KR20090056527A - Improved process for the preparation of atorvastatin calcium salt - Google Patents

Abstract

An improved manufacturing method of an atorvastatin calcium salt having high purity is provide to increase reaction speed of deprotection of phenyl boron group and minimize the generation of slaframine. A method for manufacturing an atorvastatin calcium salt comprises: a step of resolving a boronate compound in a polar organic solvent and adding hydrogen peroxide to obtains a t-butoxy ester compound; a step of reacting the t-butoxy ester compound with sodium hydroxide solution under the presence of alcohol solvent to perform deprotection a t-butoxy ester group; and a step of reacting with calcium acetate to convert the atorvastatin calcium salt.

Description

Improved process for the preparation of atorvastatin calcium salt

The present invention relates to an improved method for preparing atorvastatin calcium salt.

Atorvastatin is {R- (R *, R *)}-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-{(phenyl Amino) carbonyl} -1H-pyrrole-1-heptanoic acid hemicalcium salt [{R- (R *, R *)}-2- (4-fluorophenyl) -b, d-dihydroxy-5- (1- It is known as methylethyl) -3-phenyl-4-{(phenylamino) carbonyl} -1H-pyrrole-1-heptanoic acid hemicalcium salt], two chiral centers, both of which have an absolute configuration of R form , A substance having an absolute arrangement of R as a whole, represented by the following Chemical Formula 1. In general, atorvastatin is known as an HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent.

The manufacturing process and important intermediates of atorvastatin are U.S. Pat. And the like. Atorvastatin is usually prepared in the form of calcium salts, since atorvastatin calcium salts can be conveniently prepared in preparing pharmaceutical formulations for oral administration such as tablets, capsules, powders, and powders.

The atorvastatin calcium salt can be present in either amorphous or crystalline form (forms 1, 2, 3 and 4), and the crystalline atorvastatin calcium salt is WO 97/3958 and WO 97/3959. It is described in. Among many pharmaceutical substances, amorphous forms show different dissolution properties and bioavailability patterns compared to crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38: 2003-2007). For some therapeutic indications, bioavailability is one of the important factors in determining the form of the substance used in the pharmaceutical formulation. In the case of atorvastatin, it is known that the amorphous form has a different bioavailability depending on the size of the particles compared to the crystalline form (WO 2003068191). In the case of formulations using small particles as a raw material, there is a study showing that bioavailability can be increased by about 2 times. However, the crystallization process and the manufacturing process of the amorphous material are difficult to carry out separately, and since the product yields a mixture of amorphous-crystalline forms, neither pure crystalline nor pure amorphous forms are produced. Therefore, there is a continuous demand for a method for preparing atorvastatin in an amorphous form or converting a crystalline form into an amorphous form (WO 2006048888, WO 2006046109, WO 2006045018, WO 2006011155, WO 2005100313, European Patent 1577297). number). In addition, since amorphous particles are finer than crystalline forms, when water-soluble solvents are used, filtration takes a long time in the manufacturing process, and in the case of crystallization in organic solvents, excessive residual problem of residual solvents (Organic Process Research & development 1997, 1, 320-324), low purity problems, low chemical stability, and several studies have shown that it is possible to overcome the low stability by adding various additives (European Patent 1659110). It is also reported that it can be overcome (WO 2006039441).

According to U.S. Pat. No. 4,681,893, pyrrole is obtained through a [3 + 2] cycloaddition reaction using 2- [1,3] -dioxolan-2-yl-ethylamine ( 1 ) as starting material. Formation of the compound of the structure and then converted to the aldehyde material ( 2 ), by introducing a chiral center to separate the cis / trans mixed lactone material formed through the cyclization reaction to prepare the atorvastatin lactone ( 3 ) having a trans geometry The method is described and represented by Scheme 1 below.

According to U.S. Pat.No. 5,273,995, a compound ( 4 ) formed of a salt of S-(+)-2-acetoxy-1,1,2-triphenylethanol and magnesium in the aldehyde pyrrole derivative material ( 2 ) known in Scheme 1 It was added to increase carbon linkage, introduce t-butoxy ester group ( 5 ) through transesterification reaction, lactoneization ( 6 ) and then separation method to prepare optically pure atorvastatin lactone ( 7 ). It is described. Sodium salt formed by hydrolyzing optically pure lactone ( 7 ) with sodium hydroxide was dissolved in an excess of methanol, and added dropwise to a large amount of water dissolved in calcium chloride (CaCl ₂ ) to crystallize, filtered and dried, and then dissolved in ethyl acetate. Thereafter, excess hexane is added to crystallize. The preparation method is represented by the following scheme 2.

U.S. Patent No. 5,397,792 describes an improved method for preparing atorvastatin and is represented by Scheme 3 below. Unlike the conventional method, the patent protects the diol compound having two chiral centers with acetonide ( 8 ), and then reacts with the diketone ( 9 ) to obtain a pyrrole structure ( 10 ) through a Parr-Knorr synthesis method. ) Is prepared, followed by deprotection ( 11 ), followed by a lactone compound ( 12 ) or a preparation of the atorvastatin calcium salt. The manufacturing method has the advantage that if the optical purity of the diol compound is high, the optical purity in the final target compound can be manufactured to a high level, but there are many stages of the reaction process, using a heavy metal as a catalyst to the high-pressure hydrogen reaction There is a disadvantage to proceed. Also described is the step of preparing the lactone cyclic compound and then the atorvastatin calcium salt in order to increase the chemical purity other than the optical purity.

US Pat. No. 6,867,306 protects a diol using phenylboronic acid instead of acetonide as a diol protecting group ( 13 ), and prepares a pyrrole structure ( 14 ) by diketone ( 9 ) compound and par-nor synthesis method. It is described that the atorborstatin calcium salt can be prepared after deprotection of the phenyl boron group and the t-butoxy ester group, and is represented by the following Scheme 4.

Boronate from the patent - preparing an atorvastatin calcium salt from the atorvastatin (Boronate-atorvastatin (14), hereinafter "boronate" hereinafter) is shown in detail in Scheme 5. Corresponding intermediates ( 13 ) and ( 9 ) are prepared respectively as in steps 1) and 2), and then the boronate is prepared via par-nor synthesis as described in step 3) and then in-situ. The reaction was followed by stirring for 18 hours using a silica gel in methylene chloride solvent to deprotect the phenyl boron group ( 15 ), deprotect the t-butoxy ester group with sodium hydroxide, add acid to extract the organic layer, and ammonia gas. It is crystallized as ammonium salt ( 16 ) and separated. It is then described that conversion to calcium salts under diisopropylether and isopropanol mixed solvents affords the final compound ( 17 ) in a pharmaceutically acceptable level of purity. However, when the phenyl boron group is deprotected using silica gel in the boronate ( 14 ), the reaction time is longer than 18 hours and in some cases a longer time reaction time is required to complete the reaction is difficult Also often occurs. In addition, the t-butoxy ester compound was deprotected with sodium hydroxide, washed with distilled water and diisopropyl ether, the aqueous layer was separated, the pH was lowered with hydrochloric acid solution, extracted with diisopropyl ether, and concentrated to ethyl. It dissolves in acetate, adds ammonia gas to this solution to form atorvastatin ammonium salt, and then concentrates and removes the solvent, and dissolves in a mixed solvent of diisopropyl ether and isopropanol to convert to calcium salt. As described above, the method has a long reaction time, and it is inconvenient to pass through atorvastatin ammonium salt for purification.

Atorvastatin is a compound with a pyrrole ring structure and a complex structure having various functional groups in its chemical structure, and therefore, is known to have low thermal stability and light stability (Tetrahedron 62, 7390-7395 (2006)), and it is known that a large amount of decomposition products are produced. . According to the ICH guidelines, pharmaceutical ingredients generally vary according to daily dosage, but if they contain more than 0.15% of degradation products, they must be separated and purified to demonstrate that they are non-toxic and within the established shelf life. Although there should be no increase of the product, atorvastatin requires low purity of atorvastatin due to low thermal stability and light stability, and at the same time, the preparation method of the high purity atorvastatin calcium salt without the addition of a new step is required. need. According to U.S. Patent Application Publication No. 2007/0066835, L-lysine salt of atorvastatin is formed, separated and dried, and then reacted with calcium acetate to make atorvastatin calcium salt with high purity [purity: 99.87% to 99.9% (purity). High performance liquid chromatography (HPLC))]. In addition, the preceding researchers (Organic Process Research & development 1997, 1, 320-324) tried to increase the purity of the final compound by preparing and crystallizing the lactone intermediate in toluene solvent to prepare pure atorvastatin calcium salt.

As described above, in order to prepare a high-purity atorvastatin calcium salt, an additional crystallization step and a filtration step must be performed, and a lactone compound, or atorvastatin ammonium salt and atorvastatin lysine salt forming step for further purification before the preparation of the atorvastatin calcium salt is performed. Must go through. Therefore, the methods described above are not suitable for mass production because the reaction time is long and the reaction step is complicated to prepare the atorvastatin calcium salt.

While the present inventors are studying a method for mass-producing high-purity atorvastatin calcium salt in a simple manner without undergoing additional crystallization, filtration and purification steps, an aqueous hydrogen peroxide solution is used to deprotect the phenylborone group of the boronate compound. In the case of using sodium hydroxide to deprotect the t-butoxy ester compound, the reaction rate is significantly increased while minimizing the formation of the flexible substance, and high purity atorvastatin calcium salt can be prepared without the need for additional purification, separation and concentration. It was confirmed that the present invention was completed.

The present invention seeks to provide an improved process for the preparation of high purity atorvastatin calcium salts from boronate compounds.

The present invention

1) dissolving the boronate compound in a polar organic solvent and then adding an aqueous hydrogen peroxide solution to deprotect the phenyl boron group to obtain a t-butoxy ester compound, and

2) deprotecting the t-butoxy ester group by reacting the t-butoxy ester compound with an aqueous sodium hydroxide solution at room temperature in an alcohol solvent, and then reacting with calcium acetate without any separate process to convert to atorvastatin calcium salt. Comprising a step, and provides an improved method for preparing atorvastatin calcium salt represented by the following Scheme 6.

Hereinafter, the present invention will be described in detail step by step.

The first step in the preparation method of the present invention is a step of deprotecting the phenyl boron group of the boronate compound, and dissolving the boronate compound in a polar organic solvent and then using an aqueous hydrogen peroxide solution for 5-6 hours at 50-70 ° C., preferably React for 4 hours. Preferably, the hydrogen peroxide is preferably used in an aqueous solution of 30 to 40%, and in the case of using hydrogen peroxide, deprotection occurs in a short time (4 hours) than when using conventional silica gel, and almost no decomposition products are generated. The t-butoxy ester compound can be separated in high yield (70% or more). The separation process of the t-butoxy ester compound proceeds as needed, and proceeding to the next step without separation does not affect the quality of the final compound. The polar organic solvent used at this time is selected from the group consisting of methanol, ethanol, ethyl acetate, acetonitrile and tetrahydrofuran, methanol or ethanol is preferred.

The second step in the preparation method of the present invention is a step of deprotecting the t-butoxy ester group and converting it to atorvastatin calcium salt. After dissolving the t-butoxy ester compound in methanol, an aqueous sodium hydroxide solution is added to the t-butoxy ester group. The group is deprotected to form atorvastatin sodium salt in solution, which is then converted to atorvastatin calcium salt by reaction with calcium acetate without further separation. The aqueous sodium hydroxide solution is used in the amount of 1.0 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents, and most preferably 1.0 equivalent to the t-butoxy ester compound. The reaction temperature is 20 to 30 ° C, preferably 25 to 30 ° C. The reaction time is 5 to 24 hours, preferably 12 hours. The reaction solvent used is preferably methanol or ethanol, most preferably methanol. It is preferred to wash with 10-40% methanol, preferably 20-30% methanol upon conversion to atorvastatin calcium salt.

The purity (HPLC area%) of the final product prepared through the above process is 99.8% or more, the individual flexible material is 0.1% or less, the main flexible material of atorvastatin calcium is 0.06%, and the epoxide (photolysis product) is 0.03%. It can be seen that the sum of the total lead substances is very pure, less than 0.2%.

As described above, the method for preparing the atorvastatin calcium salt according to the present invention uses a hydrogen peroxide solution instead of silica gel during the deprotection reaction of the phenyl boron group to significantly increase the reaction rate while minimizing the formation of the flexible substance, t-butoxy ester. In the deprotection of the group, the equivalent amount of sodium hydroxide is precisely set, and the reaction is carried out at room temperature, thereby eliminating the need for further purification, separation, and concentration, which is very economical, suitable for mass production, and highly purified amorphous and crystalline atorvastatin. Calcium salts can be prepared.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example  One  : Atorvastatin  Preparation of Calcium Salts

1-1. Atorvastatin  t- Butoxy  Manufacture of ester

300 g of boronate was dissolved in 3000 ml of methanol (MeOH) and 1000 ml of 35-37% hydrogen peroxide (H ₂ O ₂ ) was added. The temperature was raised to 60-65 ° C. and stirred for 4 hours. The reaction solution is then a clear green solution. After the reaction was completed, the mixture was concentrated in vacuo to remove methanol. Ethyl acetate and distilled water mixed solvent (EA / H ₂ O = 3000 mL / 1500 mL) were added and extracted to collect an ethyl acetate layer. The ethyl acetate layer was washed with 600 ml of water and the layers were separated, and the ethyl acetate layer was concentrated in vacuo. The concentrate was dissolved in 1380 ml of acetonitrile (CH ₃ CN), and 540 ml of distilled water (H ₂ O) was added to crystallize. Stir for 12 hours, filter, and wash with 200 ml of 70% acetonitrile aqueous solution. Vacuum drying at 40 ° C. for 12 hours afforded a white solid atorvastatin t-butoxy ester (183 g, 70% theoretical yield).

1-2. Atorvastatin  t- Butoxy  Other manufacture of esters

Atorvastatin t-butoxy ester (183 g, theoretical yield 70%) of a white solid was obtained by the same method as 1-1, except that ethanol was used instead of methanol in 1-1.

2. Atorvastatin  Preparation of Calcium Salts

129 g of the white solid atorvastatin t-butoxy ester prepared in 1-1 was added to 1820 ml of methanol, and dissolved by heating. Sodium hydroxide (NaOH, 9.34 g) was dissolved in 650 ml of water and added dropwise to the reaction solution at 25 ° C. or lower, followed by stirring at 25 to 30 ° C. for 12 hours. The reaction progress was confirmed by developing in TLC (Hexane / EA = 1/1 solution). To the solution of calcium acetate (Ca (OAc) _2, 20.34g) dissolved in 4000ml of distilled water was added dropwise for 20 minutes while maintaining the reaction solution at 25 ~ 30 ℃. The dropwise addition was completed and then filtered. Washed with 200 ml of 30% methanol. After sufficiently removing the mother liquor, it was deodorized, dried firstly, and put into a drier. After vacuum drying at 40 ° C. for 12 hours, when the water content reached 4% or less, drying was stopped to obtain 111 g of atorvastin calcium salt (88% of theoretical yield).

Experimental Example  One  : Atorvastatin  Purity Analysis of Calcium Salts

Purity analysis of the atorvastatin calcium salt prepared in Example 1 was analyzed by liquid chromatography (HPLC) according to the following conditions.

Purity Analysis Conditions

Column: Zorbax Rx C8, 5 μm, 250 mm × 4.6 mm or equivalent column,

Mobile phase: 0.05 M ammonium acetate buffer (pH 5.0) / acetonitrile / tetrahydrofuran (Linear gradient program)

Mobile phase A: 0.05 M ammonium acetate buffer (pH 5.0) / acetonitrile / tetrahydrofuran = 67/21/12

Mobile phase B: 0.05 M ammonium acetate buffer (pH 5.0) / acetonitrile / tetrahydrofuran = 54/34/12

- Linear Change Program (Linear gradient program )

A linear change program was run, starting with mobile phase A, passing mobile phase A for 40 minutes and replacing 100% of mobile phase B at 55 minutes after 15 minutes. After passing the mobile phase B 100% for 15 minutes (70 minutes after the start), a linear change program was performed to replace the mobile phase A 100% at 73 minutes and passed through the mobile phase A until 90 minutes after the initial start [Table 1 ].

(1) 15 minute linear gradient

(2) 3 minute linear change

Detector: 244 nm

Column temperature: 35 ℃ ± 2 ℃

Flow rate: 1.5 ml / min

The chromatogram of the HPLC of the atorvastatin calcium salt of the present invention is shown in FIG. 1, and the retention time of the flexible material usually contained in the atorvastatin calcium salt according to the present invention is shown in HPLC chromatogram. All.

Minutes Mobile phase A (%) Mobile phase B (%) 0.0 100 0 40.0 ⁽¹⁾ 100 0 55.0 0 100 70.0 ⁽²⁾ 0 100 73.0 100 0 90.0 100 0

As shown in Figures 1 and 2, the purity of the atorvastatin calcium salt of the present invention (HPLC area%) is 99.8% or more, the individual flexible material is 0.1% or less, the main flexible material of atorvastatin calcium is 0.06%, epoxide (Photolysis product) was 0.03%. Therefore, it can be confirmed that the atorvastatin calcium salt of the present invention was prepared with high purity.

In the method for preparing atorvastatin calcium salt according to the present invention, the reaction rate is significantly increased while the hydrogen peroxide solution is used instead of silica gel during the deprotection reaction of the phenyl boron group, while minimizing the formation of the flexible substance, and the deprotection reaction of the t-butoxy ester group. It is very economical, it is suitable for mass production, and it is possible to manufacture high purity amorphous and crystalline atorvastatin calcium salts by precisely setting the equivalent amount of sodium hydroxide and proceeding the reaction at room temperature. Do.

1 is a diagram showing an HPLC chromatogram of atorvastatin calcium salt according to the present invention.

Figure 2 is a diagram showing the retention time of the analogues usually contained in the atorvastatin calcium salt according to the present invention by HPLC chromatogram.

Claims (4)

1) dissolving the boronate compound in a polar organic solvent and then adding an aqueous hydrogen peroxide solution to deprotect the phenyl boron group to obtain a t-butoxy ester compound, and 2) deprotecting the t-butoxy ester group by reacting the t-butoxy ester compound with an aqueous sodium hydroxide solution at room temperature in an alcohol solvent, and then reacting with calcium acetate without any separate process to convert to atorvastatin calcium salt. An improved method for preparing atorvastatin calcium salt, comprising the steps of the following formula (6). <Scheme 6>

The method according to claim 1, wherein the polar organic solvent in step 1) is one selected from the group consisting of methanol, ethanol, ethyl acetate, acetonitrile and tetrahydrofuran. The method of claim 1, wherein the aqueous sodium hydroxide solution in step 2) is 1.0 to 2.0 equivalents based on t-butoxy ester compound. The method of claim 1, wherein the alcohol solvent in step 2) is selected from methanol or ethanol.

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