CA2237647A1 - 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 R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl, and R3 is (C1C4)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 R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl, and R3 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 R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl, and R3 is (C1C4)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
CA 02237647 1998-0~-14 W O 97122~84 PCT~B96/01076 PROCESSES AND INTERMEDIATES FOR PREPARING 1-BENZYL~-((5,6-DIMETHOXY-1 -INDANON~-2-YL)METHYLPIPERIDINE
Backqround of the Invention This invention relates to a novel process for the preparation o~ 1 -benzyl4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine (E2020), the compound of the formula Vll below, and to novel intermediates used in said process.
United States Patent4,895,841, issued January 23, 1990, refers to 1-benzyl-4-((5,6-dirnethoxy-1-indanon)-2-yl)methylpiperidine, methods for its preparation, useful intermediates, and to methods and pharmaceutical compositions for treating diseases caused by acetylcholinesterase activity, such as senile dementia United States Patent 1~ 4,895,841, issued January 23, 1990, is hereby incorporated by reference in its entirety.
Summarv of the Invention The present invention relates to a compound of the formula R
N~
~ 25 ~0 M e ~ Me I I I
wherein R1 is R2O(C=O)- or R3(C=o)-, R2 is (C,-C4)alkyl, and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (Cl-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl.
The present invention also relates to a compound of the formula W O 97/22584 PCT~B96/01076 ~ ~O M e Rl~ CH2 ~OMe 10 wherein R' is R2O(C=O)- or R3(C=o)-, R2 is (C1-C4)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.
The present invention also relates to a compound of the formula O
~1~ N~o M e wherein R' is R2O(C=O)- or R3(C=o)-, 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, (C,-C4)alkoxy, halo or trifluoromethyl.
The present invention also relates to a process for preparing a compound of the formula W O 97122584 PCT~B96/01076 R 1/ ~ ~ M e wherein R' is R20(C=O)- or R3(C=o)-, R2 is (C,-C4)alkyl, and R3 is (C,-C4)alkyl or 10 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 R
<~
~ ,0 M e OMe I I I
wherein R' is R20(C=O)- or R3(C=o)-, R2 is (C1-C4)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 CA 02237647 1998-0~-14 WO 97/22584 PCTnB96/0~076 Rl,N~\~ OMe wherein R' is R2O(C=O~- or R3(C=o)-, R2 is (C1-C4)alkyl, and R3 is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyi, (C1-C4)alkoxy, halo or trifluoromethyl and;
b) reacting said compound of formula ll, 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 lll) and said acetic anhydride comprises 4 molar equivalents (relative to the amount of the compound o~
the formula lll).
Preferably, said strong acid is sulfuric acid. More preferably, said sulfuric acid is concentrated sulfuric acid. Most preferably, said concentrated sulfuric acid comprises 9 molar equivalents (relative to the amount of said compound of the formula l).
A preferred embodiment of the present invention relates to any of the above processes further comprising the additional step of reacting the compound of formula I, wherein R' is R2O(C=O)- or R3(C=o)-, R2 is (C,-C4)alkyl, and R3 is (C1-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 hydroxide (preferably potassium hydroxide) to form a compound of the formula CA 02237647 l998-0~-l4 W O 97/22584 PCT~B96/01076 H~ ~OMe V I
and reacting said compound of formula Vl so formed with a benzyl halide and a base to form a compound of the formula ~"N~3 ~011 e Preferably, said benzyl halide is benzyl bromide. Preferably said base is triethanolamine .
The most preferred embodiment of the above invention relates to a process 20 wherein said compound of formula l is isolated before it is converted to the compound of formula Vl. The compound of formula l can be isolated by addition of the strongly acidic solution containing the compound of formula l to ice/water followed by extraction with an organic solvent and removal of the organic solvent.
The present invention also related to a process for preparing a compound of the 25 formula Rl N
<~
~O ~1 e ~, OMe I I I
comprising reacting a compound of the formula ~OMe ll ~\OMe I V
5 with a compound of the formula R1 N =~
/ \~
~
V
in the presence of a Lewis acid, such as aluminum trichloride, in a reaction inert solvent, such as methylene chloride.
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 Detailed DescriPtion of the Invention The compounds of formula I and E2020 can be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, compoundsof the formulae 1, 11 and 111, Vl and Vll and the groups R', R2 and R3 in the reaction schemes and discussion that follow are as defined above.
W O 97/22~84 PCT~B96/01076 ~Ot1e Rl--N' IV V
1 0 ~>
~X Orle I I I
~N , ~ 'X
Rl~ ~ ' ~ ~Olile W O 97/22584 PCT~B96/01076 !
O
R 1' N~ ~ O M e H~N~ O M e V I
ll ~ ~,L~ N~OMe ,. 30 VI I
CA 02237647 l998-0~-l4 W O 97/22584 PCT~B96/01~76 Scheme 1 refers to the process of preparing a compound of formula 1, which can be converted to a compound of the formuia Vll, E2020, by the methods of Scheme 2.
Referring to Scheme 1, the compound of the formula IV is commercially 5 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 lll 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 R' is R2O(C=O)- or R3(C=o)-, R2 is ~C1-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, in the presence of a Lewis acid in 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 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 ll can be prepared from a compound of the formula 20 lll by reacting said compound of the formula lll with a methenylation agent. Preferably, R1 is R2O(C=O)-, 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 1~1-methylthiomethylpiperdine. Preferably the methenylation agent is 25 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 e~uivalents of acetic anhydride (relative to the amount of the compound of formula lll) and 2 equivalents of tetramethyldiaminomethane (relative 30 to the amount of the compound of formula lll). 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 (~, diethyl ether and tetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride. The CA 02237647 1998-0',-14 W O 97/22584 PCT~B96/01076 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 ll by reacting said compound of the formula ll with a strong acid in a reaction inert solvent. Suitable strong acids include concentrated sulfuric acid, aluminum trichloride or concentrated hydrochloric acid, preferably concentrated sulfuric acid. When aluminum trichloride is the acid, a solvent must be used. Suitable solvents include carbon disulfide, methylene chloride ordichloroethane, preferably carbon disulfide. The reaction is performed at a temperature from about 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 Vll.
Referring to Scheme 2, a compound of the formula I can be converted into a compound of the formula Vl by reaction with a strong base in the presence of a solvent.
Preferably, the reactant is a compound of the formula 1, wherein R' is R2O(C-O)-, 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 Vl by isolating the compound of formula I before converting it into the compound of formula Vl. 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 Vll can be prepared from a compound of the r 30 formula Vl by reacting said compound of the formula Vl 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, CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 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 Vll can be converted to pharmaceutically acceptable acid addition salts of the compound of the formula Vll. The acids which are used to 5 prepare the pharmaceutically acceptable acid addition salts of the compound of formula Vll are those which form non-toxic acid addition salts, e.q., 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, 10 saccharate, benzoate, methanesulfonate and pamoate ~e.a., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The compound of the formula Vll is basic in nature and is therefore capable of forming a wide variety of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for administration to animals, 15 it is often desirable in practice to initially isolate a compound of the formula Vll from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the iatter 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 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 Vll, E2020, and its pharmaceutically acceptable 25 salts can be used to treat a disease caused by acetylcholinesterase activity, such as Alzheimers' Disease, according to the methods described in United States Patent 4,895,841, issued January 23, 1990.
Specifically, United States Patent 4,895,841 states that the in vitro acetyl cholinesterase activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, 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).
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96tO1076 The acetylcholinesterase inhibitory activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, determined according to the method of Ellman et al., expressed in terms of 50% inhibitory concentration (ICso) is 0.0053 ~M.
Other methods for determining the activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon~-2yl)methyl piperidine are described in United States Patent 4,895,841, issued January 23, 1990.
1-Benzyl~-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine is effective for treatment, prevention, remission, improvement, etc. of various kinds of senile dementia, particularly senile dementia of the Alzheimer's type; cerebrovascular disease accompanying cerebral apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc.
Further, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine has a strongand highly selective anticholinesterase action, which also renders the compound useful as a pharmaceutical based on this mode of action.
Specifically, 1-benzyl~-((5,6-dimethoxy-1-indanon)-2yl)methyl-piperidine is effective for, for example, Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskinesia other than senile dementia of the Alzheimer type.
When 1-benzyl~-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine is used as a pharmaceutical for these diseases, it may be orally or parenterally administered. In general, it is parenterally administered in the form of injections, such as intravenous, subcutaneous, and intramuscular injections, suppositories, or sublingual tablets. The dose will vary depending upon the symptom; age, sex, weight, and sensitivity of patients; method of administration; time and intervals of administration and properties, dispensing, and kind of pharmaceutical preparations so that there is no particular limitation with respect to the dose. Normally the compound may be administered in a dose of about 0.1 to 30Q mg, preferably 1 to 100 mg, per day per adult, ordinarily in one to four portions.
- 30 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.
CA 02237647 l998-0~-l4 W O 97/22584 PCTnB96/0lO76 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, 5 it is possible to Iyophilize these preparations according to an ordinary method.
Examples of the suspending agents include methylcellulose, Polysorbate 80(g), hydroxyethylcellulose, acacis, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate.
Examples of the solubiiizing agent include polyoxyethylene hydrogenated castor 10 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 (~) and are referenced to the deuterium lock signal from the sample solvent 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 32-63,um 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 60 F254) and eluted with the specific solvent designated. High Pressure Liquid 25 Chromatography (HPLC) was performed on a LDC Analytical constaMetric~ 3200 HPLC (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 20-2~oc.
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 Preparation 1 3-Pvridin~-vlProPen-2-oic acid To a solution of pyridin-4-ylcarboxaldehyde (100 gm,0.93 mol) in pyridine (100 mL) was added malonic acid (100 gm, 0.96 mol) at 90~C. After carbon dioxide (CO2) 5 evoiution subsided, the reaction slurry was diluted with methanol. The titie compound was isolated as a white solid by filtration (97 gm, 70% yield).
'H NMR (HOAc-d4) ~ 11.70 (s,1 H),8.85 (d, 2H),7.95 (d, 2H), 7.80 (d,1 H), 6.90 (d, 1H).
Preparation 2 3-Piperidin-4-vlpropanoic 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 hltered and the resulting solution of the title compound was carried directly into the next step.
'H NMR (D20) IS 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-(MethoxYcarbonyl)-piperidin-4-yllproprionic 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 (21mL, 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 sodiumsulfate and the dichloromethane displaced with isopropyl ether. The title compound was isolated as a solid by filtration (39 gm, 84%).
Mp 89-90~C. 'H NMR (CDCI3) ~S4.10 (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-Chlorocarbonvl-ethvl)-PiPeridine-1-carboxvlic acid methyl ester To a solution of the product from Preparation 3 (54.0 gm, 0.251 mol) in dichloromethane (500 mL) was added dimethylformamide (0.39 mL, 0.02 equivalents)and oxalyl chloride (22 mL, 0.26 mol). After gas evolution subsided, the formation of the title compound was complete. The solution of the title compound was carried CA 02237647 1998-0~-14 WO 97/22584 PCT~B96/01076 directly into the next step.
ExamPle 2 4-r3-(3,4-Dimethoxy-l~henvl~-3-oxo-~ropyll-piperidine-1 -carboxvlic acid methvl ester 5To the solution of the product from Example 1 at room temperature was added (25.5 mL, 0.20 mol) of 1,2-dimethoxybenzene foliowed by portion-wise addition ofaluminum 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 10then 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 LayerChromatographic (TLC) and High Pressure Liquid Chromatographic (HPLC) 15analysis 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 (Rf and t, for reaction product):
20TLC (silica gel): Rf= 0.50 (40: 60 hexane/ethyl acetate). High Pressure LiquidChromatography retention time (tr) was 12.6 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrilettriethylamine/acetic acid). 'H NMR (CDCI3) ~ 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), 251.61-1.76 (m, 4H), 1.40-1.55 (m, 1H), 1.06-1.Z1 (m, 2H). FABMS C1~3H25NO5 (M * 1)+
= 336.
ExamPle 3 4-r2-(3,4-DimethoxY-benzoyl)-allvll-pi~eridine-1 -carboxvlic acid methvl ester 30To 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 CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 temperature.
An aiiquot (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 5 by High Pressure Liquid Chromatography which showed that the starting material was consumed.
Based on the purity of the crude reaction mixture, the crude reaction material was carried directly into the next step, TLC (silica gel): R~= 0.60 (40: 60 hexane/ethyl acetate). High Pressure Liquid 10Chromatography 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) ~ 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 C19H2sNO5 (M + 1)+ = 348.
15~xample 4 4-(5,6-Dimethoxv-1 -oxo-~indan-2-vlmethvl)-piperidine-1 -carboxylic acid methvl ester The crude reaction mixture from Example 3, (0.20 mol) was treated with concentrated sulfuric acid (100 mL) at 0~C. The reaction was then allowed to stir 20 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, 25 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 min (Zorbax C8, 254 nm, 1 mL/min, 30 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 'H NMR (CDCI3) ~ 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.
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 Example 5 5,6-Dimethoxv-2-PiPeridin-4-Ylme'thYI-indan-l-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 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 methyiene chloride (3x50 mL),the combined organic layers dried with sodium sulfate, and the voiatiles 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 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 'H
NMR (CDCI3) ~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-YlmethYl)-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 chloride/methanol); High Pressure Liquid Chromatography retention = 6.01 min (Zorbax C8,254 nm,1 mL/min, eluted with 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (of the free base, DMSO-d6) ~7.06 (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.
Backqround of the Invention This invention relates to a novel process for the preparation o~ 1 -benzyl4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine (E2020), the compound of the formula Vll below, and to novel intermediates used in said process.
United States Patent4,895,841, issued January 23, 1990, refers to 1-benzyl-4-((5,6-dirnethoxy-1-indanon)-2-yl)methylpiperidine, methods for its preparation, useful intermediates, and to methods and pharmaceutical compositions for treating diseases caused by acetylcholinesterase activity, such as senile dementia United States Patent 1~ 4,895,841, issued January 23, 1990, is hereby incorporated by reference in its entirety.
Summarv of the Invention The present invention relates to a compound of the formula R
N~
~ 25 ~0 M e ~ Me I I I
wherein R1 is R2O(C=O)- or R3(C=o)-, R2 is (C,-C4)alkyl, and R3 is (C,-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (Cl-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl.
The present invention also relates to a compound of the formula W O 97/22584 PCT~B96/01076 ~ ~O M e Rl~ CH2 ~OMe 10 wherein R' is R2O(C=O)- or R3(C=o)-, R2 is (C1-C4)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.
The present invention also relates to a compound of the formula O
~1~ N~o M e wherein R' is R2O(C=O)- or R3(C=o)-, 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, (C,-C4)alkoxy, halo or trifluoromethyl.
The present invention also relates to a process for preparing a compound of the formula W O 97122584 PCT~B96/01076 R 1/ ~ ~ M e wherein R' is R20(C=O)- or R3(C=o)-, R2 is (C,-C4)alkyl, and R3 is (C,-C4)alkyl or 10 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 R
<~
~ ,0 M e OMe I I I
wherein R' is R20(C=O)- or R3(C=o)-, R2 is (C1-C4)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 CA 02237647 1998-0~-14 WO 97/22584 PCTnB96/0~076 Rl,N~\~ OMe wherein R' is R2O(C=O~- or R3(C=o)-, R2 is (C1-C4)alkyl, and R3 is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyi, (C1-C4)alkoxy, halo or trifluoromethyl and;
b) reacting said compound of formula ll, 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 lll) and said acetic anhydride comprises 4 molar equivalents (relative to the amount of the compound o~
the formula lll).
Preferably, said strong acid is sulfuric acid. More preferably, said sulfuric acid is concentrated sulfuric acid. Most preferably, said concentrated sulfuric acid comprises 9 molar equivalents (relative to the amount of said compound of the formula l).
A preferred embodiment of the present invention relates to any of the above processes further comprising the additional step of reacting the compound of formula I, wherein R' is R2O(C=O)- or R3(C=o)-, R2 is (C,-C4)alkyl, and R3 is (C1-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 hydroxide (preferably potassium hydroxide) to form a compound of the formula CA 02237647 l998-0~-l4 W O 97/22584 PCT~B96/01076 H~ ~OMe V I
and reacting said compound of formula Vl so formed with a benzyl halide and a base to form a compound of the formula ~"N~3 ~011 e Preferably, said benzyl halide is benzyl bromide. Preferably said base is triethanolamine .
The most preferred embodiment of the above invention relates to a process 20 wherein said compound of formula l is isolated before it is converted to the compound of formula Vl. The compound of formula l can be isolated by addition of the strongly acidic solution containing the compound of formula l to ice/water followed by extraction with an organic solvent and removal of the organic solvent.
The present invention also related to a process for preparing a compound of the 25 formula Rl N
<~
~O ~1 e ~, OMe I I I
comprising reacting a compound of the formula ~OMe ll ~\OMe I V
5 with a compound of the formula R1 N =~
/ \~
~
V
in the presence of a Lewis acid, such as aluminum trichloride, in a reaction inert solvent, such as methylene chloride.
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 Detailed DescriPtion of the Invention The compounds of formula I and E2020 can be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, compoundsof the formulae 1, 11 and 111, Vl and Vll and the groups R', R2 and R3 in the reaction schemes and discussion that follow are as defined above.
W O 97/22~84 PCT~B96/01076 ~Ot1e Rl--N' IV V
1 0 ~>
~X Orle I I I
~N , ~ 'X
Rl~ ~ ' ~ ~Olile W O 97/22584 PCT~B96/01076 !
O
R 1' N~ ~ O M e H~N~ O M e V I
ll ~ ~,L~ N~OMe ,. 30 VI I
CA 02237647 l998-0~-l4 W O 97/22584 PCT~B96/01~76 Scheme 1 refers to the process of preparing a compound of formula 1, which can be converted to a compound of the formuia Vll, E2020, by the methods of Scheme 2.
Referring to Scheme 1, the compound of the formula IV is commercially 5 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 lll 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 R' is R2O(C=O)- or R3(C=o)-, R2 is ~C1-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, in the presence of a Lewis acid in 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 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 ll can be prepared from a compound of the formula 20 lll by reacting said compound of the formula lll with a methenylation agent. Preferably, R1 is R2O(C=O)-, 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 1~1-methylthiomethylpiperdine. Preferably the methenylation agent is 25 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 e~uivalents of acetic anhydride (relative to the amount of the compound of formula lll) and 2 equivalents of tetramethyldiaminomethane (relative 30 to the amount of the compound of formula lll). 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 (~, diethyl ether and tetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride. The CA 02237647 1998-0',-14 W O 97/22584 PCT~B96/01076 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 ll by reacting said compound of the formula ll with a strong acid in a reaction inert solvent. Suitable strong acids include concentrated sulfuric acid, aluminum trichloride or concentrated hydrochloric acid, preferably concentrated sulfuric acid. When aluminum trichloride is the acid, a solvent must be used. Suitable solvents include carbon disulfide, methylene chloride ordichloroethane, preferably carbon disulfide. The reaction is performed at a temperature from about 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 Vll.
Referring to Scheme 2, a compound of the formula I can be converted into a compound of the formula Vl by reaction with a strong base in the presence of a solvent.
Preferably, the reactant is a compound of the formula 1, wherein R' is R2O(C-O)-, 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 Vl by isolating the compound of formula I before converting it into the compound of formula Vl. 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 Vll can be prepared from a compound of the r 30 formula Vl by reacting said compound of the formula Vl 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, CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 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 Vll can be converted to pharmaceutically acceptable acid addition salts of the compound of the formula Vll. The acids which are used to 5 prepare the pharmaceutically acceptable acid addition salts of the compound of formula Vll are those which form non-toxic acid addition salts, e.q., 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, 10 saccharate, benzoate, methanesulfonate and pamoate ~e.a., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The compound of the formula Vll is basic in nature and is therefore capable of forming a wide variety of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for administration to animals, 15 it is often desirable in practice to initially isolate a compound of the formula Vll from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the iatter 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 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 Vll, E2020, and its pharmaceutically acceptable 25 salts can be used to treat a disease caused by acetylcholinesterase activity, such as Alzheimers' Disease, according to the methods described in United States Patent 4,895,841, issued January 23, 1990.
Specifically, United States Patent 4,895,841 states that the in vitro acetyl cholinesterase activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, 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).
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96tO1076 The acetylcholinesterase inhibitory activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon)-2yl)methyl piperidine, determined according to the method of Ellman et al., expressed in terms of 50% inhibitory concentration (ICso) is 0.0053 ~M.
Other methods for determining the activity of 1-benzyl-4-((5,6-diethyoxy-1-indanon~-2yl)methyl piperidine are described in United States Patent 4,895,841, issued January 23, 1990.
1-Benzyl~-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine is effective for treatment, prevention, remission, improvement, etc. of various kinds of senile dementia, particularly senile dementia of the Alzheimer's type; cerebrovascular disease accompanying cerebral apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc.
Further, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine has a strongand highly selective anticholinesterase action, which also renders the compound useful as a pharmaceutical based on this mode of action.
Specifically, 1-benzyl~-((5,6-dimethoxy-1-indanon)-2yl)methyl-piperidine is effective for, for example, Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskinesia other than senile dementia of the Alzheimer type.
When 1-benzyl~-((5,6-dimethoxy-1-indanon)-2yl)methylpiperidine is used as a pharmaceutical for these diseases, it may be orally or parenterally administered. In general, it is parenterally administered in the form of injections, such as intravenous, subcutaneous, and intramuscular injections, suppositories, or sublingual tablets. The dose will vary depending upon the symptom; age, sex, weight, and sensitivity of patients; method of administration; time and intervals of administration and properties, dispensing, and kind of pharmaceutical preparations so that there is no particular limitation with respect to the dose. Normally the compound may be administered in a dose of about 0.1 to 30Q mg, preferably 1 to 100 mg, per day per adult, ordinarily in one to four portions.
- 30 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.
CA 02237647 l998-0~-l4 W O 97/22584 PCTnB96/0lO76 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, 5 it is possible to Iyophilize these preparations according to an ordinary method.
Examples of the suspending agents include methylcellulose, Polysorbate 80(g), hydroxyethylcellulose, acacis, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate.
Examples of the solubiiizing agent include polyoxyethylene hydrogenated castor 10 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 (~) and are referenced to the deuterium lock signal from the sample solvent 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 32-63,um 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 60 F254) and eluted with the specific solvent designated. High Pressure Liquid 25 Chromatography (HPLC) was performed on a LDC Analytical constaMetric~ 3200 HPLC (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 20-2~oc.
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 Preparation 1 3-Pvridin~-vlProPen-2-oic acid To a solution of pyridin-4-ylcarboxaldehyde (100 gm,0.93 mol) in pyridine (100 mL) was added malonic acid (100 gm, 0.96 mol) at 90~C. After carbon dioxide (CO2) 5 evoiution subsided, the reaction slurry was diluted with methanol. The titie compound was isolated as a white solid by filtration (97 gm, 70% yield).
'H NMR (HOAc-d4) ~ 11.70 (s,1 H),8.85 (d, 2H),7.95 (d, 2H), 7.80 (d,1 H), 6.90 (d, 1H).
Preparation 2 3-Piperidin-4-vlpropanoic 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 hltered and the resulting solution of the title compound was carried directly into the next step.
'H NMR (D20) IS 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-(MethoxYcarbonyl)-piperidin-4-yllproprionic 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 (21mL, 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 sodiumsulfate and the dichloromethane displaced with isopropyl ether. The title compound was isolated as a solid by filtration (39 gm, 84%).
Mp 89-90~C. 'H NMR (CDCI3) ~S4.10 (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-Chlorocarbonvl-ethvl)-PiPeridine-1-carboxvlic acid methyl ester To a solution of the product from Preparation 3 (54.0 gm, 0.251 mol) in dichloromethane (500 mL) was added dimethylformamide (0.39 mL, 0.02 equivalents)and oxalyl chloride (22 mL, 0.26 mol). After gas evolution subsided, the formation of the title compound was complete. The solution of the title compound was carried CA 02237647 1998-0~-14 WO 97/22584 PCT~B96/01076 directly into the next step.
ExamPle 2 4-r3-(3,4-Dimethoxy-l~henvl~-3-oxo-~ropyll-piperidine-1 -carboxvlic acid methvl ester 5To the solution of the product from Example 1 at room temperature was added (25.5 mL, 0.20 mol) of 1,2-dimethoxybenzene foliowed by portion-wise addition ofaluminum 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 10then 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 LayerChromatographic (TLC) and High Pressure Liquid Chromatographic (HPLC) 15analysis 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 (Rf and t, for reaction product):
20TLC (silica gel): Rf= 0.50 (40: 60 hexane/ethyl acetate). High Pressure LiquidChromatography retention time (tr) was 12.6 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrilettriethylamine/acetic acid). 'H NMR (CDCI3) ~ 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), 251.61-1.76 (m, 4H), 1.40-1.55 (m, 1H), 1.06-1.Z1 (m, 2H). FABMS C1~3H25NO5 (M * 1)+
= 336.
ExamPle 3 4-r2-(3,4-DimethoxY-benzoyl)-allvll-pi~eridine-1 -carboxvlic acid methvl ester 30To 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 CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 temperature.
An aiiquot (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 5 by High Pressure Liquid Chromatography which showed that the starting material was consumed.
Based on the purity of the crude reaction mixture, the crude reaction material was carried directly into the next step, TLC (silica gel): R~= 0.60 (40: 60 hexane/ethyl acetate). High Pressure Liquid 10Chromatography 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) ~ 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 C19H2sNO5 (M + 1)+ = 348.
15~xample 4 4-(5,6-Dimethoxv-1 -oxo-~indan-2-vlmethvl)-piperidine-1 -carboxylic acid methvl ester The crude reaction mixture from Example 3, (0.20 mol) was treated with concentrated sulfuric acid (100 mL) at 0~C. The reaction was then allowed to stir 20 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, 25 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 min (Zorbax C8, 254 nm, 1 mL/min, 30 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 'H NMR (CDCI3) ~ 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.
CA 02237647 1998-0~-14 W O 97/22584 PCT~B96/01076 Example 5 5,6-Dimethoxv-2-PiPeridin-4-Ylme'thYI-indan-l-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 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 methyiene chloride (3x50 mL),the combined organic layers dried with sodium sulfate, and the voiatiles 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 min (Zorbax C8, 254 nm, 1 mL/min, 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 'H
NMR (CDCI3) ~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-YlmethYl)-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 chloride/methanol); High Pressure Liquid Chromatography retention = 6.01 min (Zorbax C8,254 nm,1 mL/min, eluted with 600:400:2:1 water/acetonitrile/triethylamine/acetic acid). 1H NMR (of the free base, DMSO-d6) ~7.06 (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.
Claims (16)
1. A compound of the formula wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 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.
2. A compound of the formula wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C,-C4)alkoxy, halo or trifluoromethyl.
3. A compound of the formula wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 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.
4. A process for preparing a compound of the formula wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 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 the formula wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 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 the formula wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 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.
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 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 concentrated sulfuric acid.
10. A process according to claim 9 wherein said concentrated sulfuric acid comprises 9 equivalents.
11. A process according to claim 4 further comprising the additional step of reacting the compound of formula 1, wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl and R3 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 hydroxide to form a compound of the formula and reacting said compound of formula VI so formed with a benzylhalide to form a compound of the formula
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 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 wherein R1 is R2O(C=O)- or R3(C=O)-, R2 is (C1-C4)alkyl, and R3 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 reacting a compound of the formula with a compound of the formula wherein 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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US875395P | 1995-12-15 | 1995-12-15 | |
| US60/008,753 | 1995-12-15 | ||
| 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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|---|---|
| CA2237647A1 true CA2237647A1 (en) | 1997-06-26 |
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| CA002237647A Abandoned CA2237647A1 (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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| Country | Link |
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| EP (1) | EP0883607A1 (en) |
| JP (1) | JP3066083B2 (en) |
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| AR (1) | AR004368A1 (en) |
| AU (1) | AU716462B2 (en) |
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| 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) | NO982712D0 (en) |
| NZ (1) | NZ318843A (en) |
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| PE (1) | PE25698A1 (en) |
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| RO (1) | RO121382B1 (en) |
| RU (1) | RU2160731C2 (en) |
| SK (1) | SK75498A3 (en) |
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| ES2237078T3 (en) | 1998-01-16 | 2005-07-16 | Eisai Co., Ltd. | PROCEDURE TO PRODUCE DERIVATIVES OF DONEPEZILO. |
| 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 |
| US7446203B2 (en) | 2003-07-01 | 2008-11-04 | Hetero Drugs Limited | Preparation of intermediates for acetycholinesterase 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 |
| 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 |
| ES2888074T3 (en) | 2013-08-16 | 2021-12-30 | Univ 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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