SK75498A3 - Processes and intermediates for preparing 1-benzyl-4-((5,6- -dimethoxy-1-indanon)-2-yl)methylpiperidine - Google Patents

Abstract

The present invention relates to a process for preparing a compound of formula (I), wherein R<1> is R<2>O(C=O)- or R<3>(C=O)-, R<2> is (C1-C4)alkyl, and R<3> is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, comprising: a) reacting a compound of formula (III), wherein R<1> is R<2>O(C=O)- or R<3>(C=O)-, R<2> is (C1-C4)alkyl, and R<3> is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl, with a methenylation agent to form a compound of formula (II), wherein R<1> is R<2>O(C=O)- or R<3>(C=O)-, R<2> is (C1-C4)alkyl, and R<3> is (C1-C4)alkyl or phenyl optionally substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, halo or trifluoromethyl and; b) reacting said compound of formula (II), so formed, with a strong acid. The present invention further comprises the additional step of reacting the compound of formula (I) with hydroxide to form a compound of formula (VI), and reacting said compound of formula (VI) so formed with a benzyl halide and a base to form a compound of formula (VII). The present invention relates also to the novel intermediates of formulae (I), (II) and (III).

Description

Methods and intermediates for the preparation of 1-benzyl-4- (C5, S-dimethoxy-1-indanone) -2-yl) methylpiperidine

Area, techniques

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 1-benzyl-4- ((6,6-dimethoxy-1-indanon) -2-yl) methylpiperidine (E2020), a compound of formula VII below and novel intermediates therefor.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,895,841, issued Jan. 23, 1990, relates to 1-benzyl-4-CC 5,6-dimethoxy-1-indanone-2-yl) methylpiperidine, methods and intermediates therefor, methods of treatment and pharmaceutical compositions for the treatment of diseases caused by acetylcholine esterase activity such as senile dementia. This patent is incorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula III

\

Oľle c III)

Orie

R ¹ is R ^and C (C = C) - or R ³ (C = O) -;

R ² is an alkyl group having from 1 to 4 carbon atoms; and

R ²⁵ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, and trifluoromethyl.

The invention further provides a compound of the general formula

II

C II) where

R ^{@ 1} represents R @ 8 ^R @ 8 C = [J] - or R @ ³ CC = O @ 1 -;

R ²² is C 1 -C 4 alkyl; and

R ²⁵ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, and trifluoromethyl.

The present invention also provides a compound of formula I (I) wherein

R ¹ is R ^and OCC = CD- or R ^J (C = O) -;

R * is C 1 -C 4 alkyl; and

R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, and trifluoromethyl.

The present invention also provides a process for the preparation of a compound of formula I

¢ 1) where

R ¹ is R ^{I 2} = 0 DEG C. 0) - or ^R3 (C = O) -;

R ^p is alkylskuplnu 1 -C 4 alkyl; and

R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, and trifluoromethyl.

the essence of which is that

a) reacting a compound of formula III

R ¹

CIII) where

R ¹ is R (O (O) 2) - or R ³ (C = O) -;

R ^f is C1 -C4 alkyl; and

R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl;

with a methylene reagent to give a compound of formula II

where:

R ¹ represents: R ⁵ O (O = O) - or R ³ (C = O) -;

(II)

R ^f is C 1 -C 4 alkyl; and

R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl; and

b) reacting the compound of formula II so produced with a strong acid.

The methylene reagent is preferably tetramethyldiaminomethane in acetic anhydride. In a more preferred embodiment, said tetramethyldiaminomethane and acetic anhydride are added to the reaction mixture in excess.

Even more preferably, the amount of tetramethyldiaminomethane added is 2 molar equivalents (relative to the amount of the compound of formula III) and the amount of acetic anhydride is 4 molar equivalents of C relative to the amount of the compound of formula

III).

Sulfuric acid, more preferably concentrated sulfuric acid is preferred as a strong acid. In an even more preferred embodiment, the amount of concentrated sulfuric acid is 9 molar equivalents (based on the amount of compound of formula II).

In a preferred embodiment, the present invention provides any of the above methods, further comprising an additional step.

wherein the compound of formula I, wherein R ¹ is a group. R ^and O (C = O) - or R ³ (C = O) -; R ^p is C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted by one to C 1 -C 3 alkoxy C 1 -C 4 alkyl independently selected from carbon, carbon, halogen and trifluoromethyl, reacted with hydroxide ( preferably potassium hydroxide) to form a compound of formula VI

and the compound of the formula thus formed

VI is reacted with a benzyl halide and a base to give a compound of formula VII

C VII)

Benzyl halide is preferably benzyl bromide and the preferred base is triethanolamine.

In a most preferred embodiment, the present invention provides a process wherein the compound of formula I is isolated prior to its conversion into a compound of formula VI. The compound of formula I may be isolated by adding a strongly acidic solution containing the compound of formula I to an ice / water mixture and extracting the resulting mixture with an organic solvent, which is then removed.

The invention further provides a process for the preparation of a compound of formula III

R ¹

III) wherein the compound of formula IV

CIV) is reacted with a compound of formula V

CV) in the presence of a Leuis acid such as aluminum chloride in a reaction inert solvent such as methylene chloride.

A detailed description of the invention follows.

The compounds of the general formula can be prepared according to the procedures illustrated in U.S. Pat

The following reaction reactions are possible

and described in CLAL something mentioned others have in these compounds so formulas I, II and III,

VI and VII and the reaction scheme groups discussed above.

the above meaning.

If not, and discuss

R ¹ , R ²² and R ³

S c h e 'm a 1

Scheme 1 illustrates a process for preparing a compound of formula I which can be converted to a compound of formula VII, i.e., compound E2020, as shown in Scheme 2.

The following is a more detailed description of the procedure of Scheme 1: Compounds of formula IV are commercially available. Compounds of formula V are also commercially available or can be prepared by methods well known to those skilled in the art. The preparation of compounds of formula V is also directed to LIS patent application 08 / 329,352 filed October 26, 1994.

A compound of formula III can be prepared from a compound of formula V by reacting a compound of formula VI with a compound of formula V, wherein: R ¹ is R ^2: 0CC = O) - or R ³ CC = O>-; R ' ² is: C 1 -C 4 alkyl, carbon; and R ^a is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, and trifluoromethyl, in the presence of a Lewis acid in an inert solvent against this reaction. R ¹ preferably represents: R ² O (C = O) - and R 1 · ² preferably represents methyl. Suitable Lewis acids include aluminum chloride, titanium tetrachloride or boron trichloride, preferably aluminum chloride. Suitable reaction-inert solvents include methylene chloride or dichloromethane, preferably methylene chloride. The reaction is generally carried out at a temperature of from about 0 to about 85 ° C, preferably at about 30 ° C.

Compounds of formula II It is possible to prepare compounds of formula III by reacting a compound of formula III with a methylene reagent. R ^{1 is} preferably R ² O (C = O) - and R 1 is preferably methyl. Suitable methylening agents include tetramethyldiaminonethane in acetic anhydride, formaldehyde C about 37% by weight. in water) in diethylamine formaldehyde (about 37 wt.% in water) in piperidine or N-methylthionethylpiperidine. As the methylene reagent,

The tetradiamine uses ethane in acetic anhydride. When tetramethyldiaminomethane in acetic anhydride is used as the non-eluting agent.

The process is carried out using a process such as methacrylate and acetarihydride. Most preferably, the reaction is carried out using equivalents of acetic anhydride C relative to the amount of the compound of formula III) and 2 equivalents of tetramethyldiaminomethane

If a system other than tetramethyldianrine methane in acetic anhydride is used when the methylene reagent is used, solvents may be used to facilitate the reaction. Suitable solvents include acetic anhydride, ethers (e.g. diethyl ether and tetrahydrofuran), methanol, acetic acid or dioxane, preferably acetic anhydride. The reaction is carried out at a temperature of from about 0 to about 90 ° C, preferably at about 90 ° C, for about (5 to 30 hours, preferably about 12 hours).

Compounds of formula (I) It is possible to prepare compounds of formula (II) by reacting a compound of formula (II) with a strong acid in a solvent inert to the reaction. Suitable strong acids include concentrated sulfuric acid, aluminum chloride, and concentrated hydrochloric acid, preferably concentrated sulfuric acid. If aluminum chloride is used as the acid, solvents must also 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 100 ° C to about 100 ° C, preferably at about 25 ° C.

Scheme 2 shows the conversion of compounds of formula I to compound E2020, i.e. a compound of formula

Compounds of Formula I. It is possible to convert to a compound of Formula VI by reaction with a strong base in the presence of a solvent. In the reaction, the preferred compound of formula I, wherein R ¹ is R ^a OCC = O) -, and R ^a is metylskupíriu. Suitable bases include potassium hydroxide and sodium hydroxide, potassium hydroxide being preferred. Suitable solvents are, for example, lower alcohols, water or mixtures thereof, preferably a 2: 1 mixture of water and methanol. The reaction is carried out at a temperature of from about 25 to about 100 ° C, preferably at room temperature. about 100 ° C. The reaction time may vary from about. 6 to about 24 hours and preferably is about 18 hours.

The compounds of formula I are most preferably converted to a compound of formula VI by isolating the compound of formula I prior to conversion to the compound of formula VI. This isolation is carried out by pouring the strongly acidic solution containing the compound of formula I into an ice / water mixture and extracting the aqueous mixture with an organic solvent. Suitable solvents include methylene chloride, ethyl acetate and dichloroethane, preferably methylene chloride. The organic layer can be concentrated and the residue then suitable for reaction with a strong base.

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

The compound of formula VII can be converted to its pharmaceutically acceptable acid addition salts. Acids which form non-toxic addition salts, for example those containing pharmacologically acceptable anions, are used to produce pharmaceutically acceptable acid addition salts of the compound of formula VII. Examples of such salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or hydrogen sulfate, phosphate or hydrogen phosphate, acetate.

Lactate, citrate or hydrogen citrate, tartrate or hydrogelates: tartrate, sulphate, maize, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate means 1,1'-methylenebis (2-hydroxy-3-naphthoate) salts.

The compound of formula VII is basic in nature and is thus capable of forming many different salts with various inorganic and organic acids. Although these salts must be pharmaceutically suitable for administration to animals, it is in practice formula VII

Isolate from the reaction mixture first in the form of a pharmaceutically unsuitable salt and then convert it into the free base by treatment with an alkaline agent. The free base thus obtained is then converted into a pharmaceutically acceptable acid addition salt. Acid addition salts which form the basic compounds of the invention. They can be readily prepared by reacting the basic compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

The compound of formula VII E2020 and pharmaceutically acceptable salts thereof are useful for the treatment of diseases caused by acetylcholinesterase activity, such as Alhzheimer's disease, as described in US Pat. No. 4,895,841, issued Jan. 23, 1990.

In particular, U.S. Pat. No. 4,895,841 states that the in vitro activity of 1-benzyl-4-CC 5,6-dimethoxy-1-indanone-2-yl) methylpiperidine, E2020, or pharmaceutically acceptable salts thereof, and cholinesterase can be determined as described in Ellman et al., Biochem. Pharmacol. 7, 88-95 (1961).

Inhibitory activity of 1-benzyl-4 - ((5,6-dimethoxy-1-indanone) -2-ylmethylplperidine) on acetylacholinesterase as determined by the method described in Ellman et al., Expressed as 50% inhibitory concentration of CIC ₅₀ ), is 0.0053 µl. * 1.

Other methods for determining the efficacy of 1-benzyl-4-CC (5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine are described in U.S. Patent 4,895,841, issued January 23, 1990.

1-Benzyl-4-C (5,6-dimethoxy-1-indanone-2-yl) methylpiperidine is an active compound for the treatment, prevention, remission and amelioration of the condition, etc. various types of senile dementia, in particular the enema dementia of the Alzheimer type; cerebrovascular diseases, including cerebral haemorrhage or cerebral infarction.

cerebral arteriosclerosis, head injury, etc .;

aprosexia speech disturbances, emotional change hypobulia, short-term memory disorders of hallucinatory-paranoid behavioral change syndrome, etc.

accompanying encephalitis, cerebral palsy, etc.

Furthermore, 1-Benzyl-4-C (5,6-dimethoxy-1-indanone) -2-yl) methylpiperidine exhibits potent and highly selective anticholinesterase activity, which also makes the compound useful as a drug based on this type of activity.

1-Benzyl-4-C (5,6-dimethoxy-1-indanone-2-yl) methylpiperidine It is particularly effective, for example, in the treatment of Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskinesia and other senile dementia than the Alzheimer's type.

When 1-benzyl-4-CC 5,6-dimethoxy-1-indanone-2-yl) methylpiperidine is used as a medicament for the treatment of these diseases, it can be administered orally or parenterally. This compound is usually administered parenterally in the form of injections, such as intravenous, subcutaneous and intramuscular injections, or in the form of suppositories or sublingual tablets. The doses administered will vary depending on the symptoms; the age, sex, weight, and sensitivity of the patient; by the route of administration; from the time and intervals of administration and the properties, preparation and type of the pharmaceutical composition, with no particular restrictions on the dose. Typically, the compound may be administered to an adult at a dose of from about 0.1 to about 300 mg, preferably from about 1 to 100 mg / day, usually in multiple doses.

Pharmaceutical compositions in dosage forms such as injections, suppositories, sublingual tablets, tablets and capsules. They can be prepared by procedures conventional in the art.

In the preparation of injections, the active ingredient is mixed, if necessary, with a pH modifying agent, a buffer, a suspending agent, a solubilizer, a tonicity adjusting agent, a preservative, and the like. and then intravenous, subcutaneous or intramuscular injections are prepared by a conventional procedure. If necessary, these preparations may be lyophilized by conventional means.

Examples of suspension agents include methylcellulose, Polysorbate 8 O ^'A>, hydroxyetylacelulózu, gum arabic, powdered tragacanth, sodium salt. carboxymethylcelluloses and polyoxyethylene sorbitan monolaurate.

Examples of solubilizers include polyoxyethylene hydrogenated castor oil, Polysorbate 80 ^R , nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, and castor oil fatty acid ethyl ester.

Examples of stabilizers include sodium sulfite, sodium metabisulfite and ether, and examples of preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

The following examples illustrate a process for the preparation of compounds of the invention and compound E2020. These examples are illustrative only and the scope of the invention is not limited in any way.

Commercially available reagents were used without further purification. The melting points indicated are uncorrected. NMR data are reported in parts per million (δ) and are based on the deuterium encoded signal from the sample solvent and were obtained on a Bruker 300 ΙΊΗζ instrument. The abbreviation D _Ä 0 denotes deuterium dioxide and the abbreviation CDCl ₃ deuterochloroform. Unless otherwise stated, chromatography refers to silica gel column chromatography (flash chromatography). Thin Layer Chromatography (TLC) refers to silica gel plate chromatography (E. lckck, Kiesel Gel 60 F254) using the indicated solvent. High pressure liquid chromatography (UPLO) was performed on an LDC

Analytical Constal * ^R '3200' UPLO (Thermo Separation Products

What. ). A Zorbax ' ^H ' C8, 6 nm, 3.9 x 150 mm column (t * lac-1 * from Analytical, Inc., Chadds, Ford, PA, 19317, USA) was used for the HPL.C analysis using the elution elution indicated. agents. Mass spectroscopic analysis was performed by a fast atom bombardment (FABI * 1S) method on a Hewlett-Packard 59EJ9 lasslass Spectrometer (chemical ionization by a corpuscular beam).

Room temperature refers to a temperature of 20 to 25 ° C.

DETAILED DESCRIPTION OF THE INVENTION

P r e p a r a th e v y u p 1

3-Pyridin-4-yl-propen-2-enoic acid

To a solution of pyridin-4-ylcarboxaldehyde (100 g, 0.93 mol) in pyridine (100 mL) at 90 ° C was added malonic acid (100 g, 0.96 mol). After the development of carbon dioxide (CO ₂ ) ceases, the reaction is carried out

the suspension is diluted methanol. filtration the compound is isolated in the title (97g, 70% yield) in shape white solid substances. ^X H (IR (EtOAc)): 6 11.70 (s, 1H), 8.85 (d, 2H) 7.95 (d, 2H). 7.70 (d, 1H); 6.90 (d, 1 H)

P r e p a r a th e v y s s p p

3-Piperidin-4-yl-propanoic acid

The product from Preparative Procedure 1 (32 g, 0.22 mol) was dissolved, for 2ΙΊ hydrochloric acid (50 ml). The resulting solution was hydrogenated at 10 psi (10 psi) on hydrogen until a hydrogen uptake was complete. The catalyst was filtered off and the resulting solution of the title compound was used directly in the next step.

^X H NMR CD _& O): 8 3.25 m, 2H), 2, 80 m, 2H), 2.25 t, 2H), 1.75

(M, 2H), 1.50-1.10 (m, 5H). FABMS C, 1 * 1 + 1) * = 157

P r e: p a r t th e p o s p 3

3-CN (methoxycarbonyl) piperidin-4-yl-propionic acid

The product solution from Preparation 2 was basified to pH 12 with aqueous potassium hydroxide and methyl chloroformate (21 mL, 0.27 mol) was added. After 1 hour, the resulting 6ΙΊ hydrochloric acid solution was acidified to pH 1 and extracted with dichloromethane. The organic layer was dried over sodium sulfate and the dichloromethane was replaced with isopropyl ether. Filtration gave the title compound as a solid (39 g, 83%), mp 89-90 ° C.

@ ₁ H NMR (CDCl3) .delta. Δ 4.10 (m, 2H), 3.65 (c, 3H), 2.70 (m, 2H), 2.35

(M, 2H), 1.80-1.10 (m, 7H). FABMS CM + 1) * = 216

Example 1

4-C2-Chlorocarbonylethyl) -piperidine-1-carboxylic acid methyl ester

To a solution of the product from Preparation 3 (54 g, 0.251 mol) in dichloromethane (500 ml) was added dimethylformamide (0.39 ml, 0.02 equiv) and oxalyl chloride (22 ml, 0.26 mol). . After gas evolution ceases, formation of the title compound is complete. The resulting solution of the title compound was used; directly in it with 1 e d u s s t u p n i.

Example 2

4-E3- (3,4-Dimethoxyphenyl) -3-oxo-propyl] -piperidine-1k methyl ester of methyl acid

To a solution of the product of Example 1, 2b, 5 ml (0.20 mol) of 1,2-dimethoxybenzene was added at room temperature, followed by portionwise aluminum chloride (100 g, 0.75 mol). The reaction mixture was stirred at room temperature for 4 hours. Analysis by high pressure liquid chromatography showed that the reaction was complete. Quench the reaction by carefully adding water and extract the aqueous mixture with methylene chloride (2 x 500 mL). The combined organic extracts were washed with 1M sodium hydroxide (2.00 ml) and then with aqueous sodium chloride solution (2.00 ml). Finally, the organic layer is dried over sodium sulfate. The resulting solution was filtered and the solvent was removed from the filtrate under reduced pressure. An oil (¢ 67 g, quantitative yield of crude product) is obtained. Analysis by thin layer chromatography (11.0) and high pressure liquid chromatography (PLC) showed that the product was of sufficiently satisfactory purity to be used directly in the next step.

The progress of the reaction and the purity were monitored by both thin layer chromatography and high pressure chromatography using the following ¢R systems. _f at _r . for reaction product):

TLC (silica gel): Rf = 0.50 ¢ 40: 60 hexane / ethyl acetate). The retention time of _r Ct.) At a high pressure liquid chromatography was 12.6 min (Zorbax, 08, 254 nm, 1 mL / rnin, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

First 1 H NMR ¢ 0001 ^): 8 7, 55 ¢ dd 1 H, J = 8, 4 0 Hz), 7, 50 ¢ d, 1H, J = 2.0 Hz), 6.86 ¢ d, 1H, J = 8.4 Hz) , 4, 02 - 4, 20 ¢ m, 2.H) 3, 92 ¢ s, 3H), 3.91 s, 3H), 3, E > 5 ¢ 3, 3 H), 2, 93 T, 2H, J = 7, 3 Hz); 2 , 64-2.78 (m. 2H), 1.61 - 1.76 ¢ 01 , 4H), 1, 4é - 1, 55 Rome, 1H), 1 "06 - 1, 21 µm, 2H). FABMS C _ls H _as NQ _p ¢ ^ -1) - = 336

Example 3

4-L 2- (3,4-Dimethoxybenzoyl) allylpiperidine-1k methylbenzoylmethyl ester

To a solution of the product of Example 2 (63.0 g, 0.20 mol) was added acetic anhydride (76.0 mL, 0.80 mol) followed by tetramethyldiaminomethane (54 mL, 0.40 mol). The temperature of the reaction mixture was raised to 90 ° C by an exothermic reaction. After the exothermic reaction subsided, the reaction mixture was heated at 90 ° C for 3 hours and then stirred at room temperature overnight.

An aliquot (<1 mL) of the reaction mixture was removed from the reaction vessel and mixed with cold hydrochloric acid. The resulting solution was extracted with methylene chloride and treated with aqueous bicarbonate.

The organic layer was dried.

and analyzed by high pressure liquid chromatography to show that all of the starting material was consumed.

Because of the purity of the crude reaction mixture, the crude product is used directly in the next step.

TLC <silica gel): R _f = 0.60 <40:60 hexane / ethyl acetate).

HPLC retention time (t _r ) 15.9 min (Zorbax, 08, 254 nm, 1 mL / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

NMR CCDCls ^X): 6 7.35 to 7.40 <m, 2 H), 6.83 <d, 1 H), J = 8, 8 Hz);

5, 68 (s, 1H), 5.54 (s, III), 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, 1H), 1.55 - 1.75 (m, 3H), 1, 00-1 .21 <m, 2H). FABMS C ₁₉ H ₂ NO ₂ <M + 1) * = 348 P r í k 1 a d 4

4- (2,6-Dimethoxy-1-oxoindan-2-ylmethyl) piperidine-1-carboxylic acid methyl ester

The crude reaction mixture of Example 3 (0.20 mol) was added at rt. 0 ° C was added with concentrated sulfuric acid (100 ml). The reaction mixture was stirred at room temperature overnight and then subjected to HPLC analysis to indicate that the reaction was complete. The reaction mixture is quenched by pouring onto 1 kg of ice and the aqueous phase is then extracted with methylene chloride (2 x 500 mL). The combined organic extracts were washed with 500 ml of water, 500 ml of 11% sodium hydroxide and 500 ml of aqueous sodium chloride solution, dried over sodium sulfate and the volatiles were removed under reduced pressure. The oily solid was then triturated with 500 mL of isopropyl ether and the product collected by filtration. It will be obtained

40.5 g (68% of dimethoxybenzene, 88% yield based on this step) of the title compound as a yellow solid.

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

Retention time _(R t.) For high pressure liquid chromatography, is 10.1 min (Zorbax, 08, 254 nm, 1 mL / inin, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

^X 1 HNMR (CDCl _3): 8 7.15 (s, 1H), 6.85 (s, 1H), 4.08 to 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): 1 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 Ci ₉ H _{2 S} NO ₅ (M + D *) - 348

Example

5,6-Dimethoxy-2-piperidin-4-ylmethylindan-1-one

To a solution of the product of 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 reaction mixture was heated under nitrogen atmosphere overnight. HPLC analysis showed that the starting material was consumed. The aqueous phase was extracted with methylene chloride (3 x 50 mL). The combined organic layers were dried over sodium sulfate and the volatiles evaporated under reduced pressure. Thus, 3.30 g (79%) of the title compound are obtained as a solid. This product does

It is further elaborated.

The retention time Ct _r ) in high pressure liquid chromatography is 2.45 min Corbax, C8, 254 nm, 1 ml / min,

500: 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 (s, 3H) dd, 1H, J = 17.7, 8.2 Hz), 3.00-3.13 (m, 2H), 2.52-2.17 Cm, 4H), 1.70-1.94 (m (1H), 1.51-1.80 cm3, 3H), 1.02-1.35 cm3, 3H). FABFIS C ₁₇ H ₂₃ NO _{3 (} MH +) = 290

Example 1 a d 6

2- (1-Benzylpiperidin-4-ylmethyl) -5,6-dimethoxyindan-1-one

To a suspension of the title compound of Example 5 (1.82 g, 6.3 mmol) in isopropyl ether (60 mL) was added benzyl bromide (75 mL, 6.3 mmol) and triethanolamine (940 mg, 6.3 mmol). The resulting suspension was stirred at 70 ° C overnight. Analysis by high pressure liquid chromatography showed that most of the starting material was consumed. The reaction mixture is then filtered to remove the precipitated triethanolamine hydrobromide. To the resulting solution was added ether saturated with hydrogen chloride (0 mL, 12 mmol). The solvent was removed under reduced pressure and the residue was dissolved in 28 ml of hot isopropyl alcohol. The resulting solution was allowed to cool to room temperature and the precipitated solid was collected by filtration. The title compound was obtained as a white solid (1.60 g, 61%).

Csilikagél TLC): R _f = 0.60 C 90/10 methylene chloride / methanol). The retention time (tl) on high pressure liquid chromatography is: 6.01 min (max (08, 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid)).

³ H NHR Free base, DNSO-d *): δ 7.06 (s, 1H), 7.03 (s, 1H), 3.84

C s, 3H); 3 77 C s, 3H); 3, 41 C s, 2H), 3 19 C dd. 1H, J - 17, 8, 8, z Hz); 2, 71 - 2, 86 cm. 2H); 2, 58 - 2, 71 cm. 2H); 1, 82 - 1, 96 cm. 2H); 1, 52 - 1, 78 C m, 3H); 1, 31 - 1, 50 C m. 1H), 1, 08 - 1, 30 C m,

3H). FABMS C _{± 4 p} ^ H NO ₃ (M + 1) + = 380

7?

Claims (14)

A compound of formula III R ¹ CIII) where R ¹ is R ² O (C = O) - or R ³ (C = O) -; R ^f is C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl. A compound of formula II wherein R ¹ is R ^{2 (} C ⁽ C ⁾ C = O> - or R ^{3 (} C = O) -; R ² is C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl. 3. A compound of formula I (() R ¹ is R ⁵ OC (C = C) - or R ³ (C = O) -; R ^1-2 is C 1 -C 4 alkyl; R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl. A process for producing a compound of formula I wherein R ¹ is R ² O (C = O) - or R ³ (C = O) -; R ² is C 1 -C 4 alkyl; and R ²⁵ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl, characterized in that: a) reacting a compound of formula III R ¹ C III) where R ¹ represents R ² O (C = O) - or R ³ CC = C 1 -; R ^a is: C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted by one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy. halogen and trifluoromethyl; with a methylene reagent to give a compound of formula II CII) where R ^x is R = ^R OCC CJ) - or R ³ CC = O) -; R ^p is C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl; and b) reacting the compound of formula II so produced with a strong acid. 5. The process of claim 4, wherein the methylating agent is tetramethyldiaminomethane in acetic anhydride. 6. The method of claim 5, wherein tetramethyldiaminomethane and acetic anhydride are added in excess. 7. The process of claim 6 wherein the amount of tetramethyldiaminomethane added is 2 equivalents and the amount of acetic anhydride is 4 equivalents. 8. A method according to claim 4, wherein the method is as follows. This means that sulfuric acid is used as the strong acid. 9. A process according to claim 8, wherein the sulfuric acid is concentrated sulfuric acid. 10. The process of claim 9 wherein the amount of concentrated sulfuric acid added is 9 equivalents. 11. The method of claim 4, further comprising the additional step of adding a compound of formula I wherein R &lt; ¹ &gt; is R &lt; ² &^gt;-; R 1 is C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted One to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen and trifluoromethyl are reacted with hydroxide to form a compound of formula VI (VI) and the compound of formula (VI) thus formed is reacted with benzyl halido amide and a base to give a compound of formula (VII) OMe (VII) '2.Ί 12. Method according to claim 11, v y z n a č u J ú c i s a by getting like benzyl halide apply benzyl bromide. 13. Method according to claim 11, v y z n a č u J ú c i s a characterized in that triethanolamine is used as the base. n. 14. The process of claim 11, wherein the compound of formula 1 is isolated prior to reaction with a base by adding a strongly acidic solution to a mixture of ice and water and extracting the resulting mixture with an organic solvent which is extracted with an organic solvent. then remove. A process for producing a compound of formula III R ¹ CIII) where R ¹ is R ² O (C = O) - or R ³ CC = O) -; R ^a is C 1 -C 4 alkyl; and R ³ is C 1 -C 4 alkyl or phenyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, and trifluoromethyl, wherein the compound of formula (I) is C 1 -C 4; of formula IV (IV) is reacted with a compound of formula V CV) wherein R ¹ is as defined above, in the presence of Leuisic acid, in a solvent inert to the reaction. The process according to claim 15, characterized in that aluminum chloride is used as the Leuis acid and methylene chloride is used as the reaction-inert solvent.