KR19980065189A - New synthetic intermediates of moussecon and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel synthetic intermediate of Muscone and a method for producing the same, and has the following structural formula (I) or (II).

(R ¹ = Methyl, Mesyl, Benzyl, Tosyl,)

It is a novel compound of the above-mentioned structural formula (I) or (II), and has the advantage of being able to manufacture L or di-muscon with high yield and high purity from these as a precursor of mousse cone.

Description

New synthetic intermediates of moussecon and preparation method thereof

The present invention relates to a novel synthetic intermediate of Muscone and a method for preparing the same, in particular di-3-methyl-cyclopentadecan-1-one of the following structural formula (I), 1,4-di-0-alkyl Or aryl-2,3-D- stolitol ketal, and El-3-methyl-cyclopentadecan-1-one of formula (II), 1,4-di-0-alkyl or aryl-2,3-D It relates to a Sreitol ketal and a method for producing the same.

(R ¹ = Methyl, Mesyl, Benzyl, Tosyl,)

Compounds (I) and (II) having the above structural formulas include di-3-methyl-cyclopentadecan-1-one (III, hereinafter referred to as d-Muscone) and L-3-methyl- As a whole substance of cyclopentadecane-1-one (IV), hereinafter referred to as L-muscone, it is a novel synthetic intermediate, which is useful for the use of pharmaceutical raw materials for brain diseases and cardiovascular system. Mya.

Several methods have been known for the preparation of compounds (III) and (IV), but most of the production methods are not suitable for industrialization or mass production due to the low yield, high production cost, and difficult and complicated reaction conditions. It was.

( ¹ Stallberg, SS Arkiz. Kemi. 3, 517, 1951, ² Nelson, KA and Mash, EAJ Org. Chem. 51, 2721, 1986, ³ H. Nohira J. Org. Chem. 52, 1630, 1987 , ⁴ Tanaka, K. and Uscio, HJ Chem. Soc.Chem.Commun. 1, 101, 1991)

Therefore, the present inventors have studied over 10 years to solve the above technical problems, and as a result, a novel synthetic intermediate capable of mass-producing compounds (III) and (IV) can be produced. This invention was found to be useful, and the present invention was completed by finding compounds (I) and (II) and their preparation methods.

Therefore, it is an object of the present invention to prepare a mixture of compounds (I) and (II) from the following compound (V) prepared in high yield, high purity and low price and compound (I) which is a novel synthetic intermediate from the mixture thereof. , (II) and a method for producing the same.

Hereinafter, the present invention will be described in detail.

(R = Methyl, Ethyl)

(R ¹ = Methyl, Mesyl, Benzyl, Tosyl,)

In the presence of a catalyst, dimethyl-diesel-muscon ketal (VI) was prepared by ketalization of DL-muscon (V) with a ketalizing agent, and then (VI) compound was converted into 1,4-di-0-alkyl or A mixture of compounds (I) and (II) was prepared by ketal exchange with aryl-2,3-D-statitol, and from each mixture was prepared by recrystallization, chromatography, or the like. Prepare I) and (II).

The present invention will be described in more detail as follows.

The ketalization reaction was carried out by stirring montmolinonite K-10 as a catalyst and the chelating agent CH (OR) ₃ , (R = Me, Et) in an organic solvent for 1 hour and then dissolving DL-mu in an organic solvent. After adding scone (V) and stirring for 40 minutes to 90 minutes, the residue of montmolininite K-10 obtained by filtration under reduced pressure was sufficiently washed with an organic solvent, combined with the organic solvent, and distilled under reduced pressure to give a compound (VI). To prepare.

At this time, the catalyst may be dried HCl, TsOH, NH ₄ Cl, PhSO ₂ NHOH, NaOH, La (or Ce, Nd, Er, Yb) Cl ₃ , acidic ion exchange resin, montmolinonit K-10, etc. Among them, montmolinonit K-10 is most preferred.

The use amount of montmolinoite K-10 can be used 1 to 4 times by weight relative to compound (V), and it is most preferable to use 2 to 3 times.

Meanwhile, as the ketalizing agent, MeOH, MeOH / (MeO) ₄ Si, Me ₂ SO ₄ / MeOH CH (OEt) ₃ , CH (OMe) _3, and the like are used, among which CH (OEt) ₃ or CH (OMe) Most preferably, ₃ is used.

The amount of CH (OMe) ₃ can be reacted with 2-10 times in molar ratio with respect to compound (V), of which 4-8 times are most preferred.

In addition, as the organic solvent, methanol, ethanol, propyl alcohol, and the like, which are polar solvents, are used. As the nonpolar solvent, normal-hexane and carbon tetrachloride are used, and among them, normal-hexane is most preferable.

The reaction temperature can be performed at reflux or at room temperature, and most preferably at room temperature.

The ketal exchange reaction is carried out by dissolving compound (VI) in anhydrous benzene under acid catalyst, adding compound (VII), heating to dissolve, and heating for 1-2 hours, or dissolving compound (VI) in organic solvent (I) was added and stirred at room temperature for 1-2 hours to prepare a mixture of compounds (I) and (II).

On the other hand, when a catalyst is not used, compound (VI) and (iii) are dissolved and refluxed in benzene or a polar organic solvent or stirred at room temperature for 8 to 24 hours.

As the acid catalyst, trifuroboroborane isomerate, paratoluenesulfonic acid, paratoluenesulfonic acid pyridine salt, and the like can be used. Among them, trifuroboroborane isate or paratoluenesulfonic acid is most preferably used. It can be used in 0.1-0.005 molar ratio with respect to silver compound (V), It is most preferable to use in 0.01-0.03 molar ratio.

In this case, chloroform, dichloromethane, ether, ethanol, methanol, and the like may be used as the organic solvent, and among them, dichloromethane or ether is most preferable.

When the R ¹ group is a tosyl group, a mixture of compounds (I) and (II) prepared above is mixed with a polar solvent such as methanol, methanol-chloroform, hexane-chloroform, petroleum ether-chloroform, or a petroleum ether or hexane. Compounds (I) and (II) can be obtained by a recrystallization method using a nonpolar organic solvent such as these, and of these, methanol is most preferably used as a polar solvent.

In the case where the R ¹ group is methyl, mesyl, tosyl or benzyl group, a mixture of the above-mentioned compounds (I) and (II) may be added to the acetonitrile-water mixture, the chloroform-hexane mixture, and the hexane-ethyl acetate mixture. Chromatography (MPLC) can be used to obtain compounds of Compounds (I) and (II), respectively, of which acetonitrile-water mixtures are most preferred.

At this time, the size of the column was used 41.4㎜ * 250㎜, flow rate (ml / min) is 50, the detector was UV 254nm, the filler can be C ₈ , C ₁₈ can be used, of which C ₁₈ Most preferred.

Hereinafter, the present invention will be described in detail with reference to the following examples.

The scope of the claims of the present invention is not limited by the examples.

Example 1

Di-3-methyl-cyclopentadecan-1-one 1,4-di-0-tosyl-2,3-D- flake ketal [(I), R ¹ = Tosyl] and L-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-0-tosyl-2,3-D- stolitol ketal [(II), R ¹ = Tosyl]

Into a 100 ml one-necked flask filled with nitrogen, 25 g of montmolinoite K-10 and 38 ml of CH (OMe) ₃ were added and stirred at room temperature for 1 hour. 10.0 g of DL-muscon (V) dissolved in 30 ml of anhydrous hexane was added to the reactor, stirred at room temperature for 1.5 hours, and filtered under reduced pressure, and the obtained montmolinoite K-10 residue was washed with 300 ml of anhydrous hexane, and the organic 18.07 g of 1,4-di-0-tosyl-2,3-D-stitol (Ⅶ, R = tosyl) and 25 ml of dichloromethane were added to dimethyl DL-muscon ketal (VI) obtained by distillation under reduced pressure in combination with a solvent. The solution was added sequentially, 0.25 ml of trifluorouroborane acrylate was added, followed by stirring at room temperature for 2 hours.

The reaction solution was diluted with 200 ml of dichloromethane, washed with 100 ml of water and saturated brine in that order, dried over magnesium sulfate, and 27.12 g of a slightly yellow solid obtained by distillation under reduced pressure was sufficiently washed with 60 ml of hexane [(I), 25.24 g of a mixture of R ¹ = Tosyl] and [(II), R ¹ = Tosyl] was obtained.

The mixture was recrystallized three times using methanol to obtain 9.36 g (37%) of a pale yellow solid [(I), R ¹ = Tosyl] (purity 99%).

mp; 84.0-85.0 ℃

¹ H-NMR (CDCl ₃ , ppm);

7.78 (4H _tosyl , d, 8.8 Hz), 7.35 (4H _tosyl , d, 8.8 Hz), 4.10 (4H _2'2 , m), 3.92 (2H _1'1 , m), 2.46 (6H _tosyl , s), 1.60-1.06 (27H _ring , hump), 0.82 (3H ₁₆ , d, 7.0 Hz)

¹³ C-NMR (CDCl ₃ , ppm);

C _tosyl : 144.98, 144.96, 132.53, 132.50, 129.79, 127. 83, 114.37 (C ₁ ), 74.72 (C _{1 '} ), 74.40 (C ₁ ), 68.48 (C _2' ), 68.39 (C ₂ ), 43.84 (C ₂ ), 36.67 (C ₁₅ ), 36.10 (C ₄ ), 27.69 (C ₃ ), 20.67 (C ₁₆ )

C _ring : 27.01, 26.95, 26.61, 26.46, 26.43, 26.18, 25.94, 25.91, 24.82, 21.98. 21.46

Mass (m / e): 650.3 (M ⁺ ), 607.3, 531.1, 481.0, 467.1, 390.0, 369.2, 327.0, 154.8, 90.8, 68.8

IR (KBr, cm ^-1 ): 2926, 2856, 1353, 1176, 1099, 978, 939, 858, 815

= -15.67 (c 1.0, CHCl ₃ , 100 mm)

The compound ^{[(Ⅰ), R 1 =} Tosyl] the preparation and the three times re-crystallized using methanol, the compound obtained from the remaining mother liquor to the compound as a pale yellow solid ^{[(Ⅱ), R 1 =} Tosyl] 7.76g (31 %) Was obtained.

(99% purity)

(II), R ¹ = Tosyl

mp; 91.5-92.5 ℃

¹ H-NMR (CDCl ₃ , ppm);

7.77 (4H _tosyl , d, 8.8 Hz), 7.36 (4H _tosyl , d, 8.8 Hz), 4.07 (4H _2'2 , m), 3.97 (2H _1'1 , m), 2.46 (6H _tosyl , s), 1.65-1.14 (27H _ring , hump), 0.82 (3H ₁₆ , d, 7.0 Hz)

¹³ C-NMR (CDCl ₃ , ppm);

C _tosyl : 145.02, 144.99, 132.43, 132.41, 129.84, 129. 82, 127.77, 114.52 (C ₁ ), 75.00 (C _{1 '} ), 74.45 (C ₁ ), 68.46 (C _2' ), 68.34 (C ₂ ) , 44.22 (C ₂ ), 36.59 (C ₁₅ ), 35.97 (C ₄ ), 27.64 (C ₃ ), 20.86 (C ₁₆ )

C _ring : 27.03, 26.96, 26.57, 26.43, 26.29, 26.09, 25.89, 24.86, 21.78, 21.46,

Mass (m / e): 650.3 (M ⁺ ), 607.3, 531.1, 481.0, 467.1, 390.0, 369.2, 327.0, 154.8, 90.8, 68.8

IR (KBr, cm ^-1 ): 2927, 2855, 1361, 1180, 1097, 971, 945, 854, 814

= -1.48 (c 1.0, CHCl ₃ , 100 mm)

Example 2

Di-3-methyl-cyclopentadecan-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(I), R ¹ = Tosyl] and L-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(II), R ¹ = Tosyl]

18.07 g of Compound (X, R = Tosyl), 350 ml of benzene, paratoluenesulfonic acid or paratoluenesulfonic acid pyridine salt in 1 mg of Dimethyl DL-Muscon ketal (VI) was prepared in the reaction solution. Is added and heated to reflux.

After 0.5 to 1 hour, the reaction solution was cooled to room temperature, diluted with 200 ml of ether or dichloromethane, and then the same procedure as in Example 1 was carried out to obtain a mixture of the title compound (I) and (II) as a white solid. 25.24 g was obtained.

The following recrystallization operation is performed by the method similar to Example 1.

Example 3

Di-3-methyl-cyclopentadecan-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(I), R ¹ = Tosyl] and L-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(II), R ¹ = Tosyl]

Dimethyl DL-muscon ketal (VI) was prepared as in Example 1, and 1,4-di-0-tosyl-2,3-D-stitol (Ⅶ, R = Tosyl) was 18.07 g and benzene 600 ml was added and then stirred at room temperature for 1 day.

The reaction solution was diluted with 200 ml of ether or dichloromethane and the following procedure was carried out in the same manner as in Example 1 to obtain 25.26 g of a mixture of the titled compounds (I) and (II).

The following recrystallization operation is performed by the method similar to Example 1.

Example 4

Di-3-methyl-cyclopentadecan-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(I), R ¹ = Tosyl] and L-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(II), R ¹ = Tosyl]

To a 250 ml three-necked round flask, 2.0 g of DL-muscon (V), 3.6 g of compound (R, Tosyl), 0.16 g of paratoluenesulfonic acid, and 100 ml of anhydrous benzene were added to dissolve, and then the water produced was removed for 7 days. After heating and stirring, the reaction mixture was cooled to room temperature, diluted with 200 ml of ether, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and the organic solvent obtained by filtration under reduced pressure was distilled under reduced pressure to obtain the title compound ( 5.4 g of a mixture of I) and (II) was obtained.

The following recrystallization operation is performed by the method similar to Example 1.

Example 5

Di-3-methyl-cyclopentadecan-1-one 1,4-di-0-benzyl-2,3-D-statitol ketal [(I), R ¹ = Benzyl] and L-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-0-tosyl-2,3-D-statitol ketal [(II), R ¹ = Benzyl]

To a 50 ml one-necked flask filled with nitrogen, 12.5 g of montmolinonite K-10 and 18 ml of CH (OMe) ₃ were added and stirred at room temperature for 1 hour. 5.0 g of DL-muscon (V) dissolved in 15 ml of anhydrous hexane was added to the reactor and stirred at room temperature for 1.5 hours. Then, the residue obtained by filtration under reduced pressure was washed with 150 ml of anhydrous hexane. , 4.7 g of a compound (VII, R = Benzyl), 13 ml of dichloromethane, and 0.03 ml of trifururoborane isate were added to dimethyl DL-muscon ketal (VI) obtained by combining with the organic solvent and distilling under reduced pressure. Stir for 2 hours.

Dilute with 100 ml of dichloromethane, wash with 50 ml of water and saturated brine, and then dry with magnesium sulfate, filter off the organic solvent, and distillate under reduced pressure to obtain a pale yellow oily compound [(I), R 8.5 g of a mixture of ¹ = Benzyl] and [(II), R ¹ = Benzyl] was obtained.

The mixture was subjected to MPLC three times to obtain 4.08 g (48%) of the title compound (I) and (II), respectively.

At this time, the acetonitrile-water mixture was used as 85% developing solution using a 41.4mm * 250mm column ( _C18 ), the flow rate was 50ml / min, and the detector used the ultraviolet-ray 254nm.

(I), R ¹ = Benzyl

¹ H-NMR (CDCl ₃ , ppm);

7.31 (10 _Ph , m), 4.57 (4H _{3 ', 3} , s), 3.98 (2H _1,1' , m), 3.60 (4H _{2,2 '} , m), 1.78-1.10 (27H _ring , hump) , 0.95 (3H, d, 7.04 Hz)

¹³ C-NMR (CDCl ₃ , ppm);

C _Ph : 138.20, 138.15, 128.28, 127.55, 127.51, 113.39 (C ₁ ), 75.36 (C _{1 '} ), 77.30 (C ₁ ), 73.45 (C _3' ), 73.37 (C ₃ ), 70.89 (C _{2 '} ), 70.65 (C ₂ ), 44.36 (C ₂ ), 37.21 (C ₁₅ ), 36.45 (C ₄ ), 28.01 (C ₃ ), 21.18 (C ₁₆ ),

C _ring : 27.31, 27.17, 26.60, 26.64, 26.61, 26.40, 26.14, 26.11, 25.05, 22.28

IR (neat, cm ^-1 ): 3088, 3064, 3030, 2927, 2858, 1947, 1872, 1807, 1740, 1497, 1455, 1029, 735, 698

= -3.53 (c 1.0, hexane, 100 mm)

(II), R ¹ = Benzyl

¹ H-NMR (CDCl ₃ , ppm);

7.31 (10 _Ph , m), 4.58 (2H _{3 '} , s), 4.57 (2H ₃ , s), 4.0 (2H _1,1' , m), 3.59 (4H _{2,2 '} , m), 1.81-1.09 (27H _ring , hump), 0.93 (3H, d, 7.04 Hz)

¹³ C-NMR (CDCl ₃ , ppm);

C _Ph : 139.16, 128.30, 127.52, 113.51 (C ₁ ), 77.88 (C _{1 '} ), 77.31 (C ₁ ), 73.41 (C _{3', 3} ), 71.06 (C _{2 '} ), 70.80 (C ₂ ), 44.80 (C ₂ ), 37.06 (C ₁₅ ), 27.96 (C ₄ ), 27.35 (C ₃ ), 21.36 (C ₁₆ ),

C _ring : 27.20, 26.80, 26.66, 26.62, 26.53, 26.31, 26.10, 25.12, 22.12

IR (neat, cm ^-1 ): 3088, 3064, 3031, 2927, 2857, 1947, 1872, 1806, 1736, 1497, 1455, 1029, 735, 698

= 7.55 (c 1.0, hexane, 100 mm)

Claims (11)

Compound (I) or (II) having the following structural formula. (R ¹ = Methyl, Mesyl, Benzyl, Tosyl) Compound (VI), a starting material, was prepared at room temperature or reflux temperature using an organic solvent and a ketalizing agent in the presence of a catalyst, and compound (VI) was subjected to ketal exchange with compound (VII). And (II) to prepare a mixture, followed by recrystallization or chromatography with an organic solvent to separate and prepare Compound (I) or (II). (R = Me, Et) (R ¹ = Methyl, Mesyl, Benzyl, Tosyl) The catalyst of claim 2, wherein the catalyst is dried HCl, TsOH, NH ₄ Cl, PhSO ₂ NHOH, NaOH, La (or Ce, Nd, Er, Yb) Cl ₃ , acidic ion exchange resin, montmolinoite K -10 may be used, and among them, montmolinite K-10 is used. 4. The method according to claim 3, wherein the amount of the catalyst can be used 1 to 4 times by weight with respect to the compound of compound (V), of which 2 to 3 times is used. The method of claim 2, wherein the ketalizing agent may be used MeOH, MeOH / (MeO) ₄ Si, Me ₂ SO ₄ / MeOH CH (OEt) ₃ , CH (OMe) _3, etc., wherein CH (OEt) ₃ Or, CH (OMe) ₃ . The method of claim 5, wherein the ketalizing agent may be used in a molar ratio of 2 to 10 times the molar ratio of the compound of the compound (V), wherein a 4 to 8 times mole is used. The method of claim 2, wherein as the organic solvent, methanol, ethanol, propyl alcohol, and the like, which are polar solvents, are used, and as the nonpolar solvent, normal-hexane, carbon tetrachloride, and the like are used. The method of claim 2, wherein the ketal exchange reaction is carried out by dissolving the compound (VI) in anhydrous benzene under an acid catalyst, followed by heating and dissolving the compound (VII), followed by heating for 1-2 hours, or by heating the organic compound (VI). Dissolving in a solvent followed by addition of compound (iii), followed by stirring for 1-2 hours at room temperature. 3. The method according to claim 2, wherein the ketal exchange reaction is completed by dissolving the compounds (VI) and (iii) in a benzene or a polar organic solvent without a catalyst and by stirring at room temperature or by heating. 9. The acid catalyst according to claim 8, wherein trifuruoroborane isomerate, paratoluenesulfonic acid, paratoluenesulfonic acid pyridine salt is used, among which trifuroboroborane isate or paratoluenesulfonic acid is used. Way. The organic solvent according to claim 2, wherein the organic solvent is a single or two or more mixed solvents of polar or nonpolar solvents, and in particular, methanol or acetonitrile-water mixture is used. How to.