Process for preparing Donepezil and its derivatives

A process for producing a Donepezil derivative represented by the formula (I), wherein R1, R2, R3, and R4 each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having from 1 to 4 carbon atoms; R5 represents a phenyl or a substituted phenyl; and n is an integer from 0 to 2, characterized in that the process comprises: (a) a reaction of 4-pyridinecarboxaldehyde with a compound of formula (II) in the presence of a strong acid HX to form a compound of formula (III); (b) a catalytic hydrogenation of a compound of formula (III) or a compound of formula (V) to yield a compound of formula (IV); and (c) an alkylation reaction of a compound of formula (IV) to yield a compound of formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a National Stage Application of International Patent Application No. PCT/CN 2004/001227, with an international filing date of Oct. 28, 2004, which is based on Chinese Patent Application No. 200310106920.3, filed Nov. 5, 2003. The contents of both of these specifications are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel synthesis of Donepezil and derivatives thereof.

BACKGROUND OF THE INVENTION

Donepezil is an acetyl cholinesterase inhibitor exhibiting high selectivity, high bioavailability, and high potency. It is able to inhibit acetyl cholinesterase present in the brain while only slightly effecting acetylcholine levels present in other tissues, such as the myocardium and the erythrocytes specifically. Other advantages of using Donepezil include its persistent activity and good safety profile. In addition, patients taking Donepezil have good tolerance for the drug. Since Donepezil demonstrated good efficacy in the treatment of Alzheimer senile dementia, it is a very valuable drug with growing market share. Accordingly, Donepezil and its derivatives is a hot synthetic target.

The synthesis of Donepezil was first disclosed by Japan's Eisai Co. in the U.S. Pat. No. 5,100,901 (seeFIG. 1herein), with an overall yield of less than 20%.

EPO Patent EP 535496 then disclosed an economically viable scheme for the synthesis of Donepezil (seeFIG. 2herein). However, this synthetic route resulted in many by-products in the first step, and required complicated purification procedures, such as column chromatography. We have found similar problems when we attempted to repeat this process. In addition, this process was difficult to reproduce. Therefore, it inevitably lead to complex purification procedure and a poor overall yield of 29 percent (seeFIG. 2herein). We predict that this process would be difficult to employ on an industrial scale. There are no continued patent applications of EP 535496 so far.

The German Company Bayer disclosed yet another process for the production of Donepezil in the U.S. Pat. No. 5,606,064 (seeFIG. 3herein). This process consists of 2 steps. The overall yield of this process is reported as 53%. However, when scientists of Eisai Co. attempted to repeat this process, they had found that the yield for the key step, step 2, was actually only 38% (U.S. Pat. No. 6,252,081). Therefore, the total yield of the Bayer process could not have been more than 27% overall.

Recently, Eisai Co. disclosed in the U.S. Pat. No. 6,252,081 an improved route for the preparation of Donepezil (seeFIG. 4herein). This route calls for recrystallization at each step, and the yield in the key step (last step) is high, while the by-products in that step are few. Hence, this route is the most efficient process at present, with a 69% overall yield. However, this route utilizes NaH in two steps, a high concentration NaOH solution in one step, and requires absolute dry solvents in two steps. As such, the route utilizes complicated operating parameters in each step, necessitating large investment for equipment, such as moisture proof equipment and caustic resistant equipment.

Finetech also developed two novel processes (U.S. Pat. No. 6,252,081; seeFIGS. 5 and 6herein). The yield of the process as illustrated inFIG. 5was not disclosed, and the process required complicated purification techniques and column chromatography in many of its steps. Therefore, this process is not deemed suitable as an industrial process.

Although the synthesis, disclosed inFIG. 6herein, requires multiple steps, it employs purification by recrystallization and distillation rather than by column chromatography in each step; this renders the industrialization of the process possible. It is said that the process was successfully employed in a pilot plant. However, this process also requires complicated operating parameters in each step, and utilizes strong acid and caustic reagents in multiple steps, generating a lot of waste. This process requires many complicated steps, and although the yields of each step are high, the overall yield was a mere 19.3% (seeFIG. 6herein). For these reasons, the commercial value of the process is limited.

In sum, there were 6 previously disclosed processes for the preparation of Donepezil and its derivatives. Wherein the process inFIG. 1(herein) is an industrial one, processes inFIGS. 4 and 6succeeded in a pilot plant. There is no continued patent application of the process inFIG. 6(herein) after its EP application. There is also no successful report of a pilot plant of the process inFIG. 3(herein).

The processes inFIGS. 2 and 3have the shortest synthetic route. With respect to the results of the synthetic scheme illustrated herein inFIG. 2which we have repeated, because the 2,3-dihydro-5,6-dimethoxy-2-((pyridin-4-yl)methylene)inden-1-one is a conjugated system, it is difficult to hydrogenate the pyridine ring and the carbon-carbon double bond at the same time in the presence of a catalyst. If hydrogenation is performed at an elevated temperature and pressure, the carbonyl group may also be reduced to a hydroxyl group making the purification more difficult, and yielding less than 40% of the desired material after purification by column chromatography. Moreover, the process illustrated herein inFIG. 3also causes trouble in the same step of catalytic hydrogenation; although the N-benzylization on the pyridine ring can form a quaternary pyridinium salt, which makes the pyridine ring more active towards hydrogenation, the benzyl group is easily broken up by hydrogenolysis under these conditions as well. The results obtained by Eisai Co. and those obtained in our laboratory show that this reaction has many by-products, which makes the purification difficult, and the yields low.

There are two methods to solve the aforesaid problems, one is to use the synthetic scheme Eisai Co. developed as shown herein inFIG. 4: the pyridine analogues obtained from this process are not conjugated with the indanone ring; the pyridine ring can be activated through forming quaternary pyridinium salt; and as a result, the pyridine ring in the form of the N-benzyl quaternary pyridinium salt can be hydrogenated under mild reaction conditions. Consequently, the final products are obtained in higher yields.

The other method is to activate the pyridine ring by forming quaternary methyl ammonium salts rather than quaternary benzyl ammonium salts, and in this way to avoid the side reactions in the presence of a hydrogenation catalyst, as in the process disclosed by Joseph Sam (J. Hetercyclo. Chem. Vol. 2, 366;FIG. 7herein). However, although the yield of this process is said to be 100%, this process is not suitable for the preparation of Donepezil.

SUMMARY OF THE INVENTION

To overcome the disadvantages of the synthetic schemes illustrated inFIGS. 2 and 3, we have tried to activate the pyridine ring in the absence of side reactions. Using as a guide the reaction illustrated inFIG. 7, we attempted forming an activated pyridinium salt via protonating the nitrogen atom of the pyridine ring of 2,3-dihydro-2-((pyridin-4-yl)methylene)inden-1-ones with a strong acid. The conjugated pyridinium ring could be easily hydrogenated in the presence of a catalyst to form a

protonated piperidinium salt (represented by formula (IV) below), and to afford Donepezil and its derivatives (seeFIG. 8herein). In this way, not only the compounds of formula (IV) could be afforded in high yields through the hydrogenation of the pyridine ring of the compounds of formula (III) in the presence of a catalyst under mild reaction conditions, but also the compounds of formula (IV) could be converted to the target compounds easily by alkylation processes.

Accordingly, the invention relates to a process for producing of compounds represented by the following formula (I), wherein R1, R2, R3, and R4each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having 1 to 4 carbon atoms; R5represents phenyl or substituted phenyl; and n is an integer from 0 to 2, characterized in that, the process comprises the following three reactions represented inFIG. 8below:

Step one is the reaction of 4-pyridinecarboxaldehyde with a compound of the formula (II) to form a compound of the formula (III) in the presence of a strong acid, wherein R1, R2, R3, and R4each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having from 1 to 4 carbon atoms. The term “HX” refers to a strong acid which could stabilize the compound of the formula (III), including but not limited to alkyl sulfonic acid, benzene sulfonic acid, substituted benzene sulfonic acid, terephthalic sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, 1-naphthalenesulfonic acid, and 2-naphthalenesulfonic acid. Preferred acids include methyl sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, terephthalic sulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, sulfuric acid, and phosphoric acid. More preferred acids include methyl sulfonic acid, benzene sulfonic acid and p-toluenesulfonic acid.

Second step is the reaction of a compound of the formula (III) with H2in the presence of a catalyst to form the compound of the formula (IV), wherein R1, R2, R3, and R4each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having from 1 to 4 carbon atoms. The term “HX” refers to a strong acid which could stabilize the compound of the formula (III), including but not limited to alkyl sulfonic acid, benzene sulfonic acid, substituted benzene sulfonic acid, terephthalic sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, 1-naphthalenesulfonic acid, or 2-naphthalenesulfonic acid. Preferred acids include methyl sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, terephthalic sulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, sulfuric acid, and phosphoric acid. More preferred acids include methyl sulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid.

A compound of the formula (IV) could be produced by the reaction of a compound of the formula (V) with H2in the presence of a catalyst, wherein R1, R2, R3, and R4each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having from 1 to 4 carbon atoms. The term “HX” refers to a strong acid which could stabilize the compound of the formula (III), including but not limited to alkyl sulfonic acid, benzene sulfonic acid, substituted benzene sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, 1-naphthalenesulfonic acid, and 2-naphthalene sulfonic acid. Preferred acids include methyl sulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, sulfuric acid, nitric acid, and phosphoric acid. More preferable acids include methyl sulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid.

Examples of catalysts used in the hydrogenation reactions in which a compound of formula (IV) is produced from a compound of formula (III) or in which a compound of formula (V) reacts with H2include platinum, palladium, rhodium, nickel, ruthenium, and also oxides or salts thereof. Preferred are palladium on carbon, platinum on carbon, Raney nickel, platinum dioxide, platinum chloride, and palladium chloride. More preferred is platinum dioxide.

The reaction can be carried out in a pressure range from about 1 atmosphere to about 100 atmospheres of H2, preferably from about 1 to about 20 atmospheres, and more preferably from about 1 to about 5 atmospheres. The reaction generally is carried out in a temperature range from about 0 degrees Celsius to about +150 degrees Celsius, preferably from about +10 degrees Celsius to about +100 degrees Celsius, and more preferably from room temperature to about +50 degrees Celsius.

The ratio of a reactant, for example of a compound of formula (III) or formula (V) to a catalyst is from 1:0.001 to 1:0.5, and preferably from 1:0.01 to 1:0.2. A suitable solvent in this reaction may be selected from, but is not limited to, water, an alcohol, an ether, an ester, or an organic acid; preferably water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, ethyl acetate, or acetic acid; and more preferably water, methanol, ethanol, tetrahydrofuran, or acetic acid.

The third step is the reaction of Y—(CH2)n+1R5with a compound of formula (IV) in the presence of a base to give a compound of formula (I), wherein R1, R2, R3and R4each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having from 1 to 4 carbon atoms; R5represents a phenyl or a substituted phenyl; n is an integer from 0 to 2; and Y is a chlorine atom, a bromine atom, or an iodine atom.

The molar ratio of a compound of formula (IV) to a compound of formula YCH2(CH2)nR5ranges from 1:0.3 to 1:3. The molar ratio of a compound of formula (IV) to a base ranges from 1:0.3 to 1:50. More preferably the ratio of a compound of formula (IV) to a compound of formula YCH2(CH2)nR5to a base is 1 to 0.8-1.5 to 0.8-2.

Another method for the preparation of a compound of formula (I) is the reaction of OHC—(CH2)nR5with a compound of formula (IV) and H2, in the presence of a catalyst. The catalyst is platinum, palladium, nickel, rhodium, or ruthenium, or salts or oxides thereof. Preferably the catalyst is palladium on carbon, platinum on carbon, platinum dioxide, palladium chloride, platinum chloride, or Raney nickel. More preferably the catalyst is palladium on carbon. H2can be supplied at a pressure range from 1 to 100 atmospheres; and preferably at a pressure from 1 to 5 atmospheres. Adding a weak-acids salt such as sodium acetate, and potassium acetate will improve the reaction. The reaction is in general carried out in a temperature range from 0 degrees Celsius to +150 degrees Celsius; preferably, from 10 degrees Celsius to +100 degree Celsius; and more preferably from room temperature to +50 degrees Celsius.

The molar ratio of a compound of formula (IV) to a compound of formula OHC(CH2)nR5to a catalyst is 1 to 0.5-3 to 0.001-0.5. Preferably, the molar ratio of a compound of formula (IV) to a compound of formula OHC(CH2)nR5to a catalyst is 1 to 0.8-1.5 to 0.01-0.2. The solvent in this reaction may be selected from water, dichloromethane, chloroform, 1,4-dioxane, an alcohol, an ether, an ester, or an organic acid; preferably from, water, methanol, ethanol, propanol, isopropanol, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, ethyl acetate, or acetic acid; and more preferably from, tetrahydrofuran, dichloromethane, chloroform, or 1,4-dioxane.

The third method for preparation of a compound of formula (I) is the reaction of a compound of formula OHC—(CH2)nR5with a compound of formula (IV) and a reducing agent, wherein the reducing agent is selected from, but not limited to, NaBH4, B2H6, NaBH(CN)3, NaBH(AcO)3, and Ca(BH4)2. The molar ratio of a compound of formula (IV) to a compound of formula OHC(CH2)nR5to a reducing agent is 1 to 0.5-3 to 0.5-4. Preferably, the molar ratio of a compound of formula (IV) to a compound of formula OHC(CH2)nR5to a reducing agent is 1 to 0.8-1.5 to 0.8-1.5. The solvent in this reaction is selected from, but not limited to, tetrahydrofuran, dichloromethane, trichloromethane, ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, isopropanol, isopropyl ether, and acetic acid; and preferably, tetrahydrofuran dichloromethane, trichloromethane, ethyl acetate, 1,4-dioxane, 1,2-dichloroethane and acetic acid. The reaction is in general carried out in a temperature range from 0 degrees Celsius to +100 degrees Celsius; and more preferably, from room temperature to +60 degrees Celsius.

Compounds which are suitable to be used as an active pharmaceutical ingredient in therapeutic compositions and suitable to be produced by methods of this invention are compounds represented by formula (I), wherein R1, R2, R3, and R4each independently represent H, F, Me, OMe or OEt; preferably, R1and R4each independently represent H, or F; R2and R3each independently represent OMe or OEt; more preferably, R1and R4each represent H; and R2and R3each represent OMe.

Compounds which are suitable to be used as an active pharmaceutical ingredient in therapeutic compositions and suitable to be produced by methods of this invention are compounds represented by formula (I), wherein R5represents phenyl or substituted phenyl; preferably, R5represents phenyl, 3-chloropropylphenyl, 3-bromomethylphenyl, 3-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl; and more particularly, R5represents phenyl or 3-fluorophenyl.

Compounds which are suitable to be used as an active pharmaceutical ingredient in therapeutic compositions and suitable to be produced by methods of this invention are compounds represented by formula (I), wherein n is an integer from 0 to 2; preferably, n is 0 or 1; and more preferably, n is 0.

More preferably, compounds which are suitable to be used as an active pharmaceutical ingredient in therapeutic compositions and suitable to be produced by methods of this invention are compounds represented by formula (I), wherein R1and R4each represent H; R2and R3each represent OMe; R5represents phenyl or 3-fluorophenyl; and n is 0.

In certain embodiments, the invention shows advantages as explained in detail with reference to examples describing synthesis of Donepezil, wherein R1represents hydrogen, R2represents OMe, R3represents OCH3, R4represents hydrogen, R5represents phenyl, and n is 0.

The addition of the 4-pyridylmethylene moiety to the compound of formula (II) (wherein R1represents hydrogen, R2represents OMe, R3represents OCH3, and R4represents hydrogen) is described below. Specifically, the reaction of 4-pyridinecarboxaldehyde with a compound of formula (II) in the presence of p-toluenesulfonic acid under reflux conditions in the toluene as solvent results after cooling in a brown crystalline compound of formula (III). The product is obtained in a high yield of 91%. The purity of this product is greater than 98%. In addition, we have found that compounds of formula (IV) can be obtained by reacting a compound of formula (III) with H2in the presence of a catalyst, such as platinum dioxide. H2is supplied at 1 atmosphere of pressure and room temperature. The resulted reduced p-toluene-sulfonic acid salt (IV) is converted to Donepezil by the reaction with benzyl bromide. Therefore, the total yield of the Donepezil route according to this invention is as high as 82%.

Accordingly, the invention affords a process for the preparation of Donepezil and derivatives thereof, which compared with prior techniques, demonstrates the advantage of mild reaction conditions, easy operation and control, and little waste.

The implementation of syntheses of this invention can reduce the cost of producing Donepezil, improve product economics, and decrease pollution.

DETAILED DESCRIPTION OF THE INVENTION

Examples

0.96 g of 5,6-dimethoxy-1-indanone, and 0.75 g 4-pyridyl formaldehyde were added to a three-neck round bottom flask equipped with a Dean-Stark trap and an electromagnetic stirrer. 100 ml toluene was then added. Stirring continued until the reactants were dissolved. Then, 0.95 g of p-toluenesulfonic acid was added. The reaction was then carried out by refluxing for 12 hrs. After cooling, a solid was formed. The resultant solid was filtered off with suction affording 2.141 g of a yellow solid compound. The yield was 94%. 20 mL of anhydrous ethanol were added to the product, and the slurry was brought under reflux in ethanol for 30 minutes. After cooling at 5° C. for 2 hours, the resulting precipitate was filtered off with suction and after washing with 5 ml cold anhydrous ethanol and drying, 1.98 g of the title product were obtained. The melting point range was from 209-212° C.1H NMR (DMSO-d6): 8.95 (d, 2H, J=6.0 Hz), 8.23 (d, 2H, J=6.0 Hz), 7.56 (s, 1H), 7.48 (d, 2H, J=8.0 Hz), 7.27 (s, 1H), 7.22 (s, 1H), 7.12 (d, 2H, J=8.0 Hz), 4.15 (s, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 2.29 (s, 3H).

0.402 g of 2,3-dihydro-5,6-dimethoxy-2-((pyridin-4-yl)methylene)inden-1-one p-toluenesulfonic salt were dissolved in 30 mL of methanol and 33 milligram of PtO2were added. Stirring continued at room temperature, with H2being supplied at 1 atmosphere for 7 hours. Solids filtered off with suction and washed with 5 ml anhydrous methanol. After concentrating the filtrate solid was obtained. To the solid 15 mL of anhydrous isopropanol was added. The mixture was heated to dissolve solids and then cooled to 0° C. overnight. The formed precipitate was filtered off with suction to afford 0.34 g of white crystalline solid. The melting point 191-192° C. After drying, additional 46 milligrams of solid were obtained. Liquid chromatography analysis showed product of 97% purity. A total of 0.386 g of the expected product was obtained at a yield of 94%.1H NMR (DMSO-d6): 8.42 (br s, 1H), 8.18 (br s, 1H), 7.47 (d, 2H, J=8.0 Hz), 7.12 (d, 2H, J=8.0 Hz), 7.11 (s, 1H), 7.06 (s, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.20-3.38 (m, 3H), 2.82-2.95 (m, 2H), 2.60-2.75 (m, 2H), 2.29 (s, 3H), 1.85-1.95 (m, 1H), 1.65-1.85 (m, 3H), 1.20-1.40 (m, 3H).

2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-2,3-dihydro-5,6-dimethoxyinden-1-one, was prepared according to Example 3 by replacing benzyl bromide with m-fluorobenzyl bromide.

0.60 g of 2,3-dihydro-5,6-dimethoxy-2-((pyridin-4-yl)methyl)inden-1-one, and 0.36 g p-toluenesulfonic acid salt were added to 30 mL of anhydrous methanol. 60 milligrams of PtO2were added. The reaction mixture was stirred at room temperature, with H2being added at 1 atmosphere for 6 hours. Solids were filtered off. The filtrate was concentrated and dried in vacuo to afford 1.05 g of foam with 100% yield. Liquid chromatography analysis of this product showed 97% purity.

0.22 g of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt, and 0.10 g of sodium acetate were added to 60 mL of anhydrous methanol. 100 milligrams of 10% Pd/C were also added. The reaction mixture was stirred at room temperature with H2being supplied at 1 atmosphere for 10 hours. 55 milligrams of benzaldehyde were added in equal portions at 0 hrs, 2 hrs, 4 hrs, 6 hrs and 8 hrs. Solids were filtered off. The filtrate was concentrated. 30 mL of 5% aqueous Na2CO3solution were added, and the resulting mixture was extracted with 3×30 mL of ethyl acetate. The extracts were combined, washed with 15 mL of aqueous Na2CO3solution and 15 mL of aqueous NaCl solution, and dried over anhydrous MgSO4. After solids were filtered off, solvent was removed in vacuo to afford 0.67 g of product as oil. Purification on silica gel column chromatography afforded 0.11 g of title compound in 62% yield.