KR101953575B1 - Synthesis of new statin intermediates for hyperlipidemia therapy and synthetic process development for rosuvastatin - Google Patents

Abstract

The present invention relates to a novel intermediate for the synthesis of statin compounds and to a method for synthesizing statin compounds using the same.
The intermediate according to the present invention is applicable not only to rosuvastatin but also to all statins which are used as therapeutic agents for hyperlipemia.

Description

TECHNICAL FIELD The present invention relates to a novel intermediate for the synthesis of a statin-based hyperlipidemia therapeutic agent and to a process for the preparation of a rosuvastatin synthetic process using the same. BACKGROUND ART Synthesis of new statin intermediates for hyperlipidemia therapy and synthetic process development for rosuvastatin

The present invention relates to a novel intermediate for the synthesis of statin compounds and to a method for synthesizing statin compounds using the same.

Westernized eating habits have increased the incidence of hyperlipidemia in Koreans. As a result, the demand for hyperlipidemia treatment is also increasing. Currently, rosuvastatin is the most commonly used treatment for statin-based hyperlipidemia.

Rosubastatin is the most biologically relevant, statistically most effective drug to be called "super-statin", which is the most biocompatible statin-based treatment for hyperlipemia. Although the substance patent was terminated in April 2014, AstraZeneca, which is the original patent, registered rosuvastatin intermediate as a new patent for the substance patent and almost monopolized the rosuvastatin market. Therefore, it is necessary to develop a method for synthesizing rosuvastatin calcium salt using new intermediates.

As a method for preparing rosuvastatin, there can be used the method of the following Reaction Formula 2 (Patent Document 1) or the method of Reaction Formula 3 (Patent Document 2).

[Reaction Scheme 2]

[Reaction Scheme 3]

In order to prepare rosuvastatin, the following reaction scheme 4 (Patent Document 3) can be used. However, since the reaction must be carried out at -78 캜, it is not suitable as a production process.

[Reaction Scheme 4]

In the case of the method (Patent Document 4) shown below, it is not suitable for mass production because a new starting material must be synthesized without using a conventional commercialized starting material, and an optional reduction reaction must be performed.

[Reaction Scheme 5]

In the case of the method (Patent Document 5) shown below, the substance of intermediate 19M is expensive and is unsuitable for mass production.

[Reaction Scheme 6]

In the case of the following Reaction Formula 7 (Patent Document 6), there is a disadvantage in that it is unsuitable for mass production due to the optical separation process and is costly.

[Reaction Scheme 7]

Further, in the case of the following Reaction 8 (Patent Document 7), there is a problem of danger due to the use of HF for the price increase due to the use of the TBDMS protecting group and the debohobo.

[Reaction Scheme 8]

1. International Patent Application WO 2000 049014 2. Korean Patent Application No. 10-2012-008215 3. European Patent No. 52171 4. Korean Patent Application No. 10-2008-7001928 5. Korean Patent Application No. 10-2007-7012477 6. International Patent No. WO2008-053334 7. International Patent No. WO2007-039287

The present invention provides a novel intermediate for the synthesis of a statin compound and a method for synthesizing a statin compound using the same.

Reacting a compound of formula (2) with a compound of formula (3) to prepare a compound of formula (4); And

And decomposing the compound of Formula 4 to prepare a statin compound of Formula 1 or a salt thereof.

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In the above formula

R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms,

X is chloro, bromo or iodo,

Het is a substituent selected from the group consisting of the following formulas (8a) to (8d).

[Chemical Formula 8a]

[Formula 8b]

[Chemical Formula 8c]

[Chemical Formula 8d]

Further, the present invention provides a compound of the following formula (4) as an intermediate of a statin compound.

[Chemical Formula 4]

The present invention relates to a novel intermediate for the synthesis of statin compounds and to a method for synthesizing statin compounds using the same.

The intermediate according to the present invention can be applied not only to rosuvastatin but also to all statins which are used as therapeutic agents for hyperlipidemia, simplify the manufacturing process, and obtain a statin compound with high yield.

1 is a ¹ H-NMR graph and a ¹³ C-NMR graph of a compound represented by the formula (5).
2 is a ¹ H-NMR graph and a ¹³ C-NMR graph of the compound represented by the formula (7-1).
3 is a ¹ H-NMR graph and a ¹³ C-NMR graph of the compound represented by the formula (7-2).
4 is a ¹ H-NMR graph and a ¹³ C-NMR graph of the compound represented by the formula (2-1).
5 is a ¹ H-NMR graph and a ¹³ C-NMR graph of the compound represented by the formula 2-2.
6 is a ¹ H-NMR graph and a ¹³ C-NMR graph of the compound represented by the formula 4-1.
7 is a ¹ H-NMR graph and a ¹³ C-NMR graph of the compound represented by the formula 4-2.

The present invention provides a process for producing statins or salts thereof.

Reacting a compound of Formula 2 with a compound of Formula 3 to prepare a compound of Formula 4; And

And decomposing the compound of Formula 4 to prepare a statin compound of Formula 1 or a salt thereof.

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In the process of the present invention, the compound of formula (2) may be prepared by reacting a compound of formula (5) with a compound of formula (6) And

And then oxidizing the compound of formula (7) after the substitution reaction to prepare a compound of formula (2).

[Chemical Formula 5]

[Chemical Formula 6]

(7)

In the general formulas (1) to (7) of the present invention, R may be selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms, and may specifically be ethyl or isopropyl.

X may be chloro, bromo or iodo.

Also, Het may be a substituent selected from the group consisting of the following formulas (8a) to (8d).

[Chemical Formula 8a]

[Formula 8b]

[Chemical Formula 8c]

[Chemical Formula 8d]

In the present invention, the statin compound may be rosuvastatin, pitavastatin, fluvastatin or cerivastatin.

Salts of the statins in the present invention include alkali or alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium and strontium of statins; May be an ammonium salt substituted with hydrogen, lower alkyl, lower cycloalkyl, aryl or allylalkyl, and specifically may be a sodium salt, a potassium salt or a calcium salt.

In one embodiment, the process for preparing statins or salts thereof of the present invention comprises

(1) reacting a compound of formula (5) with a compound of formula (6) to produce a compound of formula (7);

(2) subjecting the compound of formula (7) to a substitution reaction and then oxidizing the compound to prepare a compound of formula (2);

(3) reacting the compound of formula (2) with a compound of formula (3) to produce a compound of formula (4); And

(4) decomposing the compound of formula (4) to prepare a statin compound of formula (1).

The above production method can be represented by the following Reaction Scheme 1.

[Reaction Scheme 1]

As shown in Scheme 1, the method for preparing the statin compound of the present invention or its salt will be described in more detail as follows.

Step (1) of the present invention is a step of reacting a compound of formula (5) with a compound of formula (6) to prepare a compound of formula (7).

In the present invention, the compound of Chemical Formula 5 may be prepared by a known method or a commercially available product may be used.

In the above step, the compound of formula (7) can be obtained by reacting the compound of formula (5) with an acetate compound of formula (6) in an organic solvent. The compound of formula (6) may be used in an amount of 0.5 to 5 molar equivalents, or 1 to 2 molar equivalents based on 1 molar equivalent of the compound of formula (5). The organic solvent may be a polar aprotic solvent, for example, dimethylsulfoxide (DMSO), dimethylformaldehyde (DMF), or a mixture thereof. In the case of DMSO or DMF, since the starting material is dissolved well in comparison with other organic solvents, it can be easily used.

 In the present invention, step (2) is a step of preparing the compound of formula (2) after the substitution reaction of the compound of formula (7).

In the above step, the compound of the formula (2) can be easily prepared by substituting the compound of the formula (7) by a conventional method and then oxidizing the compound.

The substitution and oxidation can be carried out in the presence of TEMPO (2,2,6,6-tetra-methylpiperidine-1-oxide). In particular, the reaction can be carried out by dissolving the compound of formula (7) in a solvent followed by addition of TEMSO. As the solvent, ethylacetate, dichloromethane or a mixture thereof may be used.

In the above step, at least one selected from the group consisting of a base, an oxidizing agent and a co-oxidizing agent may be further used. As the base, a carbonate, a hydroxide, a hydride, an alkoxide or an alkyl compound of an alkali metal, a carbonate, a hydroxide, a hydride, an alkoxide or an alkyl compound of an alkaline earth metal can be used. Specifically, sodium hydrogen carbonate (NaHCO ₃ ) Can be used. As the oxidizing agent, sodium hypochlorite (NaOCl), oxone, and Dess-Martin reagent can be used. As the auxiliary oxidizing agent, an alkali metal halide, an alkaline earth metal halide, or the like can be used. Specifically, sodium bromide (NaBr) can be used.

Step (3) of the present invention is a step of reacting a compound of formula (2) with a compound of formula (3) to prepare a compound of formula (4).

In the above step, the compound of formula (3) can be prepared by a known conventional method.

In this step, the compound of formula (4) can be obtained by reacting the compound of formula (2) with the compound of formula (3) in an organic solvent. The compound of Formula 3 may be used in an amount of 0.5 to 5 molar equivalents, or 1 to 2 molar equivalents based on 1 molar equivalent of the compound of Formula 2. As the organic solvent, dimethylsulfoxide (DMSO), dimethylformaldehyde (DMF) or a mixture thereof may be used. Since the solvent dissolves the starting material well in comparison with other organic solvents, it can be easily used.

In the above step, a base may be further used in the reaction. The bases can be used for the alkali metal carbonate, hydroxide, hydride, alkoxide or alkyl compound, or an alkaline earth metal carbonate, hydroxide, alkoxide or alkyl compound, or the like and, in particular potassium carbonate (K ₂ CO ₃ ) Can be used.

In the present invention, step (4) is a step of decomposing the compound of formula (4) to prepare the statin compound of formula (1).

In this step, the diol group and the R group of the compound of Formula 4 are removed. The diol group can be removed through an acid treatment using a known method, and the R group can be removed through a saponification reaction using sodium hydroxide or potassium hydroxide.

Through the above step, a statin compound or a salt thereof can be finally prepared.

In addition, the compound of the formula (IV), which is produced in the method for producing the statin of the present invention, is a novel compound used for producing a statin compound or a salt thereof. Accordingly, the present invention provides a compound of formula (4).

[Chemical Formula 4]

Wherein R may be selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms,

Het may be a substituent selected from the group consisting of the following formulas (8a) to (8d).

[Chemical Formula 8a]

[Formula 8b]

[Chemical Formula 8c]

[Chemical Formula 8d]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, by using a novel intermediate compound, it is possible to efficiently produce a statin compound or its salt by an industrially easy method as compared with the conventional method.

Hereinafter, the present invention will be described in detail with reference to examples. The following examples illustrate the invention and are not intended to limit the scope of the invention. These embodiments are provided so that the disclosure of the present invention is not limited thereto and that those skilled in the art will fully understand the scope of the present invention and that the present invention is not limited by the scope of the claims Only.

Example

Example  1. Preparation of the compound of formula (7)

In the examples, rosuvastatin calcium salt was prepared according to the following reaction scheme 1-1 or 1-2.

[Reaction Scheme 1-1]

[Reaction Scheme 1-2]

 (1) Synthesis of 7-1 (2- ethoxy -2- oksoethyl  2-(( 4R, 6S ) -6- ( hidroxymethyl ) -2,2-dimethyl-1,3- dioxan -4- yl ) acetate production

1. Compound (5) (4.0 g, 17.68 mmol, 1 eq) was dissolved in 40 ml of dimethyl sulfoxide (DMSO).

2. K ₂ CO ₃ (1.22 g, 8.84 mmol, 0.5 eq) was added, and the mixture was stirred at room temperature for 30 minutes.

3. 3.40 ml (26.52 mmol, 1.5 eq) of ethyl bromoacetate was added and the temperature was raised to 60 ° C.

4. After stirring for 5 hours, water and ethyl acetate were added to separate layers.

5. The separated organic layer was dried over MgSO ₄ and concentrated under reduced pressure to obtain crude product.

6. Column purification with ethyl acetate: n-hexane = 1: 3 gave 3.74 g (yield: 73%).

(2) Synthesis of 7-2 (2- isopropoxy -2- oksoethyl  2-(( 4R, 6S ) -6- ( hidroxymethyl ) -2,2-dimethyl-1,3-dioxan-4-yl) acetate

1. Compound (5) (3.0 g, 13.26 mmol, 1 eq) was dissolved in 30 ml of DMSO.

2. K ₂ to put the _{CO 3 0.92 g (6.63 mmol,} 0.5eq) and stirred for 30 minutes at room temperature.

3. 2.48 ml (19.89 mmol, 1.5 eq) of isopropyl chloroacetate was added and the temperature was raised to 60 ° C.

After stirring for 5 hours, the reaction was terminated and water and ethyl acetate were added to separate the layers.

5. The separated organic layer was dried with MgSO ₄ and concentrated under reduced pressure to obtain crude product.

6. Column purification with ethyl acetate: n-hexane = 1: 3 gave 3.43 g of product (yield: 85%).

Example  2. Preparation of compound of formula 2

(1) Synthesis of 2-1 (2- ethoxy -2- oksoethyl  2-(( 4R, 6S ) -6- formyl -2,2- dimethyl  -1,3-dioxan-4-yl) acetate)

1. 4.0 g (13.78 mmol, 1 eq) of the compound of formula (7-1) was dissolved in CH ₂ Cl ₂ (0.69 mmol, 0.05 eq), 0.27 g (2.76 mmol, 0.2 eq) of KBr and 2.32 g (27.56 mmol, 2 eq) of NaHCO ₃ were added to the solution.

2. An ice bath was installed and cooled to 0 ° C.

3. Using a dropping funnel, slowly add 41 g (27.56 mmol, 2eq) of NaClO 5% in water over 30 minutes, warm to room temperature and stir for 1 hour.

4. When the reaction was completed, water and CH ₂ Cl ₂ were added to separate the layers.

5. The separated organic layer was dried with MgSO ₄ and concentrated under reduced pressure to obtain crude product.

6. Column purification with ethyl acetate: n-hexane = 1: 4 gave 2.80 g of product (yield: 70%).

(2) Synthesis of 2- (2- isopropoxy -2- oksoethyl  2-(( 4R, 6S ) -6- formyl -2,2-dimethyl 1,3- dioxan -4- yl ) acetate production

1. 3.5 g (11.50 mmol, 1 eq) of formula 7-2 was dissolved in CH ₂ Cl ₂ (0.25 g, 2.30 mmol, 0.2 eq) and 1.93 g (23.00 mmol, 2 eq) of NaHCO ₃ were added to the reaction mixture, followed by addition of 0.090 g (0.58 mmol, 0.05 eq) of TEMPO.

2. An ice bath was installed and cooled to 0 ° C.

3. Using a dropping funnel, slowly add 34 g (23.00 mmol, 2 eq) of NaClO 5% in water over 30 minutes, warm to room temperature and stir for 1 hour.

4. When the reaction was completed, water and CH ₂ Cl ₂ were added to separate the layers.

5. The separated organic layer was dried with MgSO ₄ and concentrated under reduced pressure to obtain crude product.

6. Purification of the residue by column chromatography with ethyl acetate: n-hexane = 1: 4 gave 2.95 g of the product (yield: 85%).

Example  3. Preparation of the compound of formula 4

(1) Synthesis of 4-1 (2- ethoxy -2- oksoethyl  2- ((4R, 6S) -6- (E) -2- (4- (4-fluorophenyl) -6-isopropyl-2- (N- methylmethylsulfonamido) pyrimidin- -dimethyl-1,3-dioxan-4-yl) acetate)

1. 3.91 g (5.7 6 mmol, 1.0 eq) of TMPBr and 2.39 g (17.27 mmol, 3 eq) of K ₂ CO ₃ were added to 15 ml of DMSO and stirred.

2. The compound of Formula 2-1 (1.66 g, 5.76 mmol, 1.0 eq) was dissolved in 5 ml of DMSO and added.

3. After raising the temperature to 60 ° C, the mixture was stirred for 6 hours.

4. After the reaction was completed, the reaction mixture was cooled to room temperature and then layered using water and toluene.

5. The separated organic layer was dried with MgSO ₄ and concentrated under reduced pressure to obtain crude product.

6. Purification of the residue by column chromatography with ethyl acetate: n-hexane = 1: 5 gave 1.18 g of the product (yield: 34%).

(2) Synthesis of 4-2 (2- isopropoxy -2- oksoethyl  2- ((4R, 6S) -6- (E) -2- (4- (4-fluorophenyl) -6-isopropyl-2- (N- methylmethylsulfonamido) pyrimidin- -dimethyl-1,3-dioxan-4-yl) acetate

1. 6.55 g (9.66 mmol, 1 eq) of TMPBr and 4.00 g (28.98 mmol, 3 eq) of K ₂ CO ₃ were added to 20 ml of DMSO and stirred.

2. 2.92 g (9.66 mmol, 1 eq) of the compound of the formula 2-2 was dissolved in 10 ml of DMSO, and the mixture was added.

3. After raising the temperature to 60 ° C, the mixture was stirred for 6 hours.

4. After the reaction was completed, the reaction mixture was cooled to room temperature and then layered using water and toluene.

5. The separated organic layer was dried with MgSO ₄ and concentrated under reduced pressure to obtain crude product.

6. Purification of the residue by column chromatography with ethyl acetate: n-hexane = 1: 5 gave 2.95 g of the product (yield: 85%).

Example  4. Rosuvastatin  Calcium salt ( rosuvastatin  calcium salt

One. 30 ml of acetonitrile was added to 2.94 g (4.73 mmol, 1 eq) of the compound of the formula 4-2, followed by stirring.

2. Slowly add 2.36 ml (0.24 mmol, 0.05 eq) of 0.1 M HCl over 30 minutes, raise the temperature to 40 ° C and stir for 4 hours.

3. When the reaction was completed, 10 ml of water and 20 ml of tetrahydrofuran were added in the crude state after the solvent was completely blown.

4. 5.20 ml (5.20 mmol, 1.1 eq) of 1N NaOH was added and the mixture was stirred at 0 ° C for 1 hour.

5. When the reaction was completed, the solvent was completely blown and 10 ml of water was added in a crude state.

6. 0.289 g (2.60 mmol, 0.55 eq) of CaCl ₂ was dissolved in 2 ml of water and placed in a reaction vessel.

7. Stir strongly at 0 < 0 > C for 1 hour and then the precipitated solid was filtered.

8. The filtered solid was dried to give 1.9 g of product (yield: 40%).

Claims (6)

Reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4); And
Decomposing the compound of Formula 4 to produce a statin compound of Formula 1 or a salt thereof;
Process for preparing statins or salts thereof:
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In the above formula
R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms,
X is chloro, bromo or iodo,
Het is a substituent selected from the group consisting of the following formulas (8a) to (8d).
[Chemical Formula 8a]

[Formula 8b]

[Chemical Formula 8c]

[Chemical Formula 8d]

The method according to claim 1,
Wherein the salt of the statin compound of formula (1) is a sodium salt, a potassium salt or a calcium salt.
The method according to claim 1,
And R is ethyl or isopropyl.
The method according to claim 1,
Reacting a compound of formula (5) with a compound of formula (6) to produce a compound of formula (7); And
Wherein the compound of formula (7) is prepared through a substitution reaction followed by oxidation to obtain a compound of formula (2).
[Chemical Formula 5]

[Chemical Formula 6]

(7)

In the above formula
R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms,
X is chloro, bromo or iodo.
A compound of formula 4:
[Chemical Formula 4]

In Formula 4,
R is selected from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms,
Het is a substituent selected from the group consisting of the following formulas (8a) to (8d).
[Chemical Formula 8a]

[Formula 8b]

[Chemical Formula 8c]

[Chemical Formula 8d]

6. The method of claim 5,
And R is ethyl or isopropyl.

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