JP4952272B2 - (Z)-Method for producing ligustilide - Google Patents

Description

  The present invention relates to a method for producing (Z) -ligustylide.

  (Z) -ligustilide is a main component isolated from the essential oil of Cnidium officinale Makino and has physiological activities such as anticholinergic action, antispasmodic action, smooth muscle relaxation action, and antifungal action. It is also important as an intermediate for the synthesis of other phthalides. In addition, when listing Kampo prescriptions in the Japanese Pharmacopoeia, there is ligustilide as a standard product used for confirmation tests of nematode-containing prescriptions, and it is desired to perform stereoselective production thereof.

  This stereoselective method for synthesizing (Z) -ligustylide has been reported in Non-Patent Document 1 and is already generally known. That is, according to this synthesis method, according to the following synthesis route 1, 1,4-cyclohexadione monoethylene ketal (compound 1) is used as a starting material, and from compound 2 to compound 7 is the final target compound (Z) It is known that ligustilide (compound 8) can be produced.

Y. Ogawa, M. Maruno, and T. Wakamatsu, Synlett, 871(1995) Synthesis route 1

Y. Ogawa, M. Maruno, and T. Wakamatsu, Synlett, 871 (1995)

  However, the stereoselective synthesis method of (Z) -ligustylide reported in Non-Patent Document 1 has a long number of production steps and does not satisfy the yield in some production steps. . In addition, many intermediates obtained in the manufacturing process are structurally unstable, and it has been difficult to apply to scale-up. That is, in the above reaction formula, it cannot be said that the yield of the product in compound 7 is sufficient, and both compound 6 and compound 7 have a cyclohexadiene structure and are structurally unstable.

Accordingly, an object of the present invention is to provide a method capable of producing (Z) -ligustylide as a target product with a relatively simple synthesis operation and with a high yield as compared with conventional synthesis methods.
Another object of the present invention is to provide a novel intermediate necessary in the process for producing (Z) -ligustylide.

  As a result of intensive studies to solve the above problems, the present inventor has found that the object can be achieved through a synthesis process of a novel intermediate compound, and has completed the present invention.

That is, in the method for producing (Z) -ligustylide of the present invention, methyl 5-hydroxy-2- (1-pentynyl) -1-cyclohexanecarboxylate is hydrolyzed, and then a cyclization reaction is performed with a silver catalyst. ) -3-butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one;
The obtained (3Z) -3-butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one was eliminated using trifluoromethanesulfonic anhydride. To obtain ligustilide,
It is characterized by including.

  The present invention is also (3Z) -3-butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one.

  According to the present invention, (Z) -ligustylide can be increased by a simple synthetic operation compared with the conventional synthetic operation without improving the process yield and the reaction step via a structurally unstable intermediate. It can be produced in a yield.

Hereinafter, embodiments of the present invention will be specifically described.
The method of the present invention starts from methyl 5-hydroxy-2- (1-pentynyl) -1-cyclohexanecarboxylate (Compound 5), which is known in Non-Patent Document 1, etc., as shown in Synthesis Route 2 below. Step E for synthesizing (3Z) -3-butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one (compound 9) as a new intermediate Then, (Z) -ligustide (compound 8) is obtained in high yield from this compound 9 (step F).

Synthesis route 2

Hereinafter, the suitable conditions of the process E and the process F in the manufacturing method of this invention are demonstrated.
(Process E)
Compound 3 is hydrolyzed with an alkali such as sodium hydroxide in water, alcohol, preferably methanol, or a mixture of water and alcohol, and then subjected to a cyclization reaction with a silver catalyst to obtain (3Z) -3. -Butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one (compound 9) can be obtained.

  The hydrolysis reaction can be performed at room temperature, and is preferably allowed to react for 12 to 24 hours. The cyclization reaction can be carried out by acting a silver catalyst on a solution obtained by dissolving the obtained hydrolyzate carboxylic acid in N, N-dimethylformamide (DMF). This reaction can be performed at room temperature, and is preferably allowed to react for 16 to 24 hours.

(Process F)
In this step, it is important to use trifluoromethanesulfonic anhydride as a desorbing agent in dehydrating compound 9. When methanesulfonate with low desorption ability is used as the desorption agent, as shown in the following reaction formula, the desorption reaction does not proceed unless the temperature is relatively high. In addition to the desired (Z) -ligustylide (compound 8) released at the 5th and 6th positions, the compound 10 released at the 4th and 5th positions is produced. This produced compound 10 is relatively unstable under high temperature conditions, and a compound 11 that is aromatic cyclized by auto-oxidation is produced.

  Therefore, focusing on the desorption ability of the reagent, by using trifluoromethanesulfonic anhydride as a desorption agent, the desorption reaction can be performed via an intermediate having a high desorption ability at a lower temperature. As a result of diligent investigation based on the idea that the elimination of the 5,6 position progresses over the 4,5 position elimination and the selectivity is improved, trifluoromethanesulfonic anhydride was used. In the reaction, the compound 8 which is promptly converted into trifluoromethanesulfonate and rapidly eliminated at the 5- and 6-positions even under a low temperature condition of −20 ° C. is highly selective (for example, compound 8: compound 10 = 13.5: 1). It was found that a high yield can be obtained.

  At this time, methylene chloride is preferable as a reaction solvent, and thereby, elimination reaction of trifluoromethanesulfonate with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) at −20 ° C. It was found that the speed of From this, it became possible to obtain the target compound 8 in a more selective and high yield by examining the addition amount of DBU.

  In addition, as described in Non-Patent Document 1, the compound 5 which is a starting material in the present invention is obtained by the following synthesis route 3 using 1,4-cyclohexadione monoethylene ketal (compound 1) as a raw material. It can be obtained by steps A to D.

Synthesis route 3

Steps A to D from compound 1 to obtaining compound 5 can be performed in accordance with Non-Patent Document 1, and the preferred conditions and the like will be described below.
(Process A)
In Non-Patent Document 1, compound 1 which can be easily obtained in the market is treated with lithium diisopropylamide (LDA) at -20 ° C. to give lithium enolate, and then compound 2 is obtained by allowing methyl cyanoformate to act at the same temperature. It is disclosed. It is preferable to subject the starting compound 1 to LDA treatment at a low temperature of −80 to −60 ° C. and then to allow methyl cyanoformate to act on the reaction mixture, whereby methyl 5,5 in a better yield than that of Non-Patent Document 1. -Ethylenedioxy-2-cyclohexanone carboxylate (compound 2) can be obtained. At this time, compound 2 can be obtained in a relatively good yield without raising the reaction temperature to room temperature.

(Process B)
According to the synthesis method described in Non-Patent Document 1, 4,4-ethylenedioxy-2-methoxycarbonyl-1-cyclohexylnyltrifluoromethanesulfonate (Compound 3) can be suitably synthesized, but is a reaction reagent. The yield can be improved by increasing the equivalent (1.1 equivalent) of trifluoromethanesulfonic anhydride to about 1.2 equivalent, which is preferable.

(Process C)
Under the conditions described in Non-Patent Document 1, methyl 5,5-ethylenedioxy-2-phenyl is produced by the coupling method of Stille et al. (W. J Scott and JK Stille, J. Am. Chem. Soc., 1986, 108, 3033). It has been shown that (-pentynyl) -1-cyclohexanecarboxylate (compound 4) can be obtained. However, even if the reaction conditions using 1-pentyne and copper (M. Azad Hossain, Tetrahedron lett., 1997, 38, 49-52.) Are adopted without using the stannyl reagent used in this reaction. Compound 4 can be obtained at a high rate, which is preferable.

(Process D)
In addition to the reaction conditions described in Non-Patent Document 1, preferred examples of the acid catalyst used for deketalization include pyridine p-toluenesulfonate and p-toluenesulfonic acid, more preferably p-toluenesulfonic acid. Can be mentioned. Further, the reduction reaction with sodium tetrahydroborate after deprotection proceeds promptly even at a low temperature, and a good yield can be obtained.

Hereinafter, the present invention will be described based on examples.
(Synthesis Example 1)
Step A: Synthesis of methyl 5,5-ethylenedioxy-2-cyclohexanone carboxylate (Compound 2)

  To a solution of 21.5 mL (87.1 mmol) of diisopropylamine in anhydrous tetrahydrofuran (100.0 mL) was added 97.3 mL (153.7 mmol) of n-butyllithium at −20 ° C. (internal temperature) under a nitrogen atmosphere. The reaction mixture was stirred at −20 ° C. (internal temperature) for 0.5 hour. Dissolve 20.0 g (128 mmol) of 1,4-cyclohexanedione monoethylene ketal in anhydrous tetrahydrofuran (160 mL) and add to the stirring reaction mixture at −65 ° C. (internal temperature) over 30 minutes, then stir For 0.5 hour at 0 ° C. (LDA treatment). Dissolve methyl cyanoformate 12.2 mL (153.7 mmol) in anhydrous tetrahydrofuran (100.0 mL) and add dropwise to the mixture at −70 ° C. (internal temperature) over 30 minutes, then stir at −20 ° C. (internal temperature). ) For 1 hour.

  Acetic acid (18 mL) and water (50 mL) were added to the stirring reaction mixture at −20 ° C. The reaction mixture was extracted with ethyl acetate (450 mL). The combined organic phases were washed with saturated brine (150 mL) and then dried over anhydrous magnesium sulfate (20 g). After the organic phase was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (400 g, hexane: ethyl acetate (4: 1)) to obtain Compound 2 as a pale yellow solid. This compound 2 was vacuum-dried (rt / 10 mmHg).

Yield: Compound 2, 11.98 g (43.6%) of pale yellow solid
1H-NMR (CDCl ₃ ) δ: 1.84 (t, J = 6.7Hz, 2H), 2.46-2.54 (m, 4H), 3.75 (s, 3H), 3.95-4.07 (m, 4H), 12.15 (s, 1H)

(Synthesis Example 2)
Step B: Synthesis of 4,4-ethylenedioxy-2-methoxycarbonyl-1-cyclohexylnyltrifluoromethanesulfonate (Compound 3)

11.9 g (55.5 mmol) of Compound 2 and 13.8 g (67.2 mmol) of 2,6-di-tetra-butyl-4-methylpyridine were dissolved in methylene chloride (CH ₂ Cl ₂ ) (125 mL). 10.8 mL (64.4 mmol) of trifluoromethanesulfonic anhydride was added dropwise at room temperature. The reaction mixture was then stirred at room temperature for 39 hours.

  The resulting reaction mixture was diluted with diethyl ether (250 mL), and then the reaction mixture precipitate was removed by filtration. The filtrate was washed with saturated brine (250 mL). The organic phase was then dried over anhydrous magnesium sulfate (20 g). After the organic phase was distilled off under reduced pressure, the crude product was purified by column chromatography on silica gel (400 g, hexane: ethyl acetate (4: 1)) to obtain Compound 3 as a pale yellow viscous oily substance. This compound 3 was vacuum-dried (rt / 10 mmHg).

Yield: Compound 3, 17.7 g (92.1%) of pale yellow viscous oily substance
1H-NMR (CDCl ₃ ) δ: 1.91 (t, J = 6.6Hz, 2H), 2.59-2.67 (m, 4H), 3.80 (s, 3H), 3.93-4.07 (m, 4H)

(Synthesis Example 3)
Step C: Synthesis of methyl 5,5-ethylenedioxy-2- (1-pentynyl) -1-cyclohexanecarboxylate (Compound 4)

  17.7 g (51.1 mmol) of the compound 3 was dissolved in anhydrous tetrahydrofuran-triethylamine (4: 1,300 mL), 6.04 mL (61.3 mmol) of 1-pentyne, 1.78 g of dichlorobistriphenylphosphine palladium (II). (3.05 mmol) and 0.96 g (5.05 mmol) of copper (I) iodide were added. The reaction mixture was stirred at room temperature for 1 hour.

  The organic solvent of the obtained reaction mixture was distilled off under reduced pressure. To the residue was added ethyl acetate (100 mL) and saturated brine (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (300 mL). The combined organic phases were dried over anhydrous magnesium sulfate (20 g).

  After distilling off the organic solvent under reduced pressure, the residue was purified by silica gel column chromatography (400 g, hexane: diethyl ether (3: 1)) to obtain Compound 4 as a reddish brown oily substance. Compound 4 was vacuum dried (rt / 10 mmHg).

Yield: Compound 4, 13.57 g of reddish brown oily substance (quantitative yield)
1H-NMR (CDCl ₃ ) δ: 1.02 (t, J = 7.3Hz, 3H), 1.57 (m, 2H), 1.76 (t, J = 6.6Hz, 2H), 2.38 (t, J = 6.9Hz, 2H ), 2.51-2.59 (m, 4H), 3.75 (s, 3H), 3.96-4.02 (m, 4H)

(Synthesis Example 4)
Step D: Synthesis of methyl 5-hydroxy-2- (1-pentynyl) -1-cyclohexanecarboxylate (Compound 5)

  13.6 g (51.4 mmol) of Compound 4 was dissolved in acetone-water (9: 1,500 mL), and 1.90 g (13.9 mmol) of p-toluenesulfonic acid was added. The reaction mixture was stirred at 90 ° C. for 16 hours. To this reaction mixture was added saturated aqueous sodium bicarbonate (250 mL). The aqueous phase was extracted with ethyl acetate (400 mL) and dried over anhydrous magnesium sulfate (10 g).

  The organic solvent was distilled off under reduced pressure to obtain a crude ketone (11.1 g). To a solution of this crude ketone in anhydrous methanol (250 mL), a solution of 1.90 g (50.2 mmol) of sodium tetrahydroborate in anhydrous methanol (250 mL) was added dropwise at 0 ° C. over 10 minutes, and then stirred at room temperature for 15 minutes.

  The organic solvent was distilled off under reduced pressure. Saturated brine (250 mL) was added to the residue and extracted with ethyl acetate (400 mL). The combined organic phases were dried over anhydrous magnesium sulfate (15 g).

  After distilling off the organic solvent under reduced pressure, the residue was purified by silica gel column chromatography (400 g, hexane: ethyl acetate 3: 1 → 1: 1) to obtain Compound 5 as a pale yellow viscous oily substance. . Compound 5 was vacuum dried (rt / 10 mmHg).

Yield: Compound 5, 7.84 g (68.6%) of pale yellow viscous oily substance
1H-NMR (CDCl ₃ ) δ: 1.02 (t, J = 7.2Hz, 3H), 1.50-2.04 (m, 6H), 2.30-2.79 (m, 5H), 3.76 (s, 3H), 4.00 (brs, 1H)

(Synthesis Example 5)
Step E: Synthesis of (3Z) -3-butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one (Compound 9)

  7.84 g (35.3 mmol) of Compound 5 was dissolved in methanol-water (1: 1, 60 mL), and 4.24 g (106 mmol) of sodium hydroxide was added. The reaction mixture was stirred at room temperature for 20 hours. 1 mol / L hydrochloric acid (250 mL) was added to the resulting reaction mixture solution. The aqueous phase was extracted with ethyl acetate (400 mL). The combined organic phases were washed with saturated brine (250 mL) and then dried over anhydrous magnesium sulfate (15 g). The organic solvent was removed under reduced pressure to give the crude carboxylic acid as a white solid (7.12 g). 419 mg (3.88 mmol) of silver powder was added to a solution of this carboxylic acid dissolved in 60 mL of anhydrous dimethylformamide. The reaction mixture was stirred at room temperature for 22 hours.

  The insoluble catalyst in the obtained reaction mixture was removed by filtration. A saturated aqueous sodium hydrogen carbonate solution (250 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (600 mL). The combined organic phases were washed with saturated brine (100 mL) and then dried over anhydrous magnesium sulfate (20 g). After distilling off the organic solvent, the residue was purified by silica gel column chromatography (400 g, ethyl acetate-hexane 3: 2) to obtain Compound 9 as a colorless viscous oily substance. Compound 9 was vacuum dried for 1.5 hours (rt / 10 mmHg).

Yield: Compound 9, 4.40 g (59.9%) of pale yellow viscous oily substance
1H-NMR (CDCl ₃ ) δ: 0.95 (t, J = 7.3Hz, 3H), 1.33-1.91 (m, 5H), 2.22-2.70 (m, 6H), 4.12 (m, 1H), 5.16 (t, (J = 7.8Hz, 1H)

(Synthesis Example 6)
Step F: Synthesis of (Z) -ligustylide 3-[(Z) -butylidene] -4,5-dihydroisobenzofuran-1 (3H) -one (Compound 8)

Dissolve 5.10 mL (30.3 mmol) of trifluoromethanesulfonic anhydride (Tf ₂ O) in CH ₂ Cl ₂ (100 mL), and add 2.45 mL (30.3 mmol) of pyridine at −15 ° C. under a nitrogen atmosphere. did. 4.02 g (19.3 mmol) of compound 9 was dissolved in CH ₂ Cl ₂ (100 mL) and added to the stirring reaction mixture solution at −15 ° C. over 20 minutes. The reaction mixture was stirred at 0 ° C. for 1 hour.

  DBU 6.0mL (40.4mmol) was added at -15 degreeC to the reaction mixture under stirring, and it stirred at -15 degreeC for 15 minutes.

  1 mol / L hydrochloric acid (200 mL) was added to the reaction mixture. The organic phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (300 mL). The organic phase was then dried over anhydrous magnesium sulfate (20 g).

  After the solvent was distilled off, the residue was purified by silica gel column chromatography (400 g, hexane: ethyl acetate (6: 1)) to obtain Compound 8 as a pale yellow viscous oily substance. Compound 8 was vacuum dried for 1 hour (rt / 10 mmHg).

Yield: Compound 8 ((Z) -ligustylide), pale yellow viscous oily substance 3.34 g (90.9%),
The NMR separation data showed that the product was a mixture of (Z) -ligustide of compound 8 and compound 10 (isomer) (mixing ratio 22.8: 1).
1H-NMR (CDCl ₃ ) δ: 0.96 (t, J = 7.4Hz, 3H), 1.41-1.65 (m, 2H), 2.27-2.66 (m, 6H), 5.22 (t, J = 8.0Hz, 1H) , 6.00 (td, J = 3.8,9.6Hz, 1H), 6.30 (td, 2.0, 9.6Hz, 1H)

Claims (2)

After hydrolyzing methyl 5-hydroxy-2- (1-pentynyl) -1-cyclohexanecarboxylate, a cyclization reaction is carried out with a silver catalyst to obtain (3Z) -3-butylidene-6-hydroxy-4,5,6. , 7-tetrahydro-2-benzofuran-1 (3H) -one;
The obtained (3Z) -3-butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one was eliminated using trifluoromethanesulfonic anhydride. To obtain ligustilide,
A process for producing (Z) -ligustilide, comprising:   (3Z) -3-Butylidene-6-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1 (3H) -one.