PL197306B1 - Methods of obtaining 1-benzylo-4-((5,^-dimethoxy-1-indanon-2-yl) methylpiperidine and intermediate compounds - 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

(12) PATENT DESCRIPTION (19) PL (21) Filing number: 327512 (22) Filing date: October 11, 1996 (86) Date and number of the international application:

11.10.1996, PCT / IB96 / 01076 (87) International application publication date and number:

1996-06-26, WO97 / 22584 PCT Gazette No. 27/97 (11) 197306 (13) B1 (51) Int.Cl.

C07D 211/32 (2006.01) (54) New derivatives of 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine

(73) The right holder of the patent: (30) Priority: PFIZER INC., New York, US 1995-12-15, US, 60 / 008,753 (72) Inventor (s): (43) Application was announced: Keith M. Devries, Chester, US December 21, 1998 BUP 26/98 (74) Representative: (45) The grant of the patent was announced: Sulima Sophia, 31.03.2008 WUP 03/08 SULIMA-GRABOWSKA-SIERZPUTOWSKA, Patent and Trademark Office sp.j.

(57) New 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine derivatives of general formula II

wherein R ¹ is R ² O (C = O) -, wherein R ² is (C ₁ -C 4) alkyl.

PL 197 306 B1

Description of the invention

The subject of the invention are new 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine derivatives intermediates useful in the synthesis of 4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidine derivatives, which in turn, they are useful in the synthesis of 1-benzyl-4 - {[(5,6-dimethoxy-1-indanone) -2-yl] methyl} pi peridine, which is a valuable drug substance.

U.S. Patent No. 4,895,841 describes 1-benzyl-4 - {[(5,6-dimethoxy-1-indanone) -2-yl] methyl} piperidine, methods for its preparation, useful intermediates, and methods and pharmaceuticals. for the treatment of diseases caused by acetylcholine esterase activity such as senile dementia.

There was a need for new intermediates useful in the synthesis of 1-benzyl-4 - {[(5,6-dimethoxy-1-indanone) -2-yl] methyl} piperidine.

The invention relates to novel 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine derivatives of general formula II

wherein R ¹ is R ² O (C = O) -, wherein R ² is (C 1 -C 4) alkyl.

Compounds of Formula II can be prepared as outlined in Scheme 1.

PL 197 306 B1

According to scheme 1, a compound of formula II is prepared from a compound of formula III, which in turn can be prepared by reacting a compound of formula IV with a compound of formula V. Compounds of formulas IV and V are commercially available, or compounds of formula V can be prepared by known methods.

A compound of formula III can be prepared by reacting a compound of formula IV with a compound of formula V wherein R ¹ is R ² O (C = O) -, where R ² is (C 1 -C ₄ ) alkyl, preferably methyl, in the presence of a Lewis acid in a solvent which is inert under the reaction conditions. Suitable Lewis acids are aluminum trichloride, titanium tetrachloride or boron trichloride, preferably aluminum trichloride. Suitable solvents which are inert under the reaction conditions are methylene chloride or dichloroethane, preferably methylene chloride. The reaction is usually carried out at a temperature of about 0-85 ° C, preferably about 30 ° C.

A compound of formula II can be prepared by reacting a compound of formula III with a methenylating agent. Preferably R 1 is R ² O (C = O) -, wherein R 2 is methyl. Suitable methenylating agents are tetramethyl diaminomethane in acetic anhydride, formaldehyde (about 37 wt% in water) in diethylamine, formaldehyde (about 37 wt% in water) in piperidine or N-methylthiomethylpiperidine. A preferred methenylating agent is tetramethyl diaminomethane in acetic anhydride. When the methanylating agent is tetramethyl diaminomethane in acetic anhydride, the reaction is preferably carried out with an excess of tetramethyl diaminomethane and acetic anhydride. Most preferably the reaction is performed with 4 molar equivalents of acetic anhydride (based on the amount of the compound of formula III) and 2 equivalents of tetramethyl diaminomethane (based on the amount of the compound of formula III). A solvent may be used in the case of a methylene glycation agent other than tetramethyl diaminomethane in acetic anhydride 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 temperature is about 0-90 ° C, preferably about 90 ° C. The reaction may be carried out in about 6-30 hours and preferably 12 hours.

The novel 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine derivatives of formula II are useful as intermediates in the synthesis of the compound of formula VII shown in Scheme 2, which can be readily accomplished in view of the cost, availability and stability of the starting substances.

PL 197 306 B1

Following Scheme 2, a compound of formula II can be converted to a compound of formula I by reaction with a strong acid in a reaction-inert solvent. Suitable strong acids are concentrated sulfuric acid, aluminum trichloride or concentrated hydrochloric acid, preferably concentrated sulfuric acid. When the acid is aluminum trichloride then a solvent must be used. Suitable solvents are carbon disulfide, methylene chloride or dichloroethane, preferably carbon disulfide. The reaction is carried out at a temperature of about 0-100 ° C, preferably at 25 ° C.

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. A preferred reagent is a compound of formula I, wherein R ¹ is R ² O (CO) - 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 temperature is about 25-100 ° C, preferably about 100 ° C. The reaction may be carried out for about 6-24 hours, preferably about 18 hours.

A compound of formula VII can be prepared from a compound of formula VI by reaction with a benzyl halide in a reaction-inert solvent. Suitable halides are chloride, bromide and iodide, preferably bromide. Suitable solvents which are inert under the reaction conditions are diethyl ether, isopropyl ether, tetrahydrofuran, preferably isopropyl ether. The reaction temperature is about 0-70 ° C, preferably about 70 ° C.

1-Benzyl-4 - {[(5,6-dimethoxy-1-indanone) -2-yl] methyl} piperidine is effective in treating, preventing, remitting, ameliorating etc. for various types of senile dementia, especially dementia senile type of Alzheimer's; cerebrovascular diseases accompanying a cerebral stroke, e.g. cerebral haemorrhage or cerebral infarction, hardening of the arteries in the brain, head trauma, etc., and lack of attention, speech disorders, decreased willpower, emotional changes, fresh memory disorders, hallucinatory syndrome paranoia, behavioral changes, etc. associated with encephalitis, cerebral palsy, etc.

In addition, 1-benzyl-4 - {[(5,6-dimethoxy-1-indanone) -2-yl] methyl} piperidine has a strong and highly selective anticholinesterase activity, which also makes the compound useful as a pharmaceutical based on this type of action .

In particular, 1-benzyl-4 - {[(5,6-dimethoxy-1-indanone) -2-yl] methyl} piperidine is effective in the treatment of e.g. Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskinesia other than senile dementia of the Alzheimer's type.

The following are recipes and examples illustrating the preparation of the starting compounds and intermediates and the compound of Formula VII, with Example 3 illustrating the preparation of the compound of the invention.

Commercial reagents were used without further purification. The melting point values have not been corrected.

NMR data is reported in parts per million (δ) with respect to the deuterium timing signal from the solvent sample, and these data were obtained on a Bruker 300 MHz instrument. D2O is deuterium oxide. CDCh is deuterochloroform. Chromatography, unless otherwise stated, refers to column chromatography carried out using 32-63 µm silica gel under nitrogen pressure (flash chromatography). Thin layer chromatography (TLC) refers to chromatography carried out on silica gel plates (E. Merck, Kiesel Gel 60 F254) and eluted with a specific selected solvent. High pressure liquid chromatography (HPLC) was performed on a LDC Analytical constaMetric® 3200 HPLC (Thermo Separation Products Co.). For HPLC analysis, a Zorbax®C8, 60A (60x10 ¹ ° m), 3.9x150 mm column (Mac-Mod Analytical, Inc., Chadds Ford, PA 19317) eluting with the selected solvent was used. Fast Atom Bombardment Mass Spectrometry (FABMS) means analysis by mass spectrometry using a Hewlett-Packard 5989 mass spectrometer (particle beam chemical ionization). Room temperature means 20-25 ° C.

Recipe 1

3-pyridin-4-ylpropen-2-oic acid

Malonic acid (100 g, 0.96 mol) was added to a solution of pyridin-4-ylcarboxaldehyde (100 g, 0.93 mol) in pyridine (100 ml) at 90 ° C. After the evolution of carbon dioxide (CO2) was complete, the reaction slurry was diluted with methanol. The title compound was filtered off as a white solid (97 g, 70% yield).

¹ H NMR (HOAc-d4) δ 11.70 (s, 1H), 8.85 (d, 2H), 7.95 (d, 2H), 7.80 (d, 1H), 6.90 (d , 1H).

PL 197 306 B1

Recipe 2

3-piperidin-4-ylpropanoic acid

The compound of Preparation 1 (32 g, 0.22 mol) was dissolved in 2N hydrochloric acid (150 ml) and the solution was treated with 10 wt.%. 5% rhodium on carbon under a hydrogen atmosphere (310 kPa) until hydrogen gas uptake ceases. The catalyst was filtered off and the resulting title compound solution was used directly in the next step.

¹ H 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.

Recipe 3

3- [N- (methoxycarbonyl) piperidin-4-yl] propionic acid

The solution of the compound of Preparation 2 was adjusted to pH 12 with aqueous potassium hydroxide. To this solution was added methyl chloroformate (21 mL, 0.27 mol). After one hour, the solution was adjusted to pH 1 with 6N hydrochloric acid and extracted with dichloromethane. The organic layer was dried over sodium sulfate and replaced with dichloromethane with isopropyl ether. The title compound was isolated as a solid (39 g, 84%).

Mp 89-90 ° C. ¹ H NMR (CDCl) 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.

P r z k ł a d 1

4- (2-Chlorocarbonyl-ethyl) -piperidine-1-carboxylic acid, methyl ester

To a solution of the compound of preparation 3 (54.0 g, 0.251 mol) in dichloromethane (500 ml) was added dimethylformamide (0.39 ml, 0.02 eq.) And oxalyl chloride (22 ml, 0.26 mol). After the evolution of gas had ceased, the title compound was obtained.

The title compound solution was used directly in the next step.

P r z k ł a d 2

4- [3- (3,4-Dimethoxyphenyl) -3-oxopropyl] -piperidine-1-carboxylic acid methyl ester

To the solution of the compound of Example 1 was added 1,2-dimethoxybenzene (25.5 ml, 0.20 mol) at room temperature, followed by the addition of aluminum trichloride (100 g, 0.75 mol) in portions. The reaction mixture was stirred for 4 hours at room temperature. Analysis by high performance liquid chromatography showed the reaction was complete. The reaction was quenched by careful addition of water, and the mixture was extracted with methylene chloride (2 x 500 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 magnesium sulfate. The solution was filtered and the solvent removed in vacuo to give an oil (67 g, crude weight). Analysis by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) showed that the purity of the compound was sufficient for use in the next step.

The course of these reactions and the purity of the reaction products were monitored both by TLC and by high performance liquid chromatography (HPLC) with the use of the indicated systems (Rf and t _r for the reaction product):

TLC (silica gel): Rf = 0.50 (40:60 hexane / ethyl acetate). The retention time in high performance liquid chromatography (t _r ) was 12.6 min (Zorbax Ca, 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

¹ H NMR (CDCl) δ 7.55 (dd, 1H, J = 8.4, 2.0 Hz), 7.50 (d, 1H, J = 2.0Hz), 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 = 7.3Hz), 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 ^ H ^ NOs (M + 1) + = 336.

P r z k ł a d 3

4- [2- (3,4-Dimethoxybenzoyl) allyl] -piperidine-1-carboxylic acid methyl ester

To a solution of the compound of Example 2 (66.0 g, 0.20 mol) was added acetic anhydride (76.0 ml, 0.80 mol) followed by tetramethyl diaminomethane (54 ml, 0.40 mol). After exotherm, the reaction mixture was heated at 90 ° C for 3 hours and stirred overnight at room temperature.

An aliquot (1 mL) was removed from the reaction vessel and treated with cold hydrochloric acid. The solution was extracted with methylene chloride then treated with an aqueous bicarbonate solution. The organic layer was then dried and analyzed by high performance liquid chromatography which showed that the starting material had reacted.

Due to the purity of the crude reaction mixture, the crude compound was used directly in the next step.

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TLC (silica gel): Rf = 0.60 (40:60 hexane / ethyl acetate). The retention time in high performance liquid chromatography (t _r ) was 15.9 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

¹ H NMR (CDCl) δ 7.35-7.40 (m, 2H), 6.83 (d, 1H, J = 8.8 Hz), 5.68 (s, 1H), 5.54 (s , 1H), 3.944.14 (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 ^ H ^ NO6 (M + 1) + = 348.

P r z k ł a d 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) was treated with concentrated sulfuric acid (100 ml) at 0 ° C. The reaction mixture was then stirred overnight at room temperature, at which time high performance liquid chromatography analysis showed complete reaction. The reaction was quenched by adding 1 kg of ice and then the aqueous phase was extracted with methylene chloride (2 x 500 ml). The combined organic extracts were washed with 500 mL of water, 500 mL of 1N sodium hydroxide, 500 mL of brine, dried over magnesium sulfate and the solvent was removed in vacuo. The oily material was then triturated with 500 mL of isopropyl ether and the compound was filtered to give 46.5 g (68% from dimethoxybenzene, 88% per step) of the title compound as a yellow solid.

TLC (silica gel): Rf = 0.40 (40:60 hexane / ethyl acetate). The retention time in high performance liquid chromatography (t _r ) was 10.1 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

¹ H NMR (CDCl) 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, 8.3Hz), 2.62-2.82 (m, 4H), 1.1. 84-1,95 (m, 1H), 1,62-1,80 (m, 3H), ^1.251. 39 (m, 1H), 1,08-1,33 (m, 2H). FABMS C ^ H ^ NO 3 (M + 1) + = 348.

P r z k ł a d 5

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

To a solution of the compound 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 mixture was then heated under an atmosphere of nitrogen overnight at which time high performance liquid chromatography analysis showed complete reaction. The aqueous phase was extracted with methylene chloride (3 x 50 ml), the combined organic layers were dried over sodium sulfate and the volatiles were removed in vacuo to give 3.30 g (79%) of the title compound as a solid. This compound was used without further purification.

The retention time in high performance liquid chromatography (t _r ) was 2.45 min (Zorbax C ₈ , 254 nm, 1 ml / min, 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

¹ H NMR (CDCl8) 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 ¹ C 7 H ₂₃ NO ₃ (M + 1) + = 290.

P r z k ł a d 6

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

Benzyl bromide (0.75 ml, 6.3 mmol) and triethanolamine (940 mg, 6.3 mmol) were added to a suspension of the title compound of Example 5 (1.82 g, 6.3 mmol) in isopropyl ether (60 ml). . The suspension was stirred overnight at 70 &lt; 0 &gt; C after which time analysis by high performance liquid chromatography showed complete reaction. The reaction mixture was then filtered to remove the precipitated triethanolamine hydrobromide. Hydrochloric acid saturated ether (1.0 mL, 12 mmol) was added to the remaining solution and then the solvent was removed in vacuo. The residue was dissolved in 20 ml of hot isopropanol and the mixture was allowed to cool to room temperature. The precipitated solid was filtered to obtain 1.60 g (61%) of the title compound as a white solid.

TLC (silica gel): Rf = 0.60 (90:10 methylene chloride / methanol): High performance liquid chromatography retention time (t _r ) was 6.01 min (Zorbax C ₈ , 254 nm, 1 ml / min, with eluting with 600: 400: 2: 1 water / acetonitrile / triethylamine / acetic acid).

¹ H NMR (free base, DMSO-d6) 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, 8.2Hz), 2.71-2.86 (m, 2H), 2.58-2.71 (m, 2H), 1.82-1.96 (m, 2H), ^1.521. 78 (m, 3H), 1,31-1,50 (m, 1H), 1,08-1,30 (m, 3H). FABMS C2 ⁴ H ₂₉ NO3 (M + 1) + = 380.

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Claims (1)

Patent claim New 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine derivatives of general formula II in which R ¹ is R ² O (C = O) -, where R ² is (C ₁ -C 4) alkyl.