OA10694A - 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. Download PDFInfo
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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
The present invention relates to a process for preparing a compound of formula (I), wherein R<1> is R<2>O(C=O)- or R<3>(C=O)-, R<2> is (C1-C4)alkyl, and R<3> is (C1-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 formula (III), wherein R<1> is R<2>O(C=O)- or R<3>(C=O)-, R<2> is (C1-C4)alkyl, and R<3> is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, with a methenylation agent to form a compound of formula (II), wherein R<1> is R<2>O(C=O)- or R<3>(C=O)-, R<2> is (C1-C4)alkyl, and R<3> is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl and; b) reacting said compound of formula (II), so formed, with a strong acid. The present invention further comprises the additional step of reacting the compound of formula (I) with hydroxide to form a compound of formula (VI), and reacting said compound of formula (VI) so formed with a benzyl halide and a base to form a compound of formula (VII). The present invention relates also to the novel intermediates of formulae (I), (II) and (III).
Description
-1- 01 U 69 4
PROCESSES AND INTERMEDIATES FOR PREPARING 1-BENZYL-4-((5,6-DIMETHOXY-1-INDANON)-2-YL)METHYLPIPERIDINE
Backqround of the Invention
This invention relates to a novel process for the préparation of 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine (E2020), the compound of the formula VIIbelow, 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 préparation, usefulintermediates, and to methods and pharmaceutical compositions for treating diseasescaused by acetylcholinesterase activity, such as senile dementia. United States Patent4,855,841, issued January 23,1990, is hereby incorporated by référencé in its entirety.
Summary of the Invention
The présent invention relates to a compound of the formulaR1
III wherein R’“ is R2O(C=O)- or R3(C=O)-, R2 is (C^C^alkyl, and R3 is (CrC4)alkyl orpherryl optionally substituted with from one to three substituents independently selectedfrom (C,-C4)alkyl. (C,-C4)alkoxy, halo or trifluoromethyl.
The présent invention aiso relates to a compound of the formula 010694 -2-
I I wherein R1 is RZO(C=O)- or R3(C=O)-, R2 is (C^CJalkyl, and R3 is (C,-C4)alkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl.
The présent invention also relates to a compound of the formula
I whe-ein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl, and R3 is (CrC4)alkyl orphenyl optionally substituted with from one to three substituents independently selectedfrorr (C,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl.
The présent invention also relates to a process for preparing a compound of the formula -3-
wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl, and R3 is (C^CJalkyl or10 phenyl optionally substituted with from one to three substituents independently selected from (C,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl, comprising:a) reacting a compound of the formula 15 20
25 wherein R1 is R2O(C=O)- or R3(C=O)-t R2 is (C,-C4)alkyl, and R3 is (C^-CJalkyl orphenyl optionally substituted with from one to three substituents independently selectedfrom (C,-C4)alkyl, (C<C4)alkoxy, halo or trifluoromethyl, with a methenylation agent toforra a compound of the formula 30 010694 -4-
wnerein R1 is R2O(C=O)- or R3(C=O)-, R2 is (CrC4)alkyl, and R3 is (C,-C4)alkyl or ' 0 pnenyl optionally substituted with from one to three substituents independently selectedfrcm (C,-C4)alkyl, (C,-C4)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 a.- nydride. More preferably, said tetramethyldiaminomethane and acetic anhydride are 15 acded in excess. Most preferably, said tetramethyldiaminomethane comprises 2 molarecuivalents (relative to the amount ofthe compound of the formula III) and said aceticanydride comprises 4 molar équivalents (relative to the amount of the compound ofthe formula III).
Preferably, said strong acid is sulfuric acid. More preferably, said sulfuric acid 22 is ccncentrated sulfuric acid. Most preferably, said concentrated sulfuric acidcomprises 9 molar équivalents (relative to the amount of said compound of the formula N). A preferred embodiment of the présent invention relates to any of the aboveDrocesses further comprising the additional step of reacting the compound of formula 25 i wnereîn R1 is R2O(C=O)- or R3(C=O)-, R2 is (C5-C4)alkyl, and R3 is (C,-C4)alkyl orohenyi optionally substituted with from one to three substituents independently selectedfrom (C<-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, with hydroxide (preferablyoocassium hydroxide) to form a compound of the formula
3C ; r- -5- 10 15 0 1 06 9 4
VI and reacting said compound of formula VI so formed with a benzyl halide and a baseto form a compound of the formula
VII
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 présent invention also related to a process for preparing a compound of the25 formula 30 ' 'y*·*·! U 1 ! Τ*τri·’* 'BIR " « «»·β> r -6- 010694 R1
comcrising reacting a compound of the formula 15
OMe
OMe
IV 20 5 with a compound of the formula
:n the presence of a Lewis acid, such as aluminum trichloride, in a reaction inertsolvent, such as methylene chloride. -7* 01 0694
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 1, Il and III, VI and VII and the groups R’, R2 and R3 in the reaction schemes and discussion that follow are as defined above. -8- 010694 < ·ν SCHEME 1
-9- 010694 SCHEME 2
Vil 30 -10- 0 1 0694
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 aiso' 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 préparation cf compounds of the formula V. A compound of the formula III can be prepared from a compound of the formula1 ϋ IV by reacting said compound of the formula IV with a compound of the formula V, wh-erein R’ is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl, and R3 is (C,-C4)alkyl orphenyl cptionally substituted with from one to three substituents independently selectedfrom (C,-C4)alkyl, (C,-C4)alkoxy, 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,oreierabfy aluminum trichloride. Suitable reaction inert solvents include methylenechiorice or dichloroethane, preferably methylene chloride. The reaction is generallyoerfomed at a température from about 0°C to about 85°C, preferably about 30°C. A compound of the formula 11 can be prepared from a compound of the formula 2C II! cy reacting said compound of the formula lit with a methenylation agent. Preferably,R’ is R~O(C=O)-, and R2 is methyl. Suitable methenylation agents includeletrsmsthyldiaminomethane in acetic anhydride, formaldéhyde (about 37 weight % inwacer: in diethylamine, formaldéhyde (about 37 weight % in water) in piperidine or N-metny'thiomethylpiperdine. Preferably the methenylation agent is 25 :etrsmethyldiaminomethane in acetic anhydride. When tetramethyldiaminomethane inacetic anhydride is the methenylation agent it is préférable to perform the reaction withan excsss of tetramethyldiaminomethane and acetic anhydride. Most preferably, thereaciio" is performed with 4 équivalents of acetic anhydride (relative to the amount oftne compound of formula III) and 2 équivalents of tetramethyldiaminomethane (relative 30 to the amount of the compound of formula III). When the methenylation agent is othertnar teramethyîdiaminomethane in acetic anhydride a solvent may be used to facilitatetne réaction. Suitable solvents include acetic anhydride, ethers (e.q,, diethyl ether andtetranvcroffuran). methanol, acetic acid or dioxane, preferably acetic anhydride. The -11- 010694 reaction is performed at a température 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 includecarbon disulfide, methylene chloride ordichloroethane, preferably carbon disulfide. The 10 reaction is performed at a température from about 0°C to about 100°C, preferably atabout 25eC.
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 l, 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 température from about 25°C to about 100°C preferably at about 100°C. Thereaction 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 extracting the aqueous with an organic solvent. Suitable solvents include methylene chloride,ethy' acetate or dichtorothane, 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. Suitabte halides include chloride, bromide, and iodide, preferablybromide. Suitable reaction inert solvents include diethyl ether, isopropyl ether, -12- 01 0694 tetrahydrofuran, preferably isopropyl ether. The reaction is performed at a températurefrom about O°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 prépare the pharmaceutically acceptable acid addition salts of the compound of formulaVil are those which form non-toxic acid addition salts, e.q.. salts containingpr.armacologically acceptable anions, such as hydrochloride, hydrobromide,hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate. iactate,crrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, 10 ssccharate, benzoate, methanesulfonate and pamoate fe.q.. 1.1’-methylene-bis-(2-hy3roxy-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.Altnough such salts must be pharmaceutically acceptable for administration to animais, 15 it is oiten désirable in practice to initially isolate a compound of the formula VII from thereaction mixture as a pharmaceutically unacceptable sait and then simply convert thelatcsr back to the free base compound by treatment with an alkaline reagent, andsubsequently convert the fre? base to a pharmaceutically acceptable acid addition sait.The add addition salts of the base compounds of this invention are readily prepared 2C by creating the base compound with a substantially équivalent amount of the chosenminera’ or organic acid in an aqueous solvent medium or in a suitable organic solventsucn as methanol or éthanol. Upon careful évaporation of the solvent, the desired solidsait is obtained.
Compounds of the formula VII, E2020, and its pharmaceutically acceptable 25 salts can be used to treat a d sease caused by acetylcholinesterase activity, such asAlzheimers’ Disease, accordir g to the methods described in United States Patent4.855,841. issued January 23 1990.
Specifically, United Sti tes Patent 4,895,841 States that the in vitro acetylchoiinesterase activity of 1-bencyl-4-((5,6-diethyoxy-1-indanon)-2yI)methyl piperidine, 30 E2020 or a pharmaceutically acceptable sait thereof can be determined according to tne metnod of Ellman et al. Biochem. Pharmacol., 7, 88-95 (1961). -13- 010694
The acetylcholinesterase inhibitory activity of 1-benzyl-4-((5,6-diethyoxy-l-indanon)-2yl)methyl piperidine, determined according to the method of Ellman et al.,expressed in terms of 50% inhibitory concentration (IC^) is 0.0053 μΜ.
Other methods for detemnining the activity of 1-benzyl-4-((5,6-diethyoxy-l-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, prévention, remission, improvement, etc. of various kinds of senile dementia,particularly senile dementia of the Alzheimer’s type; cerebrovascular disease 10 accompanying cérébral apoplexy, e.g. cérébral hemorrhage or cérébral infarcts,cérébral arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech,hypobuüa, emotional changes, recent memory disturbance, hallucinatory-paranoidsyndrome, behavioral changes, etc. accompanying encephalitis, cérébral palsy, etc.
Further, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine has a strong 15 and highly sélective antichoiinesterase action, which also renders the compound usefulas a pharmaceutical based on this mode of action. S pe cifical ly, 1 -benzyl-4-((5,6-dimethoxy-1 -indanon)-2yl)methyl-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)methyipiperidine 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,suibcutaneous, and intramuscular injections, suppositories, or sublingual tablets. Thedose w® vary depending upon the symptom; âge, sex, weight, and sensitivity of 25 patents; method of administration; time and intervals of administration and properties,dispensing, and kind of pharmaceutical préparations 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 inoms to four portions. 30 Pharmaceutical préparations 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. -14- 010694
In preparing injections, the effective ingrédient is blended, if necessary, with apH modifier, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicityagent, a preservative, etc., followed by préparation of an intravenous, subcutaneous,or intramuscular injection according to an ordinary method. In this case, if necessary,it is possible to lyophilize these préparations according to an ordinary method.
Examples of the suspending agents include methylcellulose, Polysorbate 80®,hyc'oxyethylcellulose, acacis, powdered tragacanth, sodium carboxymethyicellulose,and polyoxyethylene sorbitan monolaurate.
Examples of the solubilizing agent include polyoxyethylene hydrogenated castoroil, °olysorbate 80®, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol®,anc 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, phénol, cresol, and chlorocresol.
The following Examples illustrate the préparation of the compounds of theprésent invention and the préparation of E2020. Commercial reagents were utilizedwithout further purification. Melting points are uncorrected. NMR data are reported inparts per million (<5) and are referenced to the deuterium lock signal from the samplesolvent and were obtained on a Bruker 300 MHz instrument. D2O refers to deuteriumoxide. CDCI3 refers to deuterochloroform. Chromatography, unless otherwise noted,refers to column chromatography performed using 32-63j/m silica gel and executedundernitrogen pressure (flash chromatography) conditions. Thin Layer Chromatograph(TLC) refers to chromatography performed on silica gel plates (E. Merck, Kiesel Gel 60F25·*) and eiuted with the spécifie solvent designated. High Pressure LiquidChromatography (HPLC) was performed on a LDC Analytical constaMetric® 3200HPLC (Thermo Séparation Products Co.). A 2orbax®C8, 60A, 3.9 x 150 mm column(Mac-Mod Analytical, Inc., Chadds Ford, PA 19317) was used for HPLC analysis andwas eiuted with the solvent indicated. Fast Atom Bombardment Mass Spectrometry(FAEMS) refers to Mass Spectroscopic analysis on a Hewlett-Packard 5989 MassSpectromeîer (Particle beam Chemical ionization). Room température refers to 20- 25°C. -15- 019694
Préparation 1 3-Pyridin-4-ylpropen-2-oic acid
To a solution of pyridin-4-ylcarboxaldehyde (100 gm. 0.93 mol) in pyridine (100mL) was added malonic acid (100 gm, 0.96 mol) at 90°C. After carbon dioxide (CO ) 5 évolution subsided, the reaction slurry was diluted with methanol. The title compoundwas isolated as a white solid by filtration (97 gm, 70% yield). Ή NMR (HOAc-d4) δ11.70 (s, 1H), 8.85 (d, 2H), 7.95 (d, 2H), 7.80 (d, 1H), 6.90 (d, 1H).
Préparation 2 10 3-Piperidin-4-ylpropanoic acid
The product from Préparation 1 (32 gm, 0.22 mol) was dissolved in 2 N hydrcchloric acid (150 mL) and treated with 10 weight percent of 5% rhodium oncarbcn under a hydrogen atmosphère (45 p.s.i.) until hydrogen gas uptake ceased;The catalyst was filtered and the resulting solution of the title compound was carried 15 directiy into the next step. 'H NMR (DjO) 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.
Préparation 3 3-FN-(Methoxycarbonyl)-piperidin-4-vnproprionic acid20 The solution of the product from Préparation 2, was brought to pH 12 with aaueous potassium hydroxide. To this solution was added methyl chloroformate (21mL, C.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, 2Hj. 1.80 -1.10 (m, 7H). FABMS (M + 1f = 216.
Example 1 4-(2-Chlorocarbonvl-ethyh-piperidine-1-carboxvlic acid methyl ester30 To a solution of the product from Préparation 3 (54.0 gm, 0.251 mol) in dichloromethane (500 mL) was added dimethylformamide (0.39 mL, 0.02 équivalents)and oxalyl chloride (22 mL, 0.26 mol). After gas évolution subsided, the formation ofthe titie compound was complété. The solution of the title compound was carried -16- 010694 directly into the next step.
Example 2 4-r3-i3.4-Dimethoxv-phenvl)-3-oxo-propyl1-piperidine-1-carboxylic acid methyl ester 5 To the solution of the product from Examplé 1 at room température 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 température. High pressure liquid chromatography analysis showed that thereaction was complété. The reaction was quenched by careful addition of water and 1C 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 thesorvent was removed in vacuo to provide an oil (67 gm, quantitative crude weight).Thin Layer Chromatographie (TLC) and High Pressure Liquid Chromatographie (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 (R, and tr for reactionproduct): 20 TLC (siiica gel): R,= 0.50 (40 : 60 hexane/ethyl acetate). High Pressure Liquid
Chromatography rétention time (tr) was 12.6 min (Zorbax Ce, 254 nm, 1 mL/min,600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (CDCI3) δ 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 C1BH25NO5 (M + 1)+ = 336.
Example 3 4-r2-(3,4-Dimethoxv-benzovh-allvn-piperidine-1- carboxylic acid methyl ester 30 To a solution of the product from Example 2 (66.0 gm, 0.20 mol) was added aceac 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 complété, thereaction was heated at 90°C for three hours and then allowed to stir ovemight at room -17- 010694 température.
An aiiquot (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): R,= 0.60 (40 : 60 hexane/ethyl acetate). High Pressure Liquid10 Chromatography rétention time (tr) was 15.9 min (Zorbax Ce, 254 nm, 1 mL/min,600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (CDCl3) δ 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 C,9H2SNO5 (M + 1)*= 348. 15 Example 4 4-(5.6»DimethoxV‘1-oxo-indan-2-vlmethvl)-pipendine-1- carboxylic acid methvl 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 ovemight at room température, at which time High Pressure Liquid Chromatographieanalysis indicated that the réaction was complété. 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 (siiica gel) R,= 0.40 (40 : 60 hexane/ethyl acetate). High Pressure LiquidChromatography rétention time (tr) was 10.1 min (Zorbax Ce, 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, E.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 C,9H25NO6 (M + 1)+= 348. ' - .’WJK.WSÆfWïarai»' ’ ’V»—·» ’rw»n-· 010694 -18-
Example 5 5,6-Dimethoxv-2-piperidin-4-vlmethvl-indan-l-one Το 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 ofwater. The mixture was then heated under a nitrogèn atmosphère ovemight, at whichtime high pressure liquid chromatographie 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 wasused without further purification.
High Pressure Liquid Chromatography rétention time (tr) was 2.45 min (ZorbaxC8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). ’HNMR (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,3H), 1.02-1.35 (m, 3H). FABMS C17H23NO3 (M + 1)+= 290.
Example 6 2-(1 -Benzvl-piperidin-4-vlmethvl)-5.6-dimethoxy«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) andtrieth3nolamine (940 mg, 6.3 mmol). The slurry was stirred ovemight, at 70eC, atwhich time high pressure liquid chromatography indicated that the starting material wasmoshy 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. Theresidje was dissolved in 20 mL of hot isopropanol and aliowed to cool to roomtempérature. The precipitated solid was filtered to provide 1.60 gm (61%) of the titlecompound as a white solid. TLC (silica gel): Rf = 0.60 (90 :10 methylene chloride/methanol); High PressureLiquid Chromatography rétention = 6.01 min (Zorbax CB, 254 nm, 1 mL/min, eluted with600:400:2:1 water/acetonitrile/triethytamine/acetic acid). ’H NMR (of the free base,DMSO-de) <S7.06 (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 tm, 3H), 1.31-1.50 (m, 1H), 1.08-1.30 (m, 3H). FABMS CMH29NO3 (M + 1)*= 380.
Claims (15)
- -19- 01 0 6 9 4 CLAIMS1. A compound of the formulaR1 1015 wherein R’ is R2O(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,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl.
- 2. A compound of the formula25 I I whe»-ein R ' is R2O(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,-C4)alkyl, (C,-C4)alkoxy. halo or trifluoromethyl. 30 3. A compound of the formula -20- 010694I wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl and R3 is (CrC4)alkyl or phenyl10 opticnally 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 formulaI wnerein R’ is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl and R3 is (C1-C4)alkyl or phenyloptionaliy substituted with from one to three substituents independently selected from(C.-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl, comprising a) reacting a compound of the formula 30 -21- 01 0694 R1wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C^CJalkyl and R3 is (C^-CJalkyl or phenyloptfonally substituted with from one to three substituents independently selected from 15 (C,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl, with a methenylation agent to forma compound of the formulaI I 25 wherein R* is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl and R3 is (C,-C4)alkyI or phenyloptionaliy substituted with from one to three substituents independently selected from(C,-C4)alkyi, (CrC4)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- 01 0694 10 comprises 2 équivalents and said acetic anhydride comprises 4 équivalents.
- 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. A process according to claim 9 wherein said concentrated sulfuric acidcomprises 9 équivalents.
- 11. A process according to claim 4 further comprising the additional step ofreaciing the compound of formula I, wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-CJalkyl and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to threesubstituents independently selected from (C,-C4)alkyl, (C,-C4)alkoxy, halo ortrifiuoromethyl, with hydroxide to form a compound of the formulaVI 20 and reacthng said compound of formula VI so formed with acorroound of the formula benzylhalide to form a
- 12. A process according to claim 11 wherein said benzyl halide is benzyl brorraide. 30
- 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 isisolafcec 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 -23- 01 0694 formula I is treated with a base.
- 15. A process for preparing a compound of the formulawherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C,-C4)alkyl, and R3 is (C,-C4)alkylor phenyt optionaliy substituted with from one to three substituents independentlyselected from (C,-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl, comprising reactings compound of the formulaIV with a compound of the formula0 010694 -24- wherein R1 is as defined above, in the presence of a Lewis acid in a reactioninert solvent.
- 16. A process according to to ciaim 15 wherein said Lewis acid is aluminumtrichloride and said reaction inert solvent is methylene chloride.
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| Application Number | Priority Date | Filing Date | Title |
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| US875395P | 1995-12-15 | 1995-12-15 |
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| Country | Link |
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| 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) | IL124452A0 (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) |
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| DE69924467T2 (en) | 1998-01-16 | 2006-02-16 | Eisai Co., Ltd. | PROCESS FOR PREPARING DONEPEZIL DERIVATIVES |
| 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) |
| WO2004082685A1 (en) * | 2003-03-21 | 2004-09-30 | Ranbaxy Laboratories Limited | 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 |
| KR20070083679A (en) | 2004-09-29 | 2007-08-24 | 케마지스 리미티드 | 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 |
| US8247563B2 (en) * | 2006-12-11 | 2012-08-21 | 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 |
| AU2014307803A1 (en) | 2013-08-16 | 2016-03-10 | Universiteit Maastricht | Treatment of cognitive impairment with PDE4 inhibitor |
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| FI95572C (en) * | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Process for the preparation of a medicament useful as a piperidine derivative or its pharmaceutical salt |
| FR2642069B1 (en) * | 1989-01-20 | 1991-04-12 | Rhone Poulenc Sante | NOVEL BENZOPYRAN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| DE4439822A1 (en) * | 1994-11-08 | 1996-08-29 | Bayer Ag | Process for the preparation of benzyl-piperidylmethyl-indanones |
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