AU7092596A - Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine - Google Patents

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

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AU7092596A
AU7092596A AU70925/96A AU7092596A AU7092596A AU 7092596 A AU7092596 A AU 7092596A AU 70925/96 A AU70925/96 A AU 70925/96A AU 7092596 A AU7092596 A AU 7092596A AU 7092596 A AU7092596 A AU 7092596A
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Keith M. Devries
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Pfizer Inc
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Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

PROCESSES AND INTERMEDIATES FOR PREPARING 1 -BENZYL-4-((5 6-
DIMETHOXY-1-INDANON)-2-YL)METHYLPIPERIDINE Background of the Invention This invention relates to a novel process for the preparation of 1 -benzyl-4-((5,6- dιmethoxy-1-ιndanon)-2-yl)methylpιperιdιne (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-
((5,6-dιmethoxy-1-ιndanon)-2-yl)methylpιperιdιne, 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
I I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C C4)alkyl, and R3 is (C^C alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl
The present invention also relates to a compound of the formula
I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C C4)alkyl, and R3 is (CrC4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (CrC4)alkyl, (CrC4)alkoxy, halo or trifluoromethyl
The present invention also relates to a compound of the formula
wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C,-C4)alkyl, and R3 is (CrC4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C C4)alkyl, (CrC4)alkoxy, halo or trifluoromethyl The present invention also relates to a process for preparing a compound of the formula
I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (CrC4)alkyl, and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C,-C4)alkyl, (CrC4)alkoxy, halo or trifluoromethyl, comprising a) reacting a compound of the formula
I I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C C4)alkyl, and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (CrC4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl, with a methenylation agent to form a compound of the formula
I I wherein R' is RO(C=0)- or R3(C=0)- R2 is (C C4)alkyl, and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C C4)alkyl, (CrC4)alkoxy, halo or trifluoromethyl 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 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 sulfuπc 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 R1 is R20(C=0)- or R3(C=0)-, R2 is (C.-C alkyl, and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C C4)alkoxy, halo or trifluoromethyl, with hydroxide (preferably potassium hydroxide) to form a compound of the formula
V I
and reacting said compound of formula VI so formed with a benzyl halide and a base to form a compound of the formula
V I I
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 ofthe formula 97/22584 PC17IB96/01076
-6-
I I I comprising reacting a compound of the formula e
e
I V
with a compound of the formula
l
V
in the presence of a Lewis acid, such as aluminum trichloride, in a reaction inert solvent, such as methylene chloride 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 I, II and III, VI and VII and the groups R\ R2 and R3 in the reaction schemes and discussion that follow are as defined above
SCHEME 1
l
IV
I I I
I I
25
30 SCHEME 2
10
VI
20
30 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 United States
Patent Application 08/329,352, filed October 26, 1994, also refers to the preparation of compounds of the formula V
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 R1 is R20(C=0)- or R3(C=0)-, R2 is (C C4)alkyl, and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, in the presence of a Lewis acid in a reaction inert solvent Preferably, R1 is R20(C=0)-, and R2 is methyl Suitable Lewis acids include aluminum trichloride, titanium tetrachloride or boron trichloride, preferably aluminum 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°C, preferably about 30°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, R1 is R20(C=0)-, and R2 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 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 the compound of formula III) When the methenylation agent is other than tetramethyldiaminomethane in acetic anhydride a solvent may be used to facilitate the reaction Suitable solvents include acetic anhydride, ethers (e g , diethyl ether and tetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride The reaction is performed at a temperature from about 0°C to about 90°C, preferably at about 90°C 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 or dichloroethane, preferably carbon disulfide The reaction is performed at a temperature from about 0°C to about 100°C, preferably at about 25°C
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 R1 is R20(C=0)-, and R2 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 25°C to about 100°C 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, tetrahydrofuran, preferably isopropyl ether The reaction is performed at a temperature from about 0°C to about 70°C, preferably about 70°C
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, e g , 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 fe g , 1 ,1 '-methylene-bιs-(2- hydroxy-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 vaπous 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 cho nesterase activity of 1-benzyl-4-((5,6-dιethyoxy-1-ιndanon)-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 ) The acetylcholinesterase inhibitory activity of 1-benzyl-4-((5,6-dιethyoxy-1 - ιndanon)-2yl)methyl piperidine, determined according to the method of Ellman et a , expressed in terms of 50% inhibitory concentration (IC50) is 0 0053 μM
Other methods for determining the activity of 1-benzyl-4-((5,6-dιethyoxy-1 - ιndanon)-2yl)methyl piperid e are described in United States Patent 4,895,841 , issued January 23, 1990
1-Benzyl-4-((5,6-dιmethoxy-1-ιndanon)-2yl)methylpιperιdιne 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, hypobu a, emotional changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes, etc accompanying encephalitis, cerebral palsy, etc
Further, 1-benzyl-4-((5,6-dιmethoxy-1-ιndanon)-2yl)methylpιperιdιne 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-dιmethoxy-1-ιndanon)-2yl)methyl-pιpeπdιne 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-dιmethoxy-1-ιndanon)-2yl)methylpιperιdine 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 e g , injections, suppositories, sublingual tablets, tablets, and capsules are prepared according to methods which are commonly accepted in the art ln 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 accordmg to an ordinary method
Examples of the suspending agents include methylcellulose Polysorbate 80® hydroxyethylcellulose, acacis, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate
Examples ofthe 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 p- hydroxybenzoate, 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 {δ) and are referenced to the deuterium lock signal from the sample solvent and were obtained on a Bruker 300 MHz instrument D20 refers to deuterium oxide CDCI3 refers to deuterochloroform Chromatography, unless otherwise noted, refers to column chromatography performed using 32-63μm silica gel and executed under nitrogen pressure (flash chromatography) conditions Thin Layer Chromatograph (TLC) refers to chromatography performed on silica gel plates (E Merck, Kiesel Gel 60 F254) and eluted with the specific solvent designated High Pressure Liquid Chromatography (HPLC) was performed on a LDC Analytical constaMetπc® 3200 HPLC (Thermo Separation Products Co ) A Zorbax®C8, 6θA, 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 20- 25°C Preparation 1 3-Pyridin-4-ylpropen-2-oic acid
To a solution of pyπdιn-4-ylcarboxaldehyde (100 gm, 0 93 mol) in pyridine (100 mL) was added malonic acid (100 gm, 0.96 mol) at 90°C After carbon dioxide (C02) evolution subsided, the reaction slurry was diluted with methanol The title compound was isolated as a white solid by filtration (97 gm, 70% yield)
1H NMR (HOAc-d4) <5 11 70 (s, 1H), 8 85 (d, 2H), 7 95 (d, 2H), 7 80 (d, 1 H), 6 90 (d, 1 H)
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 p s i ) 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 (D20) δ 3 25 (m, 2H), 2 80 (m, 2H), 2 25 (t, 2H), 1 75 (m, 2H), 1 50- 1 10 (m, 5H) FABMS (M + 1)+ = 157
Preparation 3
3-rN-(Methoxycarbonv0-piperidin-4-vπproprionic 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 89-90°C Η NMR (CDCI3) δ 4 10 (m, 2H), 3 65 (s, 3H), 2 70 (m, 2H), 2 35 (t, 2H), 1 80 -1 10 (m, 7H) FABMS (M + 1 )+ = 216
Example 1
4-(2-Chlorocarbonyl-ethyl)-piperidine-1 -carboxylic 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 directly into the next step
Example 2
4-r3-(3,4-Dimethoxy-phenvπ-3-oxo-propyπ-piperidine-1 - carboxylic 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-dιmethoxybenzene 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 (R and tr for reaction product) TLC (silica gel) R = 0.50 (40 60 hexane/ethyl acetate) High Pressure Liquid
Chromatography retention time (tr) was 12 6 mm (Zorbax C8, 254 nm, 1 mL/min 600 400.2 1 water/acetonitrile/tπethylamine/acetic acid) 1H NMR (CDCI3) δ 7 55 (dd, 1 H, J = 8 4, 2 0 Hz), 7 50 (d, 1 H, J = 2 0 Hz), 6 86 (d, 1 H, J = 8 4 Hz), 4 02-4 20 (m, 2H), 3 92 (s, 3H), 3 91 (s, 3H), 3 65 (s, 3H), 2 93 (t, 2H, J = 7 3 Hz), 2 64-2 78 (m 2H), 1 61 -1 76 (m, 4H), 1 40-1 55 (m, 1 H), 1 06-1.21 (m, 2H) FABMS C18H25N05 (M + 1 )+
= 336
Example 3
4-r2-(3,4-Dimethoxy-benzoyl)-allvπ-piperidine-1- carboxylic 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 90°C After the exotherm was complete the reaction was heated at 90°C for three hours and then allowed to stir overnight at room temperature
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 mateπal was carried directly into the next step,
TLC (silica gel) R,= 0 60 (40 60 hexane/ethyl acetate) High Pressure Liquid Chromatography retention time (tf) was 15 9 m (Zorbax C8, 254 nm, 1 mL/min 600 400 2 1 water/acetonitπle/tπethylamine/acetic acid) 1H NMR (CDCI3) δ 7 35-7 40 (m, 2H), 6 83 (d, 1 H J = 8 8 Hz), 5 68 (s, 1 H), 5 54 (s, 1 H), 3 94-4 14 (m, 2H), 3 89 (s, 3H), 3 88 (s, 3H), 3 62 (s, 3H), 2 59-2 75 (m, 2H), 2 32-2 41 (m, 2H) 1 55-1 74 (m, 3H), 1 00-1 21 ( , 2H) FABMS C19H25N05 (M + 1 )+ = 348 Example 4
4-(5,6-Dimethoxy-1 -oxo-indan-2-ylmethyl)-piperidine-1 - carboxylic acid methyl ester The crude reaction mixture from Example 3, (0 20 mol) was treated with concentrated suifuπc acid (100 L) 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) R,= 0 40 (40 60 hexane/ethyl acetate) High Pressure Liquid Chromatography retention time (tr) was 10 1 mm (Zorbax C8, 254 nm, 1 mL/min 600 400 2 1 water/acetonitπle/tπethylamine/acetic acid) 1H NMR (CDCI3) δ 7 15 (s, 1 H), 6 85 (s 1 H), 4 08-4 23 (m, 2H), 3 95 (s, 3H), 3 89 (s, 3H), 3 67 (s, 3H), 3 24 (dd, 1 H J = 17 8, 8 3 Hz), 2 62-2 82 (m, 4H), 1 84-1 95 (m, 1 H) 1 62-1 80 (m, 3H), 1 25- 1 39 (m, 1 H), 1 08-1 33 (m 2H) FABMS C19H25N05 (M + 1 )+ = 348 Example 5 5,6-Dimethoxy-2-piperidin-4-ylmethyl-indan-1 -one
To a solution of the product from Example 4 (5.0 gm, 14 4 mmol) in methanol (40 mL) was added potassium hydroxide (4 9 gm, 87 mmol) dissolved in 80 L 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 (79%) of the title compound as a solid This material was used without further purification
High Pressure Liquid Chromatography retention time (tr) was 2 45 m (Zorbax Ce, 254 nm, 1 mL/min, 600 400 2 1 water/acetonitπle/tπethylamine/acetic acid) 1H NMR (CDCI3) δ l 12 (s, 1 H), 6 82 (s, 1 H), 3 91 (s, 3H), 3 86 (s, 3H), 3 20 (dd, 1 H, J = 17 7, 8 2 Hz), 3 00-3 13 (m, 2H) 2 52-2 77 (m, 4H), 1 70-1 94 (m 1 H) 1 51 -1 80 (m 3H), 1 02-1 35 (m, 3H) FABMS C17H23N03 (M + 1 )+ = 290
Example 6 2-(1 -Benzyl-piperidin-4-ylmethvπ-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 70°C, 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 (61 %) of the title compound as a white solid
TLC (silica gel) Rf = 0 60 (90 10 methylene chloπde/methanol), High Pressure Liquid Chromatography retention = 6 01 mm (Zorbax CB, 254 nm, 1 mL/min eluted with 600 400 2 1 water/acetonitπle/triethylamine/acetic acid) 1H NMR (of the free base, DMSO-d6) <57 06 (s, 1 H), 7 03 (s, 1 H), 3 84 (s, 3H), 3 77 (s, 3H), 3 41 (s, 2H), 3 19 (dd, 1 H, J = 17 8, 8 2 Hz), 2 71-2 86 (m, 2H), 2 58-2 71 (m, 2H), 1 82-1.96 (m, 2H), 1 52- 1 78 (m, 3H), 1 31 -1 50 (m, 1 H), 1 08-1 30 (m, 3H) FABMS C24H29N03 (M + 1 )+ = 380

Claims (1)

  1. CLAIMS A compound of the formula
    I I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C,-C4)alkyl and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C,-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl 2 A compound of the formula
    I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C,-C4)alkyl and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C C4)alkyl, (CrC4)alkoxy, halo or trifluoromethyl 3 A compound of the formula
    I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (CrC4)alkyl and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C C4)alkyl (C,-C4)alkoxy halo or trifluoromethyl
    4 A process for preparing a compound of the formula
    I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C,-C4)alkyl and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, comprising a) reacting a compound of the formula
    I I I wherein R1 is R 0(C=0)- or R3(C=0)-, R2 is (C^C alkyl and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C C4)alkyl, (C C4)alkoxy, halo or trifluoromethyl, with a methenylation agent to form a compound of the formula
    I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C C4)alkyl and R3 is (CrC4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C,-C4)alkyl, (C C4)alkoxy, halo or trifluoromethyl 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 tetramethyldiaminomethane in acetic anhydride
    6 A process according to claim 5 wherein said tetramethyldiaminomethane and acetic anhydride are added in excess
    7 A process according to claim 6 wherein said tetramethyldiaminomethane compπses 2 equivalents and said acetic anhydride comprises 4 equivalents
    8 A process according to claim 4 wherein said strong acid is sulfuric acid
    9 A process according to claim 8 wherein said sulfuric acid is concentrated sulfuric acid 10 A process according to claim 9 wherein said concentrated sulfuπc acid comprises 9 equivalents
    1 1 A process according to claim 4 further comprising the additional step of reacting the compound of formula I, wherein R1 is R20(C=0)- or R3(C=0)-, R? is (C
    C4)alkyl and R3 is (C C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (CrC4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl, with hydroxide to form a compound of the formula
    V I
    and reacting said compound of formula VI so formed with a benzylhalide to form a compound of the formula
    V I I
    12 A process according to claim 11 wherein said benzyl halide is benzyl bromide 13 A process according to claim 1 1 wherein said base is triethanolamine
    14 A process according to claim 11 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 of formula I is treated with a base.
    15. A process for preparing a compound of the formula
    I I I wherein R1 is R20(C=0)- or R3(C=0)-, R2 is (C C4)alkyl, and R3 is (CrC4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, comprising reacting a compound of the formula
    I V
    with a compound of the formula
    V wherem R1 is as defined above, in the presence of a Lewis acid in a reaction inert solvent
    16 A process according to to claim 15 wherein said Lewis acid is aluminum trichloride and said reaction inert solvent is methylene chloride
AU70925/96A 1995-12-15 1996-10-11 Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine Ceased AU716462B2 (en)

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US875395P 1995-12-15 1995-12-15
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PCT/IB1996/001076 WO1997022584A1 (en) 1995-12-15 1996-10-11 Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine

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WO1999036405A1 (en) 1998-01-16 1999-07-22 Eisai Co., Ltd. Process for production of donepezil derivative
IL125809A (en) * 1998-08-17 2005-08-31 Finetech Lab Ltd Process and intermediates for production of donepezil and related compounds
US7148354B2 (en) * 2002-07-24 2006-12-12 Dr. Reddy's Laboratories Limited Process for preparation of donepezil
IL150982A (en) 2002-07-30 2007-02-11 Ori Lerman Process for the preparation of donepezil
IL151253A0 (en) * 2002-08-14 2003-04-10 Finetech Lab Ltd Process for production of highly pure donepezil hydrochloride
US6953856B2 (en) 2003-02-12 2005-10-11 Usv, Limited Process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanon)-2-yl) methyl piperidine hydrochloride (Donepezil HCI)
US6649765B1 (en) 2003-02-12 2003-11-18 Usv Limited, Bsd Marg. Process for the preparation of 1-benzyl-4(5,6-dimethoxy-1-indanon)-2-yl) methyl piperidine hydrochloride (Donepezil HCL)
EP1608371A1 (en) * 2003-03-21 2005-12-28 Ranbaxy Laboratories, Ltd. Process for the preparation of donepezil and derivatives thereof
WO2004099142A1 (en) * 2003-05-05 2004-11-18 Ranbaxy Laboratories Limited Hydrobromide salt of benzyl-piperidylmethyl-indanone and its polymorphs
AU2003247158A1 (en) 2003-07-01 2005-01-21 Hetero Drugs Limited Preparation of intermediates for acetyl cholinesterase inhibitors
CN1280273C (en) 2003-11-05 2006-10-18 天津和美生物技术有限公司 Synthesis of donepizin and its derivative
JP2008514691A (en) 2004-09-29 2008-05-08 ケマジス リミティド Use of purified donepezil maleate to produce pharmaceutically pure amorphous donepezil hydrochloride
CN100436416C (en) * 2005-07-29 2008-11-26 西南合成制药股份有限公司 Novel donepezil synthesis process
GB0515803D0 (en) 2005-07-30 2005-09-07 Pliva Hrvatska D O O Intermediate compounds
AR057910A1 (en) 2005-11-18 2007-12-26 Synthon Bv PROCESS TO PREPARE DONEPEZILO
ES2354737T3 (en) 2006-01-04 2011-03-17 Cipla Limited PROCEDURE AND INTERMEDIATE PRODUCT FOR THE PREPARATION OF DONEPEZYLO.
BRPI0720211A2 (en) * 2006-12-11 2013-12-24 Reviva Pharmaceuticals Inc INDANONE DERIVATIVE, COMPOSITION, AND, USE OF A COMPOSITION
WO2013078608A1 (en) * 2011-11-29 2013-06-06 Ziqiang Gu Donepezil pamoate and methods of making and using the same
AU2014307803A1 (en) 2013-08-16 2016-03-10 Universiteit Maastricht Treatment of cognitive impairment with PDE4 inhibitor

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DE4439822A1 (en) * 1994-11-08 1996-08-29 Bayer Ag Process for the preparation of benzyl-piperidylmethyl-indanones

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NO982712D0 (en) 1998-06-12
OA10694A (en) 2001-05-04
EP0883607A1 (en) 1998-12-16
PE25698A1 (en) 1998-05-21
AP708A (en) 1998-12-04
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AR004368A1 (en) 1998-11-04
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TW414787B (en) 2000-12-11
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MA24032A1 (en) 1997-07-01
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CA2237647A1 (en) 1997-06-26
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AP9600892A0 (en) 1997-01-31
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IS4752A (en) 1998-05-22
WO1997022584A1 (en) 1997-06-26
HN1996000065A (en) 1997-06-26
IL136420A0 (en) 2001-06-14
CZ180898A3 (en) 1999-05-12
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