KR19980065188A - 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).

It is a novel compound of the above-mentioned 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 precursors of muscon.

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, and in particular, El-3-methyl-cyclopentadecan-1-one 1,4-di-O-alkyl of formula (I) Aryl-2,3-L-stolitol ketal and di-3-methyl-cyclopentadecan-1-one 1,4-di-O-alkyl or aryl-2,3-L-stray of formula (II) It relates to tall ketal and a method for preparing them.

Compounds (I) and (II) having the above structural formula are L-3-methyl-cyclopentadecan-1-one (III, hereinafter referred to as l-Muscone), and di-3-methyl- As a whole substance of cyclopentadecane-1-one (IV), hereinafter referred to as d-Muscone, it is a new synthetic intermediate, which is expected to be useful as a raw material for medicines used in brain disease, cardiovascular system, etc. .

Several methods have been known to prepare 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.

(Reference: ¹ Srallberg, 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 compound (I) and (II) can produce compound (III) and (IV). The present invention has been found to be useful, and the present invention has been completed by finding compounds (I) and (II) and their preparation methods.

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

Hereinafter, the present invention will be described in detail.

In the presence of a catalyst, dimethyl-diesel-muscon ketal (VI) was prepared by ketalization of die-muscon (V) with a ketalizing agent, and then compound (VI) was prepared using 1,4-di-O-alkyl or A mixture of compounds (I) and (II) was prepared by ketal exchange with aryl-2,3-L- stolitol (VII), 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 Montmololinite K-10 as a catalyst and CH (OR) ₃ (R = Me, Et) as a catalyst in an organic solvent for 1 hour, and then DL-Muscon dissolved in an organic solvent in advance. After (V) was added and stirred for 40 minutes to 90 minutes, the residue of maltmolinoite 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 obtain Compound (VI). Manufacture.

In this case, as the catalyst, dried HCl, TsOH, NH ₃ Cl, PhSO ₂ NHOH, NaOH, La (or Ce, Nd, Er, Yb) Cl ₃ , an acidic ion exchange resin, montmolinonit K-10 and the like can be used. Among them, montmolinoite K-10 is preferable.

The use amount of montmolinonit 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 carried out 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, adding compound (VII), heating and dissolving for 1 to 2 hours, or dissolving compound (VI) in an organic solvent under a new catalyst. Compound (VII) 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 no catalyst is used, the compounds (VI) and (VII) are dissolved and refluxed in benzene or a polar organic solvent or stirred at room temperature for 8 to 24 hours.

Examples of the acid catalyst may include trifluororoboran sulphate, paratoluenesulfonic acid, paratoluenesulfonic acid pyridine salt, and the like. Among them, trifluororoboran sulphate or paratoluenesulfonic acid is most preferably used. It can be used in 0.1-0.005 molar ratio with respect to silver compound (V), and 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.

On the other hand, in the method of separating each of the mixtures of the compounds (I) and (II), when the R ¹ group is a tosyl group, the mixture of the compounds (I) and (II) prepared above is a polar solvent of methanol, methanol-chloroform Compounds (I) and (II) can be obtained by recrystallization using a mixture of hexane-chloroform, petroleum ether-chloroform, or a nonpolar organic solvent such as petroleum ether or hexane. Most preferably, is used.

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

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

L-3-Methyl-cyclopentadecan-1-one 1,4-di-O-tosyl-2,3-L-stolitol ketal [(I), R ¹ = Tosyl] and di-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-O-tosyl-2,3-L- 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 in advance, was added to the reactor, stirred at room temperature for 1.5 hours, and the montmolinolite K-10 residue obtained by filtration under reduced pressure was washed with 300 ml of anhydrous hexane, and the organic 18.07 g of 1,4-di-O-tosyl-2,3-L-stolitol (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 sequentially with 100 ml of water and saturated brine, 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 to give a compound having the following structural formula [(I) , 25.25 g of a mixture of R ¹ = Tosyl] and [(II), R ¹ = Tosyl].

The mixture was recrystallized three times with methanol to obtain 9.35 g (37%) of a pale yellow solid [(I), R ¹ = Tosyl] (purity 99%).

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

[α] ²⁷ _D = -1.48 (c 1.0, CHCl ₃ , 100 mm)

Wherein the compound ^{[(I), R 1 =} Tosyl] prepared, and to the compound obtained from the remaining mother liquor using methanol as a pale yellow solid was recrystallized three times to carry out the compound ^{[(II), R 1 =} Tosyl] 7.74g (31 %) Was obtained.

(99% purity)

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

[α] ²⁷ _D = -15.67 (c 1.0, CHCl ₃ , 100 mm)

Example 2

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

18.07 g of Compound (VII, R = Tosyl), 350 ml of benzene, 1 mg of paratoluenesulfonic acid or paratoluenesulfonic acid pyridine salt were added to the reaction solution of Dimethyl DL-Muscon Ketal (VI). 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. Obtained 25.25 g.

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

Example 3

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

Dimethyl DL-muscon ketal (VI) was prepared as in Example 1, and 1,4-di-O-tosyl-2,3-L- stolitol (VII, R = tosyl) 18.07 g and benzene were prepared. 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 25.25 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

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

2.0 g of DL-muscon (V), 3.6 g of compound (VII, R = tosyl), 0.16 g of paratoluene sulfonic acid, and 100 ml of anhydrous benzene were dissolved in a 250 ml three-necked copper flask to remove water produced 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 ( 5.5 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

L-3-Methyl-cyclopentadecan-1-one 1,4-di-O-benzyl-2,3-L-stolitol ketal [(I), R ¹ = Benzyl] and di-3-methyl-cyclo Preparation of pentadecane-1-one 1,4-di-O-benzyl-2,3-L- stolitol 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 in advance, 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. , 4.9 g of a compound (VII, R = Benzyl), 13 ml of dichloromethane, and 0.03 ml of trifururoborane acrylate 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 the organic solvent obtained by distilling under reduced pressure, and then have a yellowish oily substance having the following structural formula [(I), 8.5 g of a mixture of R ¹ = Benzyl] and [(II), R ¹ = Benzyl] was obtained. The mixture was subjected to MPLC three times to obtain 4.09 g (48%) of the title compound (I) and (II), respectively.

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

¹ H NMR (CDCl ₃ , ppm);

7.31 (10H _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

[α] ²⁷ _D = 7.55 (c 1.0, Hexane, 100 mm)

¹ H NMR (CDCl ₃ , ppm);

7.31 (10H _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 ), 77.36 (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

[a] ²⁷ _D = -3.53 (c 1.0, hexane, 100 mm)

Claims (11)

Compound (I) or (II) having the following structural formula. Compound (V) was prepared by using a organic solvent and a ketalizing agent under a catalyst at room temperature or reflux at room temperature or reflux temperature. Compound (VI) was subjected to ketal exchange with compound (VII) to react with compound (I). A method of preparing a mixture of (II) and then recrystallization or chromatography with an organic solvent to separate and prepare compound (I) or (II). 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, etc. can be used, and among them, the method characterized in that the use of montmolinoite K-10. The method according to claim 3, wherein the amount of the catalyst is 1 to 4 times the weight ratio of the compound of the compound (V), wherein 2 to 3 times the amount 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 according to claim 5, wherein the ketalizing agent is used in a molar ratio of 2 to 10 times the molar ratio with respect to the compound of the compound (V), wherein 4 to 8 times the mole is used. The method of claim 2, wherein the organic solvent is a polar solvent such as methanol, ethanol, propyl alcohol, and the like, and the non-polar solvent is a normal-hexane, carbon tetrachloride, etc., characterized in that the normal-hexane is used. The method of claim 2, wherein the ketal exchange reaction is carried out by dissolving compound (VI) in anhydrous benzene under an acid catalyst and then adding compound (VII), heating and dissolving and heating for 1-2 hours, or compound (VI) in an organic solvent. Dissolved in and then added to compound (VII) to completion for 1-2 hours at room temperature. The method according to claim 2, wherein the ketal exchange reaction is completed by dissolving the compounds (VI) and (VII) in benzene or a polar organic solvent without a catalyst and stirring at room temperature or by heating. 9. The acid catalyst according to claim 8, wherein trifuruoborane isomerate, paratoluenesulfonic acid, paratoluenesulfonic acid pyridine salt is used, wherein trifuroborane isomerate or paratoluenesulfonic acid is used. Way. The organic solvent according to claim 2, wherein the organic solvent is separated from the polar solvent or the nonpolar solvent using two or more mixed solvents, in particular, methanol or acetonitrile-water mixture. How to.