KR100835604B1 - Method for preparing unsaturated ketone and their derivatives for anticancer effect - Google Patents

Abstract

The present invention relates to a method for producing an unsaturated ketone of Formula 1 and its derivatives having anticancer effect.

The production method according to the present invention accelerates the reaction rate by using a hydrophilic solvent in the Baileys-Hillman reaction of methyl vinyl ketone and acetaldehyde to introduce ethyl hydroxide at the alpha-carbonyl position of methyl vinyl ketone. It allows the introduction of substituents in selective and high yields, and also enables mass synthesis of compounds. As a result, it can be widely used in the fields of medicine and fine chemistry, including the structure and activity correlation of the compound of formula (1) and its novel derivatives that can be usefully used as cancer cell death inducing activators, anticancer agents and the like.

[Formula 1]

Baileys-Hillman reaction, unsaturated ketones, derivatives, preparation method, anticancer effect

Description

Method for preparing unsaturated ketone and its derivatives having anticancer effect {Method for preparing unsaturated ketone and their derivatives for anticancer effect}

The present invention relates to a method for preparing unsaturated ketones and derivatives thereof having an anticancer effect, and more particularly, the following Chemical Formula 1 (Domestic Patent Registration No. 10-548743) isolated from soil actinomycetes BG2-41 and showing anticancer properties To a unsaturated ketone compound and derivatives thereof.

[Formula 1]

The introduction of three different substituents into unsaturated double bonds of unsaturated ketones while maintaining site selectivity and stereoselectivity is a significant chemical challenge, resulting in very low yields through several inefficient pathways.

The Baylis-Hillman reaction is a method of introducing a new alkyl or aryl group to the alpha-position of an unsaturated ketone using a Lewis base and an alkyl or aryl aldehyde used as a catalyst, and methylvinyl ketone and acet using this method. Condensation reactions under Baileys-Hilman conditions with aldehydes are already known ( Tetrahedron Lett ., 1986, 27, 5007; Tetrahedron Lett ., 1986, 27, 4307). It is also known that the compound of formula (2) is obtained by the 1,4-addition reaction when the acetate ester of the secondary alcohol, the product of the Baileys-Hillman reaction, is treated with copper iodide and phenylgrind reagent ( Synth. Comm , 1997, 27, 1157).

[Formula 2]

However, in contrast to the above known facts ( Tetrahedron Lett ., 1986, 27, 5007), in fact the condensation reaction of methylvinylketone and acetaldehyde is very low under conventional Baileys-Hilman conditions (solvent: THF; base: DABCO). There is a problem of progressing in yield or hardly progressing, and in particular, the reaction hardly proceeds when the amount of the reactant becomes larger than g-unit. This does not affect reaction rate and yield even if the reaction time is increased (7 days or more) or the reaction temperature is increased.

Problems related to the low reactivity and slow rate of the Baileys-Hillman reaction have been observed in the literature, and to solve this problem, without using a solvent or reacting under high pressure ( Tetrahedron Lett ., 1986, 27) 4307) is used, but all of the above methods are disadvantageous in that they are not suitable for mass synthesis.

Accordingly, the present inventors have made diligent efforts to develop a method for producing a large amount of the unsaturated ketone compound of Formula 1 and its derivatives, which exhibits excellent anticancer effect. The present invention has been completed by identifying new reaction conditions that can promote the reaction.

Accordingly, an object of the present invention is to provide a method for preparing an unsaturated ketone compound represented by the following Chemical Formula 1 having an anticancer effect.

Another object of the present invention to provide a method for preparing a derivative of the unsaturated ketone compound of formula (1).

Another object of the present invention to provide an unsaturated ketone compound of formula (1) and novel derivatives thereof prepared by the above method.

[Formula 1]

In order to achieve the above object, the present invention provides a method for producing an unsaturated ketone compound represented by the formula (1) having an anticancer effect.

Specifically, the present invention provides a method for preparing Formula 2, which is the main intermediate of the present invention.

That is, (1) preparing ethyl methyl vinyl ketone (Formula 3) by using methyl vinyl ketone and acetaldehyde as a starting material and a Baileys-Hillman reaction; And

[Formula 3]

(2) The present invention is obtained by converting the secondary alcohol (Formula 3), which is the product of the Baileys-Hillman reaction, prepared above into acetic acid ester (Formula 4), followed by 1,4-addition reaction of phenylgrind reagent in the presence of copper iodide. ( E ) -3-benzyl-3-penten-2-one (Formula 2) to prepare a main intermediate of the present invention comprising the formula (2) provides a method for preparing a formula (2) ).

[Formula 4]

Scheme 1

In addition, the present invention, in addition to the above process,

(3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran (THF) solvent; And

[Formula 5]

단, 상기에서 OTBDMS는 [O(tert-Butyl-dimethylsilyloxy)이다.

However, in the above OTBDMS is [O (tert-Butyl-dimethylsilyloxy).

(4) preparing Chemical Formula 1 by adding TBAF (Pyridium p-toluenedisilazide) in tetrahydrofuran solvent to prepare Chemical Formula 1; (4) provides a method of preparing an unsaturated ketone compound represented by Chemical Formula 1 further comprising: 2).

Scheme 2

The present invention provides a method for preparing a derivative of an unsaturated ketone compound represented by the formula (1) having an anticancer effect (hereinafter, see Scheme 3).

Specifically, the present invention, in addition to the production method of the formula (2) is the main intermediate of the present invention,

(3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran solvent; And

(4) reacting Chemical Formula 5 by adding sodium borohydride and cerium chloride in methanol solvent, and then adding TBAF (pyridium p-toluenesulfonate) in tetrahydrofuran solvent to prepare Chemical Formula 6; It provides a method for producing a novel derivative of the unsaturated ketone compound of formula (1) represented by the formula (6).

[Formula 6]

In addition, the present invention is in addition to the production method of the formula (2) which is the main intermediate of the present invention,

(3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran solvent; And

(4) reacting Formula 5 with PDC (Pyridinium dichromate) in a dichloromethane solvent, and then adding Pyridium p-toluenedisilazide (TBAF) in tetrahydrofuran solvent to prepare Formula 7; It provides a method for producing a novel derivative of the unsaturated ketone compound of formula (1) represented by 7.

[Formula 7]

In addition, the present invention is in addition to the production method of the formula (2) which is the main intermediate of the present invention,

(3) preparing Chemical Formula 8 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and propanealdehyde in a tetrahydrofuran solvent; And

(4) adding a 4 ′ molecular filter and PCC (pyridinium chlorochromate) to formula (8) in a dichloromethane solvent to prepare formula (9); new derivative of unsaturated ketone compound of formula (1) further comprising formula (9) It provides a method for producing.

[Formula 8]

[Formula 9]

In addition, the present invention is in addition to the production method of the formula (2) which is the main intermediate of the present invention,

(3) reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 4-t-butyldimethylsilyloxy-butanealdehyde in tetrahydrofuran solvent, and then adding TBAF (Pyridium p-toluenedisilazide) dissolved in tetrahydrofuran It provides a method for producing a novel derivative of the unsaturated ketone compound of Formula 1 represented by the following formula (10) further comprising the step of preparing a.

[Formula 10]

In addition, the present invention provides an unsaturated ketone compound represented by the formula (1) and novel derivatives thereof (see Formula 3 to Formula 10) prepared by the above method.

In the production method of the present invention,

In the step (1), the present invention preferably uses at least one or more of a hydrophilic solvent, that is, methanol, ethanol or isopropanol, more preferably characterized by a Baileys-Hillman reaction using methanol. .

The reaction solvent is most important in the present invention, and organic solvents such as tetrahydrofuran (THF), ether (ethyl ether), dimethyl formamide (DMF), and dimethyl sulfoxide ( In the case of dimethyl sulfoxide, DMSO), the reaction does not proceed at all, but when the hydrophilic solvents methanol, ethanol and isopropanol are used as the solvent, the reaction may be completed within a few minutes.

In addition, the Baileys-Hillman reaction in step (1) may include preparing ethyl hydroxide methyl ketone represented by Formula 3 through the Baileys-Hillman reaction in the presence of a Lewis base catalyst.

As the Lewis base, dimethylaminopyridine (MDAP, N, N-dimethylaminopyridine) or dabco (DABCO, 1,4-diazabicyclo [2,2,2,] octane) or the like is preferably used. More preferably, the amount of Lewis base to be used is preferably used in an amount of 0.1 to 0.3 equivalents based on ethyl methyl ketone and acetaldehyde as starting materials.

In addition, in the present invention, the Baileys-Hillman reaction of step (1) is preferably performed while maintaining a range of 0 ° C to room temperature (25 ° C), and the reaction time is preferably 30 minutes to 1 hour.

Scheme 3

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

Example 1. Preparation of 3- (1-hydroxyethyl) -3-butyn-2-one (Formula 3)

 17.4 g (247 mmol) of methyl vinyl ketone and 11.0 g (247 mmol) of acetaldehyde were dissolved in 30 mL of anhydrous methanol as a starting material, and the temperature was adjusted to 0 ° C. under a nitrogen atmosphere, followed by 4.17 g (37.1 mmol) of DABCO. ) Was added and the temperature was maintained for 1 hour to ensure good stirring.

After completion of the reaction on TLC, 10 ml of 1 N hydrochloric acid solution was added, and the resultant was concentrated under reduced pressure until the total solvent volume was reached.

After extraction three times (3 x 50 ml) with ethyl acetate (EtOAc), the combined organic solvents were collected and washed with saturated brine, dehydrated with sodium sulfate and concentrated under reduced pressure to give silica gel column chromatography (hexane: ethyl acetate = 4). 1) gave 16.7 g (146 mmol, 65%) of the desired product in oil form: ¹ H NMR (CDCl ₃ , 400 MHz) d 6.11 (s, 1H), 6.08 (s, 1H), 4.66 (br s , 1H), 3.31 (br s, 1H), 2.36 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H).

Example 2: Preparation of acetic acid 2-acetyl-1-methyl-allyl ester (Formula 4, Scheme 1)

1.0 g (8.76 mmol) of 3- (1-hydroxyethyl) -3-butyn-2-one and 1.07 g (10.5 mmol) of acetic anhydride obtained in Example 1 were dissolved in 4 ml of anhydrous ether, followed by concentrated sulfuric acid. A drop was added at 0 ° C., stirred for 3 hours, and a saturated aqueous solution of sodium hydrogen carbonate was added three times (3 × 50 mL) with ethyl acetate.

The combined extracts were washed with saturated brine, dehydrated with sodium sulfate and distilled under reduced pressure. The obtained product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 1.11 g (7.09 mmol, 85%) oil of the desired product. Obtained in the form: ¹ H NMR (CDCl ₃ , 400 MHz) d 6.11 (s, 1H), 6.00 (s, 1H), 5.73 (q, J = 6.4 Hz, 1H), 2.35 (s, 3H), 2.07 (s, 3 H), 1.34 (d, J = 6.4 Hz, 3 H).

Example 3. E ) -3-benzyl-3-penten-2-one (Formula 2, Scheme 1)

3.0 M phenyl in a mixture of 3 g (19.2 mmol) of acetic acid 2-acetyl-1-methyl-allyl ester prepared by the method of Example 2 and copper iodide (293 mg, 0.08 mmol) in 20 ml of anhydrous tetrahydrofuran 19.2 mL (57.6 mmol) of Grignard ether solution was added at minus 78 ° C. and stirred for 3 h. After completion of the reaction by addition of saturated aqueous ammonium chloride solution, the resulting aqueous layer was extracted three times with acetic acid ester (3 × 50 mL).

The collected extract was washed with saturated brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1), and the product was dried in the form of white powder (3.1 g, 17.7 mmol, 92%). Obtained: ¹ H NMR (CDCl ₃ , 400 MHz) d 7.25-7.22 (m, 2H), 7.16-7.14 (m, 3H), 6.91 (q, J = 7.0 Hz, 1H), 3.69 (s, 2H), 2.31 (s, 3H), 1.94 (d, J = 7.0 Hz, 1H) ¹³ C NMR (CDCl ₃ , 100 MHz) d 199.3, 142.5, 140.3, 140.1, 128.7, 128.7, 126.2, 31.1, 26.1, 15.5.

Example 4. E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one (Formula 5, Scheme 2)

817 mg (4.69 mmol) of ( E ) -3-benzyl-3-penten-2-one obtained in Example 3 was dissolved in 30 mL of anhydrous tetrahydrofuran, followed by 5.6 mL of 1.0 M LiHMDS (Lithium hexamethyldissilazide) tetrahydrofuran solution. (5.6 mmol) was added dropwise at −78 ° C., and a solution of 1.3 g (7.04 mmol) of 3-t-butyldimethylsilyloxy-propanealdehyde in 5 ml of anhydrous tetrahydrosilane was added all at once to the mixture stirred for 30 minutes. It was.

The reaction mass was stirred at minus 78 ° C. for 3 hours and then saturated ammonium chloride aqueous solution was added to terminate the reaction. The aqueous layer was extracted three times (3 x 300 mL) with ethyl acetate, and the combined extracts were washed with saturated brine and dehydrated with sodium sulfate.

Sodium sulfate was filtered off from the dehydrated compound solution, and the resultant was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain ( E ) -3-benzyl-8- in white powder form. 1.2 g (3.30 mmol, 70%) of t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one were obtained: ¹ H NMR (CDCl ₃ , 400 MHz) d 7.19-7.16 (m, 2H) , 7.10-7.06 (m, 3H), 6.89 (q, J = 7.0 Hz, 1H), 4.23-4.13 (m, 1H), 3.78-3.71 (m, 2H), 3.63 (s, 2H), 3.56 (d , J = 2.5 Hz, 1H0, 2.84-2.73 (m, 2H), 1.88 (d, J = 7.0 Hz, 3H), 1.63-1.58 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H ) ¹³ C NMR (CDCl ₃ , 100 MHz) d 201.4, 142.3, 140.4, 140.0, 128.8, 128.6, 126.3, 67.7, 61.6, 44.7, 38.9, 31.2, 26.3, 18.6, 15.6, 0.4, -5.1.

Example 5. E ) -3-benzyl-6,8-dihydroxy-2-octen-4-one (Formula 1, Scheme 2)

115 mg (0.32 mmol) of ( E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one prepared in Example 4 was added to 15 ml of anhydrous tetrahydrofuran. After dissolving, 0.32 ml (0.32 mmol) of 1.0 M TBAF (Pyridium p-toluenedisilazide) tetrahydrofuran solution was added at 0 ° C., followed by stirring for 3 hours.

After the reaction mixture was concentrated under reduced pressure, the concentrated mixture was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the desired compound as a white powder (76 mg, 0.31 mmol, 97%): ¹ H NMR (CD ₃ OD, 400 MHz) d 7.25-7.21 (m, 2H), 7.16-7.07 (m, 3H), 7.10 (q, J = 7.0 Hz, 1H), 4.27-4.21 (m, 1H) , 3.72 (s, 2H), 3.70 (t, J = 6.5 Hz, 2H), 3.34 (br s, 1H), 2.96 (dd, J = 16.0, 7.9 Hz, 1H), 2.81 (dd, J = 16.0, 4.6 Hz, 1H), 1.95 (d, J = 7.0 Hz, 3H), 1.71-1.63 (m, 2H) ¹³ C NMR (CD ₃ OD, 100 MHz) d 201.9, 143.2, 142.1, 129.3, 129.3, 126.8, 67.2, 60.7, 46.0, 40.6, 31.5, 15.4.

Example 6. E ) -6-benzyl-6-octene-1,3,5-triol (Formula 6, Scheme 3)

450 mg (1.24 mmol) of ( E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one prepared in Example 4 and 693 mg of CeCl ₃ 7H ₂ O 47 mg (1.24 mmol) of sodium borohydride were slowly added to a mixture of (1.86 mmol) and 20 ml of anhydrous methanol at 0 ° C. The reaction mixture was mixed at 0 ° C. for 3 hours, 1N hydrochloric acid aqueous solution was added dropwise and concentrated under reduced pressure until the volume of the mixture became ⅓.

The concentrated mixture was taken up with 50 ml of acetic acid ethyl ester, and the separated aqueous layer was extracted three times with acetic acid ethyl ester (3 × 50 ml). The combined extracts were washed with saturated brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain ( E ) -6-benzyl-1-. 413 mg (1.13 mmol, 91%) of t-butyldimethylsilyloxy-6-octene-3,5-diol were obtained in the form of a yellow syrup:

97 mg of the material was dissolved in 15 mL of anhydrous tetrahydrofuran, and then 0.27 mL (0.27 mmol) of 1.0 M TBAF tetrahydrofuran solution was added at 0 ° C. and stirred for 2 hours.

After the reaction mixture was concentrated under reduced pressure, the concentrated mixture was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 56 mg of the desired compound as a white powder: ¹ H NMR (CDCl ₃ , 400 MHz) d 7.20-7.07 (m, 5H), 5.80 (q, J = 6.7 Hz, 1H), 4.28 (br s, 1H), 4.04 (br s, 1H), 3.79-3.71 (m, 2H), 3.69-3.65 (m, 2H), 3.47 (d, J = 15.4 Hz, 1H), 3.31 (d, J = 15.6 Hz, 1H), 1.78 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H), 1.67 -1.60 (m, 1H), 1.53 (t, J = 5.6 Hz, 2H), 0.83 (s, 9H), 0.00 (s, 6H) ¹³ C NMR (CDCl ₃ , 100 MHz) d 141.0, 140.6, 140.5, 128.7, 126.2, 121.9, 73.0, 70.2, 68.3, 41.9, 38.4, 33.7, 18.5, 14.0, -5.1.

Example 7. (2 E , 5 Z ) -3-benzyl-6,8-dihydroxy-2,5-octadien-4-one (Formula 7, Scheme 3)

12 mL of ( E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one obtained by the preparation method of Example 4 (0.33 mmol) in 12 ml of anhydrous dichloromethane It was dissolved in 248 mg (0.66 mmol) of PDC (pyridinium dichromate), and the mixture was stirred vigorously at room temperature for 12 hours.

The solid obtained by adding ether to the reaction mixture was filtered by washing with dichloromethane using a short silica gel column, and the filtrate was concentrated under reduced pressure, and the obtained material was used directly in the next step without further purification.

That is, the material obtained above was dissolved in 8 ml of anhydrous tetrahydrofuran, and then 0.11 ml (0.11 mmol) of 1.0 M TBAF tetrahydrofuran solution was added at 0 ° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give (2E, 5Z) -3-benzyl-6,8-dihydroxy-. 22 mg (0.09 mmol, 27%: two process yield) of 2,5-octadien-4-one was obtained in the form of white powder: ¹ H NMR (CD ₃ OD, 400 MHz) d 7.28-7.25 (m, 2H ), 7.20-7.16 (m, 1H), 7.13-7.12 (m, 2H), 6.76 (q, J = 7.2 Hz, 1H), 5.50 (s, 1H), 4.44 (t, J = 6.7 Hz, 2H) , 3.65 (s, 2H), 2.51 (t, J = 6.8 Hz, 2H), 1.90 (d, J = 7.2 Hz, 3H) ¹³ C NMR (CD ₃ OD, 100 MHz) d 193.1, 171.1, 138.5, 133.6 , 132.7, 128.6, 127.8, 126.3, 103.3, 67.8, 36.1, 29.7, 22.7.

Example 8. E ) -3-benzyl-6-hydroxy-2-octen-4-one (Formula 8, Scheme 3)

200 mg (1.15 mmol) of (E) -3-benzyl-3-penten-2-one prepared in Example 3 was dissolved in 15 ml of anhydrous tetrahydrofuran, followed by 1.38 ml (1.38 mmol) of 1.0 M LiHMDS tetrahydrofuran solution. ) Was added dropwise at -78 ° C and stirred for 30 minutes.

0.13 mL (1.72 mmol) of propanealdehyde was added to the mixture at once, and the reaction was terminated by adding a saturated aqueous ammonium chloride solution after stirring for 4 hours at -78 ° C. The aqueous layer was extracted three times (3 x 50 mL) using ethyl acetate, and the combined extracts were washed with saturated brine and dehydrated with sodium sulfate.

Sodium sulfate was filtered off from the dehydrated compound solution, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: acet ethyl ester = 4: 1) to give 173 mg (0.75 mmol, 65%) of the desired product as a yellow syrup. Obtained: ¹ H NMR (CDCl ₃ , 400 MHz) d 7.24-7.20 (m, 2H), 7.14-7.11 (m, 3H), 6.92 (q, J = 6.8 Hz, 1H), 3.97-3.90 (m, 1H ), 3.68 (s, 2H), 2.83 (dd, J = 16.8, 4.8 Hz, 1H), 2.70 (dd, J = 16.8, 8.8 Hz, 1H), 1.92 (d, J = 7.2 Hz, 3H), 1.53 -1.43 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ¹³ C NMR (CDCl ₃ , 100 MHz) d 202.2, 142.2, 140.6, 140.0, 128.8, 128.5, 126.4, 69.7, 43.6, 31.1, 29.7, 15.6, 10.3.

Example 9. (2 E , 5 Z ) -3-benzyl-6-hydroxy-2,5-octadien-4-one (Formula 9, Scheme 3)

95 mg (0.41 mmol) of ( E ) -3-benzyl-6-hydroxy-2-octen-4-one prepared in Example 8 was dissolved in 20 ml of anhydrous dichloromethane. 265 mg (0.41 mmol) of PCC (pyridinium chlorochromate) was added thereto, and vigorously stirred at room temperature for 4 hours.

The solid obtained by adding ether to the reaction mixture was filtered using a short silica gel column, washing with dichloromethane, and concentrated under reduced pressure. The material thus obtained was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to give the desired compound in the form of 51 mg (0.22 mmol, 54%) light brown syrup: ¹ H NMR (CD ₃ OD , 400 MHz) d 15.75 (s, 1H), 7.29-7.15 (m, 5H), 6.94 (q, J = 7.1 Hz, 1H), 5.69 (s, 1H), 3.70 (s, 2H), 2.29 (q , J = 7.5 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H) For the minor compound: ¹ H NMR (CD ₃ OD, 400 MHz) d 7.29 -7.15 (m, 5H), 6.97-6.91 (m, 1H), 3.79 (s, 2H), 3.70 (s, 2H), 2.40 (q, J = 7.5 Hz, 2H), 1.97 (d, J = 7.0 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H); ¹³ C NMR (CD ₃ OD, 100 MHz) d 205.7, 197.5, 195.0, 184.4, 412.6, 142.1, 139.7, 139.6, 136.4, 136.0, 128.9, 128.8, 128.6, 128.3, 126.5, 126.4, 96.0, 53.5, 32.7, 31.8, 30.7, 30.1, 15.8, 15.2, 10.0, 7.9.

Example 10. Preparation of (E) -3-benzyl-6,9-dihydroxy-2-nonen-8-one (Formula 10, Scheme 3)

363 mg (2.09 mmol) of (E) -3-benzyl-3-penten-one prepared in Example 3 was dissolved in 15 ml of anhydrous tetrahydrofuran, followed by 3.1 ml (3.1 mmol) of 1.0 M LiHMDS tetrahydrofuran solution. It was added dropwise at -78 ° C and stirred for 30 minutes.

To the mixture was dissolved 422 mg (2.09 mmol) of 4-t-butyldimethylsilyloxy-butanealdehyde in 5 ml of anhydrous tetrahydrofuran, added at once, and stirred for 3 hours at -78 ° C. The reaction was terminated.

The aqueous layer was extracted three times (3 x 50 ml) using ethyl acetate, and the combined extracts were washed with saturated brine and dehydrated with sodium sulfate.

Sodium sulfate was filtered from the dehydrated compound solution, concentrated under reduced pressure and used for the next procedure without further purification.

The compound obtained above was dissolved in 15 ml of anhydrous tetrahydrofuran, and 5.3 mg (0.02 mmol) of pyridinium p-toluenesulfonate was added to the solution at room temperature, followed by stirring for 12 hours. 2 ml of triethylamine was added to the reaction mixture, and then the resulting mixture was concentrated under reduced pressure. ) Was obtained in the form of a yellow powder: ¹ H NMR (CD ₃ OD, 400 MHz) d 7.26-7.22 (m, 2H), 7.17-7.11 (m, 3H), 6.94 (q, J = 7.0 Hz, 1H) , 4.13-4.06 (m, 1H0, 3.68 (s, 2H), 3.65-3.59 (m, 2H), 2.83-2.78 (m, 2H), 1.95 (d, J = 7.0 Hz, 3H), 1.71-1.65 ( m, 2H), 1.65-1.53 (m, 2H) ¹³ C NMR (CD ₃ OD, 100 MHz) d 202.0, 142.1, 140.9, 139.9, 128.8, 128.5, 126.4, 68.4, 63.0, 44.1, 33.9, 31.1, 29.5 , 14.6.

The specific parts of the present invention have been described in detail above, and it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

As described above, the present invention has the effect of providing an unsaturated ketone compound represented by the formula (1) having an anticancer effect, a derivative thereof, and a method for producing the same.

The production method according to the present invention accelerates the reaction rate by using a hydrophilic solvent in the Baileys-Hillman reaction of methyl vinyl ketone and acetaldehyde to introduce ethyl hydroxide at the alpha-carbonyl position of methyl vinyl ketone. It allows the introduction of substituents in selective and high yields, and also enables mass synthesis of compounds. As a result, it can be widely used in the fields of medicine and fine chemistry, including the structure and activity correlation of the compound of formula (1) and its novel derivatives that can be usefully used as cancer cell death inducing activators, anticancer agents and the like.

Claims (15)

In the method for producing an unsaturated ketone compound and its derivatives represented by the formula (1) having an anticancer effect, (1) preparing ethyl methyl vinyl ketone (Formula 3) using methyl vinyl ketone and acetaldehyde as starting materials and performing a Baileys-Hillman reaction; And (2) The present invention is obtained by converting the secondary alcohol (Formula 3), which is the product of the Baileys-Hillman reaction, prepared above into acetic acid ester (Formula 4), followed by 1,4-addition reaction of phenylgrind reagent in the presence of copper iodide. Preparing a main intermediate of ( E ) -3-benzyl-3-penten-2-one (Formula 2); Process for preparing unsaturated ketone compounds and derivatives thereof. [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

Scheme 1

The method of claim 1, In addition to the above process, (3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldisilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran (THF) solvent; And (4) preparing Chemical Formula 1 by adding TBAF (Pyridium p-toluenesulfonate) to the Chemical Formula 5 in a tetrahydrofuran solvent. [Formula 5]

Scheme 2

However, in the above OTBDMS is [O (tert-Butyl-dimethylsilyloxy)]. The method of claim 1, In addition to the above process, (3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldisilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran solvent; And (4) reacting Chemical Formula 5 with the addition of sodium borohydride and cerium chloride in a methanol solvent, and then adding pyridium p-toluenesulfonate (TBAF) in tetrahydrofuran solvent to prepare Chemical Formula 6; A process for preparing derivatives of unsaturated ketone compounds of formula (1) represented by 6. [Formula 5]

However, in the above OTBDMS is [O (tert-Butyl-dimethylsilyloxy)]. [Formula 6]

The method of claim 1, In addition to the above process, (3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldisilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran solvent; And (4) reacting Chemical Formula 5 by adding PDC (Pyridinium dichromate) in dichloromethane solvent, and then preparing Chemical Formula 7 by adding TBAF (Pyridium p-toluenesulfonate) in tetrahydrofuran solvent. A process for preparing derivatives of unsaturated ketone compounds of formula (1) represented by 7. [Formula 5]

However, in the above OTBDMS is [O (tert-Butyl-dimethylsilyloxy)]. [Formula 7]

The method of claim 1, In addition to the above process, (3) preparing Chemical Formula 8 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldisilazide) and propanealdehyde in a tetrahydrofuran solvent; And (4) preparing a derivative of the unsaturated ketone compound represented by Chemical Formula 1 further comprising the step of preparing Chemical Formula 9 by adding a 4 ′ molecular filter and PCC (pyridinium chlorochromate) in a dichloromethane solvent. [Formula 8]

[Formula 9]

The method of claim 1, In addition to the above process, (3) reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldisilazide) and 4-t-butyldimethylsilyloxy-butanealdehyde in a tetrahydrofuran solvent, and adding TBAF (Pyridium p-toluenesulfonate) dissolved in tetrahydrofuran. To prepare a derivative of the unsaturated ketone compound of formula (1) represented by the formula (10) further comprising. [Formula 10]

The method according to any one of claims 1 to 6, Baileys-Hilman reaction in the process (1) is a method for producing an unsaturated ketone compound represented by the formula (1) and derivatives thereof, characterized in that at least one or more from the group consisting of methanol, ethanol or isopropanol. The method according to any one of claims 1 to 6, The Lewis base used in the Baileys-Hillman reaction of step (1) is dimethylaminopyridine (DMAP, N, N-dimethylaminopyridine) or dabco (DABCO, 1,4-diazabicyclo [2,2,2,] octane). Method for producing an unsaturated ketone compound represented by the formula (1) and its derivatives, characterized in that selected from the group consisting of. The method according to any one of claims 1 to 6, The amount of Lewis base used in the Baileys-Hillman reaction of step (1) is 0.1 to 0.3 equivalents based on ethyl methyl ketone and acetaldehyde as starting materials, and the unsaturated ketone compound represented by the formula (1) How to prepare. The method according to any one of claims 1 to 6, The Baileys-Hilman reaction of step (1) is carried out in the range of 0 ℃ to room temperature (25 ℃), the reaction time is unsaturated ketone compound represented by the formula (1) characterized in that it proceeds for 30 minutes to 1 hour and derivatives thereof How to prepare. A novel derivative of the unsaturated ketone compound of formula (1) prepared by the process of claim 3 and represented by the following formula (6). [Formula 6]

A novel derivative of the unsaturated ketone compound of formula (1) prepared by the process of claim 4 and represented by the following formula (7). [Formula 7]

A novel derivative of an unsaturated ketone compound of formula (1) prepared by the process of claim 5 and represented by the following formula (8). [Formula 8]

A novel derivative of the unsaturated ketone compound of formula (1) prepared by the process of claim 6 and represented by the following formula (10). [Formula 10]

A novel derivative of the unsaturated ketone compound of formula (1) prepared by the process of claim 5 and represented by the following formula (9). [Formula 9]