WO2008072074A1

WO2008072074A1 - An improved process for the preparation of purine derivative

Info

Publication number: WO2008072074A1
Application number: PCT/IB2007/003897
Authority: WO
Inventors: Ravinder Reddy Vennapureddy; Rama Shankar; Ramesh Dandala; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2006-12-11
Filing date: 2007-12-10
Publication date: 2008-06-19

Abstract

The present invention provides an improved process for the preparation of purine derivative of Formula I.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF PURINE DERIVATIVE

FIELD OF THE INVENTION

The present invention relates to an improved process for the industrial preparation of 9-[(4-acetoxy-3-acetoxymethyl)but-l-yl]-2-aminopurine of Formula I

Formula I

BACKGROUND OF THE INVENTION

Famciclovir is an orally administered prodrug of the antiviral agent Penciclovir and is chemically known as 9-[(4-acetoxy-3-acetoxymethyl)but-l-yl]-2- aminopurine. Famciclovir undergoes rapid biotransformation to the active antiviral compound Penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-I) and 2 (HS V-2) and varicella zoster virus (VZV). Famciclovir is marketed as FAMVIR and is currently used for the treatment of acute herpes zoster (Shingles).

US 5,684,153 discloses a process for preparing Famciclovir as shown below:

In the above process the 2-amino-6-chloropurine (1) is reacted with 2- acetoxymethyl-4-halobuty-l-yl-acetate (2) to give 9-[4-acetoxy-3- (acetoxymethyl)but-l-yl]-2-amino-6-chloropurine (3) which is then dechlorinated to give Famciclovir (4). Although this process is simple and straightforward, it has a number of disadvantages. The main disadvantage of this process is that N- alkylation reaction is not selective generating the undesired N-7-isomer along with the desired compound 3 in the ratio of - 80: 20. The structure of N-7-isomer is depicted below:

It is very difficult to remove the N-7 isomer impurity by conventional crystallization methods and often requires chromatographic separation. Therefore, it results in overall lower yield and low process efficiency. Additionally this process has another problem that the palladium catalyst used in the final step of synthesis result in higher residual palladium content in API product. US 5,138,057 discloses a process for preparing Famciclovir as shown below:

Chlorination

Q = Leaving group

The above process for the preparation of Famciclovir has overcome some of the disadvantages of the earlier processes, by way of improving regioselectiyity with respect to N-9 and N-7 to a ratio of 94:6. However, this process still suffers from the drawback of high pressure conditions using palladium charcoal for dechlorination in the final stage of synthesis. The Famciclovir obtained has to be purified by column chromatography which is disadvantageous.

US 5,917,041 discloses an alternative approach for the preparation of 2- aminopurine derivatives including Famciclovir wherein N-(2-amino-4,6-dichloro- 5-pyrimidinyl)formamide is reacted with 2-acetoxymethyl-4-aminobutyl-l-yl- acetate to get an intermediate which upon cyclization followed by dechlorination yields Famciclovir as shown below:

This approach has been applied for the synthesis of Abacavir. It is of interest to note that no examples for the synthesis of Famciclovir or any of its intermediates have been given. This patent describes only the synthesis of Abacavir and its intermediates. The applicant's attempt to follow the above approach of synthesis involving reaction of N-(2-amino-4,6-dichloro-5-pyrimidinyl)formamide with 2- acetoxymethyl-4-amino-but-l-yl-acetate in presence of a base did not result in the desired product, probably due to the self cyclisation of the side chain.

In the prior art, after reaction of amino side chain with formamido compound (Formula II), the intermediate obtained is cyclized using triethylorthoformate in presence of aqueous acid. A similar approach when applied by the applicants using the 4-amino-2-hydroxymethyl-l-butanol (amino side chain with hydroxyl end group), a problem was encountered in this approach. It was observed that during cyclization step a major impurity is formed, which was subsequently identified as the 6-ethoxyderivative of purine. Based on this observation, an alternative was thought of wherein dechlorination of the coupled product is carried out first followed by cyclization.

US 5,831,092 discloses another approach to avoid the N-7 isomer formation in the preparation of 9-substituted purine derivatives as shown below:

deprotection

R⁴ is a Ci -C₂₀ linear or branched, saturated or unsaturated alkyl, optionally substituted by a C_3-6 carbocylic ring, said alkyl group or carbocylic ring being optionally substituted by at least one hydroxy, thiol, Ci_-2 -alkoxy, acyl, acyloxy, carboxy, -P(O)(OH)₂, -0-P(O)(OH)₂, Ci_-5 -mono- or diacylamino, Ci_-8 - alkoxycarbonylamino or allyloxycarbonylamino group, wherein the term acyl of the definitions of group R⁴ denotes saturated or unsaturated hydrocarbon acyl having 1-10 carbon atoms.

This approach relies on the methodology of protecting the 7-position of the imidazole moiety of the guanine or purine molecule followed by the N-alkylation at the desired N-9 position. In this approach guanosine has been mainly used as a starting material wherein the benzylation of the guanosine is followed by acid hydrolysis to get 7-benzyl guanine derivative which in a number of synthetic steps is converted to desired product.

US 7,041,823 discloses another process for improved selectivity of N-9 alkylated product as shown below: + TlOEt

Polar Organic Solvent

Famciclovir

The process described above was able to limit the N-7 isomer formation. However, the thallium(I)ethoxide has been used to prepare thallium salt of 2- aminopurine. Thallium ethoxide is highly toxic and highly moisture sensitive which makes it difficult for using in industrial production. Also any trace contamination of thallium in API is unacceptable.

From the above discussion it is obvious that the prior-art process for the preparation of Famciclovir are inherently associated with a number of disadvantages and are not satisfactory from an industrial point of view and therefore not suitable for large scale production. The inventors have now developed a new industrial process that completely eliminates the possibility of N-7 isomer formation and thus making the process less laborious, yielding exclusively Famciclovir with high purity that is suitable to use as a pharmaceutical active ingredient.

Additionally, a new pyrimidine intermediate (Formula V) that is useful for the synthesis of 9-substituted-2-aminopurines such as Famciclovir is described. OBJECTIVES OF INVENTION

The objective of the present invention is to develop an improved process for the preparation of 9-[(4-acetoxy-3-acetoxymethyl)but-l-yl]-2-aminopurine without requiring laborious purification and free of impurities that is amenable to use as Active Pharmaceutical Ingredient.

Another objective of the present invention is to provide a novel intermediate that can be used for the synthesis of Famciclovir.

SUMMARY OF INVENTION

Accordingly, the present invention relates to an improved process for the preparation of 9-[(4-acetoxy-3-acetoxymethyl)but-l-yl]-2-aminopurine of Formula I

Formula I

which comprises: a) condensing the compound of Formula II,

Formula II

with a compound of Formula III,

Formula III

in presence of base in a solvent to give compound of Formula IV, Formula IV

b) dechlorinating the compound of Formula IV using a catalyst in a solvent to obtain a compound of Formula V,

Formula V

c) cyclizing the compound of Formula V with trialkylorthoformate in the presence of an acid to give compound of Formula VI,

Formula VI

d) acylating the compound of Formula VI with a suitable acylating agent to give compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes an improved process for the preparation of Famciclovir which is suitable for large scale production in high yield and with high purity.

The aim of the present invention is to eliminate the formation of N-7 isomer so as to yield Famciclovir with good quality and improved yield. This has been achieved by condensing the side chain precursor to the formamide derivative followed by dechlorination and cyclization all in a single reaction solvent and without the need for isolation of intermediates to obtain the 2-aminopurine derivatives which is further acylated to obtain Famciclovir. The compound of Formula II is condensed with the amine of Formula III. The condensation is preferably carried out at reflux temperature in solvents such as ethanol, methanol, n-butanol, isopropanol, t-butanol, acetonitrile or water, most preferably in aqueous ethanol or aqueous isopropanol in the presence of at least one equivalent of a base, such as trialkylamine or potassium or sodium carbonate or sodium bicarbonate or potassium bicarbonate, preferably triethylamine, or sodium bicarbonate, more preferably sodium bicarbonate. After completion of reaction, the salts are filtered and the solution containing compound of Formula IV is used as such for next step of dechlorination.

The compound of Formula IV is dechlorinated by catalytic hydrogenation using a metal catalyst in a solvent selected from Ci-C₆ alkyl acetate, Ci-C₆ alcohols or mixtures thereof. The alkyl acetate is preferably methyl, ethyl, propyl or butyl acetate. The Ci-C₆ alcohol is preferably selected from the group consisting of methanol, ethanol, propanol and isopropanol. Most preferably ethanol or aqueous ethanol is used as a solvent for dechlorination. The catalyst is selected from palladium, platinum, rhodium, ruthenium and raney nickel. The preferred catalyst is 5 or 10 % palladium on charcoal. The palladium on charcoal can be wet or dry. The dechlorination reaction can be done either in the presence of base such as triethylamine or in the absence of base. Hydrogen pressure maintained during the reaction is in the range of 4-6 kg/cm² and the reaction can be performed at room temperature or at -50 °C. When the reaction is carried out at -50 °C it takes less time to complete the reaction.

Alternatively, the dechlorination can also be performed using a metal catalyst in the presence of hydrogenation transfer source like ammonium formate. When ammonium formate is used the reaction is carried out in aqueous methanol or in aqueous ethanol at reflux temperature.

Accordingly a feature of the invention, is the novel compound of Formula V that can be subjected to ring closure to the corresponding 2-aminopurine derivative of Formula VI without isolation. The novel compound of Formula V are optionally isolated or continued further without isolation in the preparation of Famciclovir.

The synthesis of 9-substituted-2-aminopurines such as compound of Formula VI represents a significant improvement over previously published procedures. In the present process all the reaction steps are performed in one pot and in a single solvent thereby eliminating many operational difficulties normally associated with large-scale operation. The inventors have also found that the previously described procedure for the preparation of Famciclovir following the methods mentioned in US 5,917,041 are not viable. This procedure describes ring closure on substituted pyrimidine to form the imidazole ring of the 9-substittuted-6-chloro-2- aminopurines. The disadvantage observed with this type of ring closure is the formation of numerous impurities, because of the presence of highly labile chloro substituent at C-6 of the resulting purine moiety. One of it is the conversion of 6- chloro into 6-ethoxy group if triethylorthoformate is applied as cyclising agent. Hence, in comparison to US '041, in the process of the present invention, the compound of Formula IV is subjected to dechlorination and then cyclized to furnish the required purine derivative in high purity, yielding substantially better yields and better quality product.

The solution containing compound of Formula V is partially concentrated and hydrogen chloride dissolved in ethanol or methanol is added. The compound of Formula V is subsequently cyclized with an appropriate ring closure agent to give compound of Formula VI. The ring closure of compound of Formula V to compound of Formula VI is conveniently carried out by trialkylorthoformates like triethylorthoformate, trimethylorthoformate and diethoxymethyl acetate in presence of acids such as hydrochloric acid, sulfuric acid or methanesulfonic acid, ethanesulfonic acid etc more preferably hydrogen chloride. A catalytic quantity of water is optionally added to the reaction mixture to expedite the cyclization process. The cyclization reaction is conducted at about 50°C. The product crystallizes out as its acid addition salt from the reaction mass, which is isolated by filtration. The compound of Formula VI can be further purified by crystallization or taken as such for next stage of synthesis. The hydrochloride salt of compound of Formula VI can be crystallized with ethanol or aqueous ethanol to get highly pure intermediate.

The compound of Formula VI is acylated with a suitable acylating agent in the presence of a base to give compound of Formula I. The acylating agents used is selected from acetyl chloride, acetic anhydride, more preferably acetic anhydride. The base used as catalyst for acylation is selected from pyridine, triethylamine, N,N-dimethylamino pyridine, more preferably triethylamine. The solvent used for the acylation is selected from methylene dichloride, tetrahydrofuran, dimethyl formamide, 1,4-dioxane, more preferably methylene chloride. Dimethyl amino pyridine is used as catalyst.

The present invention is exemplified by the following examples which are provided for illustration purposes, and do not limit the scope of invention.

Example 1

Preparation of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-l-yl)purine hydrochloride

To a slurry of N-(2-amino-4,6-dichloro-5-pyrimidinyl) formamide (70 gm) in ethanol (700 ml), pulverized sodium bicarbonate (56.80 g) was added at -23⁰C and heated to 75-8O⁰C. A solution of 4-amino-2-hydroxymethylbutan-l-ol (45 gm, -95% purity) in a mixture of ethanol (200 ml) and water (20 ml) was slowly added to the refluxing reaction mass in -60 minutes. The mixture was stirred at 75-8O⁰C for 90 minutes and cooled to -23⁰C. The precipitated salts (~45g) were filtered off and then washed with ethanol (100ml). The filtrate and washings were combined and treated with activated charcoal (3 g). The solution was filtered through celite to remove carbon and the residue washed with ethanol (40 ml). To the filtrate, triethylamine (38 g) and 10% palladium on carbon (50% water paste, 10 g) were added. The slurry was transferred to an autoclave and hydrogenated at 5O⁰C and 5-6 kg/cm² for 18 hrs. After completion of the reaction, the catalyst was removed by filtration and the residue was washed with ethanol (50 ml). The combined filtrate (~1150 ml) was concentrated to -300 ml under reduced pressure at <60°C. The concentrate was cooled to 23⁰C and a solution of hydrogen chloride in ethanol (118 gm, 15% w/w) was added to the reaction mass. The resulting light yellow coloured reaction mass was stirred for 5-10 minutes and triethylorthoformate (23Og) was added. The reaction solution was heated to 45- 5O⁰C and continued stirring at 45-5O⁰C for 3 hrs. Thereafter a mixture of 6.4g concentrated hydrochloric acid and 9.6 g water was added. Stirring was continued at 45-5O⁰C for 90 minutes, to crystallize the product. The suspension was cooled to 15-18⁰C, stirred for 60 minutes and the product was filtered. The wet product was washed with ethanol (2 x 50ml, 25⁰C), and dried at 5O⁰C under reduced pressure to constant weight. (Yield 50.5 gm; light yellow powder, HPLC purity >97%.)

This product can be taken as such for famciclovir preparation or can be purified by a process described below:

The above obtained product (50.5 gm) was suspended in a mixture of ethanol (220 ml) and water (7 ml) and the slurry was refluxed for 30-40 minutes. Thereafter, cooled the mass to 8-1O⁰C and maintained for 1 hr. Product was filtered, washed with ethanol (60 ml), and dried at 5O⁰C under reduced pressure to constant weight. (Yield 43.8gm; off white powder, HPLC purity > 99.3 %.)

Example 2

Preparation of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-l-yl)purine hydrochloride.

To a slurry of N-(2-amino-4,6-dichloro-5-pyrimidinyl) formamide (42g) in 2- propanol (500 ml), triethylamine (31.4g) was added at 23⁰C. The slurry was heated to 75-8O⁰C. A solution of 4-amino-2-hydroxymethylbutan-l-ol (27gm, -95% purity) in a mixture of 2-propanol (120ml) and water (17.4 ml) was slowly added to the refluxing reaction mass in about 60 minutes. The mixture was stirred at 75-8O⁰C for 2 hrs for completion of the reaction and concentrated under reduced pressure. The resulting residue was diluted with methanol (900 ml) and treated with activated charcoal (2 g). The solution was filtered through celite and the residue was washed with methanol (80 ml). To the filtrate 10% Palladium on Carbon (50% water paste, 6g) was added. The slurry was transferred to a hydrogenation vessel and hydrogenated at ~50°C and 5-6 kg/cm² for 20 hrs. After completion of the reaction, catalyst was removed by filtration and the residue washed with methanol (50 ml). The combined filtrate was concentrated to ~130 ml under reduced pressure at < 5O⁰C. The concentrate was cooled to -23⁰C and hydrogen chloride solution in methanol (54gm, 17% w/w) was added. The light yellow coloured solution was stirred for 5-10 minutes at -23⁰C and trimethylorthoformate (96.8Og) was added. The solution was heated to about 45⁰C and continued stirring at 45-5O⁰C for 4 hrs. Thereafter, a mixture of 4gm concentrated hydrochloric acid and 6 g water was added. Stirring was continued at 45-5O⁰C for 90 minutes, product start crystallizing after 20 minutes of stirring. The suspension was cooled to 5-8⁰C, stirred for 60 minutes. Product was filtered and washed with prechilled methanol (30ml, O⁰C), and dried at 5O⁰C under reduced pressure to constant weight yield 27.4 g: off white powder, HPLC purity > 98.1%.

Example 3

Preparation of 9-[4-acetoxy-3-(acetoxymethyl)but-l-yl]-2-aminopurine (Famciclovir)

2- Amino-9-(4-hydroxy-3-hydroxymethylbut- 1 -yl)purine hydrochloride (41 gm) was suspended in methylene chloride (330 ml) and to the suspension, triethylamine (49 g) was added at 22-3O⁰C. The slurry was stirred for 10-15 minutes and 4-dimethylaminopyridine (0.82 g) was added. The slurry was cooled to 8-11⁰C and acetic anhydride (32 gm) diluted with methylene dichloride (80 ml) was added over 40-45 minutes while maintaining the temperature at 8-11⁰C. The reaction mixture was stirred for 2 hrs at 8-11⁰C, where upon the reaction mass became a clear solution. After completion of the reaction, methanol (T ml) was added to the reaction mass and stirring continued for 15-20 minutes. The reaction mass was concentrated under reduced pressure at < 45⁰C. To the concentrate, water (180 ml) was added and the content was stirred for 10-15 minutes at 40- 45⁰C to obtain a clear solution. The solution was treated with carbon (4.1gm) for 10 min. The carbon was filtered through a bed of Celite and the residue was washed with water (45 ml). The combined filtrate and washings were cooled to 15-18⁰C and stirred for 5-6 hrs to crystallize the product. Product was filtered and washed with cold water (30 ml). The product was further crystallized with n- butanol to obtain Famciclovir (37.Ig) as a white crystalline powder, HPLC > 99.7 %).

Claims

WE CLAIM

1) An improved process for the preparation of Famciclovir of Formula I

Formula I

which comprises a) condensing the compound of Formula II,

Formula II

with a compound of Formula III,

Formula III

in presence of base in a solvent to give compound of Formula FV,

Formula IV

Formula V

Formula VI

2) The process according to claim 1 , wherein the base employed is selected from triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, more preferably sodium bicarbonate.

3) The process according to claim 1, wherein the catalyst is selected from palladium, platinum, ruthenium, rhodium, raney nickel, more preferably palladium on charcoal.

4) The process according to claim 1, wherein dechlorination is carried out in C_1-6 alcohols selected from methanol, ethanol, isopropanol, n-butanol more preferably methanol.

5) The process according to claim 1, wherein the dechlorination can also be carried out in the presence of transfer hydrogenation catalyst selected from ammonium formate, formic acid more preferably ammonium formate.

6) The process according to claim 5, wherein dechlorination is carried out in methanol or ethanol.

7) The process according to claim 1, wherein the trialkylorthoformate employed is triethylorthoformate. 8) The process according to claim 1 , wherein the acid employed is selected from hydrochloric acid, sulphuric acid, methanesulfonic acid, ethanesulfonic acid, more preferably hydrochloric acid.

9) The process according to claim 1 , wherein steps (a), (b) and (c) are carried out in ethanol.

10) The compound of Formula V