CN113248380B - Synthetic method of acetic acid alpha-asaryl alcohol ester and alpha-fine octanol - Google Patents

Synthetic method of acetic acid alpha-asaryl alcohol ester and alpha-fine octanol Download PDF

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CN113248380B
CN113248380B CN202110491724.0A CN202110491724A CN113248380B CN 113248380 B CN113248380 B CN 113248380B CN 202110491724 A CN202110491724 A CN 202110491724A CN 113248380 B CN113248380 B CN 113248380B
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alpha
octanol
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acetate
asaryl
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CN113248380A (en
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郑晓晖
孙颖
白亚军
张群正
王嗣昌
王世祥
赵晔
王珍
梁晶
白育军
樊沛楠
王先梅
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Shaanxi Hongdao Institute Of Biological Analysis Science And Technology Co ltd
Northwest University
Xian Shiyou University
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    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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Abstract

The invention discloses a method for synthesizing acetic acid alpha-asaryl alcohol ester and alpha-fine octanol. The disclosed synthesis method of alpha-asaryl acetate comprises the following steps: reacting 1,2, 4-trimethoxy benzene with allyl acetate in the presence of a palladium catalyst and a ligand to generate the alpha-asaryl acetate, wherein the ligand is one or a combination of more than two of acetyl glycine, acetyl proline and nicotinoyl glycine. The disclosed synthesis method of alpha-fine octanol comprises the following steps: hydrolyzing the acetic acid alpha-asaryl alcohol ester under alkaline condition to obtain alpha-fine octanol. The method has the advantages of simple and easily obtained raw materials, high atom economy, high step economy and high yield, and is suitable for large-scale industrial production.

Description

Synthetic method of acetic acid alpha-asaryl alcohol ester and alpha-fine octanol
Technical Field
The invention relates to a method for synthesizing alpha-asaryl acetate and alpha-octanol which can be used for treating or preventing epileptic diseases; belongs to the technical field of drug synthesis.
Background
α -Fine octanol (α -asarone), chemical name: trans-3- (2, 4, 5-trimethoxyphenyl) prop-2-enyl-1-ol (E-3- (2, 4, 5-trimethoxyphenyl) prop-2-en-1-ol), also known as: trans-3 '-hydroxyasarone (E-3' -hydroxyasarone).
The acetic acid alpha-asaryl alcohol ester is an esterified derivative of alpha-fine octanol. Pharmacological studies have shown that α -asaryl acetate has significant inhibitory effects on maximal electroconvulsive induction, pentylenetetrazol-induced epilepsy symptoms in mice, and lactate dehydrogenase (Letters in Drug Design & Discovery,2020,17 (7): 891-904).
Chinese patent No. (ZL 201410692696.9, ZL 201410699506.6) successively discloses a synthesis method for obtaining trans-2, 4,5-trimethoxy cinnamate by decarboxylation of 2,4,5-trimethoxy benzaldehyde, isopropyl malonate (meldrum's acid) and fatty alcohol under the catalysis of pyridine and piperidine, and then reducing the trans-2, 4,5-trimethoxy cinnamate by a reducing agent to obtain alpha-fine octanol. The total yield is about 43 percent after 3 steps of reaction, wherein sodium borohydride does not completely reduce 2,4,5-trimethoxy cinnamate, lithium aluminum hydride and diisobutyl aluminum hydride are inconvenient to operate, easy to ignite, the reaction temperature is lower, and certain potential safety hazard is generated for the industrial production of alpha-octanol. In addition, 1,2, 4-trimethoxy benzene is used as a raw material, alpha-asaryl acetate is obtained through halogenation and Heck reaction, and alpha-fine octanol is obtained through hydrolysis. Therefore, the chemical synthesis of the alpha-fine octanol still has optimization space.
The synthesis of alpha-asaryl acetate by esterification of alpha-octanol with acetate is reported in the literature (Letters in Drug Design & Discovery,2020,17 (7): 891-904). The method needs to obtain alpha-fine octanol at first, so the cost is higher.
Disclosure of Invention
Aiming at the defects or shortcomings of the prior art, the invention provides a method for synthesizing alpha-asaryl acetate and alpha-fine octanol.
Therefore, the synthesis method of the alpha-asaryl acetate provided by the invention comprises the following steps: reacting 1,2, 4-trimethoxybenzene with allyl acetate in the presence of a palladium catalyst and a ligand to generate the alpha-asaryl acetate ((E) -3- (2, 4, 5-trimethoxyphenyl) allyl acetate), wherein the ligand is one or a combination of more than two of acetyl glycine, acetyl proline and nicotinoyl glycine.
Optionally, the palladium catalyst in the reaction (1) is selected from palladium tetratriphenylphosphine, palladium acetate and PdCl 2 (PPh 3 ) 2 、Pd 2 (dba) 3 And palladium dichloride.
Optionally, the mass ratio of the 1,2, 4-trimethoxybenzene to the allyl acetate is 1: (1-5).
Optionally, the mass ratio of the palladium catalyst to the ligand is 1: (1-3).
Optionally, the mass ratio of the 1,2, 4-trimethoxybenzene to the catalyst is 1: (0.1-1).
Further, the reaction is carried out in the presence of a palladium catalyst, a ligand and an oxidant, wherein the oxidant is selected from oxygen, air or silver acetate.
Optionally, the mass ratio of the 1,2, 4-trimethoxybenzene to the oxidant is 1: (1-100).
Optionally, the reaction is carried out at 50 ℃ to 100 ℃.
Further, the reaction is carried out in a first organic solvent selected from one or a combination of two or more of chloroform, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
The synthesis method of the alpha-fine octanol comprises the following steps: synthesizing acetic acid alpha-asaryl alcohol ester by adopting the method; then hydrolyzing the acetic acid alpha-asaryl alcohol ester in a second solvent under the alkaline condition to obtain alpha-fine octanol, wherein the second organic solvent is methanol, ethanol, isopropanol or tetrahydrofuran mixed with water.
In conclusion, the synthesis method of the acetic acid alpha-asaryl ester and alpha-octanol has the following advantages:
the synthesis method has the advantages of cheap and easily-obtained raw materials, short synthesis route, high atom utilization rate and capability of large-scale industrial production; in the synthesis process, low-temperature reaction does not exist, and the operation and control are convenient; the product yield and purity are both high, and the production cost is reduced.
Drawings
FIG. 1 is a mass spectrum of α -asaryl acetate prepared in example 2;
FIG. 2 is a hydrogen spectrum of α -asaryl acetate prepared in example 2;
FIG. 3 is a mass spectrum of α -fine octanol prepared in example 10;
FIG. 4 is a hydrogen spectrum of α -asarol prepared in example 10;
FIG. 5 is a carbon spectrum of α -octanol prepared in example 10.
Detailed Description
Unless otherwise indicated, the terms herein are to be understood according to conventional knowledge of those skilled in the art.
The synthetic route of the acetic acid alpha-asaryl alcohol ester (compound 3) and alpha-fine octanol (compound 4) is as follows:
Figure BDA0003052576130000031
1 in the reaction formula is 1,2, 4-trimethoxybenzene; 2 is allyl acetate and 3 is alpha-asaryl acetate ((E) -3- (2, 4, 5-trimethoxyphenyl) allyl acetate); 4 is alpha-fine octanol. In the reaction, an oxidizing agent may be optionally used or not. The oxidant is selected from oxygen, air or silver acetate.
Further, in order to obtain better yield, based on the technical concept of the present invention, optimization can be performed based on relevant reaction conditions, including but not limited to: the reaction temperature, the organic solvent and the dosage for reaction, the mixture ratio of reactants and the type and the dosage of the catalyst in each step. According to this concept, the present invention provides a related condition example:
in the preparation reaction of the acetic acid alpha-asaryl alcohol ester: the palladium catalyst is palladium tetratriphenylphosphine, palladium acetate and PdCl 2 (PPh 3 ) 2 、Pd 2 (dba) 3 The ligand is acetyl glycine, acetyl proline and nicotinoyl glycine; the first organic solvent is one or the combination of more than two of trichloromethane, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide. Chloroform or 1, 4-dioxane is preferably selected as the solvent. The reaction is carried out at 50-100 ℃. The reaction is preferably carried out at 80 ℃ to 90 ℃. The ligand is as follows: acetyl glycine, acetyl proline, nicotinoyl glycine. Preferably, acetyl glycine or nicotinoyl glycine is chosen as ligand. The mass ratio of the 1,2, 4-trimethoxybenzene to the allyl acetate is 1: (1-5). Preference is given to using a mass ratio of 1,2, 4-trimethoxybenzene to allyl acetate of 1:2. the mass ratio of the catalyst to the ligand is 1: (1-3). The mass ratio of catalyst to ligand is preferably chosen to be 1: (1-1.5). The mass ratio of the 1,2, 4-trimethoxybenzene to the catalyst is 1: (0.1-1). Preference is given to selecting the mass ratio of 1,2, 4-trimethoxybenzene to catalyst as 1: (0.2-0.4). The mass ratio of the 1,2, 4-trimethoxybenzene to the oxidant is 1: (1-100). Preference is given to selecting the mass ratio of 1,2, 4-trimethoxybenzene to oxidant as 1:(3～10)。
in the preparation reaction of the alpha-fine octanol, the second organic solvent is methanol, ethanol, isopropanol or tetrahydrofuran mixed with water. The volume ratio of the methanol (ethanol, isopropanol or tetrahydrofuran) to the water is 1: (1-20). Preferably, the volume ratio of methanol (or ethanol) to water is 1: (5-10). The alkali is one or the combination of more than two of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Lithium hydroxide or sodium hydroxide is preferably chosen as base. The mass ratio of the acetic acid alpha-asaryl alcohol ester to the alkali is 1 (1-10). The amount ratio of the alpha-asaryl acetate to the alkali is preferably 1 (2-5).
In the synthesis method of the present invention, the reaction substance in each step can be recovered after the reaction in the step is completed. The specific recovery method selects proper recovery means according to the physicochemical characteristics of the target product and the reaction system, and the recovery means comprises but is not limited to organic phase and aqueous phase separation, concentration, column chromatography, recrystallization, filtration and/or drying. Example (c):
recovering acetic acid alpha-asaryl alcohol ester: separating the reaction liquid with ethyl acetate and water, concentrating the organic phase to obtain coarse product of alpha-asaryl acetate, and purifying the coarse product by column chromatography or re-crystallizing to obtain alpha-asaryl acetate. Further optionally, the column chromatography uses 200-300 mesh silica gel. Recrystallizing with C1-C4 fatty alcohol/petroleum ether mixed solution.
And recovering the alpha-fine octanol, adjusting the pH of the reaction solution to be between 6 and 7, separating the solution by using an organic phase/water solution, drying the organic phase by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the alpha-fine octanol. Further optionally, the pH is adjusted with HCl, e.g. HCl at a concentration of 0.5 mol/L.
The following are specific examples provided by the inventors to further explain the technical solutions of the present invention. The starting materials, reagents and catalysts used in the following examples are all commercially available products.
Example 1:
1,2, 4-trimethoxybenzene (100.0mg, 0.6mmol), allyl acetate (178.6mg, 1.8mmol), acetylglycine (20.9mg, 0.18mmol), palladium acetate (40.0mg, 0.18mmol), were added to 10mL of chloroform under nitrogen at 80 deg.C (oil temperature) for 24 hours;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 50. 1 H NMR(600MHz,Chloroform-d)δ6.96(s,1H),6.93(d,J＝16.0Hz,1H),6.49(s,1H),6.18(dt,J＝16.0,6.7Hz,1H),4.74–4.69(m,2H),3.89(s,3H),3.85(s,3H),3.83(s,3H),2.09(s,3H).MS(+ESI)267.1[M+H] + ,289.1[M+Na] + 。
Example 2:
1,2, 4-trimethoxybenzene (100.0mg, 0.6mmol), allyl acetate (178.6mg, 1.8mmol), acetylglycine (20.9mg, 0.18mmol) and palladium acetate (40.0mg, 0.18mmol) are added into 10mL1, 4-dioxane and reacted at 50 ℃ for 24 hours under the protection of oxygen;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 50.
Example 3:
1,2, 4-trimethoxybenzene (100.0mg, 0.6mmol), allyl acetate (178.6mg, 1.8mmol), acetylglycine (20.9mg, 0.18mmol), palladium dichloride (0.18 mmol), and silver acetate (403.0mg, 1.8mmol) were added to 10mL of N, N-dimethylformamide and reacted at 60 ℃ for 24 hours under the protection of nitrogen;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 50.
Example 4:
1,2, 4-trimethoxybenzene (100.0 mg,0.6 mmol), allyl acetate (178.6 m)g,1.8 mmol), acetylglycine (20.9mg, 0.18mmol), pd 2 (dba) 3 (0.18 mmol), silver acetate (403.0mg, 1.8mmol), to 10mL of N, N-dimethylacetamide, under protection of oxygen, and reacting at 70 ℃ for 24 hours;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 1, 50, 25, 1, 10.
Example 5:
1,2, 4-trimethoxybenzene (100.0mg, 0.6mmol), allyl acetate (178.6mg, 1.8mmol), acetylglycine (20.9mg, 0.18mmol), palladium acetate (40.0mg, 0.18mmol), silver acetate (403.0mg, 1.8mmol), was charged into 10mL of N-methylpyrrolidone, and reacted at 90 ℃ C (inner temperature) for 24 hours under nitrogen atmosphere;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 50.
Example 6:
1,2, 4-trimethoxybenzene (100.0mg, 0.6mmol), allyl acetate (178.6mg, 1.8mmol), nicotinoylglycine (32.1mg, 0.18mmol), pdCl 2 (PPh 3 ) 2 (0.18 mmol), silver acetate (403.0 mg, 1.8mmol), to 10mL of dimethyl sulfoxide, under nitrogen, at 100 ℃ for 24 hours;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 50.
Example 7:
1,2, 4-trimethoxybenzene (100.0mg, 0.6 mmol), tetratriphenylphosphine palladium (1.8 mmol), acetylproline (280.3mg, 0.18mmol), palladium acetate (40.0mg, 0.18mmol) and silver acetate (403.0mg, 1.8mmol) were sequentially added to 10mL of chloroform, and reacted at 60 ℃ for 24 hours under nitrogen. Respectively adding 25mL of water and ethyl acetate, separating liquid and filtering;
the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), the organic phases were combined, dried over anhydrous sodium sulfate for 30min, and chromatographed on a silica gel column (petroleum ether: ethyl acetate =100, 1, 50, 25, 1, 10, 1, 5) to give a light yellow solid 1.3g, yield about 81.3%.
Example 8:
1,2, 4-trimethoxybenzene (100.0mg, 0.6mmol), allyl acetate (178.6mg, 1.8mmol), acetylglycine (20.9mg, 0.18mmol), palladium acetate (40.0mg, 0.18mmol) were added to 10mL of trichloromethane, and air was introduced thereto and the reaction was refluxed for 20 hours;
25mL of water and 25mL of ethyl acetate were added, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate again (15 mL × 2 times), and the organic phases were combined, dried for 30min, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =100, 1, 50, 25, 1, 10.
Example 9:
1,2, 4-trimethoxybenzene (1010g, 6 mol), allyl acetate (1802g, 18mol), acetyl proline (283g, 1.8mol), palladium acetate (347g, 1.8mol), silver acetate (301g, 1.8mol) were added to 10L of chloroform, and reacted at 60 ℃ for 28 hours;
10L of water was added, stirred for 5 minutes, separated, filtered, the aqueous phase was extracted with ethyl acetate again (5L × 2 times), the organic phases were combined, dried for 30min over anhydrous sodium sulfate, concentrated, sample-stirred, column with a diameter of 200cm, silica gel (200-300 mesh), separated (petroleum ether: ethyl acetate =100, 1, 25, 1, 10, 1, 5) to give 1205g of a light yellow solid with a yield of about 75%.
Example 10:
acetic acid alpha-asaryl ester (5.0g, 18.8mmol), lithium hydroxide (1.4g, 56.4mmol), to a mixture of methanol (7.6mL, 187.8mmol) and water (15.2mL, 0.85mol), reacted at room temperature for 5 hours under nitrogen protection;
adding ethyl acetate, separating, extracting the water phase with ethyl acetate (100 mL × 3 times), combining the organic phases, drying with anhydrous sodium sulfate for 30min, concentrating under reduced pressure, and performing silica gel column chromatography (ethyl acetate/petroleum ether system) to obtain 4.15g of pale yellow solid with a yield of about 98.6%. 1 H NMR(300MHz,DMSO-d 6 )δ7.03(s,1H),6.71(d,J＝16.1Hz,1H),6.65(s,1H),6.22(dt,J＝16.1,5.3Hz,1H),4.75(t,J＝5.5Hz,1H),4.08(td,J＝5.4,1.5Hz,2H),3.79(s,3H),3.78(s,3H),3.72(s,3H)； 13 C NMR(300MHz,DMSO-d 6 )δ171.08,169.96,143.73,142.91,128.25,121.68,116.35,115.24,73.56,69.77,36.69,21.63,21.58,20.63；MS(+ESI)225.1[M+H]。
Example 11:
acetic acid alpha-asaryl alcohol ester (1Kg, 3.8 mol), add isopropanol (1.5L) and mixed solution of sodium hydroxide aqueous solution (containing 6L of water, sodium hydroxide 451 g), react for 3h at room temperature;
ethyl acetate (4L) was added for liquid separation, the aqueous phase was extracted with ethyl acetate (4L. Times.3 times), the organic phases were combined, dried over anhydrous sodium sulfate for 1h, concentrated under reduced pressure, subjected to silica gel column chromatography (ethyl acetate/petroleum ether system), concentrated, and dried at room temperature to give 825g of a pale yellow solid with a yield of about 98%.

Claims (8)

1. A synthetic method of alpha-fine octanol is characterized by comprising the following steps:
step 1, reacting 1,2, 4-trimethoxy benzene with allyl acetate to generate alpha-asaryl acetate in the presence of a palladium catalyst and a ligand, wherein the ligand is one or a combination of more than two of acetyl glycine, acetyl proline and nicotinoyl glycine;
the palladium catalyst is selected from palladium tetratriphenylphosphine, palladium acetate and PdCl 2 (PPh 3 ) 2 、Pd 2 (dba) 3 And palladium dichloride;
and 2, hydrolyzing the acetic acid alpha-asaryl alcohol ester in a second solvent under an alkaline condition to obtain alpha-fine octanol, wherein the second organic solvent is a mixed solution of methanol, ethanol, isopropanol or tetrahydrofuran and water.
2. The method of synthesizing alpha-fine octanol according to claim 1, wherein the mass ratio of 1,2, 4-trimethoxybenzene to allyl acetate is 1: (1-5).
3. The method of synthesizing α -fine octanol of claim 1 wherein the mass ratio of palladium catalyst to ligand is 1: (1-3).
4. The method of synthesizing α -fine octanol of claim 1 wherein the mass ratio of 1,2, 4-trimethoxybenzene to catalyst is 1: (0.1-1).
5. The method of synthesizing α -fine octanol of claim 1 wherein the reaction of 1,2, 4-trimethoxybenzene with allyl acetate is carried out in the presence of a palladium catalyst, a ligand and an oxidant selected from oxygen, air or silver acetate.
6. The method of synthesizing α -fine octanol of claim 5 wherein the mass ratio of 1,2, 4-trimethoxybenzene to oxidant is 1: (1-100).
7. The method of synthesizing α -fine octanol according to claim 1 or 5, wherein the reaction of 1,2, 4-trimethoxybenzene with allyl acetate is carried out at 50 ℃ to 100 ℃.
8. The method of synthesizing α -fine octanol of claim 1 or 5, wherein the reaction of 1,2, 4-trimethoxybenzene with allyl acetate is carried out in a first organic solvent selected from one or a combination of two or more of chloroform, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
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