EP1286980A2 - Enantioselektives verfahren zur herstellung von arylierten lactonen und derivaten davon - Google Patents

Enantioselektives verfahren zur herstellung von arylierten lactonen und derivaten davon

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Publication number
EP1286980A2
EP1286980A2 EP01918212A EP01918212A EP1286980A2 EP 1286980 A2 EP1286980 A2 EP 1286980A2 EP 01918212 A EP01918212 A EP 01918212A EP 01918212 A EP01918212 A EP 01918212A EP 1286980 A2 EP1286980 A2 EP 1286980A2
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EP
European Patent Office
Prior art keywords
process according
compound
formula
aryl
group
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.)
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Application number
EP01918212A
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English (en)
French (fr)
Inventor
Tony Yantao Zhang
Hongbin 401 Qiang Wei Court ZHANG
Christophor Scott Proctor
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.)
Eli Lilly and Co
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Eli Lilly and Co
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Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1286980A2 publication Critical patent/EP1286980A2/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-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
    • C07D307/30—Heterocyclic compounds containing five-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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D315/00—Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups C07D303/00 - C07D313/00

Definitions

  • This invention relates to the art of synthetic organic chemistry. Specifically, the invention is a process to enantioselectively prepare arylated lactones of formula I:
  • Lactones, substituted lactones and derivatives thereof, or compounds containing the lactone functionality are important medicinal agents or intermediates for the preparation of medicinal agents.
  • (-)- physostigmine an alkaloid obtained from the Calabar bean fruit, has been found to be useful in the treatment of various clinical indications, including for example as a cholinesterase inhibitor.
  • Synthesis of chiral compounds with absolute stereocontrol remains a challenge. In particular, no high yield, highly enantioselective procedure has been reported for the synthesis of arylated lactones with absolute stereocontrol.
  • the present invention provides a process for preparing a compound of the formula (I) :
  • R is a H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic or heterocyclic radical;
  • Ar is an aryl group
  • R m is a single or multiple substituent on the lactone ring other than at the oc - position; and n is 1-20, comprising the steps of:
  • the present invention also provides a process for the preparation of a compound of formula (II)
  • R and R ⁇ are hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic or heterocyclic radical or combine to form a substituted or unsubstituted carbocycle or heterocycle;
  • R ⁇ and R ⁇ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic or heterocyclic radical or combine to form a substituted or unsubstituted carbocycle or heterocycle, comprising the steps of:
  • the present invention is an enantioselective process for the preparation of ⁇ -arylated lactones .
  • the present invention is an enantioselective process for the preparation of intermediates useful in the synthesis of pharmaceutically active compound.
  • halo refers to fluoro, bromo, chloro and iodo .
  • BINAP is 2 , 2 ' -bis (diphenylphosphino) - 1 , 1 ' -binaphtyl , used either as the S or R enantiomer as indicated.
  • heterocycle or “heterocyclic radical” refer to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur.
  • Typical heterocyclic radicals are pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl , thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl , triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl , indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl , thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2- A)pyridinyl, benzotriazolyl , anthranilyl, 1,2- benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl , pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridiny
  • carrier radical refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14-membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms.
  • Typical carbocyclic radicals are cycloalkyl, cycloalkenyl , phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl , stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyl , acenaphthylenyl , and anthracenyl, biphenyl , bibenzylyl and related bibenzylyl homologues represented by the formula (bb) ,
  • nl is an integer from 1 to 8.
  • aryl retains its commonly understood meaning of cyclic groups having the 4n + 2 pi electronic structure and includes for example, substituted or unsubstituted aromatic radical selected from the group comprising 2-furyl, 3-furyl, 2-thienyl 3- thienyl, 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3- benzofuryl, 4-benzofuryl , 5-benzofuryl, 6-benzofuryl, 7- benzofuryl, 2-benzothienyl, 3-benzothienyl , 4-benzothienyl , 5-benzothienyl, 6-benzothienyl , 7-benzothienyl , 1-indolyl, 2-indolyl, 3-indolyl, 4-ind
  • aryl may be at one or two carbon atoms of the aryl group, and may be with heterocyclic radical, C 1 -. 4 alkyl, C ⁇ _ 4 alkoxy, halogen, -N0 2 , -CN, -COOH, -C0NH 2 , -SR 9 , -OR 10 , -SO 3 H, -
  • R 9 and R 10 are independently hydrogen, -CF3, phenyl, - (C1-C4) alkyl, - (C1-C4) alkylphenyl or -phenyl (C1-C4) alkyl .
  • substituted aryl groups are 4-methyl-3-furyl , 3 , 4-dimethyl-2-thienyl, 2 , 4-dimethyl- 3-thienyl, 3-ethoxy-4-methyl-2-benzofuryl , 2-cyano-3- benzofuryl, 4-trifluoromethyl-2-benzothienyl, 2-chloro-3- benzothienyl, 3 , 4-dichloro-2-pyridyl, 2-bromo-3 -pyridyl, 2- fluoro-4-pyridyl, 4-fluoro-2-furyl , 2-carboxyphenyl , 4- carboxamidophenyl, 3-trifluoromethylphenyl , bromo-1- naphthyl, 2 , 3-dimethyl-l-naphthyl, 3 -carboxy-2-naphthyl , 5- carboxy-8-chloro-l-naphthyl , 3-ethyl-2-
  • non-interfering sustituent refers to radicals suitable for substitution on the lactone nucleus (depicted in Formula I) and radical (s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above.
  • Illustrative non-interfering radicals are hydrogen, - (C1-C14) alkyl , - (C2-C6) alkenyl, -(C2-C6)alkynyl, - (C7-C12 ) ralkyl, - (C7-C12 ) alkaryl , -(C3- C8) cycloalkyl, - (C3-C8 ) cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, - (C1-C6 ) alkoxy, - (C2-C6) alkenyloxy, - (C2- C6)alkynyloxy, - (C1-C12 ) alkoxyalkyl, - (Ci-
  • Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenyli idazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl , indolyl, carbazolyl, norharmanyl , azaindolyl, benzofuranyl , dibenzofuranyl , thianaphtheneyl , dibenzothiophenyl , indazolyl, imidazo ( 1.2-A) yridinyl, benzotriazolyl, anthranilyl, 1 , 2-benzisoxazolyl , benzoxazolyl, benzothiazolyl, purinyl , pryidinyl, dipyridylyl .
  • phenylpyridinyl benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl , pyrazinyl, 1, 3 , 5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl , and quinoxalinyl .
  • the term "pharmaceutically acceptable salt” refers to all non-toxic organic or inorganic acid addition salts.
  • Illustrative inorganic acids or “acidic groups” which form salts include hydrochloric, hydrobromic, sulfuric, phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
  • Illustrative acids or “acidic groups” which form suitable salts include the mono-, di- and tricarboxylic acids.
  • Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxy-benzoic, and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and 2-hydroxyethane sulfonic acid.
  • Preferred acids include those selected from the group comprising of hydrobromic acid, hydrochloric acid, camphorsulfonic acid, p-toluenesulfonic acid, and sulfuric acid.
  • a particularly preferred acidic group is hydrochloric acid. Acid addition salts formed from these acids can exist in either hydrated or substantially anhydrous form, all of which are within the scope of this invention.
  • chiral ligand is synonymous with chiral auxiliaries and refer to chiral compounds capable of forming chiral complexes with reactive agents e.g., palladium, to form chiral catalysts which aid in the stereo-differentiation of reactive sites and results in enantiomerically enriched reaction products.
  • Chiral ligands or auxilliaries have been reviewed in the literature and are known to one of skill in the art. Examples of chiral ligands include but are not limited to chiral phosphines, chiral oxazolines, and chiral binaphthyl .
  • the opposite enantiomer may be used according to the process of the invention to afford the opposite enantiomer of product, or a preponderance thereof.
  • the present invention provides a process for preparing ⁇ - aryllactones via an enantioselective palladium catalyzed carbon-carbon bond formation between an aryl source and a lactone substrate.
  • the present invention provides a process for the preparation of compounds of formula 1 or pharmaceutically acceptable salts thereof, wherein R is a hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic, heterocyclic radical ; Ar is an aryl group; R m is a single or multiple non-interfering substituent on the lactone ring other than at the -position; and n is 1-20.
  • Preferred R groups for the purpose of the invention are the R groups selected from the group consisting of hydrogen, (C ⁇ -Cg) alkyl, (C ⁇ -C]_4) alkylaryl , and arylalkyl groups.
  • R m for the purpose of the present invention is a single or multiple non-interfering substituent independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, alkylheterocyclic and arylheterocyclic radical.
  • Most preferred R m is a single or multiple non-interfering substituent independently (for multiple) selected from the group consisting of hydrogen, (C]_-Cg) alkyl, aryl, (C ] _-
  • n 1, 2, or 3.
  • a preferred R 1 group for the purpose of the present invention is a non-interfering substituent selected from the group comprising of alkyl, alkenyl, alkynyl, aryl, heteroalky, alkylaryl, arylalkyl, alkylheterocyclic and arylheterocyclic radical. Most preferred R 1 is a non- interfering substituent selected from the group consisting of (Cx-Cg) alkyl, aryl, (C1-C 4 ) alkylaryl .
  • Preferred aryl substrate or source (ArX) for the purpose of the present invention is the aryl substrate wherein X is a halogen, triflate or phosphonate. Most preferred is ArX wherein X is a bromide (Br) , Iodide (I) or triflate
  • R 2 and R ⁇ groups are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, carboxyalkyl, carboxyaryl, cyano, carbocyclic, heterocyclic or combine to with the nitrogen to which they are attached to form substituted or unsubstituted piperazinyl, piperidinyl, pyrrolidinyl , morpholino, or 1- hexamethyleneimino .
  • R 2 and R3 groups are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl or combine to with the nitrogen to which they are attached to form 4- (2- methoxyphenyl ) piperazinyl , piperidinyl, pyrrolidinyl, methylpyrrolidinyl , dimethylpyrrolidinyl , morpholino, or 1- hexamethyleneimino .
  • Preferred palladium sources include elemental palladium, elemental palladium on supports including activated carbon, or alumina.
  • palladium salts including but not limited to palladium acetate, palladium chloride, palladium bromide, and palladium complexes including but not limited to palladium bis (dibenzylideneacetone) palladium (0) (Pd(dba)2)# tris (dibenzylideneacetone) bispalladium (Pd2(dba)3), tetrakistriphenylphosphine palladium (0) (Pd(PPh3) 4) , bistriphenylphosphinepalladium (II) chloride (Pd(Ph3 ) 2CI2 ) / and palladium bistriphenylphosphine diacetate (Pd(Ph ) 2 (OAc) 2 ) •
  • Preferred chiral ligands are the chiral phosphines .
  • a most preferred chiral ligand is BINAP, either the R or S depending on the desired configuration of reaction product.
  • a most preferred palladium catalyst system for the purpose of the present invention is 5-10% palladium acetate and 5-15% R or S BINAP depending on desired product configuration .
  • the practice of the invention involves the reaction of the enolate of a lactone with an aryl source in the presence of a palladium catalyst system in a suitable solvent.
  • the lactone enolate may be generated in si tu by reacting the lactone with a suitable base, preferably a strong base, more preferably an organic base such as for example, potassium bis (trimethylsilyl) amide (KN(TMS)2) in a suitable solvent such as for example tetrahydrofuran or toluene or dioxane.
  • KN(TMS)2 potassium bis (trimethylsilyl) amide
  • This phase of the reaction is performed at a temperature of from about -80 to 150°C, preferably -20 to 30°C, and most preferably at about 20°C, depending on factors as solvent and base employed.
  • the lactone enolate may be generated separately and cannulated to the reaction flask.
  • the lactone enolate is then reacted with an aryl source such as for example aryl bromide, aryl iodide, aryltrifluoromethane sulfonate (aryl triflate) or aryl phosphonate in the presence of a palladium catalyst source, at about 80-120°C, over a period of 2 to 48 hours.
  • Preferred aryl source include the aryl bromides, aryl iodides and aryl triflates.
  • Preferred palladium catalyst source includes for example those generated from palladium acetate and a chiral ligand, and from Pd(dba)2 and a chiral ligand.
  • a preferred chiral ligand is R- (+) -BINAP or S-(-) -BINAP depending on the desired product configuration, and a preferred palladium source is palladium acetate.
  • an achiral ligand, a mixture of S and R ligands or lack of a ligand may result in a mixture of enatiomers and/or a low yield of aryl lactone.
  • the present invention includes a novel process for the production of chiral and achiral aryllactones.
  • palladium acetate and R-(+) -BINAP were added to toluene and stirred at room temperature for about 20 to 80 minutes, preferably for about 60 minutes, and preferably under nitrogen.
  • Aryl bromide and lactone e.g., ⁇ -methyl- ⁇ - butyrolactone
  • a solution of a suitable base preferably an organic base, preferably potassium bis (trimethylsilyl ) amide was added drop-wise via syringe.
  • the resulting mixture was heated at 40 to 120°C, preferably at about 100-105°C for about 10 to 30 hours, preferably about 24 hours depending on the boiling point of the solvent chosen.
  • the most preferred solvent is toluene.
  • reaction mixture was cooled, quenched with aqueous acid, preferably aqueous HCl and extracted.
  • aqueous acid preferably aqueous HCl
  • the product was chromatographed preferably on silica gel using a heptane /ethylacetate gradient.
  • the reaction product could be isolated and purified by common laboratory techniques know to one of skill in the art.
  • 2-methylbutyrolactone compound (a') was arylated with phenyl halide, preferably phenyl bromide to form compound (b' ) .
  • the process involved reacting the anion of 2-methylbutyrolactone (a' ) generated by reacting the lactone with an organic base such as potassium bis (trimethylsilyl ) amide, with R-BINAP and palladium acetate or other suitable palladium source.
  • the resulting arylated lactone (b') was subjected to a 1,2 -addition reaction, i.e., reacted with cyclohexylmagnesium bromide to afford the ketone compound (c')-
  • the Grignard reagent cyclohexylmagnesium bromide was generated using cylcohexylbromide and magnesium tunings in the presence of an aprotic solvent preferably an ether (i.e., diethyl ether).
  • an aprotic solvent preferably an ether (i.e., diethyl ether).
  • ether i.e., diethyl ether
  • the alcohol (OH) group of the compound (c') was oxidized using oxalylchloride, dimethylsufoxide and a tertiary amine base such as triethylamine (Swern oxidation) in a suitable solvant such as dichloromethane, typically at room temperature, to afford the aldehyde (d' ) •
  • a suitable solvant such as dichloromethane
  • the aldehyde (d' ) was reductively aminated by reaction with the amine, 4- (2-methoxyphenyl) piperazine, under hydrogenation conditions to afford desired product of formula (X' ) .
  • the reductive amination can be performed using suitable amines, reducing agents, and reaction conditions known to one of skill in the art. Reductive aminations may be performed step wise beginning with formation of the intermediate (often isolable) imine or enamine, and ending with reduction of the imine or enamine to the amine. Under certain conditions of substrate and reagents the two steps may be performed in the same reaction step.
  • Alcohol oxidations, Grignard reactions, reductive amination reactions are generally facile reactions, occurring at moderate temperatures and generally polar aprotic solvents.
  • General references for these reactions include Advanced Organic Chemistry, 3 rd edition, by Jerry March, Wiley-
  • the product of formula III is a key intermediate in the synthesis of physostigmine.
  • the intermediate III is converted to physostigmine by processes and procedures known to one of skill in the art and as described in Takano et. al . , Che . Pharm . Bull . 30(7) 2641-2643, 1992.
  • H 2 was introduced at 50 psi to a slurry of 0.049 g (0.023 mmol) of 5 % Pd/C and 0.20 g (0.46 mmol) of E-l- ( 4 ' - Cyclohexyl-3 ' -methyl-4 ' -oxo-3 ' -phenylbut-1-enyl) -4- (2- methoxyphenyl) piperazine, in 10 mL of IPA and mixture was shaken overnight at RT to complete reaction. The black slurry was vacuum filtered and concentrated to afford 0.19 g of crude product residue.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Furan Compounds (AREA)
EP01918212A 2000-03-24 2001-03-12 Enantioselektives verfahren zur herstellung von arylierten lactonen und derivaten davon Withdrawn EP1286980A2 (de)

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US19214800P 2000-03-24 2000-03-24
US192148P 2000-03-24
PCT/US2001/005800 WO2001072731A2 (en) 2000-03-24 2001-03-12 Enantioselective process for preparing arylated lactones and derivatives

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Publication number Priority date Publication date Assignee Title
UA66370C2 (en) 1997-12-16 2004-05-17 Lilly Co Eli Arylpiperazines having activity to setotonin 1 receptors

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Publication number Priority date Publication date Assignee Title
UA66370C2 (en) * 1997-12-16 2004-05-17 Lilly Co Eli Arylpiperazines having activity to setotonin 1 receptors

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See references of WO0172731A3 *

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