SK50052006A3 - Method of preparation of amorphous form of atorvastatin - Google Patents

Description

A process for the production of amorphous atorvastatin

Technical field

The present invention relates to a novel process for the preparation of the amorphous form of the (37 R, 5 R) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5- dihydroxyheptanoic acid, known under the non-proprietary name atorvastatin (I). Said drug is an important representative of hypolipidemic and hypocholesteric drugs.

BACKGROUND OF THE INVENTION

Atorvastatin (I) is produced according to published patents (US Patents 4,681,893; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,397,992); - [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid and a suitable water-soluble calcium salt, preferably calcium acetate or calcium chloride.

(37 R, 5 R) 7- [3-Phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropyl-pyrrol-1-yl] -3,5-dihydroxy-heptanoic acid, starting sodium salt, can be obtained from said acid which is commonly obtained from (3R, 5R) tert-butyl (6- {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl- [1,3] dioxan-4-yl) -acetate (II).

This key intermediate is first converted into the sodium salt of the corresponding acid by stirring with hydrochloric acid and then with a large excess of sodium hydroxide.

but which is accompanied by a large amount of excess hydroxide as well as sodium chloride. Acidification and extraction then provides a solution of the corresponding acid (III) without inorganic impurities. The acid thus obtained is then converted to the corresponding lactone (IV), which can be purified by crystallization, and the purified lactone is then converted to the sodium salt by stirring with an equivalent of sodium hydroxide; it is not possible to use an excess since it would in the next step with a calcium salt give calcium hydroxide which would not be completely removed from the product during subsequent processing according to said patents. However, using an equivalent of hydroxide, the reaction is lengthy and must be monitored by HPLC. Another disadvantage of this procedure is a loss of yield of about 20%.

III

IV

According to an embodiment, atorvastatin in one of the crystalline forms or atorvastatin amorphous is then obtained. The original patents (e.g., U.S. Patents 4,681,893 and 5,273,995) do not mention the form of the substance obtained under these patents. Later patents (US Patent 5,969,156 and US Patent 6,121,461) describing crystalline forms of atorvastatin state that the substance obtained according to the original patents was amorphous. In EP 839 132, describing a novel process for obtaining an amorphous form of atorvastatin by dissolving crystalline atorvastatin Form I in a non-hydroxylated solvent (referred to as tetrahydrofuran and a mixture of tetrahydrofuran and toluene) and drying it again, the original patents lead to amorphous atorvastatin, but this method is poorly reproducible. In our experience, atorvastatin obtained from the aforementioned patents (US 4,681,893 and 5,273,995) is not perfectly amorphous and shows X-ray analysis to show the presence of crystalline components. The original U.S. Pat. No. 4,681,893 also discloses the possibility of purifying a substandard substance by dissolving it in ethyl acetate, filtering through a supercel, and precipitating the solution with hexane at 50 ° C. A Ranbaxy Laboratories patent (WO 00/71116 A1) discloses converting a crystalline form of atorvastatin in a non-hydroxylated solvent and precipitating the resulting solution with a non-polar hydrocarbon solvent. A similar approach is described in Lek's patent (WO 01/42209 A1), which describes converting a crystalline form of atorvastatin to an amorphous form by dissolving in a wide range of solvents, including both non-hydroxylated solvents and lower alcohols, and subsequently precipitating these solutions with solvents in which atorvastatin is insoluble. Again, these solvents are broadly defined and include, in addition to non-polar hydrocarbon solvents, aliphatic ethers. Similar processes for obtaining amorphous atorvastatin are also disclosed in WO 03099785, WO 03093233, US 6,646,133, WO 030185547, WO 02083638, WO 02057228. All of the above precipitation-based processes result in a product that is very poorly dried and lengthy drying is thus significantly increases operating costs of production. In addition, the elevated temperature used in the drying process causes slight degradation of the product and formation of non-volatile impurities.

For these reasons, the non-polar solvents used for the precipitation are always identifiable with the amorphous atorvastatin thus produced. Larger problems are less volatile solvents, such as alkanes or cycloalkanes C5 and greater ethers rior _2, wherein the hydrocarbon radicals R ₂ and R C5 and above. In the cases where C6 and above are mentioned, it is very difficult to obtain a product which at all complies with the standards for the pharmaceutical product.

WO 03/068739 has shown that it is very advantageous to extract the sodium or triethylammonium salt of (3 R, 5 R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] Of 3,5-dihydroxyheptanoic acid, immediately after its formation from II, into ethyl acetate. This procedure allows the product to be obtained free of non-volatile impurities, but it does not avoid the remainder of the above solvents and, moreover, even ethyl acetate cannot be completely removed so that it is always present in the product in an amount of at least 1000 to 5000 ppm.

However, it has now surprisingly been found that these solvents can be removed very well without increasing the concentration of non-volatile impurities.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of the amorphous form of the hemicalcium salt of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid of the formula I

characterized in that a solution of the compound of formula I in an ester C1-C5 with an alcohol C1-C5 is injected into a hot stream of inert gas, whereupon the amorphous particles formed are sedimented and isolated.

In this way, the need to use solvents necessary to precipitate the amorphous product by the previously described methods is avoided. The corresponding ester is reliably removed. Surprisingly, this method of drying does not degrade the product and therefore does not increase the amount of nonvolatile impurities.

Preferably, the solution of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrolidin-3-yl] -3,5-dihydroxyheptanoic acid or an alkali metal salt thereof, cation R _n N ⁽⁺⁾ H (4 ''), where R is lower alkyl C1 to C5, n is 0 to 3, first extracted into an ester C1 to C5 with an alcohol C1 to C5, using calcium salt or converts calcium hydroxide to substance I.

The starting acid or salt thereof is preferably prepared from (3R, 5R) tert-butyl (6- {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl -2,2-dimethyl- [1,3] dioxan-4-yl) -acetate of formula II

converting an acid, followed by alkaline hydrolysis to the alkali metal salt or a cation, R _n N ⁽⁺⁾ H (4. _n), which is then extracted into an organic solvent, and the solution was freed from impurities by extraction with water.

From a solution of (3R, 5a) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid salt with an excess of chloride and the corresponding cation hydroxide can be acidified and extracted to give a solution of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptane acid, which is further converted into a calcium salt solution. Calcium salt, calcium hydroxide or calcium alcoholate may serve as the calcium source.

The inert gas used may preferably be nitrogen. Ethyl acetate is preferably used as the solvent when spraying the solution of compound I.

A more detailed description of the invention follows.

The amorphous form of atorvastatin is preferably obtained directly from an extract of a solution of atorvastatin hemi-calcium salt in a suitable solvent by spraying it into a stream of inert gas, preferably nitrogen. Surprisingly, it has been found that the amorphous thus obtained has better drying characteristics than the precipitated amorphous. The standard atorvastatin amorphous produced by precipitation into nonpolar solvents is poorly dried and protracted drying results in higher operating costs and also slight degradation of the product. Comparative experiments have shown that the amorphous obtained by spraying into an inert gas stream can be dried many times faster than the precipitated amorphous. The results are documented in the following table. The batch obtained by precipitation from ethyl acetate to hexane required 100 h to drop below the allowable limit (5000 ppm ethyl acetate), while the amorphous obtained by spraying with a stream of nitrogen could be dried in less than 10 hours. Moreover, the amorphous thus obtained does not contain any non-polar solvents. Last but not least, the cost of non-polar solvents is also saved.

no. lot Sum of impurities (HPLC) Ethyl acetate (ppm) Drying time (50 ° C, 100 mm) 22-33-1 (according to Ex.2) 0.55% 23600 2 22-33-1 0.55% 600 10 AE 190 (according to Ex.1) 0.56% 16500 2 AE 190 0.56% 7500 10 AE 190 0.63% 4500 100

In addition, there are no traces of non-polar solvents present in the product thus obtained, which can never be completely removed in the normal process. In intensive drying, in order to remove solvents, a highly sensitive product such as amorphous atorvastatin can undoubtedly be.

Thus, the method of the invention completely eliminates the presence of non-polar solvents and substantially reduces the drying time required to remove other solvents such as ethyl acetate. This further reduces non-volatile impurities as degradation products formed during drying.

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives to the production of atorvastatin according to the invention, are merely illustrative and do not limit the scope of the invention in any respect.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (comparative experiment)

The portion of ester II (8.7 g, 13.3 mmol) is added with stirring to a round flask containing a mixture of tetrahydrofuran (100 mL) and 10% HCl (30 mL, 0.082 mol) and the resulting solution is stirred at room temperature for 24 h. A solution of 30% NaOH (24 mL, 7.2 g, 0.18 mol) is then added dropwise over 15 min, the reaction mixture spontaneously warms up and becomes cloudy. The mixture was stirred at room temperature for 15 h and then poured into a separatory funnel containing hexane (100 mL) and demineralized water (300 mL). After thoroughly shaking and separating the layers, the lower aqueous layer is shaken with additional hexane (2 x 50 mL). The washed aqueous layer is acidified with 10% HCl to pH 4 and extracted with dichloromethane (1 x 100 ml, 2 x 50 ml, 2 x 25 ml), the organic layer is washed with saturated brine (2 x 25 ml) and dried with CaSCA (25 g). ) during the night. The desiccant was then filtered off, washed with dry dichloromethane (50 ml) and a solution of triethylamine (3 ml, 21.5 mmol) in dry dichloromethane (20 ml) was added and the solution was evaporated to room temperature after stirring for 0.5 h. dryness on a rotary evaporator. The resulting solid foam (ca. 10-11 g) was mixed with dry dichloromethane (25 mL) and evaporated again to dryness (ca. 9 g). This procedure was repeated once more to give 8.34 g of a yellowish solid foam of the triethylammonium salt (12.6 mmol, 95%). The triethylammonium salt was dissolved in ethyl acetate (50 mL) and transferred to a separatory funnel. A solution of calcium acetate monohydrate (1.2 g, 6.8 mmol) in demineralized water (10 mL) is then added and the contents of the separatory funnel are shaken. After separation, the aqueous layer is separated, the organic layer is shaken with water (2 x 10 mL) and dried with calcium sulfate. The extract thus obtained is added to 200 ml of hexane and the precipitated product is filtered off with suction, yielding 5.6 g of amorphous atorvastatin after drying.

Example 2

The portion of ester II (8.7 g, 13.3 mmol) is added with stirring to a round flask containing a mixture of tetrahydrofuran (100 mL) and 10% HCl (30 mL, 0.082 mol) and the resulting solution is stirred at room temperature for 24 h. A solution of 30% NaOH (24 mL, 7.2 g, 0.18 mol) is then added dropwise over 15 min, the reaction mixture spontaneously warms up and becomes cloudy. The mixture was stirred at room temperature for 15 h and then poured into a separatory funnel containing hexane (100 mL) and demineralized water (300 mL). After thoroughly shaking and separating the layers, the lower aqueous layer is shaken with additional hexane (2 x 50 mL). The washed aqueous layer is acidified with 10% HCl to pH 4 and extracted with dichloromethane (1 x 100 ml, 2 x 50 ml, 2 x 25 ml), the organic layer is washed with saturated brine (2 x 25 ml) and dried with CaSO 4 ( 25 g) overnight. The desiccant was then filtered off, washed with dry dichloromethane (50 ml) and a solution of triethylamine (3 ml, 21.5 mmol) in dry dichloromethane (20 ml) was added and the solution was evaporated to room temperature after stirring for 0.5 h. dryness on a rotary evaporator. The resulting rigid foam (ca. 10-11 g) was mixed with dry dichloromethane (25 ml) and evaporated again to dryness (ca. 9 g). This procedure was repeated once more to give 8.34 g of a yellowish solid foam of the triethylammonium salt (12.6 mmol, 95%). The triethylammonium salt was dissolved in ethyl acetate (50 mL) and transferred to a separatory funnel. A solution of calcium acetate monohydrate (1.2 g, 6.8 mmol) in demineralized water (10 mL) is then added and the contents of the separatory funnel are shaken. After separation, the aqueous layer is separated, the organic layer is shaken with water (2 x 10 mL) and dried with calcium sulfate. The extract thus obtained is sprayed into a stream of nitrogen and further dried in a conventional oven. 5.8 g of amorphous atorvastatin are obtained.

Example 3

To the weighed ester II (5 g, 7.6 mmol) was added tetrahydrofuran (75 mL) and after dissolution of all the material was added 10% HCl (17 mL). The mixture was stirred at room temperature for 6 h. To this solution is added a solution of 40% NaOH (10 mL) over 5 min so that the temperature does not exceed 35 ° C, and the heterogeneous mixture is stirred vigorously for 15 h and then poured into a separatory funnel containing demineralized water (150 mL) and hexane (50 mL). ml). After shaking, the organic layer is discarded and the aqueous layer is extracted with a mixture of hexane (40 mL) and tetrahydrofuran (10 mL). After complete separation, the aqueous layer is extracted with ethyl acetate (1 x 40 mL, 4 x 20 mL). The ethyl acetate extract is then shaken successively three times with demineralized water (5 ml) containing 1 g of calcium acetate in 5 ml of water each. The resulting ethyl acetate extract is washed with demineralized water (2 x 5 ml) and, after drying with calcium sulfate, is concentrated in a vacuum evaporator to a volume of 20 ml. The extract thus obtained is sprayed into a stream of nitrogen and further dried in a conventional oven. 3.8 g of amorphous atorvastatin are obtained.

Claims (9)

A process for the preparation of an amorphous form of the hemicalcium salt of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid of the formula Characterized in that a solution of the substance I in the ester C1-C5 with an alcohol C1-C5 is injected into a hot stream of inert gas, whereupon the amorphous particles formed are sedimented and isolated and optionally dried by a standard procedure. The process according to claim 1, wherein the solution of (37 R, 57 R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] acid. -3,5-dihydroxyheptane or an alkali metal salt thereof, or a salt with a cation R _n N ⁽⁺⁾ H ₍ 4 _n ), wherein R is lower alkyl C 1 to C 5, n is 0 to 3, first extracted into the ester of the acid C1 to C5 with the alcohol C1 to C5, which is then converted to the substance I by means of a calcium salt or calcium hydroxide. A process for the preparation of atorvastatin according to claim 2, characterized in that the starting acid or its salt is prepared from (37 R, 57 R) tert-butyl (6- {2- [3-phenyl-4-phenylcarbamoyl-2- ( 4-fluorophenyl) -5-isopropylpyrrol-1-yl] ethyl} -2,2-dimethyl- [1,3] dioxan-4-yl) acetate of formula II by converting by acidic and then alkaline hydrolysis to an alkali metal salt, or cation R _n N ^(+> H (4 _n )), which is subsequently extracted into an organic solvent and this solution is freed from impurities by extraction with water. Process according to claim 1 or 2, characterized in that from a solution of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] - 3,5-dihydroxyheptanoic acid with an alkali metal cation containing excess chloride and hydroxide of the corresponding cation, after acidification and extraction, gives a solution of (3 R, 5 R) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl)] -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid, which is further converted into a hemicalcium salt solution by reaction with a calcium salt, calcium hydroxide or calcium alcoholate. The process according to any one of claims 1 to 3, wherein said solution of (3 R, 5 R) -7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrole-1] is a solution. -yl] -3,5-dihydroxyheptanoic acid in the appropriate solvent is converted to the alkali metal or amine salt of R _n N ⁽⁺⁾ H (4 _n ), where R and n are as defined above. Process according to any one of claims 1 to 5, characterized in that the hemicalcium salt of the formula I is obtained by spraying into a stream of nitrogen. The process according to claim 6, characterized in that the hemicalcium salt is obtained by spraying from a solution in ethyl acetate. 8. Amorphous atorvastatin, which does not contain impurities in the form of non-polar solvents. The amorphous atorvastatin of claim 8, which does not contain any alkane or cycloalkane C 5 -C 10, or an ether of formula R 1 OR 2, wherein R 1 or R 2 may independently be a C 5 -C 10 hydrocarbon radical. Amorphous atorvastatin with ethyl acetate content below 1000 ppm.