KR19980083806A - Novel pyrrolidine derivatives and preparation methods thereof - Google Patents

Abstract

The present invention relates to a novel pyrrolidine derivative and a method for preparing the same, and more particularly, to prepare an intermediate compound represented by the following Chemical Formula 4 by reacting an allyl halide derivative with a diethyl N- protected aminomalonate. The present invention relates to a method for easily preparing a novel pyrrolidine derivative represented by the following Chemical Formula 1, which is widely applied in medicine and organic synthesis by cyclizing an intermediate compound.

[Formula 1]

[Formula 4]

In the above formula; Z, Y, R ₁ , R ₂ and R ₃ are each as defined in the detailed description of the invention.

Description

Novel pyrrolidine derivatives and preparation methods thereof

The present invention relates to a novel pyrrolidine derivative and a method for preparing the same, and more particularly, to prepare an intermediate compound represented by the following Chemical Formula 4 by reacting an allyl halide derivative with a diethyl N- protected aminomalonate. The present invention relates to a method for easily preparing a novel pyrrolidine derivative represented by the following Chemical Formula 1, which is widely applied in medicine and organic synthesis by cyclizing an intermediate compound.

[Formula 1]

[Formula 4]

In the above formula;

Z represents an amino protecting group,

Y represents a halogen atom or a hydroxy group,

R _1, R ₂ and R _{3, which} may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms, a benzyl group, a phenyl group, a substituted benzyl group or a substituted phenyl group. At this time, the substituent of the benzyl group and the phenyl group is a halogen atom or an alkyl group having 1 to 15 carbon atoms.

Pyrrolidine is used as an important intermediate in the synthesis of peptide derivatives with biological activity, and is widely used as an effective drug and sometimes as an intermediate of effective drugs in a wide variety of fields, including antibiotics, therapeutic drugs for muscle contraction, and therapeutic agents for the cardiovascular system.

The general structural formula of pyrrolidine is as shown in the following formula (11), and its activity and use vary according to each substitution position and substituent group.

[Formula 11]

Therefore, there is an urgent need for the development of a new synthetic method which is easy to introduce substituents at each position of the pyrrolidine ring. This usefulness and academic interest have led to the early development of pyrrolidine synthesis.

As an example, a method for preparing Michael by adding diethyl N -acetoaminomalonate and an α, β-unsaturated aldehyde compound has been developed [ J. Amer, Chem, Soc ., 1948, 70, 2763]. In this method, N -acetyl-2,2-diethoxycarbonylate-5- represented by the following Chemical Formula 12 by Michael addition using cinnamic aldehyde or acrylaldehyde as α, β-unsaturated aldehyde compound Hydroxypyrrolidine or N -acetyl-2,2-diethoxycarbonylate-3-phenyl-5-hydroxypyrrolidine was synthesized.

[Formula 12]

In Chemical Formula 12; R ₄ represents a hydrogen atom or a phenyl group.

However, in the case of the above production method, it is difficult to introduce a substituent at the C-4 position, and it is not desirable to introduce a substituent other than a hydrogen atom or a phenyl group at the C-3 position, and only a hydroxyl group is always introduced at the C-5 position. There is this.

Another manufacturing method is a method for preparing pyrrolidine through a haloactamization process in which an olefinic amide is treated with halogen under basic conditions [ J. Amer, Chem. Soc ., 1982, 104, 3233]. In order to synthesize the pyrrolidine derivatives by this method, it is not only inconvenient to synthesize the olefinic amide precursor, but also it is very difficult to introduce another substituent at the C-3 or C-4 position of the pyrrolidine. In addition, among the olepic amide precursors, trimethylsilyl trifluoromethanesulfonate is used as a raw material, which is expensive and has a large amount of flammability and corrosion, which makes it difficult to use in mass production.

Accordingly, the present inventors have concentrated on a method of preparing a pyrrolidine derivative which can easily introduce various substituents at each position of pyrrolidine, and can easily introduce various substituents at the C-4 position.

As a result, the allyl halide derivative and the diethyl N- protected aminomalonate are substituted to obtain an N -protected aminoallyl compound as an intermediate compound, which is then cyclized to almost quantitatively obtain the target pyrrolidine derivative. The present invention was completed by preparing in phosphorus yield.

Accordingly, an object of the present invention is to provide a novel pyrrolidine derivative and a novel method for preparing the same which are widely applied in the field of medicine and organic synthesis.

The present invention is characterized by the novel pyrrolidine derivative represented by the following formula (1).

Formula 1

In the above formula; Z, Y, R ₁ , R ₂ and R ₃ are each as defined above.

In addition, the present invention relates to a method for preparing a pyrrolidine derivative from diethyl N- protected aminomalonate, wherein the allyl halide derivative represented by the following formula (2) and the diethyl N- protected amino mal represented by the following formula (3) Preparing an intermediate compound represented by the following Chemical Formula 4 by substituting a nate reaction; And a method for preparing a pyrrolidine derivative represented by the following Chemical Formula 1 by cyclization of the compound represented by Chemical Formula 4.

[Formula 2]

[Formula 3]

Formula 4

In the above formulas; X represents a halogen atom, and Z, Y, R ₁ , R ₂ and R ₃ are each as defined above.

Referring to the present invention in more detail as follows.

The pyrrolidine derivative represented by Formula 1 prepared by the preparation method according to the present invention may remove various amine protecting groups (Z) at the N-1 position to introduce various substituents, and at the C-2 position, diethylcar The introduction of a carbonate group allows the introduction of alcohol through a reduction reaction, the removal of ethyl carbonate groups through a decarbonation reaction, or the introduction of various other substituents at this position. Halogen atoms are introduced at the C-4 position. It is a useful compound which can be useful for introducing various substituents and can also introduce various substituents for C-5. Therefore, the pyrrolidine derivatives represented by the general formula (1) prepared in the present invention are very useful compounds with easy introduction of various substituents at each substituent position, and are excellent intermediates in their usefulness.

In addition, Z introduced as an amino protecting group in the present invention is formyl, acetyl, trifluoro acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, t -butoxycarbonyl, benzyloxycarbonyl, p -meth Oxybenzyloxycarbonyl, trichloroethoxycarbonyl, benzyl, p -methoxybenzyl, trityl and tetrahydropyranyl groups can be applied. Most preferred is an acetyl group.

A method for preparing a pyrrolidine derivative represented by Chemical Formula 1 according to the present invention is briefly shown in Scheme 1 below.

Scheme 1

In Scheme 1; Z, X, R ₁ , R ₂ and R ₃ are each as defined above.

First, the allyl halide derivative represented by Formula 2 and the diethyl N- protected aminomalonate represented by Formula 3 are reacted for 2 to 4 hours at a temperature of -20 to 100 ° C. in the presence of a base, and the N is represented by Formula 4 Obtain quantitatively protected aminoallyl compounds. The reaction of the compounds represented by the formulas (2) and (3) is a general substitution reaction, and the solvent used here is a conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, dimethylformaldehyde and the like. As the base, n -butyllithium, t -butyllithium, sodium hydride, triethylamine, potassium t -butoxide and the like are used. Most preferably, the reaction is carried out at 40 to 50 ° C. for 2 to 4 hours using a dimethylformaldehyde solvent and a potassium carbonate base.

The prepared compound represented by the formula (4) is a pyrrolidin derivative represented by the formula (1a) (Y = halogen atom) by adding a halogenating agent in the presence or absence of a base and the halo- N -ring reaction at a temperature of 0 to 30 ℃ ) Is obtained quantitatively. The average production yield is at least 90%. In this case, the halogenating agent may be bromine (Br ₂ ), iodine (I ₂ ), bromosuccinimide, iodine succinimide, chlorosuccinimide, and as the base may be used potassium carbonate, sodium carbonate. As the reaction solvent, an organic solvent such as dichloromethane, chloroform, tetrachloromethane, acetonitrile, tetrahydrofuran, or a mixed solvent of these organic solvents and water can be used. Reaction temperature range is 0-30 degreeC . Preferably, bromine (Br ₂ ) and potassium carbonate are reacted at room temperature in a mixed solvent of acetonitrile and water. Another preferred example is the reaction at room temperature in a chloroform solvent using N -bromosuccinimide.

As another method, the compound represented by Chemical Formula 4 is reacted with m -chloroperbenzoic acid in dichloromethane solvent at room temperature in the presence of sodium bicarbonate (NaHCO ₃ ) to obtain an N -acetylaminoepoxy compound represented by Chemical Formula 5. It is also possible to quantitatively obtain a pyrrolidine derivative (Y = OH) represented by Chemical Formula 1b by cyclization reaction at a temperature of -78 to 100 ° C. in a tetrahydrofuran solvent in the presence of an organic base. At this time, the epoxidation reaction of the compound represented by the formula (4) has an average production yield of 80% or more. In the cyclization reaction of the compound represented by the formula (5), tetrahydrofuran, dimethylformamide, dichloromethane, acetonitrile, benzene, toluene and the like are used as the reaction solvent, and triethylamine and n -butyllithium are used as the organic base. , Lithium diisopropylamine, lithium hexamethyldisilazane, alkali metal alkoxide and the like. In addition, the reaction may be performed in combination with a Lewis acid such as boron trifluoride etherate (BF ₃ · OEt ₂ ) or the like. Most preferably, the cyclization reaction is carried out at -78 to 20 ° C using an alkali metal t -butoxide base as borontrifluoride etherate and a base in a tetrahydrofuran solvent.

In the production method according to the present invention as described above, it is very useful for the industrial production of pyrrolidine derivatives, since the starting materials and reagents that are useful for mass supply are used, the manufacturing process is relatively simple, and the reaction is almost quantitative.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited by the Examples.

Example 1: 4,4-diethylcarboxylate-4- N- Synthesis of Acetylamino-1-butene

Allyl bromide (4.58 mL, 52.9 mmol) was added to dimethylformaldehyde (25 mL), and diethyl N -acetoaminomalonate (10 g, 46 mmol) and potassium carbonate (7 g, 50.6 mmol) were added thereto. Stirred for time. The reaction solution was cooled to room temperature, diluted with ethyl ether (200 mL), washed with water and brine, and dried over anhydrous magnesium sulfate. After the reaction solution was filtered, the target compound 11.9 (quantitative yield) was obtained in a liquid phase under reduced pressure.

R _f : 0.6 (hexane / ethylacetate = 2/1)

¹ H-NMR (CDCl ₃ , ppm): δ 1.28 (t, 6H), 2.05 (s, 3H), 3.09 (d, 2H), 4.27 (q, 4H), 5.13 (dd, 2H), 5.57 ( m, 1H), 6.75 (bs, 1H)

Example 2: 4,4-diethylcarboxylate-4- N Synthesis of Acetylamino-1-butene

Allyl chloride (0.43 mL, 5.29 mmol) was added to dimethylformaldehyde (2 mL), and diethyl N -acetoaminomalonate (1 g, 4.6 mmol) and potassium carbonate (0.7 g, 5.06 mmol) were added thereto, followed by 50 ° C temperature. After stirring for 2 hours in the same manner as in Example 1 to obtain 1.18g (quantitative yield) of the target liquid in the liquid phase.

Example 3: N Synthesis of -acetyl-4-iodo-2,2-diethylcarboxylate pyrrolidine

4,4-Diethylcarboxylate-4- N -acetylamino-1-butene (6.7 mL, 26 mmol) was dissolved in a mixed solvent of acetonitrile (45 mL) and water (5 mL), followed by potassium carbonate (3.78 g, 27 mmol) was added. Bromine (1.47 mL, 29 mmol) was slowly added dropwise to the reaction solution at room temperature, followed by stirring for 10 minutes. A small amount of sodium thiosulfate solution was added to the reaction solution to terminate the reaction. Ethyl acetate (250 ml) was added, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 8.4 g (yield: 95.8%) of the target liquid.

R _f : 0.6 (25% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.25 to 1.33 (m, 6H), 2.02 (s, 3H), 2.53 (dd, 1H), 2.76 (dd, 1H), 3.21 (d, 2H), 4.19-4.30 (m, 4H), 5.20-5.23 (m, 1H)

Example 4: N- Synthesis of Acetyl-4-bromo-2,2-diethylcarboxylate pyrrolidine

4,4-Diethylcarboxylate-4- N -acetylamino-1-butene (6.7 mL, 26 mmol) was dissolved in a mixed solvent of acetonitrile (45 mL) and water (5 mL), followed by potassium carbonate (3.78 g, 27 mmol) was added. A solution of iodine (6.9 g, 28 mmol) dissolved in acetonitrile (5 mL) was slowly added dropwise to the reaction solution, followed by the same method as in Example 3 to obtain 8.67 g (yield: 91%) of the target product in a liquid phase. Got it.

R _f : 0.3 (25% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.25 to 1.33 (m, 6H), 2.02 (s, 3H), 2.51 (dd, 1H), 2.75 (dd, 1H), 3.15 (d, 2H), 4.18-4.30 (m, 4H), 4.35-4.50 (m, 1H)

Example 5: 4,4-diethylcarboxylate-4- N Synthesis of Acetylamino-1-phenyl-1-butene

Diethyl N -acetoaminomalonate (7.17 g, 33.0 mmol) was dissolved in dimethylformaldehyde (20 mL), cinnamil chloride (4 mL, 28.7 mmol) and potassium carbonate (5.9 g, 42.7 mmol) were added and 50 ° C. Stir at temperature for 3 hours. The reaction solution was cooled to room temperature, ethyl ether (300 mL) was added, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The filtrate distilled under reduced pressure was crystallized in a 1: 1 mixture of n- hexane and ethyl ether (100 ml) to obtain 7.5 g (yield: 78.4%) of the target substance as a white solid.

R _f : 0.5 (10% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.29 (t, 6H), 2.07 (s, 3H), 3.25 (dd, 2H), 4.27 (q, 4H), 5.90 to 6.00 (m, 1H), 6.46 (d, 1 H), 7.24 to 7.72 (m, 5 H)

Example 6: N Synthesis of -acetyl-2,2-diethylcarboxylate-4-bromo-5-phenyl pyrrolidine

4,4-diethylcarboxylate-4- N -acetylamino-1-butene (3 g, 9 mmol) was dissolved in a mixed solvent of acetonitrile (45 mL) and water (5 mL), followed by potassium carbonate (1.3 g). , 9.4 mmol) was added and bromine (0.5 mL, 0.7 mmol) was slowly added at room temperature and stirred for 10 minutes. The residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 2.5 g (yield: 67.4%) of the target substance in a liquid phase.

R _f : 0.4 (10% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.34-1.42 (m, 6H), 1.80 (s, 3H), 3.02 (dd, 1H), 3.15 (dd, 1H), 4.25-4.27 (m, 1H) , 4.32 to 4.41 (m, 4H), 5.30 (d, 1H), 7.37 to 7.46 (m, 3H), 7.62 to 7.75 (m, 2H)

Example 7: 2-chloromethyl-4,4-diethylcarboxylate-4- N Synthesis of Acetylamino-1-butene

Diethyl N- acetoaminomalonate (1 g, 4.6 mmol) was dissolved in dimethylformaldehyde (3 mL) and potassium carbonate (0.95 g, 6.9 mmol) was added. Then, 3-chloro-2-chloromethyl-1-propene (0.53 mL, 4.6 mmol) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 4 hours. The reaction solution was cooled to room temperature, ethyl ether (50 mL) was added, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The reaction solution was filtered and the residue obtained by drying under reduced pressure was separated by column chromatography to obtain 1.1 g (yield 78.2%) of the target substance as a white solid.

R _f : 0.6 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.28 (t, 6H), 2.05 (s, 3H), 3.30 (s, 2H), 3.96 (s, 2H), 4.23 to 4.32 (m, 4H), 5.01 (s, 1H), 5.27 (s, 1H), 6.80 (bs, 1H)

Example 8: N Synthesis of -acetyl-2,2-diethylcarboxylate-4-bromo-4-chloromethyl pyrrolidine

2-chloromethyl-4,4-diethylcarboxylate-4- N -acetylamino-1-butene (3.30 mg, 1.08 mmol) was dissolved in a mixed solvent of acetonitrile (3 mL) and water (0.5 mL). Potassium carbonate (156 mg, 1.13 mmol) was then added, and a solution of bromine (0.56 mL, 1.19 mmol) in acetonitrile (1.5 mL) was slowly added at room temperature. After stirring for 30 minutes, the residue obtained by treatment in the same manner as in Example 3 was separated by silica gel chromatography to obtain 4.00 mg of the target compound (yield 96.3%) in the liquid phase.

R _f : 0.6 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.25-1.37 (m, 6H), 2.01 (s, 3H), 2.16 (s, 2H), 3.53 (d, 1H), 3.69 (d, 1H), 4.13 (s, 2H), 4.28 ~ 4.33 (m, 4H)

Example 9: 4,4-diethylcarboxylate-4- N Synthesis of -acetylamino-1,2-oxylane-butane

4,4-Diethylcarboxylate-4- N -acetylamino-1-butene (2 g, 7.77 mmol) was dissolved in chloroform (30 mL) and sodium bicarbonate (1.63 g, 19.40 mmol) was added. A solution of m -chloroperbenzoic acid (2.3 g, 10 mmol, 75% used) in chloroform (30 mL) was slowly added to the reaction solution at 0 ° C. After stirring at room temperature for 12 hours, dichloromethane (100 ml) was added, the organic layer was washed with sodium bicarbonate aqueous solution and brine, and dried over anhydrous magnesium sulfite. After filtration and concentration under reduced pressure, the residue was separated by column chromatography to obtain 1.52 g (yield: 71.6%) of the title compound in the liquid phase.

R _f : 0.2 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.25 to 1.31 (m, 6H), 2.09 (s, 3H), 2.18 to 2.25 (m, 1H), 2.48 (dd, 1H), 2.75 (dd, 1H) , 2.89-2.95 (m, 2H), 4.23-4.32 (m, 4H), 7.00 (bs, 1H)

Example 10: N Synthesis of -acetyl-2-diethylcarboxylate-4-hydroxy pyrrolidine

4,4-Diethylcarboxylate-4- N -acetylamino-1,2-oxylane-butane (500 mg, 1.83 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and boron tree at -78 ° C. Fluoride etherate (0.26 mL, 2.01 mmol) was added slowly, stirred for 10 min at the same temperature followed by addition of potassium t -butoxide (279 mg, 2.49 mmol). After slowly raising the reaction temperature to -20 ° C, the mixture was stirred for 30 minutes and a small amount of an aqueous ammonium chloride solution was added to terminate the reaction. Ethyl acetate (50 ml) was added to the reaction solution, washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by filtration and drying under reduced pressure was crystallized using ethyl ether to obtain 375 mg (yield 75%) of the title compound as white crystals.

R _f : 0.1 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.24 to 1.31 (m, 6H), 2.08 (s, 3H), 2.44 to 2.56 (m, 2H), 3.48 to 3.52 (m, 1H), 3.63 (dd , 1H), 3.61 to 3.02 (m, 1H), 4.21 to 4.30 (m, 4H), 7.06 (bs, 1H)

Example 11: 4,4-diethylcarboxylate-4- N- Synthesis of Acetoamino-2-benzyl-1-butene

Diethyl N- acetoaminomalonate (1.74 g, 8 mmol) was dissolved in dimethylformaldehyde (5 mL), 2-benzyl-3-chloro-propene (1.4 g, 8 mmol) and potassium carbonate (1.33 g, 9.6 mmol) was added and stirred at 50 ° C. for 4 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 2.63 g (yield 95%) of the target substance as an off-white solid.

R _f : 0.5 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.25 (t, 6H), 2.05 (s, 3H), 3.11 (s, 2H), 3.24 (s, 2H), 4.21-4.28 (m, 4H), 4.83 (d, 1H), 4.85 (d, 1H), 6.86 (bs, 1H), 7.11 ~ 7.32 (m, 5H)

Example 12 Synthesis of N -Acetyl-2,2-diethylcarboxylate-4-bromo-4-benzyl pyrrolidine

4,4-Diethylcarboxylate-4- N- acetoamino-2-benzyl-1-butene (750 mg, 2.2 mmol) was dissolved in chloroform (10 mL) and N -bromosuccinimide ( 385 mg, 2.2 mmol) was added. After stirring at the same temperature for 10 minutes, the residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 810 mg (yield 86.4%) of the target substance in the liquid phase.

R _f : 0.4 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.27 to 1.34 (m, 6H), 2.09 (s, 3H), 2.56 (d, 1H), 2.78 (d, 1H), 3.02 (s, 2H), 3.16 (d, 1H), 3.27 (d, 1H), 4.20-4.37 (m, 4H), 7.26-7.37 (m, 5H)

Example 13: 4,4-diethylcarboxylate-4- N- Acetoamino-1- p Synthesis of Bromophenyl-1-butene

Diethyl N- acetoaminomalonate (217 mg, 1 mmol) was dissolved in dimethylformaldehyde (1 mL), and p -bromosinamylbromide (275 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added thereto. It stirred at 50 degreeC temperature for 4 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 380 mg (yield 92%) of the target substance in a liquid phase.

R _f : 0.4 (25% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.28 (t, 6H), 2.07 (s, 3H), 3.24 (dd, 1H), 4.27 (q, 4H), 5.89 to 6.00 (m, 1H), 6.48 (d, 1H), 7.04 (d, 2H), 7.47 (d, 2H)

Example 14: N- Acetyl-2,2-diethylcarboxylate-4-bromo-5- p Synthesis of Bromophenyl Pyrrolidine

4,4-Diethylcarboxylate-4- N- acetoamino-1- p -bromophenyl-1-butene (100 mg, 0.24 mmol) was dissolved in chloroform (5 mL) and N- bromo at room temperature. Succinimide (43 mg, 0.24 mmol) was added. After stirring at the same temperature for 10 minutes, the residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 105 mg (yield 89%) of the target product in the liquid phase.

R _f : 0.3 (25% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ1.33-1.42 (m, 6H), 1.82 (s, 3H), 3.01 (dd, 1H), 3.13 (dd, 1H), 4.24-4.28 (m, 1H ), 4.32 to 4.43 (m, 4H), 5.32 (d, 1H), 7.35 (d, 2H), 7.74 (d, 2H)

Example 15: 4,4-diethylcarboxylate-4- N- Synthesis of Acetoamino-2-methyl-1-butene

Diethyl N- acetoaminomalonate (500 mg, 2.3 mmol) was dissolved in dimethylformaldehyde (2 mL), 3-bromo-2-methyl-propene (311 mg, 2.3 mmol) and potassium carbonate (476 mg, 3.5 mmol) was added and stirred at 50 ° C. for 3 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 600 mg of the target compound (yield 96%) in the liquid phase.

R _f : 0.6 (30% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.27 (t, 6H), 1.95 (s, 3H), 2.05 (s, 3H), 3.24 (s, 2H), 4.19 to 4.27 (m, 4H), 4.80 (d, 1H), 4.91 (d, 1H), 6.85 (bs, 1H)

Example 16: N- Synthesis of Acetyl-2,2-diethylcarboxylate-4-bromo-4-methyl pyrrolidine

4,4-diethyl-carboxylic carbonate -4- N-acetonitrile-amino-2-methyl-1-butene (271 ㎎, 1 mmol) was dissolved in chloroform (5 ㎖), N at room temperature-bromosuccinimide ( 180 mg, 1 mmol) was added. After stirring at the same temperature for 10 minutes, the residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 319 mg of the target product (yield 91%) in the liquid phase.

R _f : 0.5 (30% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.26 to 1.34 (m, 6H), 1.75 (s, 3H), 2.07 (s, 3H), 2.56 (d, 1H), 2.76 (d, 1H), 3.14 (d, 1H), 3.24 (d, 1H), 4.20-4.35 (m, 4H)

Example 17: 5,5-diethylcarboxylate-5- N- Synthesis of Acetyl-2-pentene

Diethyl N- acetoaminomalonate (500 mg, 2.3 mmol) was dissolved in dimethylformaldehyde (2 mL), crotyl chloride (0.22 mL, 2.3 mmol) and potassium carbonate (476 mg, 3.5 mmol) were added and the temperature was 50 ° C. Stirred for 3 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 605 mg (yield 97%) of the target substance in a liquid phase.

R _f : 0.6 (30% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 1.28 (t, 6H), 1.62 (d, 3H), 2.04 (s, 3H), 4.26 (q, 4H), 5.11 (dd, 2H), 5.29- 5.32 (m, 1H), 5.51-5.57 (m, 1H), 6.75 (bs, 1H)

Example 18: N- Synthesis of Acetyl-2,2-diethylcarboxylate-4-bromo-5-methyl pyrrolidine

5,5-Diethylcarboxylate-5- N - acetyl-2-pentene (100 mg, 0.37 mmol) was dissolved in chloroform (2 mL) and N -bromosuccinimide (67 mg, 0.37 mmol) at room temperature. ) Was added. After stirring at the same temperature for 10 minutes, the residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 121 mg (yield 93%) of the target compound in the liquid phase.

R _f : 0.4 (30% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ1.23 (d, 3H), 1.27 to 1.38 (m, 6H), 2.01 (s, 3H), 2.79 (d, 2H), 3.75 to 3.78 (m, 1H ), 4.20 to 4.29 (m, 4H), 4.70 to 4.73 (m, 1H)

Example 19: 1,1-diethylcarboxylate-1- N- Synthesis of Acetoamino-3-undecene

Diethyl N- acetoaminomalonate (217 mg, 1 mmol) was dissolved in dimethylformaldehyde (1 mL), 1-chloro-2-dodecene (189 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) Was added and stirred at 50 ° C. for 5 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 321 mg (yield 87%) of the target substance in a liquid phase.

R _f : 0.6 (30% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 0.99 (t, 3H), 1.21-1.38 (m, 16H), 1.43-1.50 (m, 2H), 2.01 (s, 3H), 2.19-2.28 (m , 2H), 3.08 (d, 2H), 4.19-4.27 (m, 4H), 5.60-5.85 (m, 1H), 5.71-5.78 (m, 1H), 6.78 (bs, 1H)

Example 20 Synthesis of N- Acetyl-2,2-diethylcarboxylate-4-bromo-5-octyl pyrrolidine

1,1-diethylcarboxylate-1- N- acetoamino-3-undecene (100 mg, 0.27 mmol) was dissolved in chloroform (5 mL), and N -bromosuccinimide (21 mg, 0.27 mmol) was added. After stirring at the same temperature for 30 minutes, the residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 102 mg (yield 84%) of the target substance in the liquid phase.

R _f : 0.4 (30% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 0.98 (t, 3H), 1.21-1.37 (m, 16H), 1.41-1.48 (m, 2H), 1.72-1.79 (m, 2H), 2.02 (s , 3H), 2.79 (d, 2H), 3.67-3.78 (m, 1H), 4.17-4.25 (m, 4H), 4.70-4.78 (m, 1H)

Example 21: 4,4-diethylcarboxylate-4- N- Acetylamino-1- p Synthesis of -octylphenyl-1-butene

Diethyl N- acetoaminomalonate (241 mg, 1.11 mmol) was dissolved in dimethylformaldehyde (2 mL), and p -octylcinnamilbromide (360 mg, 1.11 mmol) and potassium carbonate (153 mg, 1.82 mmol) were added. It stirred at 50 degreeC temperature for 3 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 440 mg of the target compound (yield 89.0%) as a white solid.

R _f : 0.4 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 0.99 (t, 3H), 1.26-1.38 (m, 16H), 1.54-1.62 (m, 2H), 2.06 (s, 3H), 2.58 (t, 2H) ), 3.23 (d, 2H), 4.24 to 4.34 (m, 4H), 5.84 to 5.94 (m, 1H), 6.43 (d, 1H), 6.79 (s, 1H), 7.12 (d, 2H), 7.23 ( d, 2H)

Example 22: N- Acetyl-2,2-diethylcarboxylate-4-bromo-5- p Synthesis of -octylphenylpyrrolidine

4,4-Diethylcarboxylate-4- N- acetylamino-1- p -octylphenyl-1-butene (100 mg, 0.22 mmol) was dissolved in chloroform (2 mL) and N -bromosuccisin at room temperature. Imide (40 mg, 0.22 mmol) was added and stirred at the same temperature for 10 minutes. The residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 98 mg (yield 85%) of the target substance in a liquid phase.

R _f : 0.5 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 0.99 (t, 3H), 1.27-1.38 (m, 16H), 1.47-1.59 (m, 2H), 1.94 (s, 3H), 2.10-2.20 (m , 2H), 2.61 (t, 2H), 4.23 to 4.32 (m, 4H), 4.46 to 4.50 (m, 2H), 4.92 (d, 1H), 7.17 (d, 2H), 7.32 (d, 2H)

Example 23: 4,4-diethylcarboxylate-4- N- Acetoamino-2- p Synthesis of -octylbenzyl-1-butene

Diethyl N- acetoaminomalonate (217 mg, 1 mmol) was dissolved in dimethylformaldehyde (1 mL), 2- p -octylbenzyl-3-chloro-propene (175 mg, 1 mmol) and potassium carbonate (207 Mg, 1.5 mmol) was added and stirred at a temperature of 50 ° C for 4 hours. The residue obtained by treating the reaction solution in the same manner as in Example 1 was separated by silica gel column chromatography to obtain 400 mg (yield 87%) of the target substance in the liquid phase.

R _f : 0.6 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 0.99 (t, 3H), 1.24-1.37 (m, 16H), 1.54-1.61 (m, 2H), 2.07 (s, 3H), 2.58 (t, 2H) ), 3.10 (s, 2H), 3.22 (s, 2H), 4.19-4.26 (m, 4H), 4.83 (d, 1H), 4.85 (d, 1H), 6.85 (bs, 1H), 7.10-7.31 ( m, 4H)

Example 24: N -Acetyl-2,2-diethylcarboxylate-4-bromo-4- p Synthesis of -octylbenzyl pyrrolidine

4,4-Diethylcarboxylate-4- N- acetoamino-2- p -octylbenzyl-1-butene (100 mg, 0.22 mmol) was dissolved in chloroform (5 mL) and N -bromosuccisin at room temperature. Imide (39 mg, 0.22 mmol) was added. After stirring at the same temperature for 10 minutes, the residue obtained by treating the reaction solution in the same manner as in Example 3 was separated by silica gel column chromatography to obtain 100 mg (yield 85%) of the target substance in the liquid phase.

R _f : 0.5 (50% ethyl acetate / hexane)

¹ H-NMR (CDCl ₃ , ppm): δ 0.99 (t, 3H), 1.26-1.35 (m, 16H), 1.45-1.65 (m, 2H), 1.93 (s, 3H), 2.55 (d, 1H) ), 2.61 (t, 2H), 2.78 (d, 1H), 3.01 (s, 2H), 3.16 (d, 1H), 3.25 (d, 1H), 4.19-4.37 (m, 4H), 7.11 (d, 2H), 7.22 (d, 2H)

The phyllolidine derivatives represented by the general formula (1) prepared in the present invention can be widely applied in medicine and organic synthesis, and are particularly useful as intermediates in the preparation of compounds useful as antibiotics, muscle contractile diseases, and cardiovascular therapeutics.

Reference Examples 1 and 2 below are examples of preparing novel quinolone derivatives that can be used as antibiotics using the phyllolidine derivatives of the present invention.

Reference Example 1 Synthesis of 4-bromo-4-methyl-2,2-dihydroxyethyl pyrrolidine

Lithium aluminum hydride (108 mg, 2.85 mmol) in suspension suspended in tetrahydrofuran (10 mL).N -A solution of acetyl-2,2-diethylcarboxylate-4-bromo-4-methyl pyrrolidine (200 mg, 0.57 mmol) dissolved in dried tetrahydrofuran (2 mL) was slowly added dropwise at 0 ° C. It was. After stirring at 20 ° C. for 5 hours, ethyl acetate (30 mL) and ice water (10 mL) were added to the reaction solution to terminate the reaction. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to add diethyl ether (10 mL) to crystallize. The crystals were filtered, washed with diethyl ether (5 mL), and concentrated under reduced pressure at 20 ° C. for 2 hours to obtain 50 mg of the target compound (yield 41.8%) as a white solid.

R _f : 0.1 (ethyl acetate)

¹ H-NMR (CDCl ₃ , ppm): δ 1.73 (s, 3H), 2.20 (bs, 3H), 2.54 (d, 1H), 2.70 (d, 1H), 3.10 (d, 1H), 3.21 ( d, 1H), 3.59 (d, 2H), 3.67 (d, 2H)

Reference Example 2 Synthesis of Carboxylic Acid

4-Bromo-4-methyl-2,2-dihydroxyethyl pyrrolidine (50 mg, 0.2380 mmol) was dissolved in acetonitrile (2 mL) and 1-cyclopropyl-6,7-difluoro- 8-Chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (50 mg, 0.167 mmol) was added to acetonitrile (3 mL) and 1,8-diazabicyclo [5.4.0] undes. A solution dissolved in -7-ene (0.036 mL, 0.2380 mmol) was added. Triethylamine (0.12 mL, 0.8472 mmol) was added to the reaction solution. The mixture was heated to reflux for 12 hours, cooled to room temperature, and stirred for 1 hour. The precipitated crystals were filtered and washed sequentially with acetonitrile, dichloromethane and diethyl ether to obtain 40 mg (yield 48.9%) of the target substance as a pale yellow solid.

R _f : 0.1 (ethyl acetate / methanol = 3/1)

¹ H-NMR (DMSO-d ₆ , ppm): δ 0.99 to 1.23 (m, 4H), 1.74 (s, 3H), 2.54 (d, 1H), 2.72 (d, 1H), 3.10 to 3.27 (m , 3H), 3.59 (d, 2H), 3.69 (d, 2H), 7.84 (d, 1H), 8.81 (s, 1H)

Experimental Example 1: In vitro ( in vitro Antibacterial Activity Test

In order to clarify the pharmacological usefulness of the quinolonecarboxylic acid derivative (Reference Example 2) in which the novel pyrrolidine derivative according to the present invention was substituted, the following antimicrobial activity experiment was conducted. At this time, the antimicrobial test method agar medium dilution method [Japanese Chemotheraphy Society; Chemotheraphy, Vol. 29, 76-79 (1981).

In addition, the test strain was continuously passaged three times or more (37 ℃, 18 hours) in Muller-Hinton agar (Muller-Hinton agar) to have the optimum activity, and then again in Muller-Hinton broth (Muller-Hinton broth) Inoculation was incubated for 18 hours at 37 ℃. The culture solution was diluted to about 18 concentrations (CFU) of bacterial solution per ml, and the Mueller-Hinton agar medium containing 100 to 0.002 µg / g of the test compound diluted in twofold steps using a microorganism inoculator. Ml) was inoculated at a concentration of 5 μl. After incubating the medium for 18 hours at 37 ° C., the agar plates inoculated by diluting stepwise two times were lined up and visually observed to determine the concentration of the antimicrobial material whose growth was inhibited. / Ml). The results are shown in Table 1 below.

TABLE 1

Strain Reference Example 2 Compound Ciprofloxacin Streptococcus pyogenes 308A 0.781 3.125 Streptococcus pyogenes 77A 0.195 0.781 Streptococcus faecium MD8b 0.781 0.391 Staphylococcus aureus SG511 0.049 0.195 Staphylococcus aureus 285 0.098 0.781 Staphylococcus aureus 503 0.049 0.391 Esherichia coli 078 0.007 0.004 Esherichia coli DC0 0.391 0.195 Esherichia coli DC2 0.098 0.098 Esherichia coli TEM 0.025 0.013 Esherichia coli 1507E 0.025 0.013 Pseudomonas aeruginosa 9027 0.781 0.391 Pseudomonas aeruginosa 1771 1.563 0.195 Salmonella typhimurium (Salmonella typhimurium) 0.025 0.007 Klebsiella oxytoca 1082E 0.004 0.002 Klebsiella aerogenes 1522E 0.025 0.013 Enterobacter clocae P99 0.007 0.013 Enterobacter clocae 1321E 0.007 0.002

As described above, the preparation method according to the present invention can easily introduce various substituents at each position of pyrrolidine, and the novel pyrrolidine derivatives prepared by the preparation method of the present invention are substituted with various substituents. The castle is very excellent.

Claims (12)

The pyrrolidine derivative represented by the following formula (1). Formula 1 In the above formula; Z represents an amino protecting group, Y represents a halogen atom or a hydroxy group, R _1, R ₂ and R _{3, which} may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms, a benzyl group, a phenyl group, a substituted benzyl group or a substituted phenyl group. At this time, the substituent of the benzyl group and the phenyl group is a halogen atom or an alkyl group having 1 to 15 carbon atoms. A process for preparing a pyrrolidine derivative from diethyl N- protected aminomalonate, Preparing an intermediate compound represented by the following Chemical Formula 4 by substituting an allyl halide derivative represented by the following Chemical Formula 2 with a diethyl N- protected aminomalonate represented by the following Chemical Formula 3; And Method for producing a pyrrolidine derivative comprising the step of preparing a pyrrolidine derivative represented by the following formula (1) by cyclizing the compound represented by the formula (4). Formula 2 Formula 3 Formula 4 Formula 1 In the above formulas; Z represents an amino protecting group, X represents a halogen atom, Y represents a halogen atom or a hydroxy group, R _1, R ₂ and R _{3, which} may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms, a benzyl group, a phenyl group, a substituted benzyl group or a substituted phenyl group. At this time, the substituent of the benzyl group and the phenyl group is a halogen atom or an alkyl group having 1 to 15 carbon atoms. The method of claim 2, wherein the substitution reaction is an organic solvent selected from tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, dimethylformaldehyde, n -butyllithium, t -butyllithium, sodium hydride, triethylamine , Potassium t -butoxide is prepared in the presence of a base selected from the method of producing a pyrrolidine derivative. The method of claim 3, wherein the substitution reaction is carried out in the presence of a dimethylformaldehyde solvent and a potassium carbonate base. The method for preparing a pyrrolidine derivative according to claim 2, wherein the compound represented by Chemical Formula 4 is prepared by a halo- N -ring reaction with a halogenating agent to prepare a compound represented by the following Chemical Formula 1a. [Formula 1a] In Formula 1a; Z, X, R _1, R ₂ and R ₃ are each as defined in claim 2 above. The halo- N -ring reaction according to claim 5, wherein a halogenating agent selected from bromine (Br ₂ ), iodine (I ₂ ), bromosuccinimide, iodine succinimide and chlorosuccinimide is used. Method for producing a pyrrolidine derivative, characterized in that. The method of claim 5, wherein in the halo- N -ring reaction, a base selected from potassium carbonate and sodium carbonate is selectively used. 6. The pyrrolidine derivative according to claim 5, wherein in the halo- N -ring reaction, dichloromethane, chloroform, tetrachloromethane, acetonitrile, tetrahydrofuran or a mixed solvent of these organic solvents and water is used. Manufacturing method. 3. The N -acetylaminoepoxy compound represented by the following Chemical Formula 5 is prepared by epoxidation of a compound represented by Chemical Formula 4 in the presence of a base with m -chloroperbenzoic acid. Method for producing a pyrrolidine derivative, characterized in that the cyclization reaction at a temperature of 100 ℃ to produce a compound represented by the following formula (1b). [Formula 5] [Formula 1b] In the above formulas; Z, R _1, R ₂ and R ₃ are each as defined in claim 2 above. The method of claim 9, wherein in the cyclization reaction of the compound represented by Formula 5, using a base selected from triethylamine, n -butyllithium, lithium diisopropylamine, lithium hexamethyldisilazane and alkali metal alkoxide Method for producing a pyrrolidine derivative characterized in that. The method for producing a pyrrolidine derivative according to claim 9 or 10, wherein boron trifluoride etherate (BF ₃ · OEt ₂ ) is used in the cyclization reaction. A method of using a pyrrolidine derivative represented by the following formula (1) as an intermediate in the preparation of a compound useful as an antibiotic, a muscle contraction treatment, a cardiovascular treatment. Formula 1 In the above formula; Z represents an amino protecting group, Y represents a halogen atom or a hydroxy group, R _1, R ₂ and R _{3, which} may be the same or different, represent a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a haloalkyl group having 1 to 5 carbon atoms, a benzyl group, a phenyl group, a substituted benzyl group or a substituted phenyl group. At this time, the substituent of the benzyl group and the phenyl group is a halogen atom or an alkyl group having 1 to 15 carbon atoms.