxides (Mixture A) and (S,S)-, (R,R)-epoxides (Mixture B).
  • the separated isomers are further converted into Nebivolol.
  • WO 2006/025070 describes an improved process for Nebivolol synthesis wherein the diasteomeric mixture of RS/SR & RR/SS of 6-Fluoro-3,4- dihydro-2-oxiran-2-yl-2H-benzopran are separated into the known mixture Aand mixture B by using column chromatography.
  • An Indian patent, IN221733 discloses reaction of (6-fluoro-3.4-dihydro-2H- chromene-2-carboxylic acid with an acid activating agent, and an amine RR'NH, wherein R and R ' are independently H, alkyl or aryl, optionally joined together with or without a heteroatom selected from O, N and S, to give (6-fluoro-3,4- dihydro-2H-chromen-2yl)methanone which is reduced using alkoxy metal hydride to obtain 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde.
  • This process also involves multiple and lengthy processes leading to increased time cycle and production cost.
  • An Indian patent application, 2703/CHE/2008 disclosesan improved process for the preparation of 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde by reducing an ester of (6-fluoro-3.4-dihydro-2H-chromene-2-carboxylic acid using Vitride at -70°C in solvents such as toluene and xylene.
  • the single step process poses dual problems of 1) conducting reaction at substantially lower temperatures between -70°C to -78°C which is not industrially feasible and the process is not scalable, and 2) formation of the alcohol impurity, 6-fluoro-3,4- dihydro-2H-chromen-2-yl)methanol, is not controlled even after conducting the reaction at -70°C to -78°C leading to yield loss, and incorporation of additional purification steps to remove the impurity, increases the production cost.
  • the U.S Patent 4,654,362 further discloses reaction of the 6-fluoro-3,4-dihydro- 2H-l-benzopyran-2-carboxaldehyde with trimethylsulfoxonium iodide to obtain mixture of RS/SR & RR/SS of 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran.
  • the stereoisomers are separated by chromatography into two racemic mixtures (R,S)-, (S,R)-epoxides (Mixture A) and (S,S)-, (R,R)-epoxides (Mixture B).
  • the objective of the present invention is to separate diastereomers of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran and to prepare the intermediate, 6-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-2-carboxaldehyde, from esters of 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxylic acid to overcome the problems stated above by minimizing the formation of alcohol impurity while performing the reduction reaction at optimum temperatures, thereby making the process industrially feasible and economically viable.
  • the present inventors have, surprisingly, found a novel process for preparation of Nebivolol or its pharmaceutically acceptable saltwhich comprises preparation of intermediate, 6-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-2-carboxaldehyde of Formula - II, converting the 6-fluoro-3,4-dihydro-2H-l-benzopyran-2- carboxaldehyde of Formula - II into mixture of [R*(S*)]-6-fluoro-3,4-dihydro-2- oxiranyl-2H-l-benzopyran and [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-l- benzopyran of Formula- V and separation of diastereomers of (R*)-6-Fluoro-3,4- dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran by forming azeotrope.
  • the invention provides a process of preparation of 6- fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde of Formula-II, which comprises;
  • the agent is forming azeotrope with one of the diastereomers, (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran and the azeotrope is getting distilled at much lower temperature enabling the isolation of the diasteromer from its mixture.
  • Another aspect of the present invention provides a novel process for preparation of Nebivolol or its pharmaceutically acceptable salt of Formula - IV, which comprises;
  • the agents are suitable solvents which are immiscible with OXI and having higher boiling points may be used to form azeotrope with diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopranof Formula-V-A.
  • Figure 1 shows schematic drawing of the system displaying separation of OXI-A and OXI-B by azeotropic distillation.
  • An azeotrope or a constant boiling mixture is a mixture of two or more liquids whose proportions cannot be altered by simple distillation. This happens because, when an azeotrope is boiled, the vapour has the same proportions of constituents as the unboiled mixture.
  • the present invention provides an improved economical process to prepare Nebivolol or it's pharmaceutically acceptable salts. Accordingly in one aspect, the invention provides a process of preparation of 6- fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde of Formula-II, which comprises;
  • the secondary amines may be open chain (R2R3NH) or a cyclic amine which may be pyrrolidine (five membered) or six membered ring of Formula-Ill;
  • R 2 and R 3 denote independently linear or branched (Cl-C8)-alkyl, cycloalkyl, phenyl and benzyl;
  • X denotes O or N-R4 ;
  • R 4 denotes H, linear or branched (Cl-C8)-alkyl, cycloalkyl,phenyl or benzyl.
  • dipropyl amine and n-methyl aniline are preferred from open chain secondary amines.
  • Morpholine and N-methyl piperazine are preferred from cyclic six membered ring of formula- Ill.
  • the reducing agents include, but not limited, to metal hydrides such as lithium aluminium hydride and sodium borohydride; alkyl aluminium hydrides such as diisobutyl aluminum hydride (DIBAL), or alkoxy aluminium hydrides such as sodium bis(2-methoxyethoxy)aluminium hydride (it is also called Vitride), lithium diethoxyaluminiumdihydride and lithium tri-tert-butoxyaluminium hydride.
  • metal hydrides such as lithium aluminium hydride and sodium borohydride
  • alkyl aluminium hydrides such as diisobutyl aluminum hydride (DIBAL), or alkoxy aluminium hydrides such as sodium bis(2-methoxyethoxy)aluminium hydride (it is also called Vitride), lithium diethoxyaluminiumdihydride and lithium tri-tert-butoxyaluminium hydride.
  • Vitride is preferred reagent from alkoxy aluminium
  • esters of 6-fluoro-3,4-dihydro-2H-l-benzopyran- 2-carboxylic acid of Formula - I, wherein Ri denotes methyl or ethyl are reduced with Vitride in presence of a morpholine or N-methyl piperazine.
  • the reducing agent and the secondary amine are separately mixed in a suitable solvent to form a mixture or complex. Then the mixture/complex is reacted with the esters of 6-fluoro-3,4-dihydro-2H-l- benzopyran-2-carboxylic acid of Formula-I to obtain the 6-fluoro-3,4-dihydro- 2H-l-benzopyran-2-carboxaldehyde of Formula-II.
  • the reducing agent is taken in a solvent, cooled the mixture to about 10°C under nitrogen followed by addition of secondary amine at the same temperature. After addition of the amine, the mixture is equilibrated for another 15 to 30 minutes. Then the mixture of reducing agent-secondary amine is added into ester of 6-fluoro-3,4-dihydro-2H-l- benzopyran-2-carboxylic acid of Formula-I for completing reduction reaction.
  • the reduction reaction may be performed in suitable solvents.
  • suitable solvents for conducting reduction reaction include, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, nitriles, ethers etc.
  • Chlorinated hydrocarbons preferably include methylenedichloride, ethyl enedi chloride, chloroform, carbon tetrachloride.
  • Nitrile solvents include acetonitrile and propionitrile.
  • Aromatic hydrocarbons preferably selected from benzene, toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane etc.
  • Ethers include tetrahydrofuran, diisopropyl ether or diethyl ether. However, most preferred solvents are toluene, xylene or tetrahydrofuran.
  • the reduction reaction is conducted typically from -25°C to 10°C temperature.
  • the preferred temperature range varies between -15°C to 0°C temperature.
  • Molar ratio of secondary amine may be used in the range of 1 mole to 4 moles relative to esters of 6-fluoro-3,4-dihydro-2H-l- benzopyran-2-carboxylic acid of Formula - I.
  • the preferred range is 1.5 to 1.7 moles.
  • Alkoxy aluminium hydrides may be used in the range of 1 to 2 moles relative to esters of 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxylic acid of Formula - I.However, the preferred range of alkoxy aluminium hydrides is 1.3 to 1.5 moles.
  • the reduction reaction completes in 2-3 hours to form 6-fluoro-3,4- dihydro-2H-l-benzopyran-2-carboxaldehyde.
  • the mass is quenched with methanol followed by dilute hydrochloric acid.
  • the reaction mass is extracted with suitable solvents followed by concentration to isolate the 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde.
  • Nebivolol or its pharmaceutically acceptable salts such as hydrochloride or hydrobromide salts. Accordingly the 6-fluoro-3,4-dihydro-2H-l-benzopyran-2- carboxaldehyde prepared as per the present invention mentioned above is converted into Nebivolol or its pharmaceutically acceptable salt.
  • 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde is reacted with trimethylsulfoxonium iodide in presence of base, sodium methoxide, in dimethyl sulfoxide solvent to obtain mixture of [R*(S*)]-6-fluoro-3,4-dihydro- 2-oxiranyl-2H-l-benzopyran of formula- Vaand [R*(R*)]-6-fluoro-3,4-dihydro-2- oxiranyl-2H-l-benzopyran of formula- Vb.
  • a process for preparation of Nebivolol or its pharmaceutically acceptable salt which comprises isolation of one ofdiastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran having RS/SR configuration from the mixture of (R*)-6-Fluoro-3,4-dihydro-2- ((S*)-oxiran-2-yl)-2H-benzopranhaving RS/SR and (R*)-6-Fluoro-3,4-dihydro-2- ((R*)-oxiran-2-yl)-2H-benzopran having RR/SS configuration by adding an agent to form azeotrope.
  • the agents are suitable solvents which are immiscible with OXI and having higher boiling points may be used to form azeotrope with diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopranof Formula- V-A.
  • the suitable solvents for forming azeotrope may include but not limited to glycols, sulfolenes, glymes, glycerol ethers, hydrocarbons, crown ethers such as 12-crown-4, nitrobenzene, biphenyl, diphenylether, acetophenone.
  • Glycols include glycerol, monoethyleneglycol, diethyleneglycol, triethyleneglycol, 1,3- Proapnediol, 1,4-Butanediol, 1,2-Butanediol and 1,3-Butanediol.
  • Sulfolenes include 2-sulfolene, 3-sulfolene, 3-methyl-2-sulfolene, 3-methyl-3-sulfolene, and 3-ethyl-3-sulfolene.
  • Glymes include diglyme, triglyme, tetraglyme.
  • Glycerol ethers include 1,2,3-trimethoxy propane, 1,2,3-triethoxy propane.
  • Hydrocarbons include open chain hydrocarbons like 2-methyldecane, 3-methyldecane, 9- butyldocosane and cyclic hydrocarbons like l-methyl-2-pentyl cyclohexane.
  • preferred solvent is monoethyleneglycol ordiethyleneglycol.
  • the process involves addition of agent to the OXI and heated under vacuum at about 2 torr to form azeotrope. It is surprisingly found that OXI-A isomer forms azeotrope with the agent at much lower vapor temperature of 69- 70°C (when monoethyleneglycol used as agent) which is collected as distillate.
  • the azeotrope containing two layers- top layer (agent) and bottom layer-(OXI-A rich layer) are separated, the top layer is refluxed back to the distillation flask. The azeotropic distillation is carried out till maximum OXI-A isomer is separated from OXI-B.
  • Nebivolol hydrochloride salt [[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-l-benzopyran- 2-methanol] is debenzylated using hydrogen in presence of Pd/C catalyst in acetic acid solvent. After completion of reaction, catalyst is separated by filtration. The filtrate containing Nebivolol base is treated with acid (HX) such as hydrogen chloride gas to obtain Nebivolol hydrochloride salt in one pot.
  • HX acid
  • Stage-1 Preparation of Methyl 6-fluoro-3,4-dihydro-2H-l-benzopyran-2- carboxylate.
  • Stage-2 Preparation of 6-fluoro-3,4-dihydro-2H-l-benzopyran-2- carboxaldehyde (Formula-II).
  • reaction mixture was then quenched into ice-cold water, aqueous layer extracted with MDC. MDC layer was washed with water and concentrated. Concentrated mass then distilled under vacuum to give 69 gm of 6-fluoro-3,4- dihydro-2-oxiranyl-2H-l-benzopyran as a mixture of A and B.
  • Packed column is used to provide rectification stages for enrichment of azeotropic composition in the distillate (OXI-A + mono ethylene glycol). Provision of sufficient rectification stages ensures more pure heterogeneous azeotrope obtaining at the top.
  • Vacuum was applied from the top of the condenser using high vacuum pump with vacuum gauge.
  • Top layer 21 gm; was of monoethylene glycol.

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

Abstract

La présente invention concerne un nouveau procédé de préparation de nébivolol ou de son sel pharmaceutiquement acceptable. Plus particulièrement, l'invention se rapporte à un procédé économique amélioré pour la préparation de l'intermédiaire 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldéhyde de Formule II, consistant à convertir le 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldéhyde de Formule II en un mélange de [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyrane et [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran de Formule V, et à séparer les diastéréomères de (R*)-6-fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopyran par formation d'un azéotrope.
PCT/IN2016/050144 2015-05-19 2016-05-18 Procédé de préparation de nébivolol et de son sel Ceased WO2016185492A1 (fr)

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IN1978MU2015 2015-05-19
IN1978/MUM/2015 2015-05-19

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025070A2 (fr) * 2004-07-30 2006-03-09 Torrent Pharmaceuticals Limited Nebivolol et ses sels pharmaceutiquement acceptables, procede de preparation et compositions pharmaceutiques de nebivolol
WO2010089764A2 (fr) * 2009-01-05 2010-08-12 Msn Laboratories Limited Procédé amélioré d'élaboration d'hydrochlorure de nébivolol
US20120108826A1 (en) * 2009-07-23 2012-05-03 Zach System Spa Process for preparing nebivolol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025070A2 (fr) * 2004-07-30 2006-03-09 Torrent Pharmaceuticals Limited Nebivolol et ses sels pharmaceutiquement acceptables, procede de preparation et compositions pharmaceutiques de nebivolol
WO2010089764A2 (fr) * 2009-01-05 2010-08-12 Msn Laboratories Limited Procédé amélioré d'élaboration d'hydrochlorure de nébivolol
US20120108826A1 (en) * 2009-07-23 2012-05-03 Zach System Spa Process for preparing nebivolol

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