AP708A - Processes and intermediates for preparing 1-Benzyl-4-((5,6-Dimethoxy-1-Incanon)-2-Y1) Methylpiperidine. - Google Patents
Processes and intermediates for preparing 1-Benzyl-4-((5,6-Dimethoxy-1-Incanon)-2-Y1) Methylpiperidine. Download PDFInfo
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- AP708A AP708A APAP/P/1996/000892A AP9600892A AP708A AP 708 A AP708 A AP 708A AP 9600892 A AP9600892 A AP 9600892A AP 708 A AP708 A AP 708A
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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
Abstract
This invention relates to a novel process for the preparation of 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine and to novel intermediates used in said process.
Description
. PC9209 AP . Ο Ο 7 Ο 8 5 PROCESSES AND INTERMEDIATES FOR PREPARING 1-BENZYL-4-((5,6-
DlMETHOXY-1-INDANON)-2-YL)METHYLPIPERIDlNE
Background of the Invention
This invention relates to a novel process for the preparation of 1-benzyi-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine (E2020), the compound of the formula VII 10 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-dimethoxy-1-indanon)-2-yl)methylpiperidine, methods for its preparation, usefulintermediates, and to methods and pharmaceutical compositions for treating diseasescaused by acetylcholinesterase activity, such as senile dementia. United States Patent 15 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• R1
APZP/ 96/00892 wherein R1 isR2O(C=O)- or R3(C=O)-, R2 is (C^CJalkyl, and R3 is (C^CJalkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C^CJalkyl, (C^CJalkoxy, halo or trifluoromethyl.
The present invention also relates to a compound of the formula 35 AP . 0 0 7 0 8 -2-
Otle one 11 10 wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C^CJalkyl, and R3 is (C^CJalkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C^CJalkyl, (CrC4)alkoxy, halo or trifluoromethyl.
The present invention also relates to a compound of the formula
AP/P/ 9 6 / 0 0 8 9 2 wherein R1 is R2O(G=O)- or R3(C=O)-, R2 is (C^CJalkyl, and R3 is (C^C^alkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C^CJalkyl, (C^C^alkoxy, halo or trifluoromethyl. 25 The present invention also relates to a process for preparing a compound of the formula 30 AP. Ο Ο 7 Ο 8 -3-
Ofle
One
I wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl, and R3 is (C,-C4)alkyl or10 phenyl optionally substituted with from one to three substituents independently selected from (C.,-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, comprising:a) reacting a compound of the formula R1
AP/P/ 96/00892
I I I 25 wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C^CJalkyl, and R3 is (C^CJalkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C,-C4)alkyl, (C^CJalkoxy, halo or trifluoromethyl, with a methenylation agent toform a compound of the formula 30
I I wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl, and R3 is (CrC4)alkyl or 10 phenyl optionally substituted with from one to three substituents independently selectedfrom (C^CJalkyl, (C^CJalkoxy, 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 15 added in excess. Most preferably, said tetramethyldiaminomethane comprises 2 molarequivalents (relative to the amount of the compound of the formula III) and said aceticanhydride comprises 4 molar equivalents (relative to the amount of the compound ofthe formula III).
Preferably, said strong acid is sulfuric acid. More preferably, said sulfuric acid 20 is concentrated sulfuric acid. Most preferably, said concentrated sulfuric acidcomprises 9 molar equivalents (relative to the amount of said compound of the formulaII). A preferred embodiment of the present invention relates to any of the aboveprocesses further comprising the additional step of reacting the compound of formula 25 I, wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C^CJalkyi, and R3 is (C^C^alkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C^CJalkyi, (C1-C4)alkoxy, halo or trifluoromethyl, with hydroxide (preferablypotassium hydroxide) to form a compound of the formula-
2 6 8 0 0 / 9 6 /d/dV 30 AP. ο ο 7 Ο 8 -5-
One OMe
VI and reacting said compound of formula VI so formed with a benzyl halide and a baseto form a compound of the formula
Preferably, said benzyl halide is benzyl bromide. Preferably said base istriethanolamine.
The most preferred embodiment of the above invention relates to a process20 wherein said compound of formula I is isolated before it is converted to the compoundof formula VI. The compound of formula I can be isolated by addition of the stronglyacidic 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 the25 formula AP/P/ 9 6 / 0 0 8 9 2 30 AP .00708
CM 05
CO o> o to 05
IV ο 5 with a compound of the formula
in the presence of a Lewis acid, such as aluminum trichloride, in a reaction inertsolvent, such as methylene chloride.
V 15 ΆΡ.00708 -7-
Detailed Description of the Invention
The compounds of formula I and E2020 can be prepared as described in thefollowing reaction schemes and discussion. Unless otherwise indicated, compounds5 of the formulae I, II and III, VI and VII and the groups R1, R2 and R3 in the reaction schemes and discussion that follow are as defined above. AP/P/ 96/00892 AP . u ύ 7 Ο 8 -8- SCHEME 1
T^Cl 0 AP/PZ 96/008 9 2 30
Ar . w ύ 7 Ο 8 -9- SCHEME2
30
VII AP . ϋο 7 0 8 -10-
Scheme 1 refers to the process of preparing a compound of formula I, whichcan be converted to a compound of the formula VII, E2020, by the methods of Scheme2.
Referring to Scheme 1, the compound of the formula IV is commercially5 available. Compounds of the formula V are also commercially available or can beprepared by methods well known to those of ordinary skill in the art. United StatesPatent 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 10 IV by reacting said compound of the formula IV with a compound of the formula V, wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C^-CJalkyl, and R3 is (C1-C4)alkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C,-C4)alkyl, (Ο,-CJalkoxy, halo or trifluoromethyl, in the presence of a Lewis acidin a reaction inert solvent. Preferably, R1 is R2O(C=O)-, and R2 is methyl. Suitable 15 Lewis acids include aluminum trichloride, titanium tetrachloride or boron trichloride,preferably aluminum trichloride. Suitable reaction inert solvents include methylenechloride or dichloroethane, preferably methylene chloride. The reaction is generallyperformed at a temperature from about 0°C to about 85°C, preferably about 30°C. k A compound of the formula II can be prepared from a compound of the formula 20 III by reacting said compound of the formula III with a methenylation agent. Preferably,O R1 is R2O(C=O)-, and R2 is methyl. Suitable methenylation agents include tetramethyldiaminomethane in acetic anhydride, formaldehyde (about 37 weight % inwater) in diethylamine, formaldehyde (about 37 weight % in water) in piperidine or N-methylthiomethylpiperdine. Preferably the methenylation agent is 25 tetramethyldiaminomethane in acetic anhydride. When tetramethyldiaminomethane inacetic anhydride is the methenylation agent it is preferable to perform the reaction withan excess of tetramethyldiaminomethane and acetic anhydride. Most preferably, thereaction is performed with 4 equivalents of acetic anhydride (relative to the amount ofthe compound of formula III) and 2 equivalents of tetramethyldiaminomethane (relative 30 to the amount of the compound of formula III). When the methenylation agent is otherthan tetramethyldiaminomethane in acetic anhydride a solvent may be used to facilitatethe reaction. Suitable solvents include acetic anhydride, ethers (e.g., diethyl ether andtetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride. The AP/P/ 96/00892 AP. ο ο 7 Ο 8 -11- reaction is performed at a temperature from about O°C to about 90°C, preferably atabout 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 5 II by reacting said compound of the formula II with a strong acid in a reaction inertsolvent. Suitable strong acids include concentrated sulfuric acid, aluminum trichlorideor concentrated hydrochloric acid, preferably concentrated sulfuric acid. Whenaluminum trichloride is the acid, a solvent must be used. Suitable solvents include - carbon disulfide, methylene chloride or dichloroethane, preferably carbon disulfide. The 10 reaction is performed at a temperature from about 0°C to about 100°C, preferably atabout 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 15 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 R2O(C=O)-, andR2 is methyl. Suitable bases include potassium hydroxide and sodium hydroxide,preferably potassium hydroxide. Suitable solvents include lower alcohols, water ormixtures thereof, preferably a 2:1 water/methanol mixture. The reaction is performed 20 at a temperature from about 25°C to about 100°C preferably at about 100°C. The(H 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 offormula VI by isolating the compound of formula I before converting it into thecompound of formula VI. A compound of formula I is isolated by pouring the acidic 25 solution containing the compound of formula I over an ice/water mixture and extractingthe aqueous with an organic solvent. Suitable solvents include methylene chloride,ethyl acetate or dichlorothane, preferably methylene chloride. The organic layer canbe 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 30 formula VI by reacting said compound of the formula VI with a benzyl halide in areaction inert solvent. Suitable halides include chloride, bromide, and iodide, preferablybromide. Suitable reaction inert solvents include diethyl ether, isopropyl ether, AP/P/ 9 6 / 0 0 8 9 2 AP .00708 -12- tetrahydrofuran, preferably isopropyl ether. The reaction is performed at a temperaturefrom about 0°C to about 70°C, preferably about 70°C.
The compound of formula VII can be converted to pharmaceutically acceptableacid addition salts of the compound of the formula VII. The acids which are used to 5 prepare the pharmaceutically acceptable acid addition salts of the compound of formulaVII are those which form non-toxic acid addition salts, e.g., salts containingpharmacologically 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, 10 saccharate, benzoate, methanesulfonate and pamoate |e.g., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The compound of the formula VII is basic in nature and is therefore capable offorming a wide variety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable for administration to animals, 15 it is often desirable in practice to initially isolate a compound of the formula VII from thereaction mixture as a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkaline reagent, andsubsequently 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 20 by treating the base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitable organic solventsuch as methanol or ethanol. Upon careful evaporation of the solvent, the desired solidsalt is obtained.
Compounds of the formula VII, E2020, and its pharmaceutically acceptable 25 salts can be used to treat a disease caused by acetylcholinesterase activity, such asAlzheimers’ Disease, according to the methods described in United States Patent4,895,841, iss'ued January 23, 1990.
Specifically, United States Patent 4,895,841 states that the in vitro acetylcholinesterase activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, 30 E2020, or a pharmaceutically acceptable salt thereof can be determined according to the method of Ellman et al. Biochem. Pharmacol,, 7, 88-95 (1961). AP/P/ 96/00‘8 92 AP . 0 0 7 0 8 -13-
The acetylcholinesterase inhibitory activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, determined according to the method of Ellman et ak,expressed in terms of 50% inhibitory concentration (IC50) is 0.0053 μΜ.
Other methods for determining the activity of 1-benzyl-4-((5,6-diethyoxy-1-5 indanon)-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 fortreatment, prevention, remission, improvement, etc. of various kinds of senile dementia,particularly senile dementia of the Alzheimer’s type; cerebrovascular disease 10 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-paranoidsyndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc.
Further, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2yI)methyIpiperidine has a strong 15 and highly selective anticholinesterase action, which qlso renders the compound usefulas a pharmaceutical based on this mode of action.
Specifically, 1 -benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methyI-piperidine iseffective for, for example, Huntington’s chorea, Pick’s disease and delayed ataxia ortardive dyskinesia other than senile dementia of the Alzheimer type. 20 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. Ingeneral, it is parenterally administered in the form of injections, such as intravenous,subcutaneous, and intramuscular injections, suppositories, or sublingual tablets. Thedose will vary depending upon the symptom; age, sex, weight, and sensitivity of 25 patients; method of administration; time and intervals of administration and properties,dispensing, and kind of pharmaceutical preparations so that there is no particularlimitation with'respect to the dose. Normally the compound may be administered in adose of about 0.1 to 300 mg, preferably 1 to 100 mg, per day per adult, ordinarily inone to four portions. 30 Pharmaceutical preparations in the dosage form of, e.g., injections, suppositories, sublingual tablets, tablets, and capsules are prepared according tomethods which are commonly accepted in the art.
CM cr> co o o co a. < . 0 v 7 Ο 8 -14-
Ιη preparing injections, the effective ingredient is blended, if necessary, with apH modifier, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicityagent, a preservative, etc., followed by preparation of an intravenous, subcutaneous,or intramuscular injection according to an ordinary method. In this case, if necessary, 5 it is possible to lyophilize these preparations according to an ordinary method.
Examples of the suspending agents include methylcellulose, Polysorbate 80®,hydroxyethylcellulose, acacis, powdered tragacanth, sodium carboxymethylcellulose,and polyoxyethylene sorbitan monolaurate.
Examples of the solubilizing agent include polyoxyethylene hydrogenated castor10 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, andexamples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. 15 The following Examples illustrate the preparation of the compounds of the present invention and the preparation of E2020. Commercial reagents were utilizedwithout further purification. Melting points are uncorrected. NMR data are reported inparts per million (d) and are referenced to the deuterium lock signal from the samplesolvent and were obtained on a Bruker 300 MHz instrument. D2O refers to deuterium 20 oxide. CDCI3 refers to deuterochloroform. Chromatography, unless otherwise noted,refers to column chromatography performed using 32-63jum silica gel and executedunder nitrogen pressure (flash chromatography) conditions. Thin Layer Chromatograph(TLC) refers to chromatography performed on silica gel plates (E. Merck, Kiesel Gel 60F254) and eluted with the specific solvent designated. High Pressure Liquid 25 Chromatography (HPLC) was performed on a LDC Analytical constaMetric® 3200HPLC (Thermo Separation Products Co.). A Zorbax®C8, 60A, 3.9 x 150 mm column(Mac-Mod Analytical, Inc., Chadds Ford, PA 19317) was used for HPLC analysis andwas eluted with the solvent indicated. Fast Atom Bombardment Mass Spectrometry(FABMS) refers to Mass Spectroscopic analysis on a Hewlett-Packard 5989 Mass 30 Spectrometer (Particle beam chemical ionization). Room temperature refers to 20- AP/P/ 96/00892 25°C. ftP . υ Ο 7 Ο 8 -15-
Preparation 1 3-Pyridin-4-ylpropen-2-oic acid
To a solution of pyridin^f-ylcarboxaldehyde (100 gm, 0.93 mol) in pyridine (100mL) was added malonic acid (100 gm, 0.96 mol) at 90°C. After carbon dioxide (CO2) 5 evolution subsided, the reaction slurry was diluted with methanol. The title compoundwas isolated as a white solid by filtration (97 gm, 70% yield). 1H NMR (HOAc-d4) δ 11.70 (s, 1H), 8.85 (d, 2H), 7.95 (d, 2H), 7.80 (d, 1H), 6.90 (d, 1H).
Preparation 2 10 3-Piperidin-4-yipropanoic acid
The product from Preparation 1 (32 gm, 0.22 mol) was dissolved in 2 Nhydrochloric acid (150 mL) and treated with 10 weight percent of 5% rhodium oncarbon 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 15 directly into the next step. 1H NMR (D2O) 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-(Methoxvcarbonvl)-piperidin-4-vllproprionic acid20 The solution of the product from Preparation 2, was brought to pH 12 with aqueous potassium hydroxide. To this solution was added methyl chloroformate (21mL, 0.27 mol). After one hour, the solution was brought to pH 1 with 6 N hydrochloricacid and extracted with dichloromethane. The organic layer was dried with sodiumsulfate and the dichloromethane displaced with isopropyl ether. The title compound 25 was isolated as a solid by filtration (39 gm, 84%).
Mp 89-90°C. 1H NMR (CDCI3) δ 4.10 (m, 2H), 3.65 (s, 3H), 2.70 (m, 2H), 2.35(t, 2H), 1.80 -1'.1O (m, 7H). FABMS (M + 1)+= 216.
Example 1 4-(2-Chlorocarbonyl-ethvl)-piperidine-1-carboxylic acid methyl ester 30 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 ofthe title compound was complete. The solution of the title compound was carried CMCPOOoo*—coσ>
CL
CL < AP . υ 0 7 Ο 8 -16- directiy into the next step.
Example 2 4-i3-(3.4-Dimethoxv-phenvl)-3-oxo-propvn-piperidine-1- carboxylic acid methyl ester 5 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 ofaluminum trichloride (100 gm, 0.75 mol). The reaction mixture was stirred for 4 hoursat room temperature. High pressure liquid chromatography analysis showed that the - reaction was complete. The reaction was quenched by careful addition of water and 10 then extracted with methylene chloride (2x500 mL). The combined organic extractswere 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 thesolvent was removed in vacuo to provide an oil (67 gm, quantitative crude weight).Thin Layer Chromatographic (TLC) and High Pressure Liquid Chromatographic (HPLC) 15 analysis indicated that the product was of sufficient purity to proceed directly into thenext step.
The progress and purity of these reactions was monitored by both TLC and HighPressure Liquid Chromatography using the systems indicated (Rf and ζ for reactionproduct): 20 TLC (silica gel): Rf= 0.50 (40 : 60 hexane/ethyl acetate). High Pressure Liquid
Chromatography retention time (tf) was 12.6 min (Zorbax C8, 254 nm, 1 mL/min,600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (CDCI3) 5 7.55 (dd,1H, J = 8.4, 2.0 Hz), 7.50 (d, 1H, J = 2.0 Hz), 6.86 (d, 1H, 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), 25 1.61-1.76 (m, 4H), 1.40-1.55 (m, 1H), 1.06-1.21 (m, 2H). FABMS C18H25NO5 (M + 1)+ = 336.
Example 3 4-r2-(3,4-Dimethoxv-benzovl)-allyll-piperidine-1- carboxylic acid methyl ester 30 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, thereaction was heated at 90°C for three hours and then allowed to stir overnight at room oo o <o co σ> a 32 «c AP. U 0 70 8 -17- temperature.
An aliquot (1 ml) was removed from the reaction vessel and treated with coldhydrochloric acid. The solution was extracted with methylene chloride followed bytreatment with aqueous bicarbonate. The organic layer was then dried and analyzed 5 by High Pressure Liquid Chromatography which showed that the starting material wasconsumed.
Based on the purity of the crude reaction mixture, the crude reaction materialwas carried directly into the next step, TLC (silica gel): Rf= 0.60 (40 : 60 hexane/ethyl acetate). High Pressure Liquid10 Chromatography retention time (tr) was 15.9 min (Zorbax C8, 254 nm, 1 mL/min,600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (CDCI3) <5 7.35-7.40(m, 2H), 6.83 (d, 1H, J = 8.8 Hz), 5.68 (s, 1H), 5.54 (s, 1H), 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 (m, 2H). FABMS C19H25NO5 (M + 1)+ = 348. 15 Example 4 4-f5.6-Dimethoxy-1 -oxo-indan-2-vlmethyn-piperidine-l - carboxylic acid methyl ester
The crude reaction mixture from Example 3, (0.20 mol) was treated withconcentrated sulfuric acid (100 mL) at 0°C. The reaction was then allowed to stir 20 overnight at room temperature, at which time High Pressure Liquid Chromatographicanalysis indicated that the reaction was complete. The reaction was quenched bypouring onto 1 kg of ice, and the aqueous phase was then extracted with methylenechloride (2x500 mL). The combined organic extracts were washed with 500 mL ofwater, 500 mL of 1 N sodium hydroxide, 500 mL of brine, dried over sodium sulfate, 25 and the volatiles removed in vacuo. The oily solid was then triturated with 500 mL ofisopropyl ether, and the product was filtered to provide 46.5 gm (68% fromdimethoxybenzene, 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 (tf) was 10.1 min (Zorbax C8, 254 nm, 1 mL/min, 30 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (CDCI3) <5 7.15 (s, 1H), 6.85 (s, 1H), 4.08-4.23 (m, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.67 (s, 3H), 3.24 (dd,1H, J = 17.8, 8.3 Hz), 2.62-2.82 (m, 4H), 1.84-1.95 (m, 1H), 1.62-1.80 (m, 3H), 1.25-1.39 (m, 1H), 1.08-1.33 (m, 2H). FABMS C19H25NO5 (M + 1)+= 348. AP/P/ 96/00892 AF.0 0 70 8 -18-
Example 5 5,6-Dimethoxv-2-piperidin-4-vlmethvl-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 mL of 5 water. The mixture was then heated under a nitrogen atmosphere overnight, at whichtime high pressure liquid chromatographic analysis indicated that the starting materialwas consumed. The aqueous phase was extracted with methylene chloride (3x50 mL),the combined organic layers dried with sodium sulfate, and the volatiles stripped invacuo to provide 3.30 gm (79%) of the title compound as a solid. This material was 10 used without further purification.
High Pressure Liquid Chromatography retention time (tr) was 2.45 min (ZorbaxC8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1HNMR (CDCI3) «5 7.12 (s, 1H), 6.82 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.20 (dd, 1H, J =17.7, 8.2 Hz), 3.00-3.13 (m, 2H), 2.52-2.77 (m, 4H), 1.70-1.94 (m, 1H), 1.51-1.80 (m, • 15 3H), 1.02-1.35 (m, 3H). FABMS C17H23NO3 (M + 1)+= 290.
Example 6 2-(1-Benzvl-piperidin-4-vlmethvn-5,6-dimethoxv-indan-1-one
To a slurry of the title compound from Example 5 (1.82 gm, 6.3 mmol) inisopropylether (60 mL) was added benzylbromide (0.75 mL, 6.3 mmol) and 20 triethanolamine (940 mg, 6.3 mmol). The slurry was stirred overnight, at 70°C, atwhich time high pressure liquid chromatography indicated that the starting material wasmostly consumed. The reaction mixture was then filtered to remove precipitatedtriethanolamine hydrobromide. To the remaining solution was added ether saturatedwith hydrochloric acid (1.0 mL, 12 mmol), and the solvent was removed in vacuo. The 25 residue was dissolved in 20 mL of hot isopropanol and allowed to cool to roomtemperature. The precipitated solid was filtered to provide 1.60 gm (61%) of the titlecompound as a white solid. TLC (silica gel): = 0.60 (90:10 methylene chloride/methanol); High PressureLiquid Chromatography retention = 6.01 min (Zorbax C8,254 nm, 1 mL/min, eluted with 30 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). ’H NMR (of the free base, DMSO-d6) <57,06 (s, 1H), 7.03 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.41 (s, 2H), 3.19 (dd,1H, 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, 1H), 1.08-1.30 (m, 3H). FABMS C24H29NO3 (M + 1)+=380. AP/P/ 96/008 9 ?
Claims (16)
- AP . ο Ο 7 Ο 8 10
- 2. A compound of the formula/96/00392 wherein R1 is R2O(C=O> or R3(C=O)-, R2 is (C^CJalkyl and R3 is (C1-C4)alkyl or phenyloptionally substituted with from one to three substituents independently selected from(C^CJalkyl, (C^CJalkoxy, halo or trifluoromethyl. 30
- 3. A compound of the formula AP. Ο Ο 7 Ο 8 -ΣΟ-wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (CrC4)alkyl and R3 is (C1-C4}alkyl or phenyl10 optionally substituted with from one to three substituents independently selected from (C^C^alkyl, (C.,-C4)alkoxy, halo or trifiuoromethyl.
- 4. A process for preparing a compound of the formula 96/00892£ i < wherein R1 is RZO(C=O)- or R3(C=O)-, Rz is (C,-C4)alkyl and R3 is (CrC4)alkyl or phenyloptionally substituted with from one to three substituents independently selected from(C^CJalkyl, (C^CJalkoxy, halo or trifiuoromethyl, comprising a) reacting a compound of the formula 30 AP. Ο Ο 7 Ο 8 -21- R1I 11 wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (CrC4)alkyl and R3 is (C.,-C4)alkyl or phenyloptionally substituted with from one to three substituents independently selected from 15 (C^CJalkyl, (C^CJalkoxy, halo or trifluoromethyl, with a methenylation agent to forma compound of the formulaAP/P/ 96/0089 2 I I 25 wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (CrC4)alkyl and R3 is (CrC4)alkyl or phenyloptionally substituted with from one to three substituents independently selected from(C^C^alkyl, (C1-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 30 tetramethyldiaminomethane in acetic anhydride.
- 6. A process according to claim 5 wherein said tetramethyldiaminomethaneand acetic anhydride are added in excess.
- 7. A process according to claim 6 wherein said tetramethyldiaminomethane -22- comprises 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 concentratedsulfuric acid. 10
- 10. A process according to claim 9 wherein said concentrated sulfuric acidcomprises 9 equivalents.
- 11. A process according to claim 4 further comprising the additional step ofreacting the compound of formula I, wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl and R3 is (C^CJalkyl or phenyl optionally substituted with from one to threesubstituents independently selected from (C^CJalkyl, (C^CJalkoxy, halo ortrifluoromethyl, with hydroxide to form a compound of the formulac\i co co o o to C7> and reacting said compound of formula VI so formed with a benzylhalide to form a20 compound of the formulaVII
- 12. A process according to claim 11 wherein said benzyl halide is benzyl bromide.
- 13. A process according to claim 11 wherein said base is triethanolamine.
- 14. A process according to claim 11 wherein said compound of formula I isisolated by addition of the strongly acidic solution to ice/water followed by extractionwith an organic solvent and removal of the organic solvent before the compound of 30 ΛΡ.00708 -23- formula I is treated with a base.
- 15 wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (CrC4)alkyl, and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to three substituents independentlyselected from (C.,-C4)alkyl, (C^CJalkoxy, halo or trifluoromethyl, comprising reactinga compound of the formula 20AP/PZ 96/0089^ IV 25 with a compound of the formula R1—N \ 30 Cl V AF. 0 0 7 0 8 -24- wherein R1 is as defined above, in the presence of a Lewis acid in a reactioninert solvent.15. A process for preparing a compound of the formula15 wherein R1 is RZO(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl and R3 is (C,-C4)alkyl or phenyloptionally substituted with from one to three substituents independently selected from(C^C^alkyl, (C^CJalkoxy, halo or trifluoromethyl.
- 16. A process according to to claim 15 wherein said Lewis acid is aluminumtrichloride and said reaction inert solvent is methylene chloride. Patsd this..................................... . day of T9 P/ 96/00892ΛΤΕΝ THE
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US875395P | 1995-12-15 | 1995-12-15 |
Publications (2)
| Publication Number | Publication Date |
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| AP9600892A0 AP9600892A0 (en) | 1997-01-31 |
| AP708A true AP708A (en) | 1998-12-04 |
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| APAP/P/1996/000892A AP708A (en) | 1995-12-15 | 1996-12-12 | Processes and intermediates for preparing 1-Benzyl-4-((5,6-Dimethoxy-1-Incanon)-2-Y1) Methylpiperidine. |
Country Status (33)
| Country | Link |
|---|---|
| EP (1) | EP0883607A1 (en) |
| JP (1) | JP3066083B2 (en) |
| KR (1) | KR20000064387A (en) |
| AP (1) | AP708A (en) |
| AR (1) | AR004368A1 (en) |
| AU (1) | AU716462B2 (en) |
| BG (1) | BG102525A (en) |
| BR (1) | BR9612018A (en) |
| CA (1) | CA2237647A1 (en) |
| CO (1) | CO4750831A1 (en) |
| CZ (1) | CZ180898A3 (en) |
| DZ (1) | DZ2141A1 (en) |
| GT (1) | GT199600092A (en) |
| HN (1) | HN1996000065A (en) |
| HR (1) | HRP960592A2 (en) |
| HU (1) | HUP9904275A3 (en) |
| IL (3) | IL136420A0 (en) |
| IS (1) | IS4752A (en) |
| MA (1) | MA24032A1 (en) |
| NO (1) | NO982712L (en) |
| NZ (1) | NZ318843A (en) |
| OA (1) | OA10694A (en) |
| PE (1) | PE25698A1 (en) |
| PL (1) | PL197306B1 (en) |
| RO (1) | RO121382B1 (en) |
| RU (1) | RU2160731C2 (en) |
| SK (1) | SK75498A3 (en) |
| TN (1) | TNSN96153A1 (en) |
| TW (1) | TW414787B (en) |
| UY (1) | UY24401A1 (en) |
| WO (1) | WO1997022584A1 (en) |
| YU (1) | YU49486B (en) |
| ZA (1) | ZA9610533B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| 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) |
| 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) |
| US20070129549A1 (en) * | 2003-03-21 | 2007-06-07 | Yatendra Kumar | Stable lamotrigine pharmaceutical compositions and processes for their preparation |
| WO2004099142A1 (en) * | 2003-05-05 | 2004-11-18 | Ranbaxy Laboratories Limited | Hydrobromide salt of benzyl-piperidylmethyl-indanone and its polymorphs |
| WO2005003092A1 (en) | 2003-07-01 | 2005-01-13 | 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 |
| WO2006035433A2 (en) | 2004-09-29 | 2006-04-06 | Chemagis Ltd. | Use of purified donepezil maleate for preparing 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 |
| AU2007203969B2 (en) * | 2006-01-04 | 2012-04-05 | Cipla Limited | Process and intermediate for preparation of donepezil |
| CA2672212A1 (en) * | 2006-12-11 | 2008-06-19 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors |
| WO2013078608A1 (en) | 2011-11-29 | 2013-06-06 | Ziqiang Gu | Donepezil pamoate and methods of making and using the same |
| EP3033082B1 (en) | 2013-08-16 | 2021-06-16 | Universiteit Maastricht | Treatment of cognitive impairment with pde4 inhibitor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296560A2 (en) * | 1987-06-22 | 1988-12-28 | Eisai Co., Ltd. | 1,4-Substituted piperidines as acetylcholinesterase inhibitors and their use for the treatment of Alzheimer's disease |
| EP0379441A1 (en) * | 1989-01-20 | 1990-07-25 | Rhone-Poulenc Sante | Benzopyrane derivatives, their preparation and pharmaceutical compositions containing them |
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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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- 1996-10-11 CA CA002237647A patent/CA2237647A1/en not_active Abandoned
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- 1996-10-14 TW TW085112515A patent/TW414787B/en not_active IP Right Cessation
- 1996-10-15 HN HN1996000065A patent/HN1996000065A/en unknown
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- 1996-12-09 PE PE1996000883A patent/PE25698A1/en not_active Application Discontinuation
- 1996-12-10 AR ARP960105577A patent/AR004368A1/en unknown
- 1996-12-11 DZ DZ960186A patent/DZ2141A1/en active
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- 1996-12-12 AP APAP/P/1996/000892A patent/AP708A/en active
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- 1996-12-13 HR HR60/008,753A patent/HRP960592A2/en not_active Application Discontinuation
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- 1998-06-05 OA OA9800076A patent/OA10694A/en unknown
- 1998-06-09 BG BG102525A patent/BG102525A/en unknown
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|---|---|---|---|---|
| EP0296560A2 (en) * | 1987-06-22 | 1988-12-28 | Eisai Co., Ltd. | 1,4-Substituted piperidines as acetylcholinesterase inhibitors and their use for the treatment of Alzheimer's disease |
| EP0379441A1 (en) * | 1989-01-20 | 1990-07-25 | Rhone-Poulenc Sante | Benzopyrane derivatives, their preparation and pharmaceutical compositions containing them |
Non-Patent Citations (1)
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| CHEMICAL & PHARMECEUTICAL BULLETIN, Vol. 41, No. 3, pp.528-538, 3 March 1993, XP002018693ISHIHARA Y. ET AL.: "Central cholinergic agents. IV. Synthesis and acetylcholinesterase inhibitory activities of .omega.-[N-ethyl-N(phenylmethyl)amino]-1-phenyl-1-alkanones and analogues with partial conformational restriction" * |
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