JP2005521716A5

JP2005521716A5 -

Info

Publication number: JP2005521716A5
Application number: JP2003580257A
Authority: JP
Filing date: 2002-03-28
Publication date: 2008-05-29
Anticipated expiration: 2022-03-28

Description

（実施例Ｖ）
（１−（２，４，５−トリメトキシフェニル）−１−プロパノールの調製）：４０ｍＬのＴＨＦ中のイソアコラモン（１．１２ｇ、０．００５モル）の溶液を、−５℃で攪拌した。水（１．２〜１．８ｍＬ）中のＮａＢＨ_４（０．２４〜０．３９ｇ）の予め冷却した溶液を滴下し、一方、反応混合物の温度を０℃未満に維持した。ＮａＢＨ_４の添加の完了後、数滴の１０％ＮａＯＨを添加し、そして反応混合物を、一晩、室温で攪拌した。最後に、この反応混合物を、飽和塩化アンモニウム溶液（２０ｍＬ）で希釈し、そして室温で２０分間攪拌し続けた。ＴＨＦを減圧下で除去し、そしてこの混合物をＥｔＯＡｃで２回抽出した。このＥｔＯＡｃ溶液をＨ_２Ｏで２回（２回）洗浄し、ブラインで２回洗浄し、そして濾過した。濾液を硫酸ナトリウムで乾燥させ、そしてエバポレートして乾固させた。エバポレーションで得られた残留物は、次の工程で十分に純粋であると分かったが、酢酸エチルを２５％まで割合を増加しながら、ヘキサン−酢酸エチル混合物を使用して中性アルミナカラムでクロマトグラフィーにかけて、１−（２，４，５−トリメトキシ）フェニル−１−プロパノール（１．０１ｇ、８９％）を液体として得、これを、結晶化後、白色固体を得た；Ｒ_ｆ０．７８（ヘキサン中２８％酢酸エチル）；ｍｐ９８〜９９℃； (Example V)
(Preparation of 1- (2,4,5-trimethoxyphenyl) -1-propanol): A solution of isoacolamon (1.12 g, 0.005 mol) in 40 mL of THF was stirred at −5 ° C. A pre-cooled solution of NaBH ₄ (0.24-0.39 g) in water (1.2-1.8 mL) was added dropwise while maintaining the temperature of the reaction mixture below 0 ° C. After completion of the NaBH ₄ addition, a few drops of 10% NaOH were added and the reaction mixture was stirred overnight at room temperature. Finally, the reaction mixture was diluted with saturated ammonium chloride solution (20 mL) and kept stirring at room temperature for 20 minutes. The THF was removed under reduced pressure and the mixture was extracted twice with EtOAc. The EtOAc solution was washed twice with H ₂ O (twice), washed twice with brine and filtered. The filtrate was dried over sodium sulfate and evaporated to dryness. The residue obtained by evaporation was found to be sufficiently pure in the next step, but on a neutral alumina column using a hexane-ethyl acetate mixture with increasing proportion of ethyl acetate to 25%. Chromatography gave 1- (2,4,5-trimethoxy) phenyl-1-propanol (1.01 g, 89%) as a liquid, which gave a white solid after crystallization; R _f 0. 78 (28% ethyl acetate in hexane); mp 98-99 ° C;

Claims

Toxic β-asarone (cis isomer) or of pharmacologically active α-asarone (trans isomer) of formula II from β-asarone rich Acorus calmus oil containing α-isomer and γ-isomer A process for preparation comprising the following steps:
(A) β-asarone or α-asarone and γ- using 10% Pd / C catalyst with or without ammonium formate at room temperature and under pressure of 0-276 kPa ( 0-40 psi ) A process of hydrogenating β-asarone rich ginger oil including asalone,
(B) purifying the product of step (a) on silica gel by performing column chromatography to obtain a compound of formula (I)

Obtaining a compound of
(C) DDQ containing silica or alumina as necessary in an anhydrous organic solvent at room temperature for 0.5 to 72 hours under inert atmosphere in a compound of formula (I) obtained in step (b) Dehydrogenating by treating with,
(D) filtering the reaction mixture of step (c) to remove the precipitated (DDQH ₂ ), washing the residue with an organic solvent and obtaining a combined clear filtrate;
(E) concentrating the combined filtrate of step (d) and pouring the concentrate into water and extracting with a water-immiscible organic solvent;
(F) The organic solvent extracts of step (e) are combined and washed with brine, 10% aqueous bicarbonate, followed by brine again, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Obtaining a residue,
(G) The residue of step (f) is purified on a silica gel column and eluted with a mixture of hexane: ethyl acetate to give α-asarone as a viscous liquid and formula (IIa)

Obtaining a yellow solid characterized as trans-2,4,5-trimethoxycinnamaldehyde of
(H) A viscous liquid containing α-asarone is crystallized using a hexane: methanol mixture, and α-asarone (II) is crystallized.

To obtain a white solid,
Including the process.

Toxic β-asarone (cis isomer) or of pharmacologically active α-asarone (trans isomer) of formula II from β-asarone rich Acorus calmus oil containing α-isomer and γ-isomer A process for preparation comprising the following steps:
(I) 16 to 20 hours, at room temperature, treating a compound of formula (I) with DDQ in aqueous organic solvents, process,
(J) filtering the reaction mixture of step (i) to remove the precipitated solid (DDQH ₂ ), washing the residue with an organic solvent and obtaining a clear solution;
(K) Evaporate the clear solution of step (j), pour the residue into water, extract with organic solvent, wash the organic solvent extract with brine, dry over anhydrous sodium sulfate and filter And evaporating to obtain a residue,
(L) Purify the residue of step (k) on a silica gel column and elute with a mixture of hexane: ethyl acetate to obtain a viscous liquid fraction containing isoacolamon, which is crystallized from ethyl acetate: hexane To formula (III)

Obtaining white crystals of isoacoramon
(M) The compound of formula (III) of step (l) is treated with sodium borohydride in an organic solvent in the presence of an aqueous alkali hydroxide solution in the temperature range of -5 ° C to room temperature for 16-20 hours Process to process,
(N) diluting the reaction mixture of step (m) with saturated ammonium chloride solution and stirring for 20-30 minutes;
(O) removing the organic solvent from the solution of step (n) under reduced pressure and extracting the aqueous layer with ethyl acetate;
(P) washing the ethyl acetate layer of step (o) with water, drying the ethyl acetate layer over anhydrous sodium sulfate, filtering, and evaporating the organic solvent to dryness to obtain a residue;
(Q) Purify the residue of step (p) on a neutral alumina column using hexane: ethyl acetate eluent to obtain a compound of formula (IIIa)

Obtaining 1- (2,4,5-trimethoxy) -phenyl-1-propanol
(R) dehydrating the compound of formula (IIIa) by treatment with a dehydrating agent in an aromatic hydrocarbon solvent at reflux temperature using a Dean-stack apparatus for continuous removal of water;
(S) pouring the reaction mixture of step (r) into cold water, extracting with an aromatic hydrocarbon solvent, and separating the organic layer;
(T) The organic layer of step (s) is washed again with brine, saturated bicarbonate solution, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated with organic solvent to remove the residue. Obtaining step,
(U) purifying the residue of step (t) on a silica gel column and eluting with a hexane: ethyl acetate mixture to obtain a white solid α-asarone of formula (II);
Encompasses,
Here, the compound of formula (I) has the following steps:
(A) β-asarone or α-asarone and γ- using 10% Pd / C catalyst with or without ammonium formate at room temperature and pressure of 0 to 276 kPa (0 to 40 psi) A process of hydrogenating β-asarone rich ginger oil including asalone,
(B) purifying the product of step (a) on silica gel by performing column chromatography to obtain a compound of formula (I)

Obtaining a compound of
Obtained by
process.

A process according to claim 1, in step (c) and (d), the anhydrous organic solvent used is methanol, ethanol, hexane, benzene, toluene, Ru is selected from the group consisting of tetrahydrofuran and dioxane ,process.

2. Process according to claim 1, wherein in step (c) the molar ratio of DDQ to 2,4,5-trimethoxyphenylpropane used is in the range from 1: 1 to 1.3: 1. ,process.

3. Process according to claim 2 , wherein in step (i) the molar ratio of DDQ used to 2,4,5-trimethoxypropane of formula (I) is from 1.6: 1 to 2.1. A process that is in the range of: 1.

A process according to claim 1, wherein the dehydrogenation of 2,4,5-trimethoxypropane of formula (I) results in 51% yield of α-asarone of formula ( II ) and 11% yield. A process providing a yellow solid 2,4,5-trimethoxycinnamaldehyde of the formula ( IIa )

A process according to claim 1, in step (c), the addition of catalytic amounts of silica gel or alumina, up to 72% the yield of α- asarone and trans-2,4,5 Torimetoki cinnamaldehyde Increase the process to 18%.

A process according to claim 1, in step (e), water-immiscible organic solvent used is Ru is selected from carbon tetrachloride, dichloromethane and chloroform, process.

The process according to claim 2 , wherein in steps (i) and (j) the organic solvent used is selected from the group consisting of methanol, ethanol, hexane, benzene, toluene, tetrahydrofuran and dioxane. process.

The process according to claim 2 , wherein in step (i) the ratio of water: organic solvent used is in the range of 0.1: 9.9 to 1: 9.

A process according to claim 2, in step (k), the organic solvent used is methanol, ethanol, Ru is selected from the group consisting of tetrahydrofuran and dioxane, process.

The process according to claim 2 , wherein in step (m) the organic solvent used is tetrahydrofuran.

A process according to claim 2, in the step (r), the dehydrating agent used is Ru is selected from the group consisting of p- toluenesulfonic acid and thionyl chloride pyridine, process.

A process according to claim 2, in the step (r), the aromatic hydrocarbon solvent used is benzene, Ru is selected from the group consisting of toluene, and xylene, process.

The process of claim 2 , wherein step (u) yields up to 87% α-asarone.

The process according to claim 1 or 2 , wherein the process is carried out at a temperature in the range of 20C to 70C for 4 to 12 hours.

The process according to claim 1 or 2 , wherein the α-asarone does not include β-asarone and γ-asarone.

4. The process according to claim 3, wherein in steps (c) and (d), the anhydrous organic solvent is anhydrous dioxane.

9. The process of claim 8, wherein in step (e), the water immiscible organic solvent is dichloromethane.

10. Process according to claim 9, wherein in steps (i) and (j) the organic solvent used is ethanol.

10. Process according to claim 9, wherein in steps (i) and (j) the organic solvent used is tetrahydrofuran.

12. Process according to claim 11, wherein in step (k) the organic solvent used is dioxane.

14. Process according to claim 13, wherein in step (r) the dehydrating agent used is p-toluenesulfonic acid.

15. Process according to claim 14, wherein in step (r) the aromatic hydrocarbon solvent used is toluene.