KR101548885B1 - Method for preparing (s)-pregabalin precursor by catalytic enantioselective micahel reaction and method for preparing (s)-pregabalin using the (s)-pregabalin precursor - Google Patents

Abstract

According to the present invention, a method for preparing chiral (S)-pregabalin precursors includes a step of enabling an asymmetric Michael reaction of beta-isobutyl nitro alkyne and malonate in the presence of a difunctional chiral catalyst. Accordingly, the present invention can synthesize chiral (S)-pregabalin precursors with high optical selectivity and reactivity under conditions of being harmless to a human body and not causing environmental pollution at low costs by using a catalyst safe to use.

Description

METHOD FOR PREPARING (S) -PREGABALIN PRECURSOR BY CATALYTIC ENANTIOSELECTIVE MICHEL REACTION AND METHOD FOR PREPARING (S) -PREGABALINE PRECURSOR USING THE SAME S) -PREGABALIN USING THE (S) -PREGABALIN PRECURSOR}

The present invention relates to a process for preparing (S) -Pregabalin precursor via asymmetric Michael catalysis and a process for preparing (S) -Pregabalin using the same, and to a process for preparing (S) -pregabalin (S) -pregabalin precursors via asymmetric Michael catalysis and to a process for the preparation of (S) -pregabalin using the same.

(S) -Pregabalin is a medicinal product having analgesic, anticonvulsive and anti-anxiety activity and has been marketed by Pfizer, Inc. as a product bearing the trademark LYRICA Is an important medicinal product that has a huge demand worldwide. Therefore, many manufacturing methods for economically synthesizing (S) -pregabalin have been researched and developed.

(S) -Pregabalin are known, but most of the existing methods are not environmentally friendly, such as using a toxic metal that is not present in pharmaceuticals as a catalyst, or as a medicament through expensive and toxic organic solvents . From this point of view, the method of synthesizing (S) -pregabalin in an economical and environmentally friendly manner would be of great value.

It is an object of the present invention to provide a method for preparing a chiral (S) -pregabalin precursor in an economical and environmentally friendly manner through a reaction at a high reaction rate.

It is another object of the present invention to provide a process for preparing (S) -Pregabalin using (S) -Preparin precursors.

A method for preparing a chiral (S) -pregabalin precursor through asymmetric Michael catalysis to solve one object of the present invention is provided. The method includes asymmetric Michael reaction of beta-isobutyl nitroalkene represented by the formula (2) and malonate represented by the formula (3) in the presence of a bifunctional chiral catalyst represented by the formula (1).

[Chemical Formula 1]

(2)

(3)

R ₁ represents an ethyl group or a vinyl group, Ar represents a substituted or unsubstituted aryl group, R ₂ and R ₃ each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl Or a substituted or unsubstituted heteroaryl group.

In one embodiment, the asymmetric Michael reaction can produce a chiral (S) -pregabalin precursor represented by Formula 4 below.

[Chemical Formula 4]

R ₂ and R ₃ each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

In one embodiment, Ar in formula (1) represents a phenyl group, a naphthalenyl group, an anthracenyl group or a pyrenyl group, and at least one hydrogen atom of Ar is an alkyl group in which at least one hydrogen atom is substituted or unsubstituted with a halogen atom Or a halogen atom. At this time, Ar may be a 3,5-bis (trifluoromethyl) phenyl group.

In one embodiment, the chiral catalyst represented by Formula 1 may include a compound represented by Formula 5 below.

[Chemical Formula 5]

In one embodiment, the chiral catalyst represented by the formula (1) may include a compound represented by the following formula (6).

[Chemical Formula 6]

In one embodiment, the content of the chiral catalyst represented by the formula (1) may be from 2 mol% to 50 mol% based on the beta-isobutyl nitroalkyne represented by the formula (2).

In one embodiment, the content of malonate represented by the formula (3) may be 1 to 5 equivalents based on the amount of the beta-isobutyl nitroalkyne represented by the formula (2).

In one embodiment, the asymmetric Michael reaction can be performed at -20 < 0 > C to 100 < 0 > C. Preferably, the asymmetric Michael reaction can be carried out at -15 [deg.] C to 50 [deg.] C.

In one embodiment, the asymmetric Michael reaction can be carried out in at least one selected from an organic solvent, pure distilled water, aqueous inorganic salt solution and saturated aqueous inorganic salt solution.

In one embodiment, the asymmetric Michael reaction can be carried out in at least one selected from aqueous sodium chloride solution, aqueous lithium chloride solution, aqueous cesium chloride solution and aqueous potassium chloride solution. Preferably, the asymmetric Michael reaction can be carried out in aqueous sodium chloride solution.

A further aspect of the present invention is a process for preparing (S) -pregabalin using (S) -pregabalin precursor. In this method, the (S) -pregabalin precursor is prepared according to the process for preparing the (S) -plavarin precursor of the present invention as described above and used to prepare (S) -pregabalin.

According to the process for preparing the (S) -pregabalin precursor through the asymmetric Michael catalysis of the present invention and the process for preparing (S) -Preparboline using the same, a metal catalyst which is harmful to the human body is used or an expensive Instead of using a solvent, the (S) -pregabalin precursor is produced in the presence of a chiral catalyst, which can be easily synthesized from a natural product, and a hydrophobic hydration effect is greatly exhibited. Therefore, a conventional organic solvent is used (S) -pregabalin precursor at a significantly faster rate than the conventional method, and is environmentally safe and non-explosive. In addition, a precursor for preparing (S) -Pregabalin, which is a blockbuster drug, can be synthesized to have a high enantiomeric selectivity using a water or inorganic salt aqueous solution as a medium. In addition, it can be synthesized as (S) -pregabalin drug using the (S) -pregabalin precursor prepared through the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The present invention is capable of various modifications and various forms, and specific embodiments are illustrated in the drawings and described in detail in the text. It is to be understood, however, that the invention is not intended to be limited to the particular forms disclosed, but on the contrary, is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention. Like reference numerals are used for like elements in describing each drawing.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In the present application, the term "comprises" or "having ", etc. is intended to specify that there is a feature, step, operation, element, part or combination thereof described in the specification, , &Quot; an ", " an ", " an "

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the contextual meaning of the related art and are to be interpreted as either ideal or overly formal in the sense of the present application Do not.

(S) -Preparin < / RTI > Precursor

The method for producing a chiral (S) -pregabalin precursor according to the present invention comprises reacting a compound represented by the formula (3) with a compound represented by the formula (3) in the presence of a bifunctional chiral catalyst represented by the formula (1) And reacting the malonate represented by the asymmetric Michael.

[Chemical Formula 1]

(2)

(3)

R ₁ represents an ethyl group or a vinyl group, Ar represents a substituted or unsubstituted aryl group, R ₂ and R ₃ each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl Or a substituted or unsubstituted heteroaryl group.

For example, Ar may be an aryl group having 6 to 20 carbon atoms, and at least one of the hydrogen atoms of Ar may be substituted with a substituent. Examples of the substituent include a halogen group and an alkyl group having 1 to 3 carbon atoms, and at least one of the hydrogen atoms of the alkyl group may be substituted with a halogen atom. For example, Ar may include a phenyl group, a naphthalenyl group, an anthracenyl group, or a pyrenyl group. In another example, the substituent may be a trifluoromethyl group, and Ar is a 3,5-bis (trifluoromethyl) phenyl group (3,5-bis (trifluoromethyl) phenyl group) in which two hydrogen atoms are substituted with a trifluoromethyl group. bis (trifluoromethyl) phenyl group).

For example, R ₂ and R ₃ may each independently be an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms, or a heteroaryl group having 4 to 10 carbon atoms. At this time, at least one hydrogen atom of each of the alkyl group, cycloalkyl group, aryl group or heteroaryl group of R ₂ and R ₃ may be substituted by a substituent. Here, the substituent may include an alkyl group having 1 to 12 carbon atoms.

Through the asymmetric Michael reaction, a chiral (S) -pregvaline precursor represented by the following general formula (4) is prepared.

[Chemical Formula 4]

R ₂ and R ₃ each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

In the present invention, the bifunctional chiral catalyst represented by the general formula (1) comprises a derivatized bifunctional cinchona alkaloid comprising a quinuclidine group as a base portion and a squaramide group as an acidic portion, It is a kind of catalyst compound. In the present invention, the bifunctional chiral catalyst represented by the general formula (1) exhibits a bifunctional property capable of simultaneously activating the beta-isobutyl nitroalkyne represented by the general formula (2) and the malonate represented by the general formula (3). The production process according to the present invention can be carried out in an organic solvent or an aqueous solution of water or an inorganic salt but can be carried out in the presence of a bifunctional chiral catalyst represented by the general formula (1) (S) -Pregabalin precursor having a very high optical purity can be rapidly produced using the malonate represented by the general formula (3) and a yield of more than 90% at the maximum with an optical purity of at most 90% .

For example, the bifunctional chiral catalyst represented by the formula (1) may include a compound represented by the following formula (5).

[Chemical Formula 5]

For example, the bifunctional chiral catalyst represented by the formula (1) may include a compound represented by the following formula (6).

[Chemical Formula 6]

The malonate represented by the formula (3) is a nucleophile participating in the asymmetric Michael reaction. Examples of the compound represented by the formula (3) include a compound represented by the following formula (7) and a compound represented by the following formula (8).

(7)

[Chemical Formula 8]

The temperature of the stirring step of stirring for the asymmetric Michael reaction of the compounds represented by the formulas (1) to (3) can be selected within a suitable range by a person skilled in the art, but from the viewpoints of the yield of the reaction and the optical selectivity, , Particularly preferably -15 ° C to 50 ° C.

The asymmetric Michael reaction can be carried out without limitation in an organic solvent or an aqueous solution of water or an inorganic salt. However, when the reaction is carried out in an aqueous solution of water or an inorganic salt, the reaction rate can be improved through the hydrophobic hydration effect. The hydrophobic hydration effect is the effect that substances that do not mix with water excrete and come out of the water in the presence of water. When the asymmetric Michael reaction is carried out in an aqueous solution of water or an inorganic salt, the reaction rate may be two times faster than that in an organic solvent such as dichloromethane.

Examples of the inorganic salt aqueous solution include sodium chloride aqueous solution, lithium chloride aqueous solution, potassium chloride aqueous solution and cesium chloride aqueous solution. These may be used alone or in combination of two or more. Most preferably, an aqueous solution of sodium chloride can be used as the inorganic salt aqueous solution in consideration of the yield and economical efficiency of the reaction.

In the present invention, the content of the bifunctional chiral catalyst represented by the general formula (1) can be suitably selected according to the content of the beta-isobutylnitroalkyne represented by the general formula (2), but is preferably 2 mol% %) To 50 mol%.

The content of malonate represented by the general formula (3) may be suitably in the range of the conventional art based on the content of the beta-isobutylnitroalkyne represented by the general formula (2), but is preferably 1 to 5 equivalents, more preferably 1 To 3 equivalents.

As described above, instead of using a metal catalyst harmful to human body, or using an expensive and environmentally harmful organic solvent, the (S) -pregabalin precursor is produced in the presence of a chin catalyst based on Shin- (S) - pregabalin precursor can be prepared at a remarkably rapid reaction rate when reacted in water or in an aqueous solution of an inorganic salt, since it is highly hydrophobic and hydrated. In addition, a precursor for preparing (S) -Pregabalin, which is a blockbuster drug, can be synthesized to have a high enantiomeric selectivity using a water or inorganic salt aqueous solution as a medium.

In addition, the (S) -pregabalin precursor prepared through the present invention can be used to synthesize (S) -Pregabalin pharmaceuticals.

For example, (S) -pregabalin medicines can be prepared according to the following synthetic reaction schemes.

[Synthetic reaction formula]

Specifically, a chiral (S) -Preparazine precursor represented by the formula (4) (R ₂ , R ₃ = Me) is reacted with Raney-Ni and H ₂ (hydrogen) in the presence of an ethanol solvent at room temperature for 12 hours, Gamma lactam can be produced in a yield of 94%. The resulting (S) -Pregabalin-hydrochloride can be obtained from the obtained isobutyl-gamma-lactam in an aqueous solution of 100 ^° C HCl for 24 hours and neutralized through a basic solution such as NaOH (aq. (S) -Pregabalin can be synthesized.

(Reference: SL Poe, M. Kobaslija and DT McQuade, J. Am. Chem. Soc. , 2007, 129 , 9216-9221.)

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention as defined by the appended claims. And it is natural that such variations and modifications are included in the appended claims.

Example 1: Preparation of chiral (S) -pregabalin precursor

1.0 mmol of beta-isobutylnitroalkane represented by the formula (2), 2.0 mmol of the malonate represented by the formula (7) and 0.05 mmol of the chiral catalyst represented by the formula (6) were dissolved in 3.0 mL of saturated sodium chloride aqueous solution as a brine At 0 < 0 > C for 9 hours.

After completion of the stirring, the reaction mixture was extracted with dichloromethane solvent, the solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain a chiral (S) -pregabalin precursor (93% yield).

The prepared chiral (S) -pregabalin precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL OD-H, 90:10, hexane: isopropyl alcohol, 220 nm, 1.0 ml), t (by-product) = 5.8 min, t (main product) = 11.6 min, 91% ee (optically selective), (S) -form.

^{1 H NMR (300 MHz, CDCl} 3, Me 4 Si): δ 4.71 (dd, J = 13.4 Hz and J = 5.3 Hz, 1H), 4.52 (dd, J = 13.4 and J = 6.4 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.67 (d, J = 5.5 Hz, 1H), 2.96 (dq, J = 7.0 and J = 5.5 Hz, 1H), 1.71-1.58 1.37-1.27 (m, 2H), 0.94 (d, J = 2.4 Hz, 3H), 0.91 (d, J = 2.7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.37, 168.18, 76.67, 52.84, 52.71, 52.32, 38.90, 34.88, 25.12, 22.37, 22.13.

Example 2: Preparation of chiral (S) -pregabalin precursor

30 mmol of beta-isobutylnitroalkane represented by the formula (2), 60 mmol of the malonate represented by the formula (7) and 1.5 mmol of the bifunctional chiral catalyst represented by the formula (6) were stirred with 90 mL of a saturated aqueous sodium chloride solution at -2 DEG C for 24 hours After the addition of methyl cyclohexane to the reaction mixture, the reaction mixture was filtered, the methyl cyclohexane solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain a chiral (S) -pregabalin precursor (90% yield). The prepared chiral (S) -pregabalin precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL OD-H, 90:10, hexane: isopropyl alcohol, 220 nm, 1.0 ml / min, t (by-product) = 5.8 min, t (main product) = 11.6 min, 91% ee, (S) -form).

Example 3: Preparation of chiral (S) -pregabalin precursor

0.5 mmol of beta-isobutylnitroalkane represented by the formula (2), 1.0 mol of the malonate represented by the formula (7) and 0.025 mmol of the bifunctional chiral catalyst represented by the formula (6) were stirred with 1.5 mL of a saturated aqueous sodium chloride solution at 20 DEG C for 9 hours Methyl cyclohexane was added to the reaction mixture and the mixture was filtered to recover the bifunctional chiral catalyst represented by Chemical Formula 6. The methyl cyclohexane solvent was removed under reduced pressure and the product was separated by chiral chromatography to obtain chiral ( S) -Pregabalin precursor (94% yield).

The prepared chiral (S) -pregabalin precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL OD-H, 90:10, hexane: isopropyl alcohol, 220 nm, 1.0 ml / min, t (by-product) = 5.8 min, t (main product) = 11.6 min, 91% ee, (S) -form).

Example 4: Preparation of chiral (S) -pregabalin precursors in organic solvents

0.5 mmol of beta-isobutylnitroalkane represented by the formula (2), 1.0 mmol of the malonate represented by the formula (7) and 0.025 mmol of the bifunctional chiral catalyst represented by the formula (6) were reacted with 3.0 mL of dichloromethane at 20 DEG C for 9 hours After stirring, the solvent was removed under reduced pressure and the product was isolated using column chromatography to give a chiral (S) -pregabalin precursor (15% yield).

The prepared chiral (S) -pregabalin precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL OD-H, 90:10, hexane: isopropyl alcohol, 220 nm, 1.0 ml / min, t (by-product) = 5.8 min, t (main product) = 11.6 min, 83% ee, (S) -form.

The production process according to Example 4 showed that the reaction progressed in the aqueous solution was 6 times faster than the reaction progressed in dichloromethane despite the lower reaction temperature under the same reaction conditions as in Example 1 Can be confirmed.

Comparative Example 1: Preparation of chiral (S) -pregabalin precursor using the catalyst analog (Formula 9) in an organic solvent

[Chemical Formula 9]

0.5 mmol of beta-isobutylnitroalkane represented by the formula (2), 1.0 mmol of the malonate represented by the formula (7) and 0.025 mmol of the bifunctional chiral catalyst represented by the formula (9) were stirred at 20 DEG C with 3.0 mL of dichloromethane.

After stirring for 9 hours, 0.3 mL of the reaction mixture solution was taken out under reduced pressure, dissolved in the solvent of CDCl _3, and the progress of the reaction was confirmed by ¹ H NMR. The ¹ H NMR integration ratio of the product (Formula 4) versus the starting material (Formula 2) was determined and a conversion of 2% was confirmed.

After stirring for 24 hours, 0.3 mL of the reaction mixture solution was taken out under reduced pressure, dissolved in the solvent of CDCl _3, and the progress of the reaction was confirmed by ¹ H NMR. The ¹ H NMR integration ratio of the product (Formula 4) versus the starting material (Formula 2) was determined and a conversion of 4% was confirmed.

The prepared chiral (S) -pregabalin precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL OD-H, 90:10, hexane: isopropyl alcohol, 220 nm, 1.0 ml / min, t (by-product) = 5.8 min, t (main product) = 11.6 min, 93% ee, (S) -form.

Compared with the above-mentioned Example 1, when the catalyst represented by the general formula (9) is used under the same reaction conditions, it can be confirmed that the reaction progresses significantly slower as compared with the case of using the compound represented by the general formula (6).

Claims (14)

Reacting asymmetric Michael with beta-isobutyl nitroalkene represented by the formula (2) and malonate represented by the formula (3) in the presence of a bifunctional chiral catalyst represented by the formula (1)
Process for producing chiral (S) -pregabalin precursor represented by formula (4):
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In Formula (1), R ₁ represents an ethyl group or a vinyl group, Ar represents a substituted or unsubstituted aryl group,
In formulas (3) and (4), R ₂ and R ₃ each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
delete The method according to claim 1,
Ar in formula (1) represents a phenyl group, a naphthalenyl group, an anthracenyl group, or a pyrenyl group,
At least one hydrogen atom of Ar is
(S) -Preparin precursor is characterized in that at least one hydrogen atom is substituted or unsubstituted with an alkyl group or a halogen atom substituted or unsubstituted with a halogen atom.
The method according to claim 1,
(S) -Preparin precursor, wherein Ar is a 3,5-bis (trifluoromethyl) phenyl group.
The method according to claim 1,
The chiral catalyst represented by the formula (1)
A process for preparing a chiral (S) -plavarin precursor, which comprises a compound represented by the following formula (5).
[Chemical Formula 5]

The method according to claim 1,
The chiral catalyst represented by the formula (1)
A process for preparing a chiral (S) -pregabalin precursor, which comprises a compound represented by the following formula (6).
[Chemical Formula 6]

The method according to claim 1,
The content of the chiral catalyst represented by the formula (1)
(S) -Preparin precursor is characterized in that it is from 2 mol% to 50 mol%, based on the beta-isobutylnitroalkyne represented by the formula (2).
The method according to claim 1,
The content of malonate represented by the general formula (3)
(S) -Preparin precursor is 1 to 5 equivalents based on the beta-isobutylnitroalkyne represented by the general formula (2).
The method according to claim 1,
The asymmetric Michael reaction
(S) -Preparin precursor is carried out at -20 < 0 > C to 100 < 0 > C.
The method according to claim 1,
The asymmetric Michael reaction
(S) -Preparin precursor is carried out at -15 to 50 < 0 > C.
The method according to claim 1,
Wherein the asymmetric Michael reaction is carried out in at least one selected from the group consisting of an organic solvent, purified distilled water, an aqueous solution of an inorganic salt and a saturated aqueous solution of an inorganic salt.
The method according to claim 1,
Wherein the asymmetric Michael reaction is carried out in at least one selected from aqueous sodium chloride solution, aqueous lithium chloride solution, aqueous cesium chloride solution and aqueous potassium chloride solution.
The method according to claim 1,
Wherein the asymmetric Michael reaction is carried out in aqueous sodium chloride solution. ≪ RTI ID = 0.0 > 11. < / RTI >
Preparing a chiral (S) -pregabalin precursor according to claim 1; And
(S) -pregabalin comprising the step of preparing (S) -pregabalin using the (S) -pregabalin precursor.