AU761622B2 - 3-acyl-3-phenylpropene derivatives, 3-acyl-3- phenylpropanal derivatives and process for their preparation - Google Patents

Description

S&FRef: 508489D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

0 0.

e 0 Name and Address of Applicant: Actual Inventor(s): Address for Service: Eli Lilly and Company Lilly Corporate Center Indianapolis Indiana 46285 United States of America Alexander Glenn Godfrey, Daniel Timothy Kohlman, John Cunningham O'Toole, Yao-Chang Xu, Tony Yantao Zhang Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) 3-acyl-3-phenylpropene Derivatives, 3-acyl-3phenylpropanal Derivatives and Process for their Preparation Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c 3-acyl*3-phenylpropene Derivatives, 3-acyl-3-phenylpropanal Derivatives and Process for their Preparation The present invention provides new intermediates which are useful for manufacturing compounds for the treatment of diseases which are caused or affected by disorders of those serotonin-affected neurological systems, particularly those relating to the 1lA receptor.

The present invention provides a compound of the formula: 0 0

H'

**wherein RI is H, C1-6alkyl, Ci-6alkoxy, Cl-6alkylthio; R 2 is phenyl, naphthyl or C3.l2cycloalkyl substituted with one or two substituents selected from. the group consisting of H, C1-6alkyl, Cl-6alkoxy, Cli0 6alkylthio, C2-6alkenyl, C2-6alkynyl, C 1 -6alkylhalo, C3-8CYCloalkyl, C-C8cycloalkenyl or halo; R 3 is selected from the group consisting of H, Ci-6alkyl, C1-6alkoxy, Cl-6alkylthio, C2-6alkenyl, C2-6alkynyl, Cl.

6alkylhalo, C3-8cycloalkyl, C3-8CYCloalkenyl or halo.

The invention also provides a process for the preparation of a compound of the formula 1: 0 0 H

QR

wherein R 1 is H, Cl-6alkyl, Cl-6alkoxy, Cl-6alkylthio; R 2 is phenyl, naphthyl or C3-l2cycloalkyl substituted with one or two substituents selected from the group consisting of H, C1-6alkyl, Cl-6alkoxy, Cl- 6alkylthio, C2-6alkenyl, C2.6alkynyl, Cl-6alkylhalo, C3-8CYCloalkyl, C3-8CYCloalkenyl or halo; R 3 is selected from the group consisting of H, Cl-6alkyl, Cl-6alkoxy, Cl-6alkylthio, C2-6alkenyl, C2-6alkynyl, Cl- Galkyihalo, C3-8cycloalkyl, C3-8cycloalkenyl or halo, comprising, treating a compound of formula 11 0 qQI wherein R 1

R

2 and R 3 are described as above, with a suitable base and a compound of formula Ill: x SIIl wherein X is a suitable leaving group, to provide the compound of formula IV 0 QRR2 R 3 IV LibC/508489D1speci and oxidising the compound of formula IV with a suitable oxidising agent to provide the compound of formula I.

The invention further provides a compound of formula: 0 R2 Q R

R

3

IV

wherein R 1 is C 16 alkyl, or Cl.ealkylthio; R 2 is phenyl, naphthyl or C 3 1 2 cycloalkyl substituted with one or two substituents selected from the group consisting of H, Ci.

6 alkyl, Cl-alkoxy, Cl6alkylthio, C2.ealkenyl, C2-6alkynyl,

C

1 .6alkylhalo, C3-8cycloalkyl, C3.scycloalkenyl or halo; R 3 is selected from the group consisting of H, C 16 alkyl, Ci.

6 alkoxy, C1-alkylthio, C2.

6 alkenyl, C 2 -6alkynyl, C 1 alkylhalo, C 3 .scycloalkyl, C 3 .scycloalkenyl or halo; or wherein R 1 is H, C 1 .6alkyl, Cl .alkoxy, Clealkylthio; R 2 is C3 1 2 cycloalkyl substituted with one or two substituents selected from the group consisting of H, Cs.

6 alkyl, Cl.

6 alkoxy, C 1 ,.alkylthio, C2-6alkenyl, C2-6alkynyl,

C

16 alkylhalo, C 3 .scycloalkyl, C-Cscycloalkenyl or halo; R 3 is selected from the group consisting of H, Cl.ealkyl,

C

16 alkoxy, C 16 ealkylthio, C 26 alkenyl, C26alkynyl, Cl- 6 alkylhalo, C3.acycloalkyl, C 38 cycloalkenyl or halo.

Description of Preferred Embodiments In the present document, all descriptions of concentrations, amounts, ratios and the like will be expressed in weight units unless otherwise stated. All temperatures are in degrees Celsius.

The Compounds It is believed that the general description of the compounds above is sufficient to explain their nature to the skilled reader; attention to the Examples which follow is also encouraged. Some additional description will be provided to assure that no misunderstanding occurs.

In the general description, the general chemical terms are all used in their normal and customary 20 meanings. For example, the small alkyl and alkoxy groups, such as C 16 alkyl and C 1 alkoxy groups include, depending on the size of the groups, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, pentyl, 3-methylbutyl, hexyl, and branched hexyl groups, and the corresponding alkoxy groups, as may be allowed by the individually named groups. Where a number of possible substituent groups are permitted on a group, such as the one to three alkyl, alkoxy or halo groups permitted or an Ar group, it will be understood by the reader that only substitution which is electronically and sterically feasible is intended.

The term "alkenyl" as used herein represents an unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl as well as dienes and trienes of straight or branched chains.

The term "alkynyl" denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl as well as diand triynes.

The term "Cl.6alkylthio" defines a straight or branched alkyl chain having one to six carbon atoms attached to the remainder of the molecule by a sulfur atom. Typical C 16 alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

The term "Cl.ealkylhalo" refers to alkyl substituents having one or more independently selected halo atoms attached at one or more available carbon atoms. These terms include chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl, 3-bromopropyl, 2-bromopropyl, 3-chlorobutyl, 2,3-dichlorobutyl, 3-chloro-2-bromobutyl, trichloromethyl, dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl, 1,1-dichloropropyl, and the like. More preferred C 16 alkylhalo groups are trichloromethyl, trichloroethyl, and trifluoromethyl. The most preferred C 16 alkylhalo is trifluoromethyl.

LibC/508489D1speci The term "C3-8cycloalkyl" includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "C3-scycloalkyl" includes C3-6cycloalkyl.

The term "C3-scycloalkenyl" represents an olefinically unsaturated ring having 3 to 8 carbon atoms including groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. The term "C3-8cycloalkenyl" includes C3-6cycloalkenyl.

The term "aryl" represents phenyl or naphthyl.

The term "bicyclic" represents either an unsaturated or saturated stable 7 to 12-membered bridged or fused bicyclic carbon ring. The bicyclic ring may be attached at any carbon atom which affords a stable structure. The term includes, but is not limited to, naphthyl, dicyclohexyl, dicylohexenyl, and the like.

The term, "mono or bicyclic heteroaryl radical", refers to radicals derived from monocyclic or polycyclic, aromatic 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 pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, indolizinyl, isoquinolyl, benzothienyl, isoindolizinyl, oxazolyl, 15 indolyl, carbazolyl, norharmanyl, azaindolyl, dibenzofuranyl, thianaphthenyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, anthranilyl, purinyl, pyridinyl, phenylpyridinyl, pyrimidinyl, pyrazinyl, quinolinyl.

The terms "halo" or "halide" are used in the above formula to refer to fluoro, chloro, bromo or odo.

The term "aprotic solvent" refers to polar solvents of moderately high dielectric constant which do not contain an acidic hydrogen. Examples of common aprotic solvents are dimethylsulfoxide (DMSO), dimethylformamide, sulfolane, tetrahydrofuran, diethyl ether, methyl-t-butyl ether, or 1,2dimethoxyethane.

The term "protic solvent" refers to a solvent containing hydrogen that is attached to oxygen, and hence is appreciably acidic. Common protic solvents include such solvents as water, methanol, ethanol, 2-propanol, and 1-butanol.

The term "inert atmosphere" refers to reaction conditions in which the mixture is covered with a layer of inert gas such as nitrogen or argon.

As used herein, the term "Me" refers to a -CH 3 group, the term "Et" refers to a -CH 2

CH

3 group and the term "Pr" refers to a -CH 2

CH

2

CH

3 group.

As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral centre" refers to a carbon atom to which four different groups are attached.

The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric LibC/508489D1speci 4 enrichment achieved is the concept of enantiomeric excess, or which is found using the following equation: E' E 2 ee= x100 E' E 2 wherein E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.

Thus, if the initial ratio of the two enantiomers is 50:50, such as the is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in 15 the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc. 1981. Examples of resolutions include recrystallisation techniques or chiral chromatography.

The reader will understand that the preferred classes of compounds may be combined to form additional, broader or narrower classes of preferred compounds: a) R 1 is H; b) R 1 is Ci-6alkyl or C 1 20 6alkoxy; c) R 1 is Ci-2alkyl or C1.2alkoxy; d) R 2 is phenyl; e) R 2 is C3-8cycloalkyl; f) R 2 is C3-6cycloalkyl; g)

R

2 is cyclohexyl; h) R 3 is Ci-6alkyl, C1ealkoxy or halo; i) R 3 is Ci4alkyl, C14alkoxy or halo; j) X is -C=O; k) X is -CHOH; and I) X is -CH 2 Many of the compounds of Formula I and Formula IV are optical isomers. For example, the compounds have an asymmetric centre (or chiral centre) at the carbon atom to which R 1 and X are attached. However, when a compound of the present invention is named without an indication of asymmetric form, any and all of the possible asymmetric forms are intended. This invention is not limited to any particular isomer but includes all possible individual isomers and racemates.

The intermediates and final products may be isolated and purified by conventional techniques, such as, purification with chromatography using silica gel or recrystallisation of crystalline isolates.

It will be readily appreciated by the skilled artisan that the starting materials which are not described are either commercially available or can be readily prepared by known techniques from commercially available starting materials. All other reactants used to prepare the compounds in the instant invention are commercially available.

The compounds of the invention are generally prepared according to the following schemes.

Scheme I o

H

R

2 R 2

R

2 3 R' 3 (3) LibC/508489D1speci I Starting material is treated with a base, preferably potassium t-butoxide, followed by alkylation with 2-bromomethyl-l,3-dioxolane. Other appropriate bases include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, caesium carbonate and the like.

The reaction is preferably conducted in a solvent such as dimethylsulfoxide at a temperature of 15°C to reflux, with a temperature of 45-55°C being most preferred, and is substantially complete in 1 to 24h to prepare intermediate Treatment of with an acid, such as hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent, achieves aldehyde Generally, the reaction is conducted in a protic solvent, such a mixture of aqueous acid and acetone, at temperatures of from about 5 0 C to 75°C, preferably at ambient temperature.

Starting material is either commercially available or can be prepared by coupling [See Nahm and Weinreb, Tetrahedron Lett., 22, 3815, (1981)] and as described in Scheme II, below.

Scheme II 2

SH

3 cO'N R2 R

R

cH 3

R

3 3 (1) M is a metallic salt, such as lithium or magnesium halide. The reaction is preferably conducted under an inert atmosphere preferably nitrogen, in an aprotic solvent, such as tetrahydrofuran, at ambient temperatures.

Scheme III Et EtO

O

o o o 0

C

B) (9) In scheme III, step A, the ester of structure is treated with benzylmagnesium chloride or benzylmagnesium bromide under standard conditions well known in the art to provide the ketone of structure For example, about 1.05 to about 1.leq of a suitable amine, such as dimethylamine is dissolved in a suitable organic solvent, such as tetrahydrofuran (cooled to about under an inert atmosphere. The solution is warmed to room temperature and 1.0eq of the ester are added with stirring. Then approximately 1.0 to 1.05eq of benzylmagensium chloride is slowly added to the solution, maintaining the temperature at about 15-20°C with a cooling bath during the addition. After addition is complete, the reaction is stirred at room temperature for about 1 to 2h, then cooled to less than 0°C and then carefully quenches with a suitable acid, such as HCI. The quenched reaction is then extracted with a suitable organic solvent, such as t-butyl methyl ether (hereinafter referred to as MTBE), the organic layers are combined, dries over anhydrous magnesium sulfate, filtered and concentrated to provide ketone Ketone can be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the purified material. Alternatively, the crude ketone can be carried on to step B.

LibC/508489D1speci I 6 In Scheme III, step B, ketone is alkylated with bromoacetadehyde diethylacetal, and then iodomethane, under conditions well known in the art to provide compound of structure For example, ketone (11) is dissolved in a suitable organic solvent, such as methylsulfoxide and treated with about 1.05 to about 1.1eq of a suitable base, such as potassium t-butoxide. The reaction is stirred for about 15 to 30min and about 1.0 to about 1.05eq of bromoacetaldehyde diethtylacetal is added dropwise to the reaction. One of ordinary skill in the art would readily appreciate that bromoacetaldehyde dimethylacetal, bromoacetaldehyde ethylene acetal and the like may be used in place of the corresponding diethylacetal. The reaction mixture is then heated to about 50°C for about 2 to 2.5h. The reaction mixture is then cooled with an ice/water bath and about 2.2eq of a suitable base, such as potassium t-butoxide is added. The reaction is allowed to stir for about 15 to with continued cooling and then about 1.5 to about 1.8eq of iodomethane is added dropwise to the reaction mixture keeping the temperature of the mixture below 41*C, preferably below 21°C. After .addition is complete, the reaction is warmed to room temperature and stirred for about 1 to 4h. The reaction mixture is then partitioned between water and a suitable organic solvent, such as MTBE. The 15 layers are separated and the organic phase is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound In Scheme III, step C, compound is hydrolysed under acidic conditions to provide aldehyde in a manner analogous to the procedure described in Scheme I. More specifically, for example, compound is dissolved in a suitable organic solvent, such as acetone and treated with a suitable acid, such as hydrochloric acid. The reaction mixture is stirred for about 1 to 3h at room temperature.

The reaction mixture is then extracted with a suitable organic solvent, such as ethyl acetate or methylene chloride, the organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide aldehyde Aldehyde (9) .i can be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.

Alternatively, compounds of structure can be prepared following the procedure described in scheme IV. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.

Scheme IV 0 OH 0 RH R^R 2 R R 2

X

R3 (10) R2M (11) R 3 (12) R(1) (13) 0 0 0

H

OQ R2 1 R2

R

3 (14) 3 (3) In Scheme IV, step A, aldehyde (10) is combined with a suitable organometallic reagent (11) under conditions well known in the art to provide school Example of suitable organometallic reagents include Grignard Reagents, alkyllithium reagents, alkylzinc reagents, and the like. Grignard LibC/508489D1speci Reagents are preferred. For examples of typical Grignard Reagents and reaction conditions, see J.

March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2 nd Edition, McGraw- Hill, pages 836-841 (1977). More specifically, aldehyde (10) is dissolved in a suitable organic solvent, such as tetrahydrofuran or toluene, cooled to about -5 0 C and treated with about 1.1 to 1.2eq of a Grignard reagent of formula (11) wherein M is MgCI or MgBr. The reaction is allowed to stir for about to 2h, then quenched, and alcohol (12) is isolated. For example, the reaction mixture is poured onto ice-cold 1N HCI, the quenched mixture is extracted with a suitable organic solvent, such as toluene, the organic extracts are dried either azeotropically or over a suitable drying agent, such as anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide alcohol (12).

In Scheme IV, step B, alcohol (12) is oxidised under standard conditions well known in the art, such as those described by J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2 nd Edition, McGraw-Hill, pages 1082-1084 (1977), to provide ketone [Ketone is the starting material used in Scheme I above.] For example, alcohol (12) is dissolved in a suitable organic solvent, such as methylene 15 chloride, the solution cooled with a set ice-acetone bath, and treated with 2.5 to 3.0eq of dimethylsulfoxide. After stirring for about 30min, the reaction is then treated with about 1.8eq of P20 5 The reaction is allowed to stir for about 3h and then, preferably, treated over about 30min with about 3.5eq of a suitable amine, such as triethylamine. The cooling bath is then removed and the reaction is allowed to stir for about 8 to 16h. The ketone is then isolated by standard extraction techniques well known in the art. The above oxidation is also performed using standard Swern Oxidation conditions which are well known to one of ordinary skill in the art.

In Scheme IV, step C, ketone is treated with a suitable base followed by addition of the alkene wherein X is a suitable leaving group, to provide compound For example, ketone is combined with an excess of alkene (13) in a suitable organic solvent, such as tetrahydrofuran, and cooled with a wet ice acetone bath. Examples of suitable leaving groups are CI, Br, I, tosylate, mesylate, and the like. Preferred leaving groups are Cl and Br. About 1.1eq of a suitable base is added and the reaction is allowed to stir for about 2h at room temperature. Examples of suitable bases are potassium t-butoxide, sodium hydride, NaN(Si(CH 3 LDA, KN(Si(CH3) 3 2 NaNH 2 sodium ethoxide, sodium methoxide and the like. Potassium t-butoxide is the.preferred suitable base. The reaction is then quenched with aqueous acid and compound (14) is isolated by extraction with a suitable organic solvent, such as heptane. The heptane extracts are washed with sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide compound (14).

In scheme IV, step D, compound (14) is treated with a suitable oxidising agent to provide aldehyde [Aldehyde is also prepared in Scheme Examples of suitable oxidising agents are ozone, NalO4/Osmium catalyst, and the like. Ozone is the preferred oxidising agent. Examples of suitable oxidising reagents and conditions are described by J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2 nd Edition, McGraw-Hill, pages 1090-1096 (1977).

For example, compound (14) is dissolved in a suitable organic solvent, such as methanol, a small amount of Sudan III is added, and the solution is cooled to about -20°C. Ozone is bubbled into LibC/508489D1speci the solution for about 4 hours until the pink colour turns to a pale yellow colour. The Me 2 S is added to the reaction mixture and the cooling bath is removed. Concentration of the reaction mixture under vacuum provides the intermediate dimethylacetal of aldehyde This dimethylacetal is readily hydrolysed under standard acidic conditions to provide aldehyde Alternatively, direct acidic workup of the crude reaction mixture provides aldehyde Alternatively, aldehyde can be obtained directly by ozonolysis of (14) in a non-acetal forming solvent, such as methylene chloride.

The following examples represent typical syntheses of the compounds of Formula I and formula IV as described generally above. These examples are illustrative only and are not intended to limit the invention in any way. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: "aq" refers to aqueous; "eq" refers to equivalents; refers to grams; "mg" refers to milligrams; refers to litres; "mL" refers to millilitres; "IL" refers to microlitres; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "min" refers to minutes; refers to hours; refers to degrees Celsius' "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid 15 chromatography; "Rf" refers to retention factor; "Rt" refers to retention time; refers to part per million down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,Ndimethylformamide; "IPA" refers to isopropyl alcohol; "iPrOAc" refers to isopropyl acetate; "AcOH" refers to acetic acid; "HRMS" refers to high resolution mass spectrometry; "Et 3 N" refers to triethylamine; "LDA" refers to lithium diisopropyl amide; "RT" refers to room temperature; "SRI" refers to serotonin reuptake inhibitor; "aq" refers to aqueous; and "MTBE" refers to t-butyl methyl ether.

Example 1 0 0 0 3-benzoyl-3-phenylpropionaldehyde A. Preparation of 2- (2'-benzoyl-2-'-phenyl)ethyl-1,3-dioxolane: To a stirred suspension of sodium hydride (61.25mmol) in 150mL of dimethylformamide at 0 C under nitrogen was added dropwise a solution of deoxybenzoin (50.96mmol) in 150mL of tetrahydrofuran. The mixture was stirred at 0 C for 1h and room temperature for 1h. To the mixture 2-bromomethyl-1,3-dioxolane (60.55mmol) and catalyst potassium iodide (6.0mmol) were added. The mixture was heated to reflux for 13h. After cooling, diethylether (300mL) and water (300mL) were added. The organic layer was separated and washed with water (150mL x Purification by flash chromatography using hexanes and ethyl acetate gave 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane (8.18g; 57%).

B. Preparation of 3-benzoyl-3-phenylpropionaldehyde.

To 100mL of acetone was added 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane (8.85mmol) and 100mL of 2N hydrochloric acid solution. After the mixture was stirred at room temperature for 7h, 100mL of 2N sodium hydroxide was added. Acetone was evaporated and the residue was extracted with diethylether and hexanes 100mL x The combined organic layer was dried (sodium LibC/508489D1speci sulfate), filtered and concentrated. The residue was found to be rather pure material (3-benzoyl-3phenylpropionaldehyde) and therefore used for next step.

Example 2 0

H

0 0 3-cyclohexanecarbonyl-3-phenylpropionaldehyde Preparation of cyclohexyl benzyl ketone.

To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42mmol) in 30mL of tetrahydrofuran at 0 0 C under nitrogen was added a solution of benzyl magnesium chloride (2.0M in tetrahydrofuran, 4.5mL, 9.0mmol). The mixture was stirred at 0 0 C for 30min and at room temperature for 1h. Diethylether (50mL) and water (20mL) were added. The organic layer was separated, dried, filtered, and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05g) in 70% yield as oil.

B. Preparation of 2-(2'-cyclohexanecarbonyl-2'-phenyl)ethyl-1,3-dioxolane.

Following the procedures described in the Example 1, Step A, the reaction of cyclohexylbenzyl ketone (5.09mmol) and 2-bromomethyl-1,3-dioxolane (7.63mmol) in the presence of sodium hydride (5.60mmol) gave 2-(2'-cyclohexanecarbonyl-2'-phenyl)ethyl-1,3-dioxolane (0.86g) in 59% yield.

S: Preparation of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde.

Following the procedures described in the Example 1, Step B, the reaction of cyclohexanecarbonyl-2'-phenyl)ethyl-1,3-dioxolane (2.98mmol) with 1N hydrochloric acid gave 3- 20 cyclohexanecarbonyl-3-phenylpropionaldehyde as a crude product in 100% yield.

Example 3 0

H

0 CH 3 3-benzoyl-3-phenylbutyraldehyde Preparation of 2-(2'-benzoyl-2'-phenyl)propyl-1,3-dioxolane.

Following the procedures described in the Example 1, Step A, the reaction of 2-(2'-benzoyl-2'phenyl)ethyl-1,3-dioxolane (3.54mmol) and iodomethane (10.62mmol) in the presence of sodium hydride (4.25mmol) gave 2-(2'-benzoyl-2'-phenyl)propyl-1,3-dioxolane (0.60g).

Preparation of 3-benzoyl-3-phenylbutyraldehyde.

Following the procedures described in the Example 1, Step B, the reaction of 2-(2'-benzoyl-2'phenyl)propyl-1,3-dioxolane (0.60g) with 3N hydrochloric acid gave 3-benzoyl-3-phenylbutyraldehyde as a crude product (0.32g).

In like manner 3-cycloheptanecarbonyl-3-phenylpropionaldehyde and 3-cyclopentanecarbonyl- 3-phenylpropionaldehyde can be prepared.

LibC/508489D1speci Example 4

OOH

H

1 -cyclohexyl-2-phenyl-butan-1 -one-4-al 00 Preparation of 2-phenyl-1-cyclohexane-ethan-1-one.

Scheme III, Step A: A 5L reaction vessel was charged with tetrahydrofuran (1.05L) under an atmosphere of nitrogen. The solution was cooled with an acetone/ice bath to about -5 0 C. :Liquid dimethylamine (115.9g, 2.57mol) was then added through a teflon addition tube. The cooling bath was removed and the solution was allowed to warm to about 15-20 0 C. Methyl cyclohexanecarboxylate (341.7g, 2.40mol) was then added resulting in a tea-coloured solution. Then benzylmagnesium chloride (2.52L of a 2.0M solution in THF, 246mol) was slowly added at a rate to complete addition in about 1.8 to about 2.2h. A cooling bath was applied to maintain the temperature of the reaction mixture at about 15-20 0 C during the addition. After the benzylmagnesium chloride solution was added, the resulting slurry was stirred at room temperature for about 1-2h. The reaction 15 mixture was then cooled to less than 0°C. Concentrated HCI (709.7g, 7.2mol) was combined with water (3.08L) and the solution was cooled to less than 5 0 C. The dilute acid mixture was added to a 22L reaction vessel with an ice bath applied to the vessel. The above-chilled reaction mixture was S.*o then slowly poured into the chilled dilute acid solution with stirring. An extreme exotherm occurs (Use Caution!). Addition rate of the reaction mixture should be controlled to maintain the temperature of the quench solution below 45°C. After addition of the reaction mixture to the dilute acid solution, the quenched reaction mixture was cooled to room temperature and the pH was adjusted to about 6.5 to with a sufficient amount of concentrated HCI. The quenched reaction mixture was extracted with MTBE (1.71L). The layers were separated and the organic layer was washed with a water/MTBE mixture (1.03L/1.37L) followed by a second washing with a water/MTBE mixture (1.03L/1.03L). The 25 organic layers were combined, washed, with brine (683mL), dried over anhydrous magnesium sulfate '(167g), filtered and concentrated under vacuum. The crude oil was dried under house vacuum for 16h to provide crude 2-phenyl-1-cyclohexane-ethan-1-one (522.3g). This crude material was used in the next reaction without further purification.

OP CH 3 0 Preparation of 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane LibC/508489D1speci 11 Scheme III, Step B; 2-phenyl-1-cyclohexane-ethan-1-one (8.26g, 40.8mmol) was combined with DMSO (45mL) in a 3-necked, 250mL round bottom flask equipped with a magnetic stir bar, thermocouple-digital thermometer unit and an addition funnel. To the stirring solution was added potassium t-butoxide (5.04g, 44.9mmol). A 16°C exotherm was observed and the yellow solution became dark brown. The reaction mixture was stirred for an additional 15min after addition was complete, and then bromoacetaldehyde diethylacetal (8.26g, 41.9mmol) was added dropwise via the addition funnel over approximately 10min. The reaction mixture was then heated at 50 0 C for 2 to during which the reaction mixture became yellow. The reaction mixture was then cooled with an ice/water bath to about 9.5 0 C and potassium t-butoxide (10.07g, 89.7mmol) was added resulting in an exothermic reaction and change in colour from yellow to brown. With the cooling bath still in place, the reaction mixture was stirred for an additional 15min followed by dropwise addition of iodomethane (10.26g, 72.3mmol, neat). The temperature of the reaction mixture was maintained at or below 21 C.

Any exotherm during the iodomethane addition should be maintained below 41-43oC, which is the boiling point of iodomethane. After addition was complete, the reaction mixture was allowed to stir for 15 1 to 4h at room temperature. The reaction mixture was then partitioned between MTBE (100mL) and water (100mL). The organic phase was washed with water (3 X 50mL), dried over anhydrous magnesium sulfate, suction filtered and concentrated under vacuum to provide crude 1,1-diethoxy-3phenyl-3-cyclohexanecarbonyl-butane (13.6g) as a yellow oil. This crude material was used in the .next reaction without further purification.

0 C 2O H 0 20 H Preparation of 1-cyclohexyl-2-phenyl-butan-1-one-4-al Scheme III, Step C; 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane (74.4g, 224mmol) was dissolved in acetone (800mL) followed by addition of 3.ON HCI (800mL). The reaction mixture was stirred for 1h at room temperature. It was then concentrated under vacuum to less than /2 its original volume and then extracted with methylene chloride (800mL). The organic extract was then washed with brine (300mL), dried over anhydrous magnesium sulfate, suction filtered and concentrated under vacuum to provide crude 3-phenyl-3-cyclohexanecarbonyl-butan-l-al (57.8g).

Alternatively, the dried and filtered methylene chloride solution can be used directly in the next step without concentration.

Example Preparation of 2-phenyl-2-methyl-4-pentenoyl cyclohexane and 4-Cyclohexyl-3-methyl-4-oxo-3phenylbutyraldehyde

HO

O: CH 3 LibC/508489D1speci li'p e 12 Preparation of l-Cyclohexyl-2-phenylpropanol Scheme IV, step A: To a solution of cyclohexylmagnesium chloride (50mmol) in 25mL of and 40mL of THF at -5°C was added a solution of 2-phenylpropanaldehyde (5.36g, 40mmol) in of THF. The reaction mixture exothermed to 5°C. After stirring at room temperature for 75 min, the solution was poured onto ice cold 1 N HCI, extracted with toluene, dried over MgSO4, and concentrated to give the title compound as a colourless oil (6.15g, 70%) 1 H NMR (d6-DMSO) 6 7.23-7.30 2H, phenyl CH), 7.15-7.22 3H, phenyl CH), 4.17-4.51 (br s, 1H, 3.23-3.33 (m, 1H, R 2 CHOH), 2.78 (dq, J 7.0 Hz, J 7.1 Hz, 1H, -CH(CH 3 1.23-1.83 6H, cyclohexyl CH), 1.20 J 6.9 Hz, 3H, -CH(CH 3 0.88-1.18 5H, cyclohexyl CH).

0 o

CH

3 Preparation of cyclohexyl 1-phenylethyl ketone.

Scheme IV, Step B: DMSO (118mL, 1.6674mol) was added dropwise to a solution of 126.42g (0.579mol) of 1-cyclohexyl-2-phenylpropanol in 1737mL of CH 2

CI

2 (cooled in a wet ice acetone bath).

After 29 min, 147.93g (1.0422mol) of P20 5 was added. After 11min, the cooling bath was removed.

15 An aliquot quenched with Et 3 N showed complete reaction within 3h at RT. The reaction mixture was cooled in a wet ice acetone bath. Et3N (282mL, 2.0265mol) was added dropwise to the cooled reaction mixture over a 30min period. The cooling bath was removed and the mixture was stirred overnight at RT. The reaction mixture was quenched by dropwise addition of 500mL of 3N HCI (aq) (pH After shaking in separatory funnel, the aqueous phase was removed. The organic phase was 20 washed with 500mL of 3N HCI (aq) (pH washed twice with 1L of 10% K2C03 (aq) (pH 12;12), washed three times with 500mL of NaOCI (aq) solution, washed with 1L of water, washed with 1L of NaCI dried over MgSO4, gravity filtered and concentrated under vacuum with dry ice trap to collect Me2S. An amber oil of the title compound (107.01g, 85.437%) was obtained; 1 H NMR (d 6 -DMSO): 6 7.30-7.37 2H, phenyl CH), 7.21-7.28 3H, phenyl CH), 4.08 J 6.9 Hz, 1H, -CH(CH 3 2.40-2.49 1H, cyclohexyl CH), 1.82-1.84 1H, cyclohexyl -CH 2 1.67- 1.69 1H, cyclohexyl -CH 2 1.52-1.63 1H, cyclohexyl -CH 2 1.34-1.43 1H, cyclohexyl

CH

2 1.26 J 6.9 Hz, 3H, -CH(CH3)Ph), 1.01-1.24 4H, cyclohexyl -CH 2 O CH Preparation of 2-phenyl-2-methyl-4-pentenoyl cyclohexane Scheme IV, step C; A solution of 31.39g (0.2797mol) of t-BuOK in 100mL of THF was added dropwise to a solution of 55.00g (0.2543mol) of cyclohexyl 1-phenylethyl ketone and 26.4mL (0.3052mol) of allyl bromide in 136mL of THF (cooled in a wet ice acetone bath). THF washings (16mL) were added to the reaction mixture. The cooling bath was removed after addition. After reaction completion the reaction mixture was quenched with 300mL of 1N HCI (pH 0) and LibC/508489D1speci 9 1 4 13 extracted with 300mL of heptane. The heptane extract was washed with 10% NaHCO 3 (aq) (pH 9), dried over MgSO4, gravity filtered and concentrated under vacuum to afford 59.70g (91.58%) of title compound as an amber oil: 1 H NMR (d 6 -DMSO) 5 7.32-7.42 2H, phenyl CH), 7.24-7.31 3H, phenyl CH), 5.34-5.47 1H, -CH=CH2), 5.02 (dd, J 17.1 Hz, J 2.1 Hz, 1H, -CH=CH-H (trans)), 4.97 (ddd, J 10.2 Hz, J 2.2 Hz, J 1.0 Hz, 1H, -CH=CH-H (cis, W-coupling)), 2.66 (ddd, J 14.2 Hz, J 6.9 Hz, J 1.0 Hz, 1H, -CH2CH=CH2), 2.59 (ddd, J 14.2 Hz, J 7.3 Hz, J 1.0 Hz, 1H, CH2CH=CH 2 2.38-2.49 1H, cyclohexyl CH), 1.48-1.69 4H, cyclohexyl -CH 2 1.46 3H,

CH(CH

3 1.36-1.44 1H, cyclohexyl -CH2), 0.82-1.36 5H, cyclohexyl -CH2).

H

0

CH

3 44 \0 10 Preparation of4-Cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde Scheme IV, Step D: Ozone was bubbled through a cloudy mixture of 56.50g (0.2204mol) of 2phenyl-2-methyl-4-pentenoyl cyclohexane and a small amount (-10mg) of Sudan III in 220mL of MeOH (cooled in a dry ice acetone bath at -20°C) for 4h until pink colour turned to pale yellow colour.

After all of the olefin was consumed, Me2S (50mL) was added to reaction mixture. The cooling bath ,o 15 was removed. The exotherm rose to 38°C and mixture was cooled in cooling bath until there was no exotherm. Then the cooling bath was removed and the mixture was stirred overnight. The reaction solution was concentrated under vacuum with dry ice trap to collect excess Me2S to afford 83.65g of crude 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethylacetal as a pink oil: 1 H NMR (d 6 DMSO) 6 7.34-7.39 2H, phenyl CH), 7.24-7.30 3H, phenyl CH), 3.99 (dd, J 4.2 Hz, J 5.9 20 Hz, 1H, CH(OCH 3 2 3.14 3H, CH(OCH3)2), 3.06 3H, CH(OCH3)2), 2.34-2.43 1H, cyclohexyl CH), 2.10-2.20 2H, -CH2CH(OCH 3 2 1.55-1.67 1H, cyclohexyl -CH2), 1.53 3H, R2C(CH3)Ph), 0.80-1.52 9H, cyclohexyl -CH2).

To a solution of 82.65g (66.29g, 0.2177mol) of 4-cyclohexyl-3-methyl-4-oxo-3phenylbutyraldehyde dimethylacetal in 539mL of acetone was added 539mL of 3N HCI (aq) at RT.

After reaction completion the mixture was concentrated to 426.5g (or 1/3 volume) of residue (RT- The residue contained mostly water (pH 0) and was extracted twice with 300mL of MTBE.

The MTBE extract was washed with 300mL of 25% NaCI dried over MgSO4, gravity filtered and concentrated to afford 54.92g (97.65%) of title compound as a pink oil: 1 H NMR (d6-DMSO) 6 9.54 (t, J 2.0 Hz, 1H, -CHO), 7.36-7.43 2H, phenyl CH), 7.28-7.35 3H, phenyl CH), 2.95 (dd, J 16.6 Hz, J 1.9 Hz, 1H, CH2CHO), 2.85 (dd, J 16.6 Hz, J 1.7 Hz, 1H, CH2CHO), 2.41-2.49 (m, 1H, cyclohexyl CH), 1.72 3H, R 2

C(CH

3 0.85-1.66 10H, cyclohexyl -CH2).

LibC/508489D1speci

Claims (2)

1. A compound of the formula: 0 0 H A 1R2 QR wherein R 1 is H, Ci-6alkyI, C1-6alkoxy, CI-6alkylthio; R 2 is phenyl, naphthyl or C3l12cycloalky substituted with one or two substituents selected from the group consisting of H, C 1 -6alkyl, C 1 -6alkoxy, Ci- 6 alkylthio, C2-6alkenyl, C2-6alkynyl, Ci-6alkylhalo, C3-8CYCloalkyl, C-C~cycloalkenyl or halo; R 3 is .selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, Ci-6alkylthio, C2-6alkenyl, C 2 -6alkynyl, Ci- 6alkylhalo, C3-8cycloalkyl, C3-8cycloalkenyl or halo. A compound according to claim 1, wherein R 1 is CH 3 R 2 is cyclohexyl; and R 3 is hydrogen.

93. A 3-acyl-3-phenylpropanal derivative, substantially as hereinbefore described with reference to any one of the examples. 4. A process for the preparation of a compound of the formula 1: 0 H 15 wherein RI is H, C1i6alkyl, C1-6alkoxy, Ci-6alkylthio; R 2 is phenyl, naphthyl or C3-12CYCloalkyl substituted with one or two substituents selected from the group consisting of H, Ci-6alkyl, Ci-6alkoxy, Ci- 6alkylthio, C2-6alkenyl, C2-6alkynyl, Ci-6alkylhalo, C3-8CYCloalkyI, C-C8cycloalkenyl or halo; R 3 is selected from the group consisting of H, C1-6alkyl, C 1 -6alkoxy, Ci-6alkylthio, C2-6alkenyl, C2-6alkynyl, Ci- 6alkylhalo, C3-8CYCloalkyl, C3-8cycloalkenyl or halo, comprising, treating a compound of formula 11 0 QR QQ3 wherein R 1 R 2 and R 3 are described as above, with a suitable base and a compound of formula Ill: x SIll wherein X is a suitable leaving group, to provide the compound of formula IV 0 R 3 IV LibC/5O5489D1 sped 'K and oxidising the compound of formula IV with a suitable oxidising agent to provide the compound of formula I. A process according to claim 4, wherein R 1 is CH 3 R 2 is cyclohexyl; and R 3 is hydrogen. 6. A process according to claim 5, wherein X is Br or Cl. 7. A process according to claim 6, wherein the suitable oxidising agent is ozone. 8. A process according to claim 7, wherein the suitable base is potassium t-butoxide. 9. A process for the preparation of a 3-acyl-3-phenylpropanal derivative, said process being substantially as hereinbefore described with reference to any one of the examples. A 3-acyl-3-phenylpropanal derivative prepared by the process of any one of claims 4 to 9. 11. A compound of formula: 0 R R 2 R 3 IV wherein R 1 is Cl.6alkyl, or Cl. 6 alkylthio; R 2 is phenyl, naphthyl or C3-.2cycloalkyl substituted with one or two substituents selected from the group consisting of H, C1.6alkyl, Cl.6alkoxy, Cl. 6 alkylthio, C2- 6alkenyl, C2-6alkynyl, Ci. 6 alkylhalo, C3.scycloalkyl, C3.8cycloalkenyl or halo; R 3 is selected from the S*group consisting of H, C-.6alkyl, Cl.6alkoxy, Cl. 6 alkylthio, C2-6alkenyl, C2-6alkynyl, Cl.ialkylhalo, C3- 8cycloalkyl, C3.8cycloalkenyl or halo. 12. A compound according to claim 11, wherein R 1 is methyl; R 2 is cyclohexyl; and R 3 is *.eb hydrogen. 13. A compound of formula: 0o SR 2 R R 3 IV wherein R 1 is H, Cli6alkyl, Cl.6alkoxy, C 16 alkylthio; R 2 is C3-12cycloalkyl substituted with one or two substituents selected from the group consisting of H, Cl.salkyl, Cl.6alkoxy, Ci-.alkylthio, C2-6alkenyl, C2.6alkynyl, C 16 alkylhalo, C3.8cycloalkyl, C-C8cycloalkenyl or halo; R 3 is selected from the group S 25 consisting of H, Ci.salkyl, Cl. 1 alkoxy, Cl.6alkylthio, C2-6alkenyl, C2-6alkynyl, C 1 6 alkylhalo, C3- o* 8cycloalkyl, C3.8cycloalkenyl or halo. 14. A 3-acyl-3-phenylpropene derivative, substantially as hereinbefore described with reference to any one of the examples. Dated 4 April 2003 ELI LILLY AND COMPANY Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON LibC/508489D1 speci