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WO2009112203A1 - Procédé de fabrication d’une diphénylazétidinone - Google Patents

Procédé de fabrication d’une diphénylazétidinone Download PDF

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Publication number
WO2009112203A1
WO2009112203A1 PCT/EP2009/001598 EP2009001598W WO2009112203A1 WO 2009112203 A1 WO2009112203 A1 WO 2009112203A1 EP 2009001598 W EP2009001598 W EP 2009001598W WO 2009112203 A1 WO2009112203 A1 WO 2009112203A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
butyl
ethylmorpholine
ethyldiisopropylamine
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/EP2009/001598
Other languages
German (de)
English (en)
Inventor
Theodor Andreas Wollmann
Bernd Junker
Bernhard Otto
Claus-Jürgen MAIER
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.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
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 DE102008059772A external-priority patent/DE102008059772A1/de
Application filed by Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of WO2009112203A1 publication Critical patent/WO2009112203A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the invention relates to an improved process for the preparation of a diphenylazetidinone.
  • WO2004 / 087655 describes a diphenylazetidinone of the formula I and also syntheses of this compound.
  • the compound of the formula I can be used, for example, as a cholesterol-lowering agent.
  • HOBt 1-hydroxybenzotriazole
  • EDC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • the object of the present invention was now to provide an improved process for the preparation of the compound of the formula I, the abovementioned
  • the improved process should also enable a preparation of the compound of the formula I in a large-scale production process.
  • the process should be as economic as possible, i. cost-effective, environmentally friendly and safe can be performed.
  • the object is achieved by production method A)
  • the compound of the formula IV is reacted with a compound of the formula V or salts thereof to give the compound of the formula I.
  • Preferred compounds of the formula III are alkyl acid halides and haloformic acid alkyl esters, particularly preferably isobutyl chloroformate.
  • R 1 is an alkyl radical having 1 to 6 C atoms. In a further embodiment, R 1 is a methyl radical, ethyl radical, isopropyl radical, n-butyl radical, isobutyl radical or tert-butyl radical.
  • R1 is an -O-alkyl radical having 1 to 17 carbon atoms.
  • R 1 is an -O-alkyl radical having 1 to 6 C atoms.
  • R 1 is -O-methyl, -O-ethyl, -O-isopropyl, -O-n-butyl, -O-iso-butyl or -O-tert-butyl.
  • alkyl radical is meant a straight or branched hydrocarbon chain of one to eighteen carbons, e.g. Methyl, ethyl, iso -propyl, n-butyl, iso-butyl, tert -butyl, hexyl, heptyl, octyl.
  • Hal is understood to mean a halogen radical which may have the meaning Br, Cl or I.
  • HaI has the meaning Cl.
  • An aryl radical is understood as meaning a phenyl, naphthyl or biphenyl radical in which one or more CH groups can be replaced by O, N or S.
  • the aryl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , CN, COO (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl ] 2> cycloalkyl, (Ci-C, 0) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, O- (C, -C 6) alkyl, O- ( C 2 -C 6) -alkenyl, O- (C 2 -C 6) -alkynyl, O- CO- (C r C6) alkyl, 0-CO- (Ci-C6) - aryl, 0-CO - (C 1 -C 6 ) -heterocycle, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S-
  • step a) the compound of formula II is dissolved in a suitable solvent at -30 0 C to + 70 ° C, preferably at -1O 0 C to + 50 ° C, particularly preferably at 20 0 C to 45 ° C and within from 30 to 150 minutes, preferably 60-120 minutes with a suitable base, then to a temperature of -30 0 C to 50 0 C, preferably at -10 0 C to 30 0 C, particularly preferably at -5 0 C bis 1O 0 C cooled and within 5 - 100 minutes, preferably added 5-60 minutes of a compound of formula III, particularly preferably isobutyl chloroformate.
  • a cooled to -10 ° C to 30 ° C, preferably -10 0 C to 0 ° C solution of the compound III, preferably isobutyl chloroformate, are presented in a suitable Amsterdamsmettel and then the compound of formula II and a suitable base in a suitable solvent at -30 ° C to + 70 ° C, preferably at -10 0 C to + 40 0 C, more preferably at -5 ° C to 0 ° C within 30 to 150 minutes, preferably 60-120 minutes added become.
  • the reaction mixture is then stirred at -10 0 C to 40 0 C, preferably at -10 0 C to 10 0 C for 15 to 150 minutes, preferably 30 - 120 minutes.
  • reaction mixture can now either be used directly in the subsequent reaction, or the product of formula IV formed is isolated.
  • the reaction mixture is used directly.
  • the solvent is evaporated in vacuo.
  • the reaction mixture is washed with water before evaporation of the solvent.
  • Suitable bases are exemplified by tertiary amines such as triethylamine, ethyldimethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine, N-methylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, preferably triethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine, N-methylmorpholine Particularly preferred are triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine.
  • tertiary amines such as triethylamine, ethyldimethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine, N-methylmorpholine, tetra
  • Suitable solvents are, for example, customary aprotic organic solvents, for example toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, preferably 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone, particularly preferred is N-methylpyrrolidone.
  • customary aprotic organic solvents for example toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or
  • step b) within 5 to 60 minutes, preferably 10 to 45 minutes, the compound of formula V or its salts is dissolved in a suitable solvent to give a solution of product IV (prepared as described above, either using reaction solution directly or the isolated product dissolved in a suitable solvent) and optionally a suitable one Base in a suitable solvent at -10 ° C to 40 ° C, preferably -5 ° C to 10 ° C added.
  • Suitable bases are, for example, tertiary amines such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine,
  • Tetramethylethylenediamine, guanidine or alkylguanidines particularly preferred are triethylamine or N-ethylmorpholine.
  • Suitable solvents are, for example, conventional aprotic organic solvents such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltertrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone; N-methylpyrrolidone is particularly preferred.
  • conventional aprotic organic solvents such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltertrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone; N-methylpyrrolidone is particularly preferred.
  • the reaction mixture is stirred for 5 to 150 minutes, preferably 30 to 120 minutes at -10 ° C to 40 ° C, preferably at -5 ° C to 10 ° C, and then with water or a saline solution and a suitable solvent at 10 ° C. - Washed 80 ° C, preferably at 10 ° C - 30 ° C.
  • the organic phase can then be washed with alkaline and acidic aqueous solutions. After concentrating the organic solution, it is metered into a suitable solvent or solvent mixture, whereby the product of formula I is precipitated.
  • Suitable solvents for extraction are n-butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, more preferably n-butanol and 2-methyltetrahydrofuran.
  • Suitable solvents for the precipitation of product I are acetone, diisopropyl ether and water and mixtures thereof.
  • Phase is separated and extracted successively with in each case 100 ml of 0.5 N hydrochloric acid and saturated sodium bicarbonate solution. There remain about 200 mL of butanol phase. This is added dropwise to 2.6 L pre-cooled to 10 ° C diisopropyl ether. The precipitate is filtered off and stirred again with 0.6 L diisopropyl ether. After aspirating and drying at 20-25 ° C in vacuo to obtain 41.5 g of the compound of formula I.
  • the solid still contains n-butanol and is stirred twice with in each case 880 ml of water at 0 to 5 ° C for one hour and dried after the second suction at 40 ° C in a vacuum. This gives 34.5 g of the compound of formula I.
  • step b) Preparation of the compound of the formula I
  • the suspension obtained in step a) is added at -2 to -3 ° C. within 25 minutes
  • step a) The suspension obtained in step a) is metered at 0 to 10 0 C within 10 minutes to a solution of 3.24 g (7.24 mmol) of the compound of formula V and 0.92 g (8 mmol) of N-ethylmorpholine in 4 ml of N-methylpyrrolidine , Then you still stir
  • the reaction mixture is added to 90 ml of 4% saline and 108 ml of 2-methyltetrahydrofuran.
  • the aqueous phase is extracted twice with 13.5 ml each of 2-methyltetrahydrofuran.
  • the combined organic phases are rested for 30 minutes with 23.5 ml of 4% saline solution and 0.6 ml of 33% NaOH solution. It is neutralized with 0.6 ml of 30% HCl solution.
  • Phase is washed 4 times with 25 ml of 4% saline and concentrated to a volume of 32 ml in vacuo.
  • the resulting solution is added at 40 ° C within 10 minutes to a pre-cooled to 0 ° C mixture of 165 ml of diisopropyl ether and 41 ml of acetone.
  • the precipitate is filtered off with suction and washed again with 20 ml of diisopropyl ether. After drying at 40 ° C. in vacuo, 4.9 g of the compound of the formula I are obtained.
  • step a) The suspension obtained in step a) is metered at 0 to 6 ° C within 20 minutes to a solution of 4.51 g (10.0 mmol) of the compound of formula V and 0.7 g (3.0 mmol) of tributylamine in 5.5 ml of N-methylpyrrolidine. Then it is stirred for 2 h at this temperature. The reaction mixture is added to 150 ml of 4% saline and 40 mL n-butanol. The aqueous phase is extracted twice with 10 ml of n-butanol. The combined organic phases are extracted three times with 34 ml of 4% saline solution and eight times with 17 ml of 4% saline solution.
  • step b) Preparation of the compound of formula I
  • the suspension obtained in step a) is cooled to 0-5 ° C and within 1
  • Phases are washed five times with 20 ml of 4% sodium chloride solution.
  • the organic solution is added over 10 minutes to a pre-cooled to 0 ° C mixture of 150 ml of diisopropyl ether and 38 ml of acetone.
  • the precipitate is stirred for 20 minutes, filtered off with suction and washed again with 30 ml of diisopropyl ether. After drying at 40 ° C in vacuo to obtain 3.35 g of
  • step b) Preparation of the compound of the formula I
  • the suspension obtained in step a) is added over 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of the formula V and 1.14 ml (7.4 mmol) of N-ethyldiisopropylamine in 20 ml of dimethylformamide , Then it is stirred for 2.5 hours at 40 0 C after.
  • the reaction mixture is added to 90 ml of 4% saline and 1 10 ml of 2-methyl-tetrahydrofuran.
  • the aqueous phase is extracted twice with 7 ml of 2-methyl-tetrahydrofuran.
  • the combined organic phases are washed five times with 20 ml of 4% sodium chloride solution.
  • step a) The suspension obtained in step a) is added over 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of the formula V and 1.04 ml (7.4 mmol). Triethylamine added in 20 ml of dimethylformamide. Then it is stirred for 2 hours at 40 ° C after. The reaction mixture is added to 90 ml of 4% saline and 110 ml of 2-methyl-tetrahydrofuran. The aqueous phase is extracted twice with 7 ml of 2-methyl-tetrahydrofuran. The combined organic phases are washed five times with 20 ml of 4% sodium chloride solution.

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

Abstract

L'invention concerne un procédé amélioré de fabrication d'une diphénylazétidinone.
PCT/EP2009/001598 2008-03-14 2009-03-06 Procédé de fabrication d’une diphénylazétidinone Ceased WO2009112203A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP08004862.2 2008-03-14
EP08004862 2008-03-14
US4529908P 2008-04-16 2008-04-16
US61/045,299 2008-04-16
DE102008059772A DE102008059772A1 (de) 2008-12-01 2008-12-01 Verfahren zur Herstellung eines Diphenylazetidinons
DE102008059772.4 2008-12-01

Publications (1)

Publication Number Publication Date
WO2009112203A1 true WO2009112203A1 (fr) 2009-09-17

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ID=40823593

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/001598 Ceased WO2009112203A1 (fr) 2008-03-14 2009-03-06 Procédé de fabrication d’une diphénylazétidinone

Country Status (1)

Country Link
WO (1) WO2009112203A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8003636B2 (en) * 2007-11-13 2011-08-23 Sanofi-Aventis Deutschland Gmbh Certain crystalline diphenylazetidinone hydrates, pharmaceutical compositions thereof and methods for their use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087655A1 (fr) * 2003-04-01 2004-10-14 Sanofi-Aventis Deutschland Gmbh Nouveau diphenylazetidinone a proprietes physiologiques ameliorees, procedes de production associe, medicaments contenant les composes et leurs utilisations
US7067689B1 (en) * 2005-07-08 2006-06-27 Microbia, Inc. Process for production of pentahydroxyhexylcarbamoyl alkanoic acids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087655A1 (fr) * 2003-04-01 2004-10-14 Sanofi-Aventis Deutschland Gmbh Nouveau diphenylazetidinone a proprietes physiologiques ameliorees, procedes de production associe, medicaments contenant les composes et leurs utilisations
US7067689B1 (en) * 2005-07-08 2006-06-27 Microbia, Inc. Process for production of pentahydroxyhexylcarbamoyl alkanoic acids

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8003636B2 (en) * 2007-11-13 2011-08-23 Sanofi-Aventis Deutschland Gmbh Certain crystalline diphenylazetidinone hydrates, pharmaceutical compositions thereof and methods for their use

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