Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
  • C07D309/30—Oxygen atoms, e.g. delta-lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
• • 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
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

• the field of the invention relates to processes for the preparation of trans-isomers of diphenylazetidinone derivatives, using a chiral delta-lactone. It also relates to processes for the preparation of the chiral delta-lactone. The invention also relates to pharmaceutical compositions that include the trans-isomers of diphenylazetidinone derivatives.
• Diphenylazetidinone derivatives such as ezetimibe are useful as hypocholesterolemic agents, for the prevention and treatment of atherosclerosis.
• Several processes have been reported for the preparation of diphenylzetidinones for example, in U.S. Patent Nos. 5,631,365; 5,886,171; 6,207,822; 6,133,001; and 5,856,473.
• R 1 and R 2 are identical or different, and represent hydrogen, halogen or an alkoxy group, and R 3 represents hydrogen, alkyl or a hydroxy protecting group.
• the process includes reacting a chiral delta-lactone of formula II,
• R , and R are as defined above, in the presence of a base.
• R 1 and R are as defined above; and hydrolyzing the chiral hydroxyester to obtain the chiral hydroxyacid of formula IN.
• a pharmaceutical composition that includes a therapeutically effective amount of trans-isomer of a diphenylazetidinone derivative or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, excipients or diluents.
• the inventors have developed an efficient process for the preparation of trans- isomers of diphenylazetidinone of formula I, or a salt thereof, wherein R 1 and R 2 are identical or different, and represent hydrogen, halogen or an alkoxy group, and R 3 represents hydrogen, alkyl or a hydroxy protecting group.
• the process involves reacting a chiral delta-lactone of formula II, with a diphenyl imine of formula III, in the presence of a base, wherein R 1 , R 2 and R 3 are as defined above.
• halogen includes fluorine, chlorine, bromine, and iodine.
• hydroxy protecting groups include aralkyl such as benzyl, alkyl such as methyl and ethyl, alkoxyalkyl such as methoxymethyl, and trialkylsilyl such as trimethylsilyl and tert- butyldimethylsilyl groups.
• alkyl groups include methyl, ethyl, n-propyl,
• R and R represent fluorine and R 3 represents hydrogen in the compounds of formula I.
• Examples of a base which can be used in the reaction of chiral delta-lactone of formula II with diphenyl imine of formula III include an alkyl lithium such as n-butyl- lithium, a metal hydride such as sodium hydride, a metal alkoxide such as sodium methoxide, and a metal amide such as sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, lithium bistrimethylsilylamide, lithium dicyclohexylamide and lithium diisopropylamide.
• the reaction may be carried out at a temperature from about -100°C to about 50°C, for example at a temperature from about -80°C to about 0°C. hi particular, it may be carried out at a temperature from about -60°C to about -40°C.
• Suitable solvents for reaction of the compounds of formula II with compounds of formula III are inert organic solvents that do not change under the reaction conditions.
• solvents include ethers, such as dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran (THF); chlorinated hydrocarbons such as methylene dichloride and ethylene dichloride; hydrocarbons such as hexane, cyclohexane, toluene, and xylene; dipolar aprotic solvents such as dimethylformamide, dimethyl sulphoxide, N- methylpyrrolidone; and mixtures thereof.
• ethers such as dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran (THF); chlorinated hydrocarbons such as methylene dichloride and ethylene dichloride; hydrocarbons such as hexane, cyclohexane
• Cosolvents such as hexamethylphosphoramide (HMPA), Hexamethyl phosphorus triamide (HMPT), N,N-dimethylimidazolidinone (DMI) and l,3-dimethyl-3 ,4,5,6- tetrahydro-2-(lH)-pyrimidinone (DMPU) may also be added.
• HMPA hexamethylphosphoramide
• HMPT Hexamethyl phosphorus triamide
• DI N,N-dimethylimidazolidinone
• DMPU l,3-dimethyl-3 ,4,5,6- tetrahydro-2-(lH)-pyrimidinone
• the reaction can be quenched by an acid such as acetic acid or hydrochloric acid, and the trans azetidinones of formula I can be recovered by extraction followed by crystallization or column chrornatography.
• an acid such as acetic acid or hydrochloric acid
• the hydroxy substituent present in the imine intermediate of formulas III can be protected.
• a protecting group is present, an additional step comprising removal of the protecting group by conventional techniques is needed.
• the protecting group is a benzyloxy group
• a debenzylation reaction with a hydrogenating agent such as palladium on carbon and ammonium formate can be conducted; an alkoxy group can be converted to a hydroxy group by treatment with a Lewis acid, and a silyl protecting groups can be removed by treatment with fluoride, to obtain a compound of formula I wherein R 3 is hydrogen.
• the diphenylimines of formula III can be prepared from suitably substituted benzaldehydes and anilines by procedures well known in the art.
• Trans-isomers of diphenylazetidinones of formula I can form alkali metal salts at the phenolic hydroxyl position.
• the salt can be prepared by contacting the diphenylazetidinone of formula I with a sufficient amount of alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydrides such as sodium hydride, or alkali metal bicarbonates such as sodium bicarbonate in a suitable solvent.
• the inventors have also developed a process for the preparation of the chiral delta- lactone of formula II, wherein R 1 represents hydrogen, halogen or an alkoxy group.
• the process involves cyclizing a chiral hydroxyacid of formula IN in the presence of an acid or a salt of a weak base to obtain the chiral lactone of formula II.
• a weak base Both organic and inorganic acids may be used.
• suitable acids include hydrochloric, p-toluenesulfonic, acetic, and methanesulfonic acids.
• suitable salts of a weak base include pyridinium p-toluenesulfonate, and pyridine hydrobromide.
• the cyclization reaction may be carried out at a temperature from about -20°C to about 120°C, or at a temperature from about 0°C to about 60°C. In particular, it may be carried out at a temperature from about 10°C to about 40°C.
• the cyclization reaction may be carried out in a suitable solvent.
• suitable solvent includes any solvent or solvent mixtures which are inert and do not change under the reaction conditions, may be used in the cyclization reactions.
• solvents include ethers such as diethyl ether, dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran; chlorinated hydrocarbons such as methylene dichloride and ethylene dichloride; esters such as ethyl acetate and isopropyl acetate; ketones such as acetone and methylisobutylketone (MLBK); hydrocarbons such as hexane, toluene, and xylene; acetonitrile; dipolar aprotic solvents such as dimethylfo ⁇ namide, dimethylsulphoxide, N-methylpyrrolidone, sulpholane; and mixtures thereof.
• ethers such as diethyl ether, dibutyl ether, methyl tert-butyl
• the inventors have also developed a process for the preparation of chiral hydroxyacid of formula IN, wherein R 1 represents hydrogen, halogen or an alkoxy group.
• the process involves stereoselectively reducing benzoyl butyrate of formula NI, wherein R 1 represents hydrogen, halogen or an alkoxy group, and R is an alkyl group, to obtain chiral hydroxyester of formula N; and hydrolyzing the resulting chiral hydroxyester of formula N.
• the stereoselective reduction of the compound of formula NI to the compound of formula N may be achieved by reduction with a chiral reducing agent or by using a reducing agent in the presence of a chiral catalyst.
• chiral reducing agents used for the reduction are those customarily used in organic chemistry.
• chiral reducing agents include chiral boranes such as (-)- ⁇ 3-chlorodiisopinocampheylborane (DIP-Cl), (S)-BI ⁇ AP, (S)-BINAL-H and compounds of structures as shown below:
• reducing agents include sodium borohydride, sodium cyanoborohydride and a borane complex such as borane-THF, and borane-dimethylsulfide complex.
• Examples of chiral catalysts which may be used with the above reducing agents can be the same as the chiral boranes exemplified above as chiral reducing agents.
• the addition of a dilute acid, such as hydrochloric acid, followed by extraction with a suitable solvent produces the compounds of formula V.
• the reduction temperature may be varied depending on the choice of a catalyst and/or a reducing agent employed. For example, the reduction may be carried out at a temperature range from about -80°C to about 100°C, or at a temperature from about -40°C to about 40°C. i particular, it may be carried out at a temperature from about -25°C to about -10°C.
• Suitable solvents for reduction of the compounds of formula VI are the customary inert solvents that do not change under the reaction conditions.
• solvents include ethers, such as dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran; chlorinated hydrocarbons such as methylene dichloride and ethylene dichloride; alcohols such as methanol, ethanol and isopropanol; esters such as ethyl acetate and isopropyl acetate; hydrocarbons such as hexane, toluene, and xylene; dipolar aprotic solvents such as dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidone; and mixtures thereof.
• ethers such as dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran
• chlorinated hydrocarbons such as methylene dichloride and
• the compounds of formula VI can be prepared by conventional esterification of the corresponding acids with suitable alcohols. These acids are known compounds, and can be produced by methods known in the art such as the procedure disclosed in U.S. Patent No. 6,207,822.
• the compounds of formula IN and formula N may be isolated during the reaction, or allowed to react further in situ to form the chiral lactone of formula II.
• the 4-(4-fluorobenzoyl)butyric acid (lOOg, 0.476mol) obtained in example 1 was dissolved in 1050ml of methanol and 100ml of 16% methanolic hydrochloric acid was added. The reaction was monitored to completion by TLC and the solvent was evaporated under vacuum. The residue was taken-up in 400ml dichloromethane and washed twice with 250ml of 5% sodium bicarbonate solution and then with 500ml of saturated brine solution. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate and hexane to yield the pure product (85.7g, yield: 80%).
• reaction mass was then poured into a 500ml mixture of methylene chloride and satd. sodium bicarbonate solution (3:2).
• the aqueous layer was separated and washed with 200ml of methylene chloride and acidified to pH ⁇ 2 at 0°C with 6M hydrochloric acid.
• the aqueous layer was saturated with sodium chloride and extracted twice with ethyl acetate (200ml).
• the organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was taken in 11 of toluene and treated with a solution of pyridinium 4-toluenesulfonate (5.7g, lOmol %) dissolved in 200ml methylenechloride.
• the intermediate trans l-(4-fluorophenyl)-3-[3(S)-(4-fluorophenyl-3- hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (5g, lmmol) was dissolved in 85ml methanol and the solution was deaerated. Ammonium formate (6.3 lg, lOmmol), 10%) palladium on carbon (3.6g) and formic acid (0.5ml) was added to the solution. The reaction was heated to 55°C and monitored to completion by TLC. The reaction mixture was filtered over a filtration aid to remove the 'palladium on carbon' and washed with methanol.

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• 2004
  • 2004-05-05 EP EP04731224A patent/EP1626954A2/de not_active Withdrawn
  • 2004-05-05 WO PCT/IB2004/001396 patent/WO2004099132A2/en not_active Ceased
  • 2004-05-05 CN CNA2004800162566A patent/CN1805926A/zh active Pending
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