AU716462B2

AU716462B2 - Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine

Info

Publication number: AU716462B2
Application number: AU70925/96A
Authority: AU
Inventors: Keith M. Devries
Original assignee: PFIZER; Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1995-12-15
Filing date: 1996-10-11
Publication date: 2000-02-24
Anticipated expiration: 2016-10-11
Also published as: AU7092596A; IL136421A0; MX9804820A; NZ318843A; EP0883607A1; AP708A; OA10694A; NO982712D0; JP3066083B2; CA2237647A1; HRP960592A2; HUP9904275A2; PE25698A1; IL124452A0; CO4750831A1; NO982712L; KR20000064387A; MA24032A1; PL197306B1; HN1996000065A

Description

Processes and Intermediates for Preparing 1 -benzyl-4-((5,6dimethoxy-1 -indanon)-2-yl)methylpiperidine Background of the Invention This invention relates to a novel process for the preparation of 1-benzyl-4-((5,6dimethoxy-l-indanon)-2-yl)methylpiperidine (E2020), the compound of the formula VII below, and to novel intermediates used in said process.

United States Patent 4,895,841 issued January 23, 1990, refers to 1-benzyl-4-((5,6dimethoxy-l-indanon)-2-yl)methylpiperidine, methods for its preparation, useful intermediates, and to methods and pharmaceutical compositions for treating diseases caused by acetylcholinesterase activity, such as senile dementia. United States Patent 4,895,841, issued January 23, 1990, is hereby incorporated by reference in its entirety.

Summary of the Invention The present invention relates to a compound of the formula

R

N

O e 00 e SOMe 15 III Swherein R 1 is R20(C=0)- and R 2 is (C 1

-C

4 )alkyl.

The present invention also relates to a compound of the formula OMe R OMe wherein R 1 is R 2 and R 2 is (C 1

-C

4 )alkyl.

[R:\LIBH]332.doc:tab The present invention also relates to a compound of the formula 0 W~e R'---OWe wherein R' is R 2 and W 2 is methyl.

The present invention also relates to formula a process for preparing a compound of the OMe 'OMe wherein R1 is R 2 and R 2 is (CI-C 4 )alkyl, comprising: a) reacting a compound of the formula

R\

0 0 0 SO *00 0 04 *a 0

III

wherein R' is R 2 and W7 is (Ci-C 4 )alkyl, with a methenylation agent to form a compound of the formula Rl'wherein R1 is R 2

W

2 is (C 1

-C

4 )alkyl, and; b) reacting said compound of formula II, so formed, with a strong acid.

Preferably, said methenylation agent is tetramethyldiaminomethane in acetic anhydride. More preferably, said tetramethyldiaminomethane and acetic anhydride are [RALIBfl332.doc ab added in excess. Most preferably, said tetramethyldiaminomethane comprises 2 molar equivalents (relative to the amount of the compound of the formula III) and said acetic anhydride comprises 4 molar equivalents (relative to the amount of the compound of the formula III).

Preferably, said strong acid is sulfuric acid. More preferably, said sulfuric acid is concentrated sulfuric acid. Most preferably, said concentrated sulfuric acid comprises 9 molar equivalents (relative to the amount of said compound of the formula II).

A preferred embodiment of the present invention relates to any of the above processes further comprising the additional step of reacting the compound of formula I, wherein R 1 is

R

2 and R 2 is (Ci-C 4 )alkyl, with hydroxide (preferably potassium hydroxide) to form a compound of the formula 0 o.° [R\LIBH]332.doc:tab EDITORIAL NOTE Ng. 70925/96 This specification does not contain a page numbered 4.

WO 97/22584 PCT/IB96/01076 0 H OMe

VI

and reacting said compound of formula VI so formed with a benzyl halide and a base to form a compound of the formula 0 OMe N'OMe

VII

Preferably, said benzyl halide is benzyl bromide. Preferably said base is triethanolamine.

The most preferred embodiment of the above invention relates to a process wherein said compound of formula I is isolated before it is converted to the compound of formula VI. The compound of formula I can be isolated by addition of the strongly acidic solution containing the compound of formula I to ice/water followed by extraction with an organic solvent and removal of the organic solvent.

The present invention also related to a process for preparing a compound of the formula WO 97/22584 PCT/IB96/01076 .OMe SMoe

III

comprising reacting a compound of the formula with a compound of the formula in the presence of a Lewis acid, such as aluminum trichloride, in a reaction inert solvent, such as methylene chloride.

WO 97/22584 PCT/IB96/01076 Detailed Description of the Invention The compounds of formula I and E2020 can be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, compounds of the formulae 1, II and III, VI and VII and the groups R 2 and R 3 in the reaction schemes and discussion that follow are as defined above.

WO 97/22584 WO 9722584PCT/1B96/O1 076 -8- SCHEME 1 aome OMe I v R No

_I

0

I

li~e "0 le '011 e WO 97/22584 WO 9722584PCT/IB96/O1 076 -9- SCHEME 2 0 Olle 104 0 Ofle ONe 204 0 ONe

"'N

vI I Scheme 1 refers to the process of preparing a compound of formula I, which can be converted to a compound of the formula VII, E2020, by the methods of Scheme 2.

Referring to Scheme 1, the compound of the formula IV is commercially available.

Compounds of the formula V are also commercially available or can be prepared by methods well known to those of ordinary skill in the art.

A compound of the formula III can be prepared from a compound of the formula IV by reacting said compound of the formula IV with a compound of the formula V, wherein

R

1 is R 2 and R 2 is (C 1

-C

4 )alkyl, in the presence of a Lewis acid in a reaction inert solvent. Preferably, R' is R20(C=O)-, and R 2 is methyl. Suitable Lewis acids include aluminium trichloride, titanium tetrachloride or boron trichloride, preferably aluminium trichloride. Suitable reaction inert solvents include methylene chloride or dichloroethane, preferably methylene chloride. The reaction is generally performed at a temperature from about 0°C to about 85 0 C, preferably about 30 0

C.

A compound of the formula II can be prepared from a compound of the formula III by reacting said compound of the formula III with a methenylation agent. Preferably R' is

R

2 and R 2 is methyl. Suitable methenylation agents include tetramethyldiaminomethane in acetic anhydride, formaldehyde (about 37 weight in water) in diethylamine, formaldehyde (about 37 weight in water) in piperidine or S. N-methylthiomethylpiperdine. Preferably the methenylation agent is tetramethyldiaminomethane in acetic anhydride. When tetramethyldiaminomethane in acetic anhydride is the methenylation agent it is preferable to perform the reaction with an excess of tetramethyldiaminomethane and acetic anhydride. Most preferably, the reaction is performed with 4 equivalents of acetic anhydride (relative to the amount of the compound of formula III) and 2 equivalents of tetramethyldiaminomethane (relative to the amount of 25 the compound of formula III). When the methenylation agent is other than 9 tetramethyldiaminomethane in acetic anhydride a solvent may be used to facilitate the Sreaction. Suitable solvents include acetic anhydride, ethers diethyl ether and tetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride. The 9 9 o [R:\LIBH]332.doc:tab WO 97/22584 PCT/IB96/01076 -11reaction is performed at a temperature from about 00C to about 90C, preferably at about 900C. The reaction time may vary from about 6 hours to about 30 hours.

Preferably the reaction time is about 12 hours.

A compound of the formula I can be prepared from a compound of the formula II by reacting said compound of the formula II with a strong acid in a reaction inert solvent. Suitable strong acids include concentrated sulfuric acid, aluminum trichloride or concentrated hydrochloric acid, preferably concentrated sulfuric acid. When aluminum trichloride is the acid, a solvent must be used. Suitable solvents include carbon disulfide, methylene chloride ordichloroethane, preferably carbon disulfide. The reaction is performed at a temperature from about 00C to about 1000C, preferably at about 250C.

Scheme 2 refers to the conversion of compounds of the formula I into E2020, the compound of the formula VII.

Referring to Scheme 2, a compound of the formula I can be converted into a compound of the formula VI by reaction with a strong base in the presence of a solvent.

Preferably, the reactant is a compound of the formula I, wherein R' is R 2 and

R

2 is methyl. Suitable bases include potassium hydroxide and sodium hydroxide, preferably potassium hydroxide. Suitable solvents include lower alcohols, water or mixtures thereof, preferably a 2:1 water/methanol mixture. The reaction is performed at a temperature from about 250C to about 1000C preferably at about 100'C. The reaction time may vary from about 6 to about 24 hours, preferably about 18 hours.

The compound of formula I is most preferably converted into a compound of formula VI by isolating the compound of formula I before converting it into the compound of formula VI. A compound of formula I is isolated by pouring the acidic solution containing the compound of formula I over an ice/water mixture and extracting the aqueous with an organic solvent. Suitable solvents include methylene chloride, ethyl acetate or dichlorothane, preferably methylene chloride. The organic layer can be concentrated and is then suitable for treatment with a strong base.

A compound of the formula VII can be prepared from a compound of the formula VI by reacting said compound of the formula VI with a benzyl halide in a reaction inert solvent. Suitable halides include chloride, bromide, and iodide, preferably bromide. Suitable reaction inert solvents include diethyl ether, isopropyl ether, WO 97/22584 PCT/IB96/01076 -12tetrahydrofuran, preferably isopropyl ether. The reaction is performed at a temperature from about 0 C to about 70°C, preferably about 700C.

The compound of formula VII can be converted to pharmaceutically acceptable acid addition salts of the compound of the formula VII. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the compound of formula VII are those which form non-toxic acid addition salts, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate 1,1'-methylene-bis-(2hydroxy-3-naphthoate)] salts.

The compound of the formula VII is basic in nature and is therefore capable of forming a wide variety of different salts with various inorganic and organic acids.

Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula VII from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.

The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.

Compounds of the formula VII, E2020, and its pharmaceutically acceptable salts can be used to treat a disease caused by acetylcholinesterase activity, such as Alzheimers' Disease, according to the methods described in United States Patent 4,895,841, issued January 23, 1990.

Specifically, United States Patent 4,895,841 states that the in vitro acetyl cholinesterase activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, E2020, or a pharmaceutically acceptable salt thereof can be determined according to the method of Ellman et al. Biochem. Pharmacol., 7, 88-95 (1961).

WO 97/22584 PCT/IB96/01076 -13- The acetylcholinesterase inhibitory activity of 1-benzyl-4-((5,6-diethyoxy-1indanon)-2yl)methyl piperidine, determined according to the method of Ellman et al., expressed in terms of 50% inhibitory concentration (ICo) is 0.0053 pM.

Other methods for determining the activity of 1-benzyl-4-((5,6-diethyoxy-1indanon)-2yl)methyl piperidine are described in United States Patent 4,895,841, issued January 23, 1990.

1-Benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine is effective for treatment, prevention, remission, improvement, etc. of various kinds of senile dementia, particularly senile dementia of the Alzheimer's type; cerebrovascular disease accompanying cerebral apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc.

Further, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine has a strong and highly selective anticholinesterase action, which also renders the compound useful as a pharmaceutical based on this mode of action.

Specifically, 1 -benzyl-4-((5,6-dimethoxy-1 -indanon)-2yl)methyl-piperidine is effective for, for example, Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskinesia other than senile dementia of the Alzheimer type.

When 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine is used as a pharmaceutical for these diseases, it may be orally or parenterally administered. In general, it is parenterally administered in the form of injections, such as intravenous, subcutaneous, and intramuscular injections, suppositories, or sublingual tablets. The dose will vary depending upon the symptom; age, sex, weight, and sensitivity of patients; method of administration; time and intervals of administration and properties, dispensing, and kind of pharmaceutical preparations so that there is no particular limitation with respect to the dose. Normally the compound may be administered in a dose of about 0.1 to 300 mg, preferably 1 to 100 mg, per day per adult, ordinarily in one to four portions.

Pharmaceutical preparations in the dosage form of, injections, suppositories, sublingual tablets, tablets, and capsules are prepared according to methods which are commonly accepted in the art.

WO 97/22584 PCT/IB96/01076 -14- In preparing injections, the effective ingredient is blended, if necessary, with a pH modifier, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent, a preservative, etc., followed by preparation of an intravenous, subcutaneous, or intramuscular injection according to an ordinary method. In this case, if necessary, it is possible to lyophilize these preparations according to an ordinary method.

Examples of the suspending agents include methylcellulose, Polysorbate hydroxyethylcellulose, acacis, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, Polysorbate 80®, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol®, and an ethyl ester of castor oil fatty acid.

Examples of stabilizer include sodium sulfite, sodium metasulfite, and ether, and examples of the preservative include methyl p-hydroxybenzoate, ethyl phydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

The following Examples illustrate the preparation of the compounds of the present invention and the preparation of E2020. Commercial reagents were utilized without further purification. Melting points are uncorrected. NMR data are reported in parts per million and are referenced to the deuterium lock signal from the sample solvent and were obtained on a Bruker 300 MHz instrument. D 2 0 refers to deuterium oxide. CDCI, refers to deuterochloroform. Chromatography, unless otherwise noted, refers to column chromatography performed using 32-63/m silica gel and executed under nitrogen pressure (flash chromatography) conditions. Thin Layer Chromatograph (TLC) refers to chromatography performed on silica gel plates Merck, Kiesel Gel F254) and eluted with the specific solvent designated. High Pressure Liquid Chromatography (HPLC) was performed on a LDC Analytical constaMetric® 3200 HPLC (Thermo Separation Products A Zorbax®C8, 60A, 3.9 x 150 mm column (Mac-Mod Analytical, Inc., Chadds Ford, PA 19317) was used for HPLC analysis and was eluted with the solvent indicated. Fast Atom Bombardment Mass Spectrometry (FABMS) refers to Mass Spectroscopic analysis on a Hewlett-Packard 5989 Mass Spectrometer (Particle beam chemical ionization). Room temperature refers to 0

C.

WO 97/22584 PCT/IB96/01076 Preparation 1 3-Pyridin-4-ylpropen-2-oic acid To a solution of pyridin-4-ylcarboxaldehyde (100 gm, 0.93 mol) in pyridine (100 mL) was added malonic acid (100 gm, 0.96 mol) at 900C. After carbon dioxide (CO,) evolution subsided, the reaction slurry was diluted with methanol. The title compound was isolated as a white solid by filtration (97 gm, 70% yield).

'H NMR (HOAc-d 4 6 11.70 1H), 8.85 2H), 7.95 2H), 7.80 1H), 6.90 1H).

Preparation 2 3-Piperidin-4-ylpropanoic acid The product from Preparation 1 (32 gm, 0.22 mol) was dissolved in 2 N hydrochloric acid (150 mL) and treated with 10 weight percent of 5% rhodium on carbon under a hydrogen atmosphere (45 until hydrogen gas uptake ceased.

The catalyst was filtered and the resulting solution of the title compound was carried directly into the next step.

'H NMR (D 2 0) 6 3.25 2H), 2.80 2H), 2.25 2H), 1.75 2H), 1.50- 1.10 5H). FABMS (M 157.

Preparation 3 3-[N-(Methoxvcarbonyl)-piperidin-4-ylproprionic acid The solution of the product from Preparation 2, was brought to pH 12 with aqueous potassium hydroxide. To this solution was added methyl chloroformate (21 mL, 0.27 mol). After one hour, the solution was brought to pH 1 with 6 N hydrochloric acid and extracted with dichloromethane. The organic layer was dried with sodium sulfate and the dichloromethane displaced with isopropyl ether. The title compound was isolated as a solid by filtration (39 gm, 84%).

Mp 89-900C. 'H NMR (CDCI 3 64.10 2H), 3.65 3H), 2.70 2H), 2.35 2H), 1.80 -1.10 7H). FABMS (M 1) 216.

Example 1 4-(2-Chlorocarbonvl-ethvl-piperidine--carboxvlic acid methyl ester To a solution of the product from Preparation 3 (54.0 gm, 0.251 mol) in dichloromethane (500 mL) was added dimethylformamide (0.39 mL, 0.02 equivalents) and oxalyl chloride (22 mL, 0.26 mol). After gas evolution subsided, the formation of the title compound was complete. The solution of the title compound was carried WO 97/22584 PCT/IB96/01076 -16directly into the next step.

Example 2 4- 3-(3,4-Dimethoxy-pheny l-3-oxo-propvy-piperidine-1carboxylic acid methyl ester To the solution of the product from Example 1 at room temperature was added (25.5 mL, 0.20 mol) of 1,2-dimethoxybenzene followed by portion-wise addition of aluminum trichloride (100 gm, 0.75 mol). The reaction mixture was stirred for 4 hours at room temperature. High pressure liquid chromatography analysis showed that the reaction was complete. The reaction was quenched by careful addition of water and then extracted with methylene chloride (2x500 mL). The combined organic extracts were washed with 1 N sodium hydroxide (200 mL), followed by brine (200 mL). Finally, the organic layer was dried over sodium sulfate. The solution was filtered and the solvent was removed in vacuo to provide an oil (67 gm, quantitative crude weight).

Thin Layer Chromatographic (TLC) and High Pressure Liquid Chromatographic

(HPLC)

analysis indicated that the product was of sufficient purity to proceed directly into the next step.

The progress and purity of these reactions was monitored by both TLC and High Pressure Liquid Chromatography using the systems indicated and tr for reaction product): TLC (silica gel): 0.50 (40 60 hexane/ethyl acetate). High Pressure Liquid Chromatography retention time (tr) was 12.6 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 waterlacetonitrile/triethylamine/acetic acid). 'H NMR (CDCI,) 6 7.55 (dd, 1H, J 8.4, 2.0 Hz), 7.50 1H, J 2.0 Hz), 6.86 1H, J 8.4 Hz), 4.02-4.20 (m, 2H), 3.92 3H), 3.91 3H), 3.65 3H), 2.93 2H, J 7.3 Hz), 2.64-2.78 2H), 1.61-1.76 4H), 1.40-1.55 1H), 1.06-1.21 2H). FABMS C,,H 2 sNO, (M 1)' 336.

Example 3 4.(34-Dimethox-benzo)-allll-piperidinecarboxvlic acid methyl ester To a solution of the product from Example 2 (66.0 gm, 0.20 mol) was added acetic anhydride (76.0 mL, 0.80 mol) followed by tetramethyldiaminomethane (54 mL, 0.40 mol). The reaction exothermed to 900C. After the exotherm was complete, the reaction was heated at 90°C for three hours and then allowed to stir overnight at room WO 97/22584 PCT/IB96/01076 -17temperature.

An aliquot (1 ml) was removed from the reaction vessel and treated with cold hydrochloric acid. The solution was extracted with methylene chloride followed by treatment with aqueous bicarbonate. The organic layer was then dried and analyzed by High Pressure Liquid Chromatography which showed that the starting material was consumed.

Based on the purity of the crude reaction mixture, the crude reaction material was carried directly into the next step, TLC (silica gel): Rf= 0.60 (40 60 hexane/ethyl acetate). High Pressure Liquid Chromatography retention time (tr) was 15.9 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 'H NMR (CDCI 3 6 7.35-7.40 2H), 6.83 1H, J 8.8 Hz), 5.68 1H), 5.54 1H), 3.94-4.14 2H), 3.89 3H), 3.88 3H), 3.62 3H), 2.59-2.75 2H), 2.32-2.41 2H), 1.55-1.74 (m, 3H), 1.00-1.21 2H). FABMS C,,H 25 NO, (M 348.

Example 4 4-(5,6-Dimethoxy-1 -oxo-indan-2-vlmethyl)-piperidine-1 carboxylic acid methyl ester The crude reaction mixture from Example 3, (0.20 mol) was treated with concentrated sulfuric acid (100 mL) at 0°C. The reaction was then allowed to stir overnight at room temperature, at which time High Pressure Liquid Chromatographic analysis indicated that the reaction was complete. The reaction was quenched by pouring onto 1 kg of ice, and the aqueous phase was then extracted with methylene chloride (2x500 mL). The combined organic extracts were washed with 500 mL of water, 500 mL of 1 N sodium hydroxide, 500 mL of brine, dried over sodium sulfate, and the volatiles removed in vacuo. The oily solid was then triturated with 500 mL of isopropyl ether, and the product was filtered to provide 46.5 gm (68% from dimethoxybenzene, 88% per step) of the title compound as a yellow solid.

TLC (silica gel) 0.40 (40 60 hexane/ethyl acetate). High Pressure Liquid Chromatography retention time (tr) was 10.1 min (Zorbax 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1 H NMR (CDCI 3 6 7.15 (s, 1H), 6.85 1H), 4.08-4.23 2H), 3.95 3H), 3.89 3H), 3.67 3H), 3.24 (dd, 1H, J 17.8, 8.3 Hz), 2.62-2.82 4H), 1.84-1.95 1H), 1.62-1.80 3H), 1.25- 1.39 1H), 1.08-1.33 2H). FABMS C 1

,H

25 NOs (M 1) 348.

WO 97/22584 PCT/IB96/01076 -18- Example 5,6-Dimethoxv-2-piperidin-4-ylmethyl-indan-1 -one To a solution of the product from Example 4 (5.0 gm, 14.4 mmol) in methanol mL) was added potassium hydroxide (4.9 gm, 87 mmol) dissolved in 80 mL of water. The mixture was then heated under a nitrogen atmosphere overnight, at which time high pressure liquid chromatographic analysis indicated that the starting material was consumed. The aqueous phase was extracted with methylene chloride (3x50 mL), the combined organic layers dried with sodium sulfate, and the volatiles stripped in vacuo to provide 3.30 gm of the title compound as a solid. This material was used without further purification.

High Pressure Liquid Chromatography retention time (tr) was 2.45 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1

H

NMR (CDC13) 67.12 1H), 6.82 1H), 3.91 3H), 3.86 3H), 3.20 (dd, 1H, J 17.7, 8.2 Hz), 3.00-3.13 2H), 2.52-2.77 4H), 1.70-1.94 1H), 1.51-1.80 (m, 3H), 1.02-1.35 3H). FABMS C 1 7

H

23

NO

3 (M 290.

Example 6 2-(1 -Benzvl-piperidin-4-vlmethyl)-5,6-dimethoxy-indan-1 -one To a slurry of the title compound from Example 5 (1.82 gm, 6.3 mmol) in isopropylether (60 mL) was added benzylbromide (0.75 mL, 6.3 mmol) and triethanolamine (940 mg, 6.3 mmol). The slurry was stirred overnight, at 700C, at which time high pressure liquid chromatography indicated that the starting material was mostly consumed. The reaction mixture was then filtered to remove precipitated triethanolamine hydrobromide. To the remaining solution was added ether saturated with hydrochloric acid (1.0 mL, 12 mmol), and the solvent was removed in vacuo. The residue was dissolved in 20 mL of hot isopropanol and allowed to cool to room temperature. The precipitated solid was filtered to provide 1.60 gm of the title compound as a white solid.

TLC (silica gel): Rf 0.60 (90: 10 methylene chloride/methanol); High Pressure Liquid Chromatography retention 6.01 min (Zorbax 254 nm, 1 mL/min, eluted with 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 'H NMR (of the free base, DMSO-d 6 67.06 1H), 7.03 1H), 3.84 3H), 3.77 3H), 3.41 2H), 3.19 (dd, 1H, J 17.8, 8.2 Hz), 2.71-2.86 2H), 2.58-2.71 2H), 1.82-1.96 2H), 1.52- 1.78 3H), 1.31-1.50 1H), 1.08-1.30 3H). FABMS C 2 4

H

2

,NO

3 (M 1) 380.

Claims

1. A compound of the formula III wherein R' is R and R 2 is (C I-C4)alkyl.

2. A compound of the formnula OMe OMe a a a. a. a. a a a Oa a a a a a. a a a a. a wherein R' is R 2 and W 2 is (CI-C 4 )alkYl.

3. A compound of the formula .OMe wherein R' is R 2 and R 2 is methyl.

4. A process for preparing a compound of the formula R 1 wherein R 1 is R 2 and R 2 is (CI-C 4 )alkyl comprising [RAIBH]332.do>c:tab a) reacting a compound of the formula R N OMe O0 OMe III wherein R 1 is R 2 and R 2 is (C 1 -C 4 )alkyl with a methenylation agent to form a compound of the formula O R 1 s ^^OOMe 2 OMe II wherein R' is R 2 and R 2 is (C1-C 4 )alkyl, and, b) reacting said compound of formula II, so formed, with a strong acid.

5. A process according to claim 4 wherein said methenylation agent is o. tetramethyldiaminomethane in acetic anhydride. S**t

6. A process according to claim 5 wherein said tetramethyldiaminomethane and acetic anhydride are added in excess. S"

7. A process according to claim 6 wherein said tetramethyldiaminomethane comprises 2 equivalents and said acetic anhydride comprises 4 equivalents.

8. A process according to any one of claims 4 to 7 wherein said strong acid is sulfuric acid.

9. A process according to claim 8 wherein said sulfuric acid is concentrated S9 sulfuric acid. 20

10. A process according to claim 9 wherein said concentrated sulfuric acid comprises 9 equivalents.

11. A process according to any one of claims 4 to 10 further comprising the additional step of reacting the compound of formula I, wherein R 1 is R 2 and R 2 is (C 1 -C 4 )alkyl with base to form a compound of the formula [R:\LIBH]332.doc:tab 0 OMe NH OMe VI and reacting said compound of formula VI so formed with benzylhalide to form a compound of the formula 0 OMe VII.

12. A process according to claim 11 wherein said benzyl halide is benzyl bromide.

13. A process according to claim 11 or claim 12 wherein said base is hydroxide.

14. A process according to claim 11 or claim 12 wherein said base is triethanolamine. A process according to any one of claims 11 to 14 wherein said compound of formula I is isolated by addition of the strongly acidic solution to ice/water followed by extraction with an organic solvent and removal of the organic solvent before the compound a of formula I is treated with a base.

15

16. A process for preparing a compound of the formula OMe OMe III wheren R* is R20(C=0)- and R2 iS (C1-C4)alkyl comprising reacting a compound of the formula OMe *IV O O Me III t i n R 2 is (C-C)lyopingratgacmoudfth formula O iv [R:\LIBH]332.doc:tab with a compound of the formula R 1 -N R C I 0 V wherein R' is as defined above, in the presence of a Lewis acid in a reaction inert solvent.

17. A process according to claim 16, wherein said Lewis acid is aluminium trichloride and said reaction inert solvent is methylene chloride.

18. A 4-[3-(3,4-dimethoxy-phenyl)-3-oxo-propyl]-piperidine-l-carboxylic acid ester, substantially as hereinbefore described with reference to any one of the examples.

19. A 4-[2-(3,4-dimethoxy-benzoyl)-allyl]-piperidine-l-carboxylic acid ester, substantially as hereinbefore described with reference to any one of the examples.

A 4-(5,6-dimethoxy-l-oxo-indan-2-ylmethyl)-piperidine-l-carboxylic acid ester, substantially as hereinbefore described with reference to any one of the examples.

21. A process for preparing 4-(5,6-dimethoxy-l-oxo-indan-2-ylmethyl)-piperidine- 1-carboxylic acid ester, substantially as hereinbefore described with reference to any one of the examples.

22. A process for preparing 4-[3-(3,4-dimethoxy-phenyl)-3-oxo-propyl]-piperidine- 1-carboxylic acid ester, substantially as hereinbefore described with reference to any one of the examples. S*

23. A 4-(5,6-dimethoxy-l-oxo-indan-2-ylmethyl)-piperidine-1-carboxylic acid ester, 20 prepared by the process of any one of claims 4 to 14 or

24. A 4-[3-(3,4-dimethoxy-phenyl)-3-oxo-propyl]-piperidine-l-carboxylic acid ester derivative prepared by the process of any one of claims 15, 16 or 21. .Dated 23 December, 1999 Pfizer Inc. *e S

25 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON o [R:\LIBH]332.doc:tab