KR101176892B1 - Method of preparing methylgerambullone and intermediates therefor - Google Patents

Abstract

The present invention relates to a method for easily preparing high yield and high purity of methylzelamblon obtained by extracting from the leaves of Glycosmis angustifolia with the fragrance , a novel intermediate for this, and a method for preparing these intermediates. It is about.

Methylzelamblon, preparation method, intermediate

Description

Method of preparing methylgeramblon and intermediates therefor {Method of preparing methylgerambullone and intermediates therefor}

The present invention relates to a method for preparing methylzelamblon and an intermediate for the same. More specifically, the present invention relates to a method for easily preparing methylzelamblon in high yield and high purity, intermediates for the same, and a method for preparing these intermediates.

Methylzelamblon is a compound having the structure of Formula 1, and is known to be obtained by extraction from the leaves of Glycosmis angustifolia , which is a kind of fragrance .

[Formula 1]

For example, reference [ Liebigs Annalen , No 10, p 1789, 1995] were able to isolate five methylsulfonyl propene amides from the leaves of several Glycosmis species in Thailand, all of which contained the phenethylamide group. One of which was methylzelamblon. Meanwhile, references [ Phytochemistry , Vol. 28, No. 3, p 1305, 1994], seven new sulfone compounds, methylsulfonepropene amide derivatives, were isolated from the leaves of Glycosmis angustifolia in Sri Lanka by methanol extraction. Blon, methyldambulin and the like. Methyldamblin, the main component, has been shown to exhibit some degree of antimicrobial effect, and methylzelamblon is also expected to be effective in antibacterial or gastrointestinal motility.

However, the preparation of methylzelamblon by the extraction method has a problem that it is difficult to proceed further research because the yield and purity is extremely low. Therefore, there has been a great demand for the development of a method capable of producing methylzelamblon with high yield and high purity, but the structure is complicated and there are no examples reported for the synthesis of methylzelamblon.

The present inventors have conducted extensive studies to develop a method for synthesizing methylzelamblon. As a result, the inventors have found that methylzelamblon can be produced in high yield and high purity using specific intermediates.

Accordingly, it is an object of the present invention to provide a method for producing methylzelamblon with high yield and high purity easily.

Another object of the present invention is to provide certain new intermediates for the preparation of methylzelamblon.

Another object of the present invention is to provide a method for preparing the intermediates.

The present invention relates to a process for easily preparing methylzelamblon in high yield and high purity, intermediates for the same, and a process for preparing these intermediates.

Method for producing methyl zelamblon of the present invention

(i) for formula (2) of 4- (2-aminoethyl) phenol to 4- (methylsulfonyl) of formula (3) was coupled to the reaction of acrylic acid of formula 5 N - (4-hydroxy-phenethyl) - N Obtaining -methyl-3- (methylsulfonyl) acrylamide;

(ii) the reaction of N- (4-hydroxyphenethyl) -N -methyl-3- (methylsulfonyl) acrylamide of the formula (5) obtained in step (i) with the compound of formula (4) ( E ) -N -methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1-enyl) -1,3- [dician] of Formula 9 -2-yl) but-2-enyloxy} phenethyl] -3- (methylsulfonyl) acrylamide; And

(iii) ( E ) -N -methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1) of formula (9) obtained in step (ii): Deprotection reaction of -enyl) -1,3- [dioxy] -2-yl) but-2-enyloxy} phenethyl] -3- (methylsulfonyl) acrylamide.

[Formula 1]

 [Formula 2]

 (3)

 [Formula 4]

 [Chemical Formula 5]

 [Chemical Formula 9]

In Formula 4, X is a hydroxy group or leaving group. As the leaving group, a chloride, bromide, mesyl, or tosyl group is preferable.

4- (2-methylaminoethyl) phenol of Formula 2 used in step (i) may be obtained by methylation of tyramine. For example, a methyl group is introduced directly into the nitrogen of tyramine using methane iodide, formaldehyde / palladium / hydrogen, sodium formaldehyde / boron hydrogen borohydride, or more preferably nitrogen of tyramine as shown in Scheme 1 below. It can be obtained by introducing a t -butyloxycarbonyl group into the compound, followed by reduction with lithium aluminum hydride.

[Reaction Scheme 1]

On the other hand, 3- (methylsulfonyl) acrylic acid of Chemical Formula 3 is reacted with propiolic acid and methylthiometal, preferably methylthio sodium, as shown in Scheme 2 below to give 3- (methylthio) acrylic acid of Chemical Formula 6 This can be obtained by an oxidation reaction.

Scheme 2

[Formula 6]

 Oxidizing agents used in the oxidation reaction include hydrogen peroxide, 3-chloroperbenzoic acid, oxone and the like. Preferably 3-chloroperbenzoic acid is used.

In step (i), as shown in the following Scheme 3, 4- (2-methylaminoethyl) phenol of the formula (2) and 3- (methylsulfonyl) acrylic acid of the formula (3) are subjected to an amide bond reaction to form N- ( 4-hydroxyphenethyl) -N -methyl-3- (methylsulfonyl) acrylamide is synthesized.

Scheme 3

The amide linkage reaction can be carried out in the presence of thionyl hydrochloride / base or phosphorus oxychloride / base. At this time, both organic base and inorganic base may be used as the base. For example, triethylamine, diisopropylamine, tributylamine, etc. may be used as the organic base, and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. And sodium hydrogencarbonate can be used. In addition, the coupling reaction is dicyclohexyldicarbodiimide / dimethylaminopyridine, dicyclohexyldicarbodiimide / 1-hydroxybenzotriazole, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride / In the presence of 1-hydroxybenzotriazole and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride / dimethylaminopyridine, dichloromethane, tetrahydrofuran, dimethylformamide and the like are used as a solvent. Can be performed. Most preferably, the coupling reaction is carried out using dimethylformamide as solvent in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride / dimethylaminopyridine. The reaction temperature is most preferably at room temperature.

In step (ii), N- (4-hydroxyphenethyl) -N -methyl-3- (methylsulfonyl) acrylamide of formula 5 and a compound of formula 4 are combined to react ( E ) -N of formula (9). -Methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1-enyl) -1,3- [dioxy] -2-yl) but-2 -Ynyloxy} phenethyl] -3- (methylsulfonyl) acrylamide is synthesized.

When X is a hydroxy group, the coupling reaction of the phenol group and the hydroxy group is performed under Mitsunobu conditions [ Organic Reactions , vol. 42, p 335)]. For example, diisopropyl azodicarboxylate, diethyl azodicarboxylate and the like can be generally used, and triphenylphosphine and tributylphosphine can be used together. The reaction temperature can be used from 0 ℃ to the heating reflux temperature, it is most preferable to proceed with the reaction using ultrasonic waves at room temperature.

In step (iii), ( E ) -N -methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1-enyl) -1, represented by Formula 9, Deprotection reaction of 3- [dithiane] -2-yl) but-2-enyloxy} phenethyl] -3- (methylsulfonyl) acrylamide to prepare methyl zelamblon of formula (1).

The deprotection reaction of dithiane may be performed using trifluoroacetic acid, aqueous mercury solution, t -butylhydroperoxide, methane iodide / water / acetonitrile, 3-chloroperbenzoic acid / acetic anhydride, and the like. Most preferably methane iodide / water / acetonitrile is used, where acetonitrile can be replaced with tetrahydrofuran, dioxane, acetone, dichloromethane, ethyl acetate and the like. The reaction temperature can be from 0 ℃ to the heating reflux temperature, the room temperature is most preferred.

The process for preparing the compounds of Formula 9 and Formula 1 is shown in Scheme 5 below.

Scheme 5

On the other hand, the present invention relates to a novel intermediate represented by the following formula (4).

[Formula 4]

Wherein X is a hydroxy group or leaving group. As the leaving group, a chloride, bromide, mesyl, or tosyl group is preferable.

On the other hand, the present invention relates to a method for preparing the intermediate of Formula 4, the method for preparing the intermediate of the present invention

(i) 2- (2-methylpropenyl)-[1,3] -dithiane of formula (7) and 2-methyl-4- ( t -butyldiphenylsilaneyloxy) but-2- of formula (8) Binding reaction of the en-1-ol; And

(ii) optionally reacting the hydroxy group with a leaving group.

[Formula 7]

[Formula 8]

In the above formula, R ₁ , R ₂ and R ₃ are each independently an alkyl group or an aryl group.

In the present specification, an alkyl group means a straight or branched hydrocarbon having 1 to 5 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t -butyl, and the like. no.

The aryl group is a simple or fused cyclic and the ring is an unsaturated hydrocarbon consisting of 5 to 15 hexagons. Examples of the aryl group include, but are not limited to, phenyl and the like.

2- (2-methylpropenyl)-[1,3] -dithiane of formula (7) used in step (i) is obtained by reacting 3-methylcrotonaldehyde with 1,3-propanedichiol under an acid catalyst. can do. In this case, as the acid catalyst, trifluoroboron ether, paratoluenesulfonic acid, sulfuric acid, camphorsulfonic acid, phosphoric acid, and the like may be used. The reaction temperature is preferably -20 ° C to room temperature, and tetrahydrofuran, dioxane, dichloromethane, or the like may be used as the reaction solvent. Most preferably, the reaction proceeds at -10 占 폚 with dichloromethane as solvent and trifluoroboron ether as acid catalyst.

Meanwhile, 2-methyl-4- ( t -butyldiphenylsilaneyloxy) but-2-en-1-ol of the formula (8) is a hydroxyl group after introducing a silane protecting group into 3-methyl-2-buten-1-ol It can be obtained by introducing. Introduction of silane protecting groups can be carried out using alkyl / arylsilyl halides and catalysts. As the catalyst, imidazole, silver nitrate, pyridine and the like can be used, and diaminopyridine can be used together. Tetrahydrofuran, dichloromethane, dimethylformamide and the like may be used as the reaction solvent, and the reaction temperature is preferably -20 ° C to room temperature. Most preferably, the reaction is carried out at room temperature using dichloromethane as a solvent and imidazole as a catalyst.

In step (i), the coupling reaction is carried out using dihydrogen using tetrahydrofuran, dimethylformamide, toluene, etc. in the presence of a base such as sodium hydride, n -butyllithium, t -butyllithium, sec -butyllithium, or the like. After preparing an anion, the reaction may be performed by reacting a compound in which the hydroxyl group of 2-methyl-4- ( t -butyldiphenylsilaneyloxy) but-2-en-1-ol of Formula 8 is substituted with a leaving group. At this time, the reaction temperature is preferably -78 to -20 ℃, most preferably -78 ℃.

Processes for preparing the compounds of Formula 7, Formula 8 and Formula 4 are shown in Scheme 4 below.

Scheme 4

On the other hand, the present invention relates to a novel intermediate represented by the following formula (5), (7), (8) or (9).

[Chemical Formula 5]

[Formula 7]

[Formula 8]

Wherein R ₁ , R ₂ and R ₃ are each independently an alkyl or aryl group, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t -butyl, or phenyl.

[Chemical Formula 9]

According to the present invention, methylzelamblon obtained by extraction from the leaves of Glycosmis angustifolia , which is a kind of fragrance family, can be easily produced in high yield and high purity using novel specific intermediates.

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

Example  One: ( E ) -3- ( Methylthio Production of Acrylic Acid

5.2 g of propiolic acid was slowly added to 39 mL of 2N-sodium hydroxide aqueous solution, and 35 g of 15% aqueous methylthiosodium solution was slowly added thereto, followed by heating to reflux for 12 hours. After cooling to 0 ° C., concentrated hydrochloric acid was slowly added to adjust the pH to 1. The resulting solid was filtered, washed with cold water, the filtrate was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale yellow solid. After combined with the solid obtained earlier, 1,000 mL of xylene was added and heated to reflux for 48 hours. The xylene was completely removed and recrystallized from ethyl acetate to give 5.6 g (yield 65.05%) of a yellow solid compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 12.04 (1H, s, -COO H ), 7.71 (1H, J = 14.8 Hz, -SC H =), 5.63 (1H, J = 14.8 Hz,- SCH = C H -COOH), 2.34 (3H, s, -SCH ₃ )

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 166.16, 147.22, 114.35, 14.17

Example  2: ( E ) -3- ( Methylsulfonyl Production of Acrylic Acid

2.02 g of ( E ) -3- (methylthio) acrylic acid obtained in Example 1 was dissolved in 250 mL of dichloromethane and cooled to 0 ° C. Then, 8.04 g of 70% 3-chloroperbenzoic acid was added, followed by stirring at 0 ° C. for 12 hours. Then, 4 g of sodium hydrogen sulfite was added thereto, stirred for 5 hours, and filtered. The filtrate was concentrated to 100 mL and the resulting solid was filtered, the filtrate was concentrated and the residue was recrystallized from isopropyl ether to give 2.7 g (100% yield) of a white solid compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 13.54 (1H, s, -COO H ), 7.64 (1H, J = 15.6 Hz, -S (O) ₂ C H =), 6.62 (1H, J = 15.6 Hz, -OSCH = C H -COOH), 3.18 (3H, s, -S (O) ₂ CH ₃ )

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 165.17, 143.01, 132.19, 41.96

Example  3: 4- (2- Methylaminoethyl Preparation of Phenolic Hydrochloride

10 g of tyramine was suspended in 100 mL of dichloromethane, 17.5 g of di-t-butyldicarbonate was added, followed by stirring for 2 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was taken up in 250 mL of anhydrous dioxane and cooled to 0 ° C. 13.8 g of lithium aluminum hydride was added thereto, stirred at room temperature for 2 hours, and heated at 90 ° C. for 24 hours. 10 mL of methanol was added to stop the reaction and 200 mL of methanol was added when no gas was generated. The resulting solid was filtered and pH was adjusted to 1 by addition of concentrated hydrochloric acid to the filtrate. After extracting with ethyl acetate using a continuous extractor, ethyl acetate was concentrated under reduced pressure to give 10.2 g of a white solid compound (yield 93%).

¹ H NMR (400 MHz, CD ₃ OD): δ = 7.11 (2H, dd , J = 6.4, 1.6 Hz, phenyl), 6.77 (2H, dd , J = 6.4, 1.6Hz, aryl), 3.19 (2H, m , -CH _2- ), 2.89 (2H, m, -CH _2- ), 2.70 (3H, s, -NC H ₃ )

¹³ C NMR (100 MHz, CD ₃ OD): δ = 156.45, 129.41, 126.64, 115.36, 50.39, 32.32, 31.12

Example  4: N -(4- Hydroxyphenethyl ) - N - methyl -3- ( Methylsulfonyl ) Acrylamide  Produce

1.44 g of 4- (2-methylaminoethyl) phenol hydrochloride obtained in Example 3, 1.15 g of ( E ) -3- (methylsulfonyl) acrylic acid obtained in Example 2, and 93 mg of dimethylaminopyridine were converted into dimethylformamide. After dissolving in 50 mL, 1.28 mL of triethylamine was added thereto. After cooling to 0 ° C., 1.16 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added and stirred at room temperature for 24 hours. 1M aqueous hydrochloric acid solution was added to adjust the pH to 5-6, and extracted with ethyl acetate. The organic layer was treated with anhydrous magnesium sulfate, dried, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 1.1 g of a white solid compound (yield: 51%).

Cis -soid

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.33 (1H, d , J = 14.4 Hz, -SO ₂ C H = CH-), 7.05 (2H, d, J = 8.4 Hz, aryl), 6.79 (2H , d, J = 8.4 Hz, aryl), 3.67 (2H, t, J = 7.2 Hz, -CH ₂ C H ₂ N), 3.01 (3H, s, -CH ₃ ), 2.91 (3H, s, -C H ₃ ), 2.81 (2H, t, J = 7.2 Hz, -C H ₂ CH ₂ N)

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 162.82, 154.87, 139.57, 133.13, 129.86, 129.77, 115.55, 50.34, 42.40, 36.29, 31.60

Tran -soid

¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.93-6.89 (3H, m, aryl and vinyl), 6.77-6.73 (3H, m, aryl and vinyl), 3.60 (2H, t, J = 6.0 Hz,- CH ₂ C H ₂ N), 3.08 (3H, s, -C H ₃ ), 2.86 (3H, s, -C H ₃ ), 2.79 (2H, t, J = 6.0 Hz, -C H ₂ CH ₂ N )

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 163.52, 155.59, 138.22, 132.03, 130.31, 128.65, 116.24, 52.44, 42.47, 34.28, 33.61

Example  5: 2- (2- Methylpropenyl )-[1,3]- Dian  Produce

After dissolving 6.7 g of 3-methylcrotonaldehyde in 30 mL of dichloromethane, 8.6 g of 1,3-propanedithiol was added and cooled to -10 ° C. Then 1 mL of trifluoroboron ether solution was added and stirred for 3 hours. The organic layer was washed with 15% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain 2- (2-methylpropenyl)-[1,3] -dicia 12.1 as a colorless liquid compound. g (yield 87.35%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 5.12 (1H, = C H ), 4.85 (1H, d, J = 10.0 Hz, -SC H S-), 2.96-2.75 (4H, m, -SC H ₂ CH ₂ C H ₂ S-), 2.10-2.04 (1H, m, -SCH ₂ C H ₂ CH ₂ S-), 1.87-1.79 (1H, m, -SCH ₂ C H ₂ CH ₂ S-), 1.73 (3H, d, J = 1.6 Hz, -CH ₃ ), 1.73 (3H, d, J = 1.2 Hz, -CH ₃ )

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 137.76, 121.19, 44.44, 30.61, 25.63, 25.00, 18.40

Example  6: 2- methyl -4- (t- Butyldiphenylsilaneyloxy ) Boot Preparation of 2-en-1-ol

After dissolving 1 g of 3-methyl-2-buten-1-ol in 5 mL of dichloromethane, 3.51 g of t -butyldiphenylsilyl chloride and 2.37 g of imidazole were added and stirred for 12 hours. Then, water was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain t -butyldiphenyl- (3-methyl-but-2-enyloxy) silane.

Meanwhile, 0.65 g of selenium dioxide was added to 5 mL of dichloromethane, cooled to 0 ° C., and 3 mL of 70% t -butylhydroperoxide was added thereto. After stirring for 1 hour at 0 ° C., the t -butyldiphenyl- (3-methyl-but-2-enyloxy) silane was added and stirred at room temperature for 2 days. Dimethyl sulfide was added to reduce t -butylhydroperoxide, followed by addition of 15% aqueous sodium hydroxide solution. Then, the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 1: 5) to obtain 2.01 g of a liquid compound (yield: 51%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.74 ~ 7.71 (4H, m, phenyl), 7.47 ~ 7.39 (6H, m, phenyl), 5.66 (1H, m, = C H ), 4.31 (2H, d , J = 6.4 Hz, -C H ₂ OTBDPS), 3.98 (2H, s, -C H ₂ OH), 1.08 (9H, s, t -butyl)

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 136.26, 135.65, 133.88, 129.65, 127.69, 124.87, 68.20, 60.81, 26.88, 19.20, 13.80

Example  7: 3- methyl -4- [2- (2- Methylpropenyl )-[1,3] Dian -2 days] Boot Preparation of 2-en-1-ol

6.02 g of 2-methyl-4- ( t -butyldiphenylsilaneyloxy) but-2-en-1-ol obtained in Example 6 was dissolved in 60 mL of anhydrous dichloromethane, and cooled to -20 ° C. 3.45 mL of triethylamine and 108 mg of dimethylaminopyridine were added followed by 4.38 g of paratoluenesulfonyl chloride. After stirring for 6 hours, 4.6 g of lithium bromide was dissolved in 60 mL of tetrahydrofuran and added slowly. After stirring for 2 hours at 0 ° C., water was added, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were then combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford (4-bromo-3-methyl-but-2-enyloxy) -t -butyldiphenylsilane.

5.94 g of 2- (2-methylpropenyl)-[1,3] dithiane obtained in Example 5 was dissolved in 20 mL of anhydrous tetrahydrofuran and cooled to -78 ° C. 60 mL of 1.7 M t -butyllithium tetrahydrofuran solution was slowly added. After stirring at −20 ° C. for 2 hours, the mixture was cooled to −78 ° C. again. Then a solution of 7 g of (4-bromo-3-methyl-but-2-enyloxy) -t -butyldiphenylsilane in 20 mL of anhydrous tetrahydrofuran was slowly added. Stir at -78 ° C for 2 hours and then at -40 ° C for 12 hours. Then water was added to stop the reaction and stirred for 2 hours at room temperature. Water and dichloromethane were added, the mixture was stirred for 1 hour, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. 30 mL of 1M tetrabutylammonium fluoride / tetrahydrofuran solution was added to the residue, followed by stirring at room temperature for 6 hours. After adding water, the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. Column chromatography (ethyl acetate: hexane = 1: 5) gave 3.65 g (yield: 80%) of a liquid compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 5.52 (1H, m, = C H ), 5.47 (1H, m, = C H ), 4.13 (2H, d, J = 6.8 Hz, -C H ₂ OH ), 2.90-2.75 (4H, m, -SC H ₂ CH ₂ C H ₂ S-), 2.75 (2H, s, -C H ₂ C (S) ₂ ), 2.01-1.84 (2H, m, -SCH ₂ C H ₂ CH ₂ S-), 1.74 (3H, s, -C H ₃ ), 1.74 (3H, s, -C H ₃ ), 1.73 (3H, s, -C H ₃ )

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 138.56, 134.52, 129.53, 127.91, 59.22, 52.68, 50.20, 27.83,27.59, 19.33, 18.12

Example  8: ( E ) - N - methyl - N -[4-{( E ) -3- methyl -4- (2- (2- Methylprop -1-enyl) -1,3- [ Dian ]-2 days) Boot -2- Nyloxy } Phenethyl ] -3- ( Methylsulfonyl ) Acrylamide  Produce

3.646 g of 3-methyl-4- [2- (2-methylpropenyl)-[1,3] dioxy-2-yl] but-2-en-1-ol obtained in Example 7, Example 4 4.4 g of N- (4-hydroxyphenethyl) -N -methyl-3- (methylsulfonyl) acrylamide and 5.55 g of triphenylphosphine obtained in the above were dissolved in 100 mL of tetrahydrofuran. Then, 3.7 g of diisopropyl azodicarboxylate (DIAD) was added and sonicated for 3 hours. The solvent was concentrated under reduced pressure, and then column chromatography (ethyl acetate: hexane = 2: 1) gave 4.5 g of a liquid compound (yield: 61%).

Cis -soid + Tran -soid

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.30 ~ 6.79 (6H, m , aryl and vinyl), 5.55 (1H, m, vinyl), 5.45 (1H, br.s, vinyl), 4.50 (1H, m , -CH ₂ O), 3.0-2.7 (11H, -C H ₂ N, -NC H ₃ , SC H _2- , -C H ₂ C H _2- ), 12.0-1.8 (2H, S-CH ₂ C H ₂ CH ₂ S-), 1.91 (3H, s, -C H ₃ ), 1.78 (3H, s, -C H ₃ ), 1.72 (3H, s, -C H ₃ )

Cis -soid

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 162.31, 157.52, 138.71, 138.69, 135.84, 133.20, 13033, 129.64, 127.75, 125.81, 114.88, 64.79, 52.51, 50.65, 42.49, 36.48, 32.50, 27.83, 27.58, 27.58, 25.25, 19.41, 18.47

Tran -soid

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 162.85, 157.89, 139.49, 138.61, 135.90, 132.31, 130.02, 129.16, 127.79, 125.65, 115.20, 64.79, 52.19, 50.14, 42.27, 34.22, 33.92, 27.83, 27.58, 27.58 25.25, 19.41, 18.47

Example  9: Methylzelamblon  Produce

( E ) -N -methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1-enyl) -1,3- [obtained in Example 8 4 g of dioxy] -2-yl) but-2-enyloxy} phenethyl] -3- (methylsulfonyl) acrylamide was dissolved in 110 mL of acetonitrile and 40 mL of water was added thereto. 20 mL of methane iodide was added and stirred at room temperature for 12 hours. Concentrated under reduced pressure to remove methane iodide and acetonitrile, extracted with dichloromethane, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (ethyl acetate: hexane = 3: 1) gave 1.77 g (yield: 54%) of white solid compounds.

Cis -soid

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.31 (1H, d, J = 14.4), 7.27 (1H, d, J = 14.4 Hz), 7.07 (2H, d, J = 8.8 Hz), 6.79 (2H , J = 8.8 Hz), 6.07 (1H, t, J = 1.2 Hz), 5.53 (1H, m), 4.51 (1H, d, J = 6.4 Hz), 3.59 (2H, t, J = 7.2 Hz), 3.10 (2H, br s), 2.97 (3H, s), 2.95 (3H, s), 2.78 (2H, t, J = 6.4 Hz), 2.10 (3H, br s), 1.84 (3H, br s), 1.70 (3H, br s)

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 198.13, 162.29, 156.5, 157.5, 139.5, 135.2, 133.3, 130.5, 129.7, 124.3, 122.8, 114.9, 64.7, 55.0, 50.6, 42.5, 36.5, 32.5, 27.7, 20.8, 17.0

Tran -soid

¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.69 to 6.95 (2H, m), 6.85 to 6.68 (2H, m), 6.07 (1H, t, J = 1.2 Hz), 5.53 (1H, m), 4.50 (d, J = 6.4 Hz), 3.55 (2H, J = 6.4 Hz), 3.10 (2H, br s), 3.00 (3H, s), 2.76 (2H, t, J = 6.4 Hz), 2.10 (3H, 1.84 (3H, br), 1.70 (3H, br)

¹³ C NMR (100 MHz, CDCl ₃ ): δ = 198.11, 162.85, 157.9, 156.5, 138.6, 135.2, 132.4, 130.0, 129.2, 124.2, 122.8, 115.2, 64.7, 55.0, 52.2, 42.5, 34.2, 34.0, 27.7, 20.8, 17.0

Claims (21)

(i) for formula (2) of 4- (2-aminoethyl) phenol to 4- (methylsulfonyl) of formula (3) was coupled to the reaction of acrylic acid of formula 5 N - (4-hydroxy-phenethyl) - N Obtaining -methyl-3- (methylsulfonyl) acrylamide; (ii) the reaction of N- (4-hydroxyphenethyl) -N -methyl-3- (methylsulfonyl) acrylamide of the formula (5) obtained in step (i) with the compound of formula (4) ( E ) -N -methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1-enyl) -1,3- [dician] of Formula 9 -2-yl) but-2-enyloxy} phenethyl] -3- (methylsulfonyl) acrylamide; And (iii) ( E ) -N -methyl- N- [4-{( E ) -3-methyl-4- (2- (2-methylprop-1) of formula (9) obtained in step (ii): A deprotection reaction of -enyl) -1,3- [dithiane] -2-yl) but-2-enyloxy} phenethyl] -3- (methylsulfonyl) acrylamide Method for preparing methylzelamblon of: [Formula 1]

 [Formula 2]

 (3)

 [Formula 4]

 [Chemical Formula 5]

 [Chemical Formula 9]

In Formula 4, X is a hydroxy group or leaving group. The method according to claim 1, wherein X is a chloride, bromide, mesyl, or tosyl group. The method of claim 1, further comprising, before step (i), introducing a t -butyloxycarbonyl group into the nitrogen of the tyramine followed by reduction to obtain 4- (2-methylaminoethyl) phenol of the formula (2). Characterized in the manufacturing method. The method of claim 1, wherein prior to step (i), propiolic acid and methylthiometal are reacted to obtain 3- (methylthio) acrylic acid represented by the following Chemical Formula 6, and then oxidized to react 3- (methylsulfonyl) acrylic acid represented by Chemical Formula 3 Method for producing a method characterized in that it further comprises the step of obtaining: [Formula 6]

The production process according to claim 4, wherein the methylthio metal is methylthio sodium. A compound according to claim 1, wherein the compound of formula 4 is 2- (2-methylpropenyl)-[1,3] -dithiane of formula 7 Method for producing a phenylsilaneyloxy) but-2-en-1-ol by the coupling reaction: [Formula 7]

[Formula 8]

[Formula 4]

Wherein X is a hydroxy group, R ₁ , R ₂ and R ₃ are each independently an alkyl group or an aryl group. 7. A process according to claim 6, wherein R ₁ , R ₂ and R ₃ are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t -butyl, or phenyl. The method of claim 6, wherein 3-methylcrotonaldehyde and 1,3-propanedichiol are reacted before the binding reaction to obtain 2- (2-methylpropenyl)-[1,3] -dithiane of the formula (7). Manufacturing method characterized in that it further comprises. The method of claim 6, wherein a silane protecting group is introduced into 3-methyl-2-buten-1-ol before the coupling reaction, and then a hydroxy group is introduced to form 2-methyl-4- ( t -butyldiphenylsilaneyloxy) of Chemical Formula 8. The method of claim 2 further comprising the step of obtaining but-2-en-1-ol. According to claim 1, wherein the compound of formula (i ') 2- (2-methylpropenyl)-[1,3] -dithiane of formula (7) and 2-methyl-4- ( t -butyldiphenylsilaneyloxy) but-2 of formula (8) Binding reaction of en-1-ol; And (ii ') a process for preparing a hydroxy group, wherein the hydroxy group is substituted with a leaving group. [Formula 7]

[Formula 8]

[Formula 4]

Wherein X is a leaving group, R ₁ , R ₂ and R ₃ are each independently an alkyl group or an aryl group. The method of claim 10, wherein X is a chloride, bromide, mesyl, or tosyl group. The process according to claim 10, wherein R ₁ , R ₂ and R ₃ are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t -butyl, or phenyl. The method of claim 10, wherein before the step (i '), 3-methylcrotonaldehyde and 1,3-propanedichiol are reacted to form 2- (2-methylpropenyl)-[1,3] -dithiane of formula (7). Method for producing a further comprising the step of obtaining. The method of claim 10, wherein a silane protecting group is introduced to 3-methyl-2-butene-1-ol before step (i '), and then a hydroxyl group is introduced to form 2-methyl-4- ( t -butyldiphenylsilane). Iloxy) but-2-en-1-ol, further comprising the step of obtaining. Compound represented by the following formula (4): [Formula 4]

Wherein X is a hydroxy group, chloride, bromide, mesyl, or tosyl group. delete Compound represented by the following formula (5): [Chemical Formula 5]

delete delete delete Compound represented by the following formula (9): [Chemical Formula 9]