KR101063146B1 - Method for preparing pitavastatin intermediate and method for preparing pitavastatin hemicalcium salt - Google Patents

Abstract

The present invention provides a method for preparing pitavastatine intermediate and a method for preparing pitavastatin hemi calcium salt using the same.

The present invention enables simple and efficient mass production of pitavastatin hemicalcium salts.

Pitavastatin, preparation method

Description

The preparation of Pitavastatine intermediate and the preparation of Pitavastatine hemi-calcium salt using the preparation method}

The present invention relates to a process for preparing pitavastatine intermediates and a novel process for preparing pitavastatin hemicalcium salts using the same.

Pitavastatine has a cholesterol lowering effect by inhibiting the activity of HMG CoA reducing agent (3-hydroxy-3-methyl-glutaryl coenzyme A reductase).

In general, medicines that exhibit cholesterol-lowering effects through HMG CoA inhibition are called 'statins', the first of which is the first generation of statins developed by microbial fermentation products, simvastatin, lovastatin, and pravastatin ( pravastatin, and the second generation of statins include synthetic statins Atorvastatin, fluvastatin, rovavastatin, pitavastatin, and the like.

Among these, pitavastatin has a low-density lipoprotein cholesterol (LDL-C) level lowering effect, and when it is lower than normal, it increases the high-density lipoprotein cholesterol (HDL-C) which may be a cause of dementia or stroke. In addition, since pitavastatin is not metabolized by CYP450, drug interactions are low, and the drug blood concentration is maintained stably in hyperlipidemic patients taking multiple drugs due to hypertension or diabetes.

For this reason, commercial production techniques of pitavastatin and its intermediates have been studied a lot, and the contents of these are described in European Patent EP 00304063; European Patent EP 0520406; United States Patent WO 04/070717; WO 02/81451; WO 02/63028; WO 05/063728; WO 03/016317; WO 03/064392 and the like.

In particular, EP 00304063 discloses a process for preparing the final pitavastatin sodium salt through a total of 10 steps using Compound A and Compound B as starting materials, as shown in the following Reaction Scheme 1.

Scheme 1

However, the preparation method according to [Scheme 1] is not only a complicated reaction step, but also requires a material that requires difficult and dangerous conditions such as DIBAL (Diisobutylaluminium hydride) and n-BuLi in several stages, There is a problem in that the stereoisomer should be separated in the step of preparing compound H in compound G, which is a process of preparing a secondary alcohol.

In addition, WO 03/070717 discloses a method for preparing pitavastatin hemi-calcium salts by starting compounds A and B from a total of five steps, as shown in Scheme 2 below.

Scheme 2

However, the manufacturing method according to [Scheme 2] is difficult to use industrially because it uses a very expensive Ru chiral catalyst and LDA (Lithium diisopropylamide) that requires a difficult process conditions.

International patent WO 03/064392 discloses a process for preparing pitavastatin hemi-calcium salt of Scheme 3 below.

Scheme 3

However, in the production method according to [Scheme 3], the compound B, which is an expensive stereoselective structure in the first step reaction, is used as a starting material, and in the three step reaction, BuLi, which requires difficult conditions in the process, is used in the fourth step. In the reaction, there are problems such as the use of an expensive base cesium carbonate, and in the seventh step, there is a lot of problems to industrialize because it is difficult to separate the isomers after the stereoselective reduction reaction.

As described above, the pitavastatin hemicalcium salt manufacturing method known to date is relatively easy to produce on a commercially acceptable scale, and therefore, it is necessary to develop a simpler and cheaper pitavastatin hemicalcium salt manufacturing process.

Therefore, the researchers have developed a method for producing pitavastatin hemicalcium salt, which is more convenient and useful for industrial production.

It is an object of the present invention to provide a method for producing a simple and efficient mass production of pitavastatin hemicalcium salt.

The present invention provides a process for preparing the compound of formula (6) which is an intermediate useful for preparing pitavastatin hemicalcium salts.

That is, the present invention provides a method for selectively preparing the compound of formula 6, which is the (E) -isomer by a wittig reaction of the compound of formula 4 and the following formula 5 in the presence of a base:

[Formula 4]

In the formula, Y is PPh ₃ ⁺ Br ^_ , P (O) (OEt) ₂ or P (O) Ph ₂ .

[Chemical Formula 5]

[Formula 6]

The base used in the compound of formula 6 of the present invention is preferably a metal hydrate, metal oxide or metal carbonate, for example potassium carbonate, sodium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium hydroxide, It is preferably one or more selected from potassium hydroxide, potassium t-butoxide and sodium methoxide. Even more preferred are lithium hydroxide or lithium hydroxide hydrate.

In this case, the base may be used in an amount of 1 to 5 equivalents based on the compound of formula 4, and the preferred equivalent amount is 1.5 to 3 equivalents. The reaction time is 1 to 10 hours, preferably 2 to 4 hours.

In addition, in the method of preparing the compound of formula 6, the dehydrating agent may be further added to promote the reaction. The dehydrating agent removes water generated during the reaction. In the present invention, a dehydrating agent generally used in the pharmaceutical manufacturing industry in the field of organic chemistry may be used. For example, a molecular sieve, magnesium sulfate, or sodium sulfate may be used. Etc.

The process for preparing the compound of formula 6 of the present invention is an ether solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, toluene, acetonitrile, dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, or methylene chloride , Halogenated solvents such as 1,2-dichloroethane, chloroform and the like, and the like, and these solvents may be used alone or as a mixed solvent. The reaction temperature is suitably in the range of 0 to 150 ° C, more preferably 30 to 100 ° C.

The process for preparing the compound of formula 6 of the present invention provides the (E) -isomer selectively and very predominantly (approximately 9: 1 molar ratio of (E)-and (Z) -isomers). Therefore, the compound of formula 6 which is 99% or more of the (E) -isomer can be obtained through a known simple recrystallization method. The solvent used for recrystallization may include polar solvents such as dichloromethane, ethyl acetate, isopropyl alcohol, methanol, diethyl ether, sulfolane and nonpolar solvents such as hexane, pentane, heptane, and at least one of these solvents. Can be selected and used as a mixed solvent.

The compound of formula (5) used in the method of preparing the compound of formula (6) of the present invention is prepared directly or by commercially available t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2- Dimethyl-1,3-dioxan-4-yl) acetate can be synthesized and used at a high yield of 90% or more through the commonly known method, Swern oxidation. For example, t-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate and oxalyl chloride And DMSO (dimethylsulfoxide) in a methylene chloride solvent to prepare a compound of formula (5).

In addition, the present invention provides a compound of formula (3) by a) introducing a bromine group to a hydroxyl group of the formula (2); b) a method of preparing the compound of formula 4 by reacting the compound of formula 3 of step a) with one selected from triphenylphosphine, ethyldiphenylphosphine and triethylphosphite:

[Formula 2]

(3)

[Formula 4]

In the formula, Y is PPh ₃ ⁺ Br ^_ , P (O) (OEt) ₂ or P (O) Ph ₂ .

In the method for preparing the compound of formula 4 of the present invention, the compound of formula 2 as a starting material may be prepared by a known method or commercially available.

In the method for preparing a compound of formula 4 of the present invention, the bromine group introduction reaction of step a) means a conventional bromine group introduction reaction in which a hydroxy group is substituted with a bromine group, and phosphorus tribromide (PBr ₃ ) or thionyl bromide It is preferable to make it, and it is more preferable to use phosphorus tribromide. In the reaction of step a), phosphorus tribromide may be used in the range of 1 to 3 equivalents relative to the compound of Formula 2, and preferably in the range of 1.05 to 1.5 equivalents. The reaction solvent is preferably a halogenated solvent, for example, ditlo methane, dichloroethane, carbon tetrachloride, chloroform, and the like, and more preferably dichloromethane. The reaction temperature is appropriately in the range of 0 to 40 ° C, preferably 0 to 20 ° C.

In the method for preparing a compound of Formula 4 of the present invention, one selected from b) triphenylphosphine, ethyldiphenylphosphine and triethylphosphite may be used in the range of 1 to 3 equivalents compared to the compound of Formula 3 It is preferably used in the range of 1.05 to 1.5 equivalents. As the reaction solvent, toluene, xylene, acetonitrile, dioxane, tetrahydrofuran, 1,2-dichloroethane, dichloromethane, chloroform and the like can be used as the non-hydrogen solvent capable of dissolving the compound of formula (3). The reaction temperature is suitably in the range of 30 to 150 ° C, preferably 90 to 120 ° C.

In addition, the present invention provides a compound of formula (7) by a) hydrolyzing the compound of formula (6) prepared by the method of the present invention in the presence of a base and deprotecting in the presence of an acid, and b) formula (7) of step a). There is provided a method of reacting a compound with a base and calcium hydrochloride to produce the pitavastatin hemicalcium salt of formula (I):

  [Formula 6]

[Formula 7]

[Formula 1]

In the method for preparing pitavastatin hemi calcium salt of the present invention, the base groups of steps a) and b) are each independently potassium carbonate, sodium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium hydroxide, potassium hydroxide. It is preferable that it is at least 1 sort (s) chosen from a hydroxide, potassium t-butoxide, and sodium methoxide, and sodium hydroxide is more preferable.

In the method for preparing pitavastatin hemicalcium salt of the present invention, the hydrolysis reaction solvent of step a) is preferably used as a mixed solvent of an organic solvent and an aqueous solution in which a base is dissolved. The organic solvent used at this time is an acetonitrile, dioxane, tetrahydrofuran, acetone or an alcohol solvent such as methanol, ethanol, isopropyl alcohol, etc. which can be mixed with water, and preferably ethanol. 2-10 N are preferable and, as for the density | concentration of the base of aqueous solution, 4-6 N are more preferable.

In the method for preparing pitavastatin hemi calcium salt of the present invention, the deprotection reaction after the hydrolysis in step a) is preferably performed by adding an acid solution to the mixed solution to lower the pH to 3 or less. Acids usable here include hydrochloric acid, sulfuric acid, triroacetic acid, toluenesulfonic acid, acetic acid, Dowex 50-W (H ⁺ ), and the like.

In the method for preparing phytavastatin hemi calcium salt of the present invention, step b) may be prepared using phytavastatin calcium salt using calcium chloride (calcium chloride) by the method disclosed in Korean Patent Application No. 1992-0011018.

The process for preparing the intermediate of the pitavastatin (Formula 6) of the present invention uses industrially safe and inexpensive bases, and optionally produces (E) -isomers, resulting in high yields and simple separation processes. In addition, the method for preparing pitavastatin calcium salt of the present invention using the same is much simpler than known methods and is economically and industrially useful.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Hereinafter, the reagents used in the examples are purchased from Aldrich, TCI, and Acros, unless otherwise noted, and ¹ H-NMR is measured using a Varian Inova 500 MHz FT-NMR (manufacturer Varian). .

Example 1 Preparation of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline

(2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) methanol (50 g) was dissolved in methylene chloride (1 L), cooled to 0 ^o C, and PBr ₃ (48.4 g) was slowly added dropwise. . After the addition was completed, the reaction temperature was raised to room temperature and stirred for 5 hours. Again, the reaction temperature was cooled to 0 ^o C using an ice bath, and 6N-NaOH aqueous solution was added dropwise until pH = 6 and saturated sodium carbonate solution was added dropwise until pH 7. . The organic layer of this solution was separated, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline (55.3) as an ivory solid. g) was obtained. (91% yield)

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.16 (m, 2H), 1.42 (m, 2H), 2.51 (m, 1H), 4.60 (s, 2H), 7.20 ~ 7.41 (m, 6H), 7.61 (m, 1 H), 8.0 (d, 1 H)

Example 2 [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -methyltriphenylfo

Preparation of Sponium Bromide

3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline (50 g) prepared in Example 1 was dissolved in toluene (1 L), and triphenylphosphine (55.2 g) was added thereto. It was stirred at reflux at 110 ^° C. for 3 hours. After cooling the reaction solution to room temperature, the resulting solid was filtered, washed with toluene (0.5 L) and dried under reduced pressure to give [2-cyclopropyl-4- (4-fluorophenyl) quinoline- as an ivory solid. 3-yl] -methyltriphenylphosphonium bromide (85 g) was obtained. (Yield 98%)

¹ H NMR (500 MHz, CDCl ₃ ): δ 0.75 (m, 2H), 1.15 (m, 2H), 2.35 (m, 1H), 5.51 (d, 2H), 8.0-8.6 (m, 23H)

Example 3 Preparation of t-Butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate

Oxalyl chloride (Oxalyl chloride, 5.8 ml) was dissolved in methylene chloride (100 ml) and cooled to -78 ^° C. To this, a solution of DMSO (6.6 ml) dissolved in methylene chloride (50 ml) was slowly added dropwise. The reaction solution was stirred for 15 minutes at -78 ^o C, and then tert-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxane A solution of -4-yl) acetate (10 g) in methylene chloride (50 ml) was slowly added dropwise and stirred for 20 minutes. Thereafter, triethylamine (16.2 ml) was added dropwise to the reaction solution at -78 ^° C., stirred for 10 minutes, the reaction temperature was gradually raised to room temperature, and the reaction was confirmed by TLC (thin-layer chromatography). ^Was cooled back to 0 ^° C. and water was added to terminate the reaction. After raising the reaction solution to room temperature, the organic layer was separated, and the obtained organic layer was washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate, concentrated to light yellow oil (t-butyl 2-((4R)). , 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate (9.5 g) was obtained. (96% yield)

^I H NMR (500 MHz, CDCl ₃ ): δ 1.45 (m, 1H), 1.46 (s, 9H), 1.46 (s, 3H), 1.50 (s, 3H), 1.85 (dt, 1H), 2.35 (dd , 1H), 2.47 (dd, 1H), 4.35 (m, 2H), 9.58 (s, 1H)

Example 4 t-butyl 2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Preparation of 2,2-dimethyl-1,3-dioxan-4-yl) acetate

[2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -methyltriphenylphosphonium bromide (28 g) prepared in Example 2 was converted to tetrahydrofuran / acetonitrile (20/1, v / v, 100ml), and 4Å (5g) of Molecular seives were added and the temperature was raised to 60 ^° C. Lithium hydroxide hydrate (2.4 g) was added to the reaction solution, and t-butyl 2-((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxane- was prepared in Example 3. A solution of 4-yl) acetate (10 g) in tetrahydrofuran / acetonitrile = 10/1 (v / v) (50 ml) was added dropwise. Thereafter, the reaction solution was stirred under reflux for 3 hours, and then the reaction solution was cooled to room temperature and concentrated under reduced pressure. This concentrate was dissolved in heptane (300ml) and washed with 0.1N HCl (200ml X 2) and saturated brine (200ml). The obtained organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained solid was recrystallized using ethyl acetate and hexane to give tert-butyl 2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) as an ivory solid. ) Quinolin-3-yl) vinyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate (15 g) was obtained. (Yield 75%, E / Z = 99/1)

^I H NMR (500 MHz, CDCl ₃ ): δ 0.95-1.6 (m, 21H), 2.25-2.55 (m, 3H), 4.01-4.55 (m, 2H), 5.60 (dd, 1H), 6.55 (d, 1H), 7.10-7.40 (m, 6H), 7.60 (t, 1H), 7.98 (d, 1H)

Example 5 (E, 3R, 5S) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhept-6-enoate Manufacture

T-butyl 2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) prepared in Example 4) -2,2-Dimethyl-1,3-dioxan-4-yl) acetate (6 g) was suspended in ethanol (10 ml), 1N aqueous sodium hydroxide solution (20 ml) was added dropwise and stirred for 2 hours. As the reaction proceeded, the suspension became a uniform solution, and the completion of the reaction was confirmed by TLC. Thereafter, water (20 ml) was added to the reaction solution, and the mixture was extracted with diethyl ether (50 ml x 2). The organic layer was discarded, the aqueous layer was adjusted to pH = 1 with concentrated hydrochloric acid and stirred for 30 minutes. After completion of the deprotection reaction, the reaction solution was extracted with chloroform (100 ml x 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E, 3R, 5S) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhept-6-enoate (4.15 g) was obtained. (Yield 85%)

^I H NMR (500 MHz, CDCl ₃ ): δ 1.10 (m, 2H), 1.40 (m, 3H), 1.61 (m, 1H), 2.40 (m, 1H), 2.52 (d, 2H), 2.85 to 3.50 (bm, 3H), 4.11-4.21 (m, 1H), 4.45 (m, 1H), 5.59 (dd, 1H), 6.62 (d, 1H), 7.09-7.41 (m, 6H), 7.65 (m, 1H ), 7.95 (d, 1 H)

Example 6 Preparation of Pitavastatin Calcium Salt

(E, 3R, 5S) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhept-6-eno prepared in Example 5. Eight (1.2 g) was dissolved in water (20 ml) and 1N aqueous sodium hydroxide solution (2.4 ml), and calcium chloride solution (0.47 g) dissolved in water (20 ml) was added to the reaction solution and stirred for 24 hours. The resulting white solid was filtered, washed with hexane (20 ml x 2) and dried to obtain pitavastatin calcium salt (0.9 g) as a white solid. (Yield 76%)

¹ H NMR (500 MHz, DMSO-d ⁶ ): δ 0.95-1.55 (m, 2H), 1.35 (t, 3H), 1.70-2.30 (m, 2H), 2.85-3.50 (m, 4H), 3.70- 4.35 (m, 1H), 5.25-5.72 (m, 1H), 6.15-6.65 (m, 1H), 6.95-8.10 (m, 8H)

Claims (12)

A compound of Formula 6, which is an (E) -isomer by a wittig reaction in the presence of a base and a dehydrating agent in a mixed solvent of the following Chemical Formula 4 and Chemical Formula 5 with one selected from dioxane and tetrahydrofuran and acetonitrile How to selectively prepare: [Formula 4]

In the formula, Y is PPh ₃ ⁺ Br ^_ , P (O) (OEt) ₂ or P (O) Ph ₂ . [Chemical Formula 5]

[Formula 6]

The method of claim 1, wherein the base is a metal hydrate, metal oxide or metal carbonate. The chemical formula according to claim 2, wherein the base is at least one selected from potassium carbonate, sodium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium hydroxide, potassium hydroxide, potassium t-butoxide and sodium methoxide. 6 Preparation of Compounds. delete delete delete delete delete delete The method of claim 1, wherein the dehydrating agent is molecular sieves, magnesium sulfate, or sodium sulfate. The method of claim 10, wherein the dehydrating agent is molecular sieves. delete