RU2160731C2 - Intermediate products for preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanone 2-yl)methylpiperidine, method of preparation thereof and method of preparing 1- benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine and use thereof - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: described are new compounds of formula I:

wherein R¹- is R²O(C=O) or R³=(C=O)-, R²-(C₁-C₄) alkyl which are useful for preparing 1-benzyl-4- [(5,6-dimethoxy-1-indanone)-2-yl] methyl-piperidine as intermediate products. Described are method of preparing thereof and new method of preparing 1-benzyl-4 (5,6-dimethoxy-1-indanone)-2-yl) methylpiperidine which has potent and very selective anticholineesterase activity. EFFECT: improved properties of the title compounds and more efficient preparation method.17 cl, 6 ex

Description

 The invention relates to a new method for producing 1-benzyl-4 - ((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine (E2020), a compound of formula VII, and to new intermediates used in this method.

 US patent 4895841 dated January 23, 1990 relates to 1-benzyl-4 - ((5,6-dimethoxy-1-indan) -2-yl) methylpiperidine, methods for its preparation, useful intermediates, and methods and pharmaceutical compositions for treating diseases caused by acetylcholinesterase activity, such as senile dementia. US patent 4895841 from 01/23/90 used as a reference in full.

где R¹ - R²O(C=O)- или R³(C=O)-, R²-(C₁-C₄) алкил, и R³-(C₁-C₄)алкил или фенил, необязательно замещенный и содержащий от одного до трех заместителей, независимо выбранных из группы, включающей (C₁-C₄)алкил, (C₁-C₆) алкоксигруппу, галоген или трифторметил.SUMMARY OF THE INVENTION
This invention relates to a compound of the formula

where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl, optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₆ ) alkoxy, halogen or trifluoromethyl.

где R¹ - R²O(C=O)- или R³(C=O)-, R²-(C₁-C₄)алкил, и R³-(C₁-C₄)алкил или фенил, необязательно замещенный и содержащий от одного до трех заместителей, независимо выбранных из группы, включающей (C₁-C₄)алкил, (C₁-C₄)алкоксигруппу, галоген или трифторметил.This invention also relates to a compound of the formula:

where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl, optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen or trifluoromethyl.

где R¹ - R²O(C=O)- или R³(C=O)-, R²- (C₁-C₄)алкил, и R³-(C₁-C₄)алкил или фенил, необязательно замещенный и содержащий от одного до трех заместителей, независимо выбранных из группы, включающей (C₁-C₄)алкил, (C₁-C₄)алкоксигруппу, галоген или трифторметил.This invention also relates to a compound of the formula:

where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl, optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen or trifluoromethyl.

где R¹ - R²O(C=O)- или R³(C=O)-, R²-(C₁-C₄)алкил, и R³-(C₁-C₄)алкил или фенил, необязательно замещенный и содержащий от одного до трех заместителей, независимо выбранных из группы, включающей (C₁-C₄) алкил, (C₁-C₄) алкоксигруппу, галоген или трифторметил, включающему следующие стадии:
а) взаимодействие соединения формулы

где R¹ - R²O(C=O)- или R³(C=O)-, R²-(C₁-C₄)алкил, и R³-(C₁-C₄)алкил или фенил, необязательно замещенный и содержащий от одного до трех заместителей, независимо выбранных из группы, включающей (C₁-C₄) алкил, (C₁-C₄)алкоксигруппу, галоген или трифторметил, с реагентом метенилирования для получения соединения формулы

где R¹ - R²O(C=O)- или R³(C=O)-, R²-(C₁-C₄) алкил, и R³-(C₁-C₄) алкил или фенил, необязательно замещенный и содержащий от одного до трех заместителей, независимо выбранных из группы, включающей (C₁-C₄) алкил, (C₁-C₄) алкоксигруппу, галоген или трифторметил; и
b) взаимодействие указанного соединения формулы II, полученного таким образом, с сильной кислотой.This invention also relates to a method for producing a compound of the formula:

where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl, optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen or trifluoromethyl, comprising the following steps:
a) the interaction of the compounds of formula

where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl, optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen or trifluoromethyl, with a methylation reagent to obtain a compound of the formula

where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl, optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen or trifluoromethyl; and
b) reacting said compound of formula II, thus obtained, 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 formula III) and said acetic anhydride includes 4 molar equivalents (relative to the amount of the compound of formula III).

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

и взаимодействие указанного соединения формулы VI, полученного таким образом, с бензилгалогенидом и основанием для получения соединения формулы

Предпочтительно, указанный бензигалогенид представляет собой бензилбромид. Предпочтительно указанное основание представляет собой триэтаноламин.A preferred embodiment of the present invention relates to any of the above methods, also comprising an additional step for reacting a compound of formula I, wherein R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ -C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ - C ₄ ) alkoxy, halogen or trifluoromethyl, with a hydroxide (preferably potassium hydroxide) to obtain a compound of the formula

and reacting said compound of formula VI, thus obtained, with benzyl halide and a base to produce a compound of formula

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

 A most preferred embodiment of the present invention relates to a process in which said compound of formula I is isolated before it is converted to a compound of formula VI. A compound of formula I can be isolated by adding a strongly acidic solution containing a compound of formula I to an ice / water mixture, followed by extraction with an organic solvent and distillation of the organic solvent.

включающему взаимодействие соединения формулы

с соединением формулы

в присутствии кислоты Льюиса, такой как трихлорид алюминия, в инертном реакционном растворителе, таком как метиленхлорид.This invention also relates to a method for producing a compound of the formula

comprising the interaction of a compound of the formula

with a compound of the formula

in the presence of a Lewis acid such as aluminum trichloride in an inert reaction solvent such as methylene chloride.

DETAILED DESCRIPTION OF THE INVENTION
Compounds of formula I and E2020 can be prepared as described in the following reaction scheme and discussion. Unless otherwise indicated, the compounds of formulas I, II and III, VI and VII and the groups R ¹ , R ² and R ³ in the reaction schemes and discussion that follow, take the meanings defined above.

 Scheme 1 relates to a method for producing a compound of formula I, which can be converted into a compound of formula VII, E2020, using the methods described in Scheme 2.

 Turning to Scheme 1. The compound of formula IV is commercially available and commercially available. Compounds of formula V are also commercially available or can be prepared by methods well known in the art. US patent application 08/329352, filed October 26, 1994, also relates to the preparation of compounds of formula V.

A compound of formula III can be prepared from a compound of formula IV by reacting said compound of formula IV with a compound of formula V, where R ¹ - R ² O (C = O) - or R ³ (C = O) -, R ² - (C ₁ - C ₄ ) alkyl, and R ³ - (C ₁ -C ₄ ) alkyl or phenyl optionally substituted and containing from one to three substituents independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) an alkoxy group, halogen or trifluoromethyl, in the presence of a Lewis acid in an inert reaction solvent. Preferably, R ¹ -R ² (O) (C = O) - and R ² is methyl. Suitable Lewis acids are aluminum trichloride, titanium tetrachloride or boron trichloride, preferably aluminum trichloride. Suitable inert reaction solvents are methylene chloride or dichloroethane, preferably methylene chloride. The reaction is usually carried out at a temperature of from about 0 ^o C to about 85 ^o C, preferably at about 30 ^o C.

A compound of formula II can be prepared from a compound of formula III by reacting said compound of formula III with a methylation reagent. Preferably, R ¹ - R ² O (C = O) - and R ² is methyl. Suitable methenylation reagents are tetramethyldiaminomethane in acetic anhydride, formaldehyde (about 37 wt.% In water) in diethylamine, formaldehyde (about 37 wt.% In water) in piperidine or N-methylthiomethylpiperidine. Preferably, the methylation reagent is tetramethyldiaminomethane in acetic anhydride. When tetramethyldiaminomethane in acetic anhydride is a methylation reagent, it is preferable to carry out the reaction with an excess of tetramethyldiaminomethane and acetic anhydride. Most preferably, the reaction is carried out with 4 equivalents of acetic anhydride (relative to the amount of the compound of formula III) and 2 equivalents of tetramethyldiaminomethane (relative to the amount of the compound of formula III). When the methylating reagent is different from tetramethyldiaminomethane in acetic anhydride, a solvent may be used to facilitate the reaction. Suitable solvents are acetic anhydride, ethers (e.g. diethyl ether and tetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride. The reaction is carried out at a temperature of from about 0 ^° C. to about 90 ^° C., preferably at a temperature of about 90 ^° C. The reaction time can vary from about 6 hours to about 30 hours. Preferably, the reaction time is about 12 hours.

A compound of formula I can be prepared from a compound of formula II by reacting said compound of formula II with a strong acid in a reaction inert solvent. Suitable strong acids include concentrated sulfuric acid, aluminum trichloride or concentrated hydrochloric acid, preferably concentrated sulfuric acid. When the acid is aluminum trichloride, a solvent must be used. Suitable solvents include carbon disulfide, methylene chloride or dichloroethane, preferably carbon disulfide. The reaction is carried out at a temperature of from about 0 ^o C to about 100 ^o C, preferably at about 25 ^o C.

 Scheme 2 relates to the conversion of compounds of formula I to E2020, a compound of formula VII.

Consider Scheme 2. A compound of formula I can be converted to a compound of formula VI by reaction with a strong base in the presence of a solvent. Preferably, the reagent is a compound of formula I, wherein R ¹ is R ² O (C = O) - and R ² is methyl. Suitable bases are potassium hydroxide and sodium hydroxide, preferably potassium hydroxide. Suitable solvents are lower alcohols, water or mixtures thereof, preferably a 2: 1 water / methanol mixture. The reaction is carried out at a temperature of 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.

 A compound of formula I is most preferably converted to a compound of formula VI by isolating a compound of formula I before converting it to a compound of formula VI. A compound of formula I is isolated by adding an acid solution containing a compound of formula I to an ice / water mixture and extracting the aqueous solution with an organic solvent. Suitable solvents are methylene chloride, ethyl acetate or dichloroethane, preferably methylene chloride. The organic layer can be evaporated and after that it is suitable for processing with a strong base.

A compound of formula VII can be prepared from a compound of formula VI by reacting said compound of formula VI with a benzyl halide in a reaction inert solvent. Suitable halides are chloride, bromide and iodide, preferably bromide. Suitable reaction inert solvents are diethyl ether, isopropyl ether, tetrahydrofuran, preferably isopropyl ether. The reaction is carried out at a temperature of from about 0 ^o C to about 70 ^o C, preferably at about 70 ^o C.

 The compound of formula VII can be converted into pharmaceutically acceptable acid addition salts of the compounds of formula VII. Acids that are used to prepare pharmaceutically acceptable acid addition salts of a compound of Formula VII are acids that form non-toxic acid addition salts, for example, salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates or bisulfates phosphates or acid phosphates, acetates, lactates, citrates or acid citrates, tartrates or bitartrates, succinates, maleates, fumarates, gluconates, sugars, benzoates, methanesulfonates or pamoates [for example mer, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)].

 The compounds of formula VII are basic in nature and therefore capable of forming a wide variety of different salts with various inorganic or organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, in practice it is often necessary to first isolate the compound of formula VII from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert the latter again to the free base by treatment with an alkaline reagent and then turn the free base into a pharmaceutically acceptable acid - additive salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

 The compounds of formula VII, E2020, and pharmaceutically acceptable salts thereof, can be used to treat a disease caused by acetylcholinesterase activity, such as Alzheimer's disease, in accordance with the methods described in US Pat. No. 4,895,841 of January 23, 1990.

 US Pat. No. 4,895,841 specifically states that in an in vitro experiment, the acetylcholinesterase activity of 1-benzyl-4 - ((5,6-diethoxy-1-indanone) -2-yl) methylpiperidine, E2020, or a pharmaceutically acceptable salt thereof can be determined in in accordance with the method described in the publication Ellman et al., Biochem. Pharmacol., 7, 88-95 (1961).

Inhibitory activity of 1-benzyl-4 - ((5,6-diethoxy-1-indanone) -2-yl) methylpiperidine in relation to acetylcholinesterase, determined in accordance with the method of Ellman et al., Expressed in terms of concentration causing 50% inhibition (IC ₅₀ ) is 0.0053 μM.

 Other methods for determining the activity of 1-benzyl-4 - ((5,6-diethoxy-1-indanone) -2-yl) methylpiperidine are described in US Pat. No. 4,895,841, filed January 23, 1990.

 1-Benzyl-4 - ((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine is effective in the treatment, prevention, remission, improvement, etc. various types of senile dementia, especially Alzheimer's type dementia, a cardiovascular disease accompanied by cerebral apoplexy, for example, cerebral hemorrhage or cerebral infarction, cerebral arteriosclerosis, head injury, etc .; and aprosexia, speech disorders, hypobulia, emotional changes, early memory disorders, hallucinatory paranoid syndrome, behavioral changes, etc., accompanying encephalitis, cortical paralysis, etc.

 In addition, 1-benzyl-4 - ((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine has a strong and highly selective anticholinesterase effect, which also makes the compound useful as a pharmaceutical based on the action of this species.

 In particular, 1-benzyl-4 - ((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine is effective, for example, for Huntington's chorea, Pick's desease, late ataxia or late dyskinesia different from senile dementia of the Alzheimer's type.

 When 1-benzyl-4 - ((5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine is used as a pharmaceutical for these diseases, it can be administered orally or parenterally. It is usually administered parenterally in the form of injection solutions, such as intravenous, subcutaneous and intramuscular injections, in the form of suppositories or tablets under the tongue. The dose will depend on the symptom, age, gender, weight and susceptibility of patients; route of administration; time and intervals of administration and properties, dispensing and type of pharmaceutical preparations, so that there are no special restrictions on the dose. Typically, the compound may be administered in a dose of from about 0.1 to 300 mg, preferably from 1 to 100 mg per day for an adult, usually in one to four doses.

 Pharmaceutical compositions in dosage form, for example, injectable solutions, suppositories, tablets for the tongue, tablets and capsules, are obtained in accordance with well-known methods.

 In preparing injection solutions, the active ingredient is mixed, if necessary, with a pH modifier, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent, a preservative, etc., followed by a solution for intravenous, subcutaneous or intramuscular injection in accordance with with the usual way. In this case, if necessary, it is possible to lyophilize these preparations in accordance with the usual method.

Examples of suspending agents include methylcellulose, polysorbate (Polysorbat) 80 ^®, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose and polyoxyethylene sorbitan monolaurate.

Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, (Polysorbat) 80 ^® , nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol (Macrogol ^® ) and castor oil fatty acid ethyl ester.

 Examples of stabilizers include sodium sulfite, sodium metasulfite and ether, and examples of preservatives include p-hydroxybenzoic acid dimethyl ether, p-hydroxybenzoic acid ethyl ester, sorbic acid, phenol, cresol and chlorocresol.

The following Examples illustrate the preparation of the compounds of this invention and the preparation of E2020. Commercial reagents were used without further purification. Melting points are uncorrected. NMR data are given in parts per million (ppm) (δ) and relate to the deuterium local signal of the solvent sample obtained on a Bruker 300 MHz instrument. D ₂ O refers to deuterium oxide. CDCl ₃ refers to deuterochloroform. Chromatography, unless otherwise indicated, refers to silica gel column chromatography with a particle size of 32-63 μm and under nitrogen pressure (flash chromatography). Thin layer chromatography (TLC) was performed on silica gel plates (E. Merck, Kiesel Gel 60 F254), eluting with a specially selected solvent. HPLC (High Pressure Liquid Chromatography) was performed on an LDC Analytical constaMetric ^® 3200 HPLC instrument (Thermo Separation Products Co.). Used for the analysis column ^{A Zorbax ® C8, 60A, 3.9} • 150 mm (manufactured by Mac-Mod Analytical, Inc, Chadds Ford, PA 19317); elution was performed with the indicated solvent. FIBMS-type mass spectrometry (FABMS) was performed on a Hewlett-Packard mass spectrometer ((Hewlett-Packard) 5989 (beam chemical ionization of particles). The room temperature was 20-25 ^o C.

Preparative example 1
3-pyridin-4-ylpropen-2-oic acid
To a solution of pyridin-4-ylcarboxaldehyde (100 g, 0.93 mol) in pyridine (100 ml) was added malonic acid (100 g, 0.96 mol) at 90 ^° C. After the evolution of carbon dioxide (CO ₂ ) ceased, the reaction suspension diluted with methanol. The target compound was isolated by filtration as a white solid (97 g, yield 70%).

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

Preparative example 2
3-piperidin-4-ylpropanoic acid
The product of Preparative Example 1 (32 g, 0.22 mol) was dissolved in 2 N hydrochloric acid (150 ml) and treated with 10 (wt.) Percent 5% rhodium on carbon under a hydrogen atmosphere of about 3 kg / cm ² (45 psi ) until hydrogen uptake ceases. The catalyst is filtered off and the resulting solution of the target compound is used directly in the next step.

NMR (D ₂ O) 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.

Preparative example 3
3- [N- (Methoxycarbonyl) piperidin-4-yl] propionic acid
The pH of the solution of the product of Preparative Example 2 was adjusted to 12 with aqueous potassium hydroxide. Methyl chloroformate (21 ml, 0.27 mol) was added to this solution. After one hour, the pH of the solution was adjusted to 1 with 6 N hydrochloric acid and extracted with dichloromethane. The organic fraction was dried with sodium sulfate and dichloromethane was replaced with isopropyl ether. The target compound is isolated as a solid by filtration (39 g, 84%).

T. pl. 89-90 ^o C. PMR (CDCl ₃ ) δ 4.10 (m, 2H), 3.65 (s, 3H), 2.70 (m, 2H), 2.35 (t, 2H), 1, 80-1.10 (m, 7H). FABMS (M + 1) ⁺ = 216.

Example 1
4- (2-Chlorocarbonylethyl) piperidine-1-carboxylic acid methyl ester
To a solution of the product of Preparative Example 3 (54.0 mg, 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 is complete, the formation of the title product is complete. A solution of the title product is used directly in the next step.

Example 2
4- [3- (3,4-Dimethoxyphenyl) -3-oxopropyl] methyl-piperidine-1-carboxylic acid methyl ester
To the solution of the product from Example 1 at room temperature, 1,2-dimethoxybenzene (25.5 ml, 0.20 mol) was added, followed by portionwise addition of aluminum trichloride (100 g, 0.75 mol). The reaction mixture was stirred for 4 hours at room temperature. Control the completeness of the reaction by HPLC until it is complete. The reaction was quenched by careful addition of water and then extracted with methylene chloride (2x500 ml). The combined organic extracts were washed with water with 1 N sodium hydroxide (200 ml), then brine (200 ml). Finally, the organic fraction is dried over sodium sulfate. The solution was filtered and the solvent was removed in vacuo to give an oil (67 g, weight of crude product). Analysis by TLC and high pressure chromatography (HPLC) shows that the product is of sufficient purity to be used directly in the next step.

The progress of the reactions and the purity of the products are monitored by TLC and HPLC using the following systems: (R _f and t _r are given for the reaction product):
TLC (silica gel): R _f = 0.50 (40:60 hexane / ethyl acetate). The retention time for HPLC (t _r ) is 12.6 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid). ₁ H-NMR (CDCl ₃ ) 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), 1.61-1.76 (m, 4H), 1.40-1.55 (m, 1H), 1.06-1.21 (m, 2H). FABMS C ₁₈ H ₂₅ NO ₅ (M + 1) ⁺ = 336.

Example 3
4- [2- (3,4-Dimethoxybenzoyl) -allyl] piperidine-1-carboxylic acid methyl ester
Acetic anhydride (76.0 ml, 0.80 mol) was added to the solution of the product from Example 2 (66.0 g, 0.20 mol), followed by treatment with tetramethyldiaminomethane (54 ml, 0.40 mol). The reaction is exothermic and the temperature rises to 90 ^o C. After the temperature stops rising, the reaction mass is heated to 90 ^o C and maintained at this temperature for three hours, and then left to mix overnight at room temperature.

 An aliquot (1 ml) was taken from the reaction vessel and treated with chilled hydrochloric acid. The solution was extracted with methylene chloride, followed by treatment with aqueous bicarbonate. The organic fraction was dried and analyzed by HPLC, which showed that the starting material was consumed.

 Based on the purity of the technical reaction mixture, the technical reaction product is used directly in the next step.

TLC (silica gel): R _f = 0.60 (40:60 hexane / ethyl acetate). The retention time determined by HPLC (t _r ) is 15.9 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid). ₁ H-NMR (CDCl ₃ ) 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 ₁₉ H ₂₅ NO ₅ (M + 1) ⁺ = 348.

Example 4
4- (5,6-Dimethoxy-1-oxoindan-2-ylmethyl) piperidine-1-carboxylic acid methyl ester
The crude reaction mixture from Example 3 (0.20 mol) is treated with concentrated sulfuric acid (100 ml) at 0 ^° C. Then the reaction mass is stirred overnight at room temperature, after which analysis by HPLC indicates that the reaction is complete. The reaction was quenched by pouring a mixture into 1 kg of ice, and the aqueous phase was extracted with methylene chloride (2x500 ml). The combined organic extracts were washed with 500 ml of water, 500 ml of 1 N sodium hydroxide, 500 ml of brine, dried over sodium sulfate and the volatile components were distilled off in vacuo. The oily solid is then triturated with 500 ml of isopropyl ether, the product is filtered off to give 46.5 g (68% dimethoxybenzene, 88% per step) of the target compound as a yellow solid.

TLC (silica gel) R _f = 0.40 (40:60 hexane / ethyl acetate).

The retention time (t _r ) is 10.1 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid). ₁ H-NMR (CDCl ₃ ) δ 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 C ₁₉ H ₂₅ NO ₅ (M + 1) ⁺ = 348.

Example 5
5,6-Dimethoxy-2-piperidin-4-ylmethylindan-1one
To a solution of the product from Example 4 (5.0 g, 14.4 mmol) in methanol (40 ml) was added potassium hydroxide (4.9 g, 87 mmol) dissolved in 80 ml of water. The mixture is then heated under an atmosphere of nitrogen and incubated overnight, after which analysis by HPLC shows that the starting product has been consumed. The aqueous phase is extracted with methylene chloride (3 x 50 ml), the combined organic fractions are dried with sodium sulfate, the volatile components are distilled off under vacuum, and 3.30 g (79%) of the target compound are obtained in the form of a solid. This product is used without further purification.

The retention time (t _f ) is 2.45 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid). ₁ H-NMR (CDCl ₃ ) δ 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 C ₁₇ H ₂₃ NO ₃ (M + 1) ⁺ = 290.

Example 6
2- (1-Benzylpiperidin-4-ylmethyl) -5,6-dimethoxyindan-1-one
To a suspension of the target compound from Example 5 (1.82 g, 6.3 mmol) in isopropyl ether (60 ml) was added benzyl bromide (0.75 ml, 6.3 mmol) and triethanolamine (940 mg, 6.3 mmol). The suspension is stirred overnight at a temperature of 70 ^o C, after which the analysis by HPLC shows that the starting material is mostly consumed. The reaction mixture was filtered to remove precipitated triethanolamine hydrobromide. To the resulting solution was added ether saturated with hydrochloric acid (1.0 ml, 12 mmol), and the solvent was distilled off in vacuo. The residue was dissolved in 20 ml of warm isopropanol and allowed to cool to room temperature. The precipitated solid precipitate was filtered, resulting in 1.60 g (61%) of the target compound as a white solid.

TLC (silica gel): R _f = 0.60 (90:10 methylene chloride / methanol); retention time determined by high pressure liquid chromatography = 6.01 min (Zorbax C ₈ , 254 nm, 1 ml / min, eluent 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid). 1 H-NMR (free base, DMSO-d ₆ ) δ 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 C ₂₄ H ₂₉ NO ₃ (M + 1) ⁺ = 380.

Claims (15)

1. The compound of formula III

where R ¹ represents R ² O (C = O) -;
R ² is O (C ₁ - C ₄ ) alkyl. 2. The compound of formula II

where R ¹ represents R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl. 3. The compound of formula I

where R ¹ represents R ² O (C = O) -;
R ² is methyl. 4. The method of obtaining the compounds of formula I

where R ¹ represents R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
including
a) the interaction of the compounds of formula III

where R ¹ - R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
with a methylation agent to obtain a compound of formula II

where R ¹ - R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
b) reacting the obtained compound of formula II with a strong acid.  5. The method according to claim 4, characterized in that said methylation agent is tetramethyldiaminomethane in acetic anhydride.  6. The method according to claim 5, characterized in that tetramethyldiaminomethane and acetic anhydride are added in excess.  7. The method according to claim 6, characterized in that the amount of tetramethyldiaminomethane is 2 equivalents and the amount of acetic anhydride is 4 equivalents.  8. The method according to claim 4, characterized in that sulfuric acid is used as a strong acid.  9. The method of claim 8, wherein the sulfuric acid is concentrated sulfuric acid.  10. The method according to claim 9, characterized in that the amount of concentrated sulfuric acid is 9 equivalents. 11. The method of obtaining the compounds of formula VII

including
a) the interaction of the compounds of formula

where R ¹ - R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
with a methylation agent to obtain a compound of formula II

where R ¹ - R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
b) reacting the obtained compound of formula II with a strong acid to obtain a compound of formula I

where R ¹ represents R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
c) reacting the obtained compound of formula I with a hydroxide to obtain a compound of formula VI

d) reacting the obtained compound of formula VI with a benzyl halide to obtain a compound of formula VII

12. The method according to claim 11, wherein the benzyl halide is benzyl bromide.  13. The method according to claim 11, characterized in that the base is triethanolamine.  14. The method according to claim 11, characterized in that the compound of formula I is isolated by adding a strongly acidic solution to a mixture of ice water, followed by extraction with an organic solvent and removing the organic solvent before treating the compound of formula I with a base. 15. The method of obtaining the compounds of formula III

R ¹ represents R ² O (C = O) -;
R ² - (C ₁ - C ₄ ) alkyl,
comprising reacting a compound of formula IV

with a compound of formula V

where R ¹ takes the values defined above,
in the presence of a Lewis acid in an inert solvent.  16. The method according to clause 15, wherein the Lewis acid is aluminum trichloride and an inert solvent is dichloromethane.