KR101548886B1 - Method for preparing (r)-rolipram precursor by catalytic enantioselective micahel reaction and method for preparing (r)-rolptram using the (r)-rolipram precursor - Google Patents

Abstract

According to the present invention, a method for preparing chiral (R)-rolipram precursors includes a step of enabling an asymmetric Michael reaction of 3-(cyclo pentoxy)-4-methoxyphenyl nitro and malonate in the presence of a soluble chiral catalyst. Accordingly, the present invention can synthesize chiral (R)-rolipram precursors at low costs by using an organic catalyst not including transition metals with high optical selectivity and reactivity in the presence of water, aqueous solution, or a mixed solution of an organic solvent which are not harmful to the human body and do not cause environmental pollution.

Description

METHOD FOR PREPARING (R) -ROLIPRAM PRECURSOR BY CATALYTIC ENANTIOSELECTIVE MICHEL REACTION AND METHOD FOR PREPARING (R) - ROLLIPRAM PRECURSOR USING THE SAME R) -ROLPTRAM USING THE (R) -ROLIPRAM PRECURSOR}

The present invention relates to a process for preparing (R) -rolipram precursor through asymmetric Michael catalysis and a process for preparing (R) -rolipram using the process. (R) -roliprazole precursor through asymmetric Michael catalysis mediated by water or an inorganic salt aqueous solution or an organic solvent in order to prepare a roll rifle, and a process for producing (R) -roliprazol using the same .

Lipripram [(±) -Rolipram] is a phosphodiesterase type 4 (PDE-IV) inhibitor and is an important medicinal substance in research for the treatment of diseases such as depression, multiple sclerosis and spinal injury. Therefore, many manufacturing methods for economically synthesizing (R) - (-) - rolipram have been researched and developed. (R) -rolipram. However, most of the conventional methods are not suitable for use as a catalyst, which is a toxic transition metal that should not be present in pharmaceuticals, or as a non-environmentally friendly . From this point of view, it is very important to develop a method for synthesizing (R) -rolipram in an economical and environmentally friendly manner.

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

Another object of the present invention is to provide a process for producing (R) -roliprazole using (R) -rolipraz precursor.

There is provided a process for preparing a chiral (R) -rolipraz precursor through asymmetric Michael catalysis to solve one object of the present invention. The method comprises reacting 3- (cyclopentyloxy) -4-methoxyphenyl nitroalkene represented by Chemical Formula 2 with [3- (cyclopentoxy) -4-methoxyphenyl nitroalkene] in the presence of a bifunctional chiral catalyst represented by Chemical Formula 1, 3 to an asymmetric Michael reaction of the malonate.

[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 chiral (R) -rolipraz precursor represented by the following general formula (4) can be prepared by the asymmetric Michael reaction.

[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 3- (cyclopentoxy) -4-methoxyphenyl nitroalkyne represented by the formula have.

In one embodiment, the content of malonate represented by formula (3) may be 1 to 5 equivalents based on 3- (cyclopentoxy) -4-methoxyphenyl nitroalkyne represented by 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 may be carried out in at least one selected from pure distilled water, aqueous solutions of inorganic salts and aqueous solutions of inorganic salts, organic solvents or mixtures thereof.

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 process for producing (R) -rolipram using an (R) -roliprazole precursor to solve the other object of the present invention is provided. In this method, the (R) -roliprazole precursor is prepared according to the process for producing the (R) -roliprazol precursor of the present invention described above and used to prepare (R) -roliprazol.

According to the process for preparing (R) -rolipram precursor through the asymmetric Michael catalysis of the present invention and the process for preparing (R) -rolipram using the same, a metal catalyst which is harmful to the human body is used, Instead of using a solvent, an (R) -rolipraz precursor is prepared in the presence of a chiral catalyst, which can be easily synthesized from a natural product, and a (R) -rol Re fl lam precursor can be produced, and an aqueous solution can be used as a solvent, so that it is environmentally safe and non-explosive and safe. In particular, a precursor for producing (R) -rolipram can be synthesized so as to have high enantiomeric selectivity using a water or inorganic salt aqueous solution as a medium. In addition, it can be synthesized as an (R) -roliprazan medicinal substance using the (R) -roliprazole 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.

(R) -rolipraz precursor

The process for preparing a chiral (R) -roliprazole precursor according to the present invention comprises reacting 3- (cyclopentoxy) -4-methoxyphenyl nitroalkyne represented by the general formula (2) with Asymmetric Michael reaction of the malonate represented by the general formula (3).

[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 (R) -rolipraz 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 is a derivative of a difunctional difunctional cinchona alkaloid catalyst compound comprising a quinuclidine group as the base moiety and a squaramide group as the acid moiety. 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) in water or an inorganic salt aqueous solution to give 3- (cyclopentoxy) -4-methoxyphenyl nitroalkyne and malonate represented by the formula (3), it is possible to rapidly produce a chiral (R) -roliprazol precursor having a very high optical purity, in particular an optical purity of at least 90% Yields a yield of at least 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 3- (cyclopentoxy) -4-methoxyphenylnaphthalene represented by general formula (2) , Preferably from 2 mol% (mole%) 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 the human body or using an expensive and environmentally harmful organic solvent, an (R) -roliprazole precursor is produced in the presence of a chin catalyst based on Shin- (R) -rolipram precursor can be produced at a remarkably faster reaction rate than a conventional method using an organic solvent in the case of reacting in an aqueous solution of water or an inorganic salt because the hydrophobic hydration effect is remarkably exhibited. It is safe because it is not explosive. In addition, a precursor for producing (R) -rolipram can be synthesized so as to have a high enantioselectivity using a water or inorganic salt aqueous solution as a medium.

In addition, (R) -roliprazole can be synthesized using the (R) -roliprazole precursor prepared through the present invention. For example, (R) -roliprazole can be prepared according to the following synthesis reaction formula.

[Synthetic reaction formula]

Specifically, a chiral (R) -rolipraz precursor represented by Chemical Formula 4 (R ₂ , R ₃ = Me) was reacted with Raney-Ni and H ₂ (hydrogen) in the presence of an ethanol solvent at room temperature for 12 hours, Cyclopentoxy) -4-methoxyphenyl-gamma-lactam-methyl ester can be prepared in a yield of 80%. (. Aq) 3- (cyclopentyl) -4- methoxyphenyl obtained-gamma lactam methyl ester was converted to LiOH / THF 1: 1 was stirred in a solution, neutralized with _{HCl (. Aq) CH 2 Cl} 2 solvent . CH ₂ Cl ₂ was removed under reduced pressure, dissolved in toluene solvent, and heated at 110 ^° C for 12 hours to carry out the de-carbonation reaction to obtain (R) -roliprazole as a colorless solid

(Reference: PS Hynes, PA Stupple, DJ Dixon, Org. Lett ., 2008 , 10 , 13893)

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 chirality (R) -rolipram precursor in a mixed medium in which an aqueous solution is mixed with an organic solvent

1.0 mmol of 3- (cyclopentoxy) -4-methoxyphenylnaphthalene represented by the formula (2), 5.0 mmol of the malonate represented by the formula (7) and 0.10 mmol of the chiral catalyst represented by the formula (6) were dissolved in a saturated aqueous sodium chloride solution sodium chloride aqueous solution) and 0.2 mL of toluene for 24 hours. After the completion of the stirring, the reaction mixture was extracted with dichloromethane (CH ₂ Cl ₂ ) solvent, the solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain a chiral (R) -roliprazole precursor (95% yield).

The prepared chiral (R) -rolipram precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL AD-H, 90:10, hexane: isopropyl alcohol, 210 nm, 1.0 ml / min, t (main product) = 19.7 min, t (by-product) = 42.2 min, 87% ee, (R) -form.

^{1 H NMR (300 MHz, CDCl3} ): δ 6.80-6.72 (m, 3H), 4.92-4.74 (m, 2H), 4.16 (td, J = 8.7 Hz and J = 5.7 Hz, 1H), 3.85 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.58 (s, 3H), 2.00 - 1.83 (m, 6H), 1.61 (bs, 2H); ¹³ C NMR (75 MHz, CDCl 3): δ 167.91, 167.28, 149.83 147.62, 128.06, 119.88, 114.557, 111.89, 80.35, 77.67, 55.87, 54.79, 53.00, 52.86, 42.58, 32.71, 24.06.

Example 2: Preparation of chirality (R) -rolipram precursor in organic solvent

1.0 mmol of 3- (cyclopentoxy) -4-methoxyphenylnaphthalene represented by the formula 2, 5.0 mmol of the malonate represented by the formula (7) and 0.10 mmol of the chiral catalyst represented by the formula (6) were dissolved in 2.0 mL of dichloromethane at 20 ° C Stir for 24 hours. After stirring was complete, the solvent was removed under reduced pressure and the product was isolated using column chromatography to give a chiral (R) -roliprazol precursor (97% yield).

The prepared chiral (R) -rolipram precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL AD-H, 90:10, hexane: isopropyl alcohol, 210 nm, 1.0 ml / min, t (main product) = 19.7 min, t (by-product) = 42.2 min, 90% ee, (R) -form.

Comparative Example 1: Preparation of chiral chiral (R) -rolipraz precursor using catalyst analogue (9)

[Chemical Formula 9]

1.0 mmol of 3- (cyclopentoxy) -4-methoxyphenylnaphthalene represented by the formula 2, 5.0 mmol of the malonate represented by the formula (7) and 0.10 mmol of the chiral catalyst represented by the formula (9) were dissolved in 2.0 mL of dichloromethane at 20 [ Stir for 24 hours. After completion of the stirring, the solvent of the reaction mixture was removed 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 25% conversion was confirmed.

The prepared chiral (R) -rolipram precursor was measured for enantiomeric excess using high performance liquid chromatography (CHIRALCEL AD-H, 90:10, hexane: isopropyl alcohol, 210 nm, 1.0 ml / min, t (main product) = 19.7 min, t (by-product) = 42.2 min, 76% ee, (R) -form.

Compared with Comparative Example 1, when the catalyst represented by Formula 9 was used under the same reaction conditions, the reaction proceeded remarkably slowly as compared with the case of using the compound represented by Formula 6, and the optical selectivity (ee) .

Claims (14)

3- (cyclopentyloxy) -4-methoxyphenyl nitroalkene] represented by the general formula (2) and a compound represented by the general formula (3) in the presence of a bifunctional chiral catalyst represented by the general formula Reacting the Nate with an asymmetric Michael;
Process for producing chiral (R) -rolipraz 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
A process for producing a chiral (R) -roliprazol precursor 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,
A process for producing a chiral (R) -roliprazole 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 producing an (R) -roliprazole precursor comprising the 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 producing a chiral (R) -roliprazole 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)
(R (CH3) 2), wherein R is 3- (cyclopentoxy) -4-methoxyphenyl nitroalkene represented by the general formula (2) ) -Rolipram precursor.
The method according to claim 1,
The content of malonate represented by the general formula (3)
(R) -roliprazole precursor, which is characterized in that it is 1 to 5 equivalents based on 3- (cyclopentoxy) -4-methoxy phenyl nitroalkyne represented by the general formula (2).
The method according to claim 1,
The asymmetric Michael reaction
(R) -rolipraz precursor is carried out at -20 < 0 > C to 100 < 0 > C.
The method according to claim 1,
The asymmetric Michael reaction
(R) -roliprazole precursor is carried out at a temperature of from -15 DEG C to 50 DEG 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 pure distilled water, an inorganic salt aqueous solution, an inorganic salt saturated aqueous solution, an organic solvent, or a mixed solution thereof.
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,
Characterized in that the asymmetric Michael reaction is carried out in aqueous sodium chloride solution.
Preparing a chiral (R) -rolipraz precursor according to claim 1; And
And (R) -rolipyrum using the (R) -rolipyrum precursor to produce (R) -rolipram.