CN101407459B - Monohydroxy-2-acyl phenylacetate, and preparation and use thereof - Google Patents

Monohydroxy-2-acyl phenylacetate, and preparation and use thereof Download PDF

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CN101407459B
CN101407459B CN2008100722341A CN200810072234A CN101407459B CN 101407459 B CN101407459 B CN 101407459B CN 2008100722341 A CN2008100722341 A CN 2008100722341A CN 200810072234 A CN200810072234 A CN 200810072234A CN 101407459 B CN101407459 B CN 101407459B
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phenylacetate
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CN101407459A (en
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张洪奎
吴乔
黄培强
沈月毛
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Xiamen University
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Abstract

The invention relates to single hydroxyl-2-acyl phenylacetic acid easter, a preparation method and the application thereof, which relates to a compound containing single hydroxyl-2-acyl phenylacetic acid easter structure, and provides single hydroxyl-2-acyl phenylacetic acid easter with novel structure, the preparation method and the application thereof. Single hydroxyl benzaldehyde 1 is used as raw material and is firstly converted into corresponding aryl benzene propanoic acid 2 by using Meldrum acid; under the effect of AlCl3, intramolecular acidylation happens to 2 to get compound 3; after passing through a protective hydroxyl, 3 is reacted with grignard reagent to get corresponding alkane coumarone 5 which is oxidized to get 2-acyl-phenylacetic acid compound 6; 6 is esterified by different sterols, and then a protecting group of 6 is removed to get the product single hydroxyl-2-acyl-phenylacetic acid easter CsM. The compound CsM can be used as potential anti cancer drug or other biological activity drugs.

Description

Monohydroxy-2-acyl phenylacetate and preparation method thereof and application
Technical field
The present invention relates to a kind of compound that contains monohydroxy-2-acyl phenylacetate structure, especially relate to a kind of monohydroxy with anti-tumor activity-2-acyl phenylacetate and preparation method thereof and application.
Background technology
Organic micromolecule compound develops into present inhibitor as the different kind organism target spot from initial cytotoxicity, is one of study hotspot of antitumor drug all the time.The compound of research and development novel structure is sought new antitumor drug, for ensureing that human health is significant.
2005; the people such as Xu Qingyan (Xu Qingyan etc.; Xiamen University's journal (natural science edition); 2005; 44; 425-428) reported separation obtains from fungus metabolite 10 structures different 3,5-dihydroxyl-2-acyl group-phenylacetate or its derivative, and find that they have different anti-tumor activities.Other document (Paranagama, P.A.et al, J.Nat.Prod.2007,70,1939-1945; Huang, Z., et al, Photochemistry, 2008,69,1604-1608) also reported 3, some biological activity test result of 5-dihydroxyl-2-capryloyl-Phenylacetic acid ethylester (Cytosporone B), and biological activity (Brady, S.F.et al, the Org.Lett.2000 of some trihydroxy--2-capryloyl-Phenylacetic acid ethylester compound, 2 (25), 4043-4046; Singh, M.Pet al, Marine Drugs, 2007,5,71-84).As the analogue of poly-hydroxy-2-acyl group-phenylacetate, monohydroxy-2-acyl group-phenylacetate compound, and their preparation comprises that with active the research of structure activity relationship has no report.By organic synthesis technology, the series compound of preparation monohydroxy-2-acyl group-phenylacetate, the structure activity relationship of carrying out antitumor action is sought its high reactivity primer, and the anti-cancer agent that has independent intellectual property right for exploitation lays the foundation.
Summary of the invention
The object of the present invention is to provide the monohydroxy of a class formation novelty-2-acyl phenylacetate (CsM) and preparation method thereof.
Another object of the present invention is to the primer of monohydroxy-2-acyl phenylacetate as antitumor drug or other active medicine.
The structural formula of monohydroxy of the present invention-2-acyl phenylacetate (CsM) is:
Wherein, R 1=C 1～C 10Alkyl or alkenyl, R 2=C 1～C 20Alkyl or alkenyl, OH are positioned at phenyl ring C3, C4 or C6.
The preparation method's of monohydroxy of the present invention-2-acyl phenylacetate route is as follows:
Figure G2008100722341D00021
The preparation method of monohydroxy of the present invention-2-acyl phenylacetate may further comprise the steps:
1) preparation hydroxy phenylpropionic acid 2
In hydroxy benzaldehyde 1, add Meldrum acid (2,2-dimethyl-1,3-diox-4, the 6-diketone), stir, add again triethylammonium formate (TEAF) solution, become the solution of 0.5～1.2mol/L, or add DMF and TEAF mixing solutions, heating, being stirred to reaction finishes, add frozen water, be adjusted to pH=1～2 with 6N hydrochloric acid, use again ethyl acetate extraction, united extraction liquid, with saturated nacl aqueous solution washing, drying, concentrating under reduced pressure, residue rapid column chromatography purifying obtains hydroxy phenylpropionic acid 2;
2) preparation indone 3
In hydroxy phenylpropionic acid 2, add sodium-chlor and anhydrous AlCl 3, stir, finish to reaction, add HCl solution, use dichloromethane extraction, united extraction liquid, through washing, drying, concentrating under reduced pressure, residue rapid column chromatography purifying obtains indone 3;
3) preparation alcoxyl indone 4
Indone 3 is dissolved in acetone, makes the solution of 0.3～0.6mol/L, add powdered anhydrous salt of wormwood, stir lower add halohydrocarbon (RX, R=CH 3, CH 2C 6H 5, X=Cl, Br, I), heating refluxes, the elimination solids adds entry to filtrate, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression is lower concentrated, the rapid column chromatography separation obtains alcoxyl indone 4;
4) preparation hydrogenation indenes 5
Alcoxyl indone 4 is dissolved in methylene dichloride, makes the solution of 0.1～0.2mol/L, add Grignard reagent R 2MgX (R 2=C 1-C 20Alkane or alkene, X=Cl, Br, I), be stirred to reaction and finish, add hydrochloric acid, stir, use dichloromethane extraction, united extraction liquid, washing, drying, decompression is lower concentrated, the rapid column chromatography separation obtains hydrogenation indenes 5;
5) preparation 2-acyl group-Arylacetic acids 6
Add the solution that hydrogenation indenes 5 is dissolved in acetone in potassium dichromate aqueous solution, add sulfuric acid again, heating is stirred, until reaction is finished, add acetone and hydrochloric acid, use ethyl acetate extraction, united extraction liquid, drying, decompression is lower concentrated, and rapid column chromatography separates, and obtains 2-acyl group-Arylacetic acids 6;
6) preparation 2-acyl group-aryl acetate 7
2-acyl group-Arylacetic acids 6 is dissolved in pure R 1OH (R 1=C 1-C 10Alkyl, thiazolinyl) in, make the solution of 0.1～0.3mol/L, stir the lower sulfur oxychloride that adds, stir, until reaction is finished, concentrating under reduced pressure, residue separate through rapid column chromatography, obtain 2-acyl group-aryl acetate 7;
7) preparation Compound C sM
For R=CH 2C 6H 5Compound 7: corresponding 2-acyl group-aryl acetate is dissolved in the methyl alcohol, make the solution of 0.1～0.3mol/L, stir lower being added in the methanol suspension of 10%Pd/C, add again formic acid, be stirred to reaction and finish, filtering Pd/C catalyzer, filtrate is concentrated, rapid column chromatography separates, and obtains Compound C sM; Or
For R=CH 3Compound 7: corresponding 2-acyl group-aryl acetate is dissolved in the methylene dichloride, makes the solution of 0.1～0.3mol/L, add anhydrous AlCl 3, stir until reaction is finished, add hydrochloric acid, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression is lower concentrated, and rapid column chromatography separates, and obtains Compound C sM.
In step 1) in, Meldrum acid (2,2-dimethyl-1,3-diox-4, the 6-diketone) add-on is 1.0～1.2 moles of hydroxy benzaldehyde 1, by volume, and best DMF: TEAF=1 in DMF and the TEAF mixing solutions: 1, the temperature of heating is preferably 95～100 ℃, and hydrochloric acid preferably adopts 6N hydrochloric acid.
In step 2) in, the add-on of sodium-chlor is preferably 10 times of mole numbers of hydroxy phenylpropionic acid 2, anhydrous AlCl 3Add-on be preferably 4 times of mole numbers of hydroxy phenylpropionic acid 2, the temperature of stirring is preferably 150 ℃, HCl solution preferably adopts 2N HCl solution.
In step 3) in, the add-on of powdered anhydrous salt of wormwood is preferably 2 times of mole numbers of indone 3, halohydrocarbon (RX, R=CH 3, CH 2C 6H 5, X=Cl, Br, I) add-on be preferably 2 times of mole numbers of indone 3, wash the most handy hydrochloric acid washing.
In step 4) in, add Grignard reagent R 2MgX (R 2=C 1-C 20Alkane or alkene, X=Cl, Br, I) time temperature be preferably 0 ℃, Grignard reagent R 2MgX (R 2=C 1-C 20Alkane or alkene, X=Cl, Br, I) add-on be preferably 1～5 times of mole number of alcoxyl indone 4, hydrochloric acid preferably adopts 2N hydrochloric acid, the time of stirring is preferably 1～2h.
In step 5) in, the concentration of potassium dichromate aqueous solution is preferably 0.4～0.8mol/L, and in molar ratio, best hydrogenation indenes 5: potassium bichromate=1: (1.2～1.6), the temperature of heating are preferably 50～60 ℃, and hydrochloric acid preferably adopts 1N hydrochloric acid.
In step 6) in, 2-acyl group-Arylacetic acids 6 is dissolved in pure R 1OH (R 1=C 1-C 10Alkyl, thiazolinyl) in temperature be preferably 0 ℃, the add-on of sulfur oxychloride is preferably 2～3 times of mole numbers of 2-acyl group-Arylacetic acids 6.
In step 7) in, by mass percentage, the consumption of Pd/C is preferably 5%～20% of compound 7; Anhydrous AlCl 3Consumption be preferably 5～10 times of mole numbers of compound 7, wash the most handy saturated nacl aqueous solution washing.
Monohydroxy of the present invention-2-acyl phenylacetate can be used as the primer of antitumor drug or other active medicine.
To compound involved in the present invention, measured their biological activity.Utilize cell toxicant mtt assay (tetramethyl-azo azoles salt trace enzyme reaction colorimetry) to carry out the anti tumor activity in vitro test.For example, Compound C sM1, CsM2, CsM4, it is active that CsM5 measures short Luc with the test of 10.00 μ g/mL concentration to cytotoxicity inhibition, dissociation constant and the fluorescein detection method of Human gastric carcinoma cell line BGC-823 respectively, and activity and the dissociation constant of Compound C sM see Table 1.
Table 1
Compound Dissociation constant (μ M) Suppress cell survival Short Luc is active
CsM1 4.98 ++ ++
CsM2 2.62 ++++ +++
CsM4 4.21 ++++ ++
CsM5 5.27 ++ +++
Experimental result shows that compound involved in the present invention can be applicable to prepare the primer of antitumor drug or other biologically active drug.
Embodiment
The invention will be further described below by embodiment.
Embodiment 1
4-hydroxyl-2-capryloyl Phenylacetic acid ethylester (Compound C sM4, R 1=C 2H 5, R 2=n-C 7H 15)
1) 4-hydroxy phenylpropionic acid (compound 2, OH are positioned at phenyl ring C4 position)
4-hydroxy benzaldehyde 1 (5mmol) and 2,2-dimethyl-1,3-diox-4, the mixture of 6-diketone (5.5mmol) under agitation adds triethylammonium formate (TEAF) solution (9mL), is heated to 95-100 ℃, stirs 3h.The careful frozen water that adds, be adjusted to pH=1-2 with 6N hydrochloric acid after, use ethyl acetate extraction, united extraction liquid washs anhydrous MgSO with saturated nacl aqueous solution 4Drying, concentrating under reduced pressure, residue rapid column chromatography purifying obtains 4-hydroxy phenylpropionic acid 2, productive rate 85%.
2) 6-hydroxyl-2,3-bihydrogen-1-indenone (compound 3, OH are positioned at the C6 position)
Add 4-hydroxy phenylpropionic acid (6mmol), NaCl (60mmol), anhydrous AlCl in the reaction flask 3(24mmol), reaction mixture adds the dissolving of 2N HCl solution at 150 ℃ of lower 2h that stir, and uses dichloromethane extraction, merges organic extracting solution, with saturated nacl aqueous solution washing, anhydrous MgSO 4Dry.Separate with rapid column chromatography after boiling off solvent under the decompression, obtain 6-hydroxyl-2,3-bihydrogen-1-indenone, productive rate 60%.
3) 6-benzyloxy-2,3-bihydrogen-1-indenone (compound 4, R=CH 2C 6H 5)
Add 6-hydroxyl-2,3-bihydrogen-1-indenone (3.12mmol), Powdered anhydrous K in the reaction flask 2CO 3(6.24mmol), 0 ℃ of lower acetone 10mL that adds stirs 15min, then to wherein dripping cylite (6.24mmol), stirs and flows through next time night.Filter, filtrate is under reduced pressure concentrated, and rapid column chromatography separates, and obtains 6-benzyloxy-2,3-bihydrogen-1-indenone 4, productive rate 90%.
4) 6-benzyloxy-1-heptyl-3H-indenes (compound 5, R=CH 2C 6H 5, R 2=n-C 7H 15)
With 6-benzyloxy-2,3-bihydrogen-1-indenone (2.4mmol) is dissolved in the 24mL dry methylene chloride, 0 ℃ of lower 2Mn-C that drips 7H 15MgCl (6mmol).Then at room temperature continue to stir 2h.Be cooled to 0 ℃, add 2N HCl solution 10mL, continue to stir 2h under the room temperature.Use dichloromethane extraction, united extraction liquid is with saturated nacl aqueous solution washing, anhydrous MgSO 4Drying, concentrating under reduced pressure, rapid column chromatography separates, and obtains 6-benzyloxy-1-heptyl-3H-indenes 5, productive rate 80%.
5) 4-benzyloxy-2-capryloyl-toluylic acid (compound 6, R=CH 2C 6H 5, R 2=n-C 7H 15)
Potassium bichromate (2.7mmol) is dissolved in 4.8mL water, adds vitriol oil 1mL again, stirs the lower 6-of adding benzyloxy-1-heptyl-3H-indenes (1.9mmol) and is dissolved in the solution of 1mL acetone.Be warming up to 50-60 ℃, stirring reaction 1h.After adding 5mL acetone, add again 1mL 1N HCl solution.Use ethyl acetate extraction, merge organic extracting solution, with saturated nacl aqueous solution washing, anhydrous MgSO 4Drying, decompression is lower concentrated, and rapid column chromatography separates, and obtains 4-benzyloxy-2-capryloyl-toluylic acid, productive rate 40%.
6) 4-benzyloxy-2-capryloyl-Phenylacetic acid ethylester (compound 7, R=CH 2C 6H 5, R 1=C 2H 5, R 2=n-C 7H 15)
4-benzyloxy-2-capryloyl-toluylic acid (0.54mmol) is dissolved in the 2.6mL dehydrated alcohol, 0 ℃ of lower sulfur oxychloride (1.1mmol) that drips, and mixture at room temperature stirs 4h.Decompression is lower concentrated, and rapid column chromatography separates, and obtains 4-benzyloxy-2-capryloyl-Phenylacetic acid ethylester, productive rate 91%.
7) 4-hydroxyl-2-capryloyl-Phenylacetic acid ethylester (Compound C sM4, R 1=C 2H 5, R 2=n-C 7H 15)
4-benzyloxy-2-capryloyl-Phenylacetic acid ethylester (0.4mmol) is dissolved in the 2.5mL methyl alcohol, is added drop-wise to 10%Pd/C (163mg) and is suspended in the suspension of 1.5mL methyl alcohol, add again formic acid 2mL, stir 24h under the air-tight state.Filter, concentrated under the filtrate decompression, the rapid column chromatography purifying obtains 4-hydroxyl-2-capryloyl-Phenylacetic acid ethylester CsM4, productive rate 85%.
Embodiment 2
4-hydroxyl-2-decanoyl-Phenylacetic acid ethylester (Compound C sM5, R 1=C 2H 5, R 2=n-C 9H 19)
The preparation of CsM5 is from embodiment 1 intermediate product 6-benzyloxy-2,3-bihydrogen-1-indenone (compound 4, R=CH 2C 6H 5) beginning.
1) 6-benzyloxy-1-nonyl-3H-indenes (compound 5, R=CH 2C 6H 5, R 2=n-C 9H 19)
According to preparation method 4 among the embodiment 1) described method, 6-benzyloxy-2,3-bihydrogen-1-indenone and Grignard reagent n-C 9H 19The MgCl reaction obtains 6-benzyloxy-1-nonyl-3H-indenes 5, productive rate 72%.
2) 4-benzyloxy-2-decanoyl-toluylic acid (compound 6, R=CH 2C 6H 5, R 2=n-C 9H 19)
According to preparation method 5 among the embodiment 1) described method, with 6-benzyloxy-1-nonyl-acid potassium dichromate oxidation of 3H-indenes, obtain 4-benzyloxy-2-decanoyl-toluylic acid 6, productive rate 45%.
3) 4-benzyloxy-2-decanoyl-Phenylacetic acid ethylester (compound 7, R=CH 2C 6H 5, R 1=C 2H 5, R 2=n-C 9H 19)
According to preparation method 6 among the embodiment 1) described method, under the sulfur oxychloride effect, 4-benzyloxy-2-decanoyl-toluylic acid ethyl esterification obtains 4-benzyloxy-2-decanoyl-Phenylacetic acid ethylester, productive rate 90%.
4) 4-hydroxyl-2-decanoyl-Phenylacetic acid ethylester (Compound C sM5, R 1=C 2H 5, R 2=n-C 9H 19)
According to preparation method 7 among the embodiment 1) described method, 4-benzyloxy-2-decanoyl-Phenylacetic acid ethylester with 10%Pd/C catalysis Deprotection, obtains 4-hydroxyl-2-decanoyl-Phenylacetic acid ethylester CsM5, productive rate 87% in methyl alcohol/formic acid medium.
Embodiment 3
4-hydroxyl-2-butyryl radicals-amyl phenylacetate (Compound C sM6, R 1=n-C 5H 11, R 2=C 3H 7)
The preparation of CsM6 is from embodiment 1 intermediate product 6-benzyloxy-2,3-bihydrogen-1-indenone (compound 4, R=CH 2C 6H 5) beginning.
1) 6-benzyloxy-1-propyl group-3H-indenes (compound 5, R=CH 2C 6H 5, R 2=C 3H 7)
According to preparation method 4 among the embodiment 1) described method, with 6-benzyloxy-2,3-bihydrogen-1-indenone Yu Geshi reagent C 3H 7The MgBr reaction, then acidic hydrolysis obtains 6-benzyloxy-1-propyl group-3H-indenes 5, productive rate 78%.
2) 4-benzyloxy-2-butyryl radicals-toluylic acid (compound 6, R=CH 2C 6H 5, R 2=C 3H 7)
According to preparation method 5 among the embodiment 1) described method, with 6-benzyloxy-1-propyl group-acid potassium dichromate oxidation of 3H-indenes, obtain 4-benzyloxy-2-butyryl radicals-toluylic acid 6, productive rate 50%.
3) 4-benzyloxy-2-butyryl radicals-amyl phenylacetate (compound 7, R=CH 2C 6H 5, R 1=C 5H 11, R 2=C 3H 7)
According to preparation method 6 among the embodiment 1) described method, under the sulfur oxychloride effect, 4-benzyloxy-2-butyryl radicals-toluylic acid Pentyl alcohol esterification obtains 4-benzyloxy-2-butyryl radicals-amyl phenylacetate, productive rate 80%.
4) 4-hydroxyl-2-butyryl radicals-amyl phenylacetate (Compound C sM6, R 1=C 5H 11, R 2=C 3H 7)
According to preparation method 7 among the embodiment 1) described method, 4-benzyloxy-2-butyryl radicals-amyl phenylacetate with 10%Pd/C catalysis Deprotection, obtains 4-hydroxyl-2-butyryl radicals-amyl phenylacetate CsM6, productive rate 81% in methyl alcohol/formic acid medium.
Embodiment 4
3-hydroxyl-2-capryloyl-Phenylacetic acid ethylester (Compound C sM1, R 1=C 2H 5, R 2=n-C 7H 15)
1) 3-hydroxy phenylpropionic acid (compound 2, OH are positioned at phenyl ring C3 position)
According to preparation method 1 among the embodiment 1) described method, change starting raw material 4-hydroxybenzene propionic aldehyde into 3-hydroxybenzene propionic aldehyde, other operations are identical, obtain the 3-hydroxy phenylpropionic acid, productive rate 85%.
2) 7-hydroxyl-2,3-bihydrogen-1-indenone (compound 3, OH are positioned at the C7 position)
According to preparation method 2 among the embodiment 1) described method, change reactant 4-hydroxy phenylpropionic acid into the 3-hydroxy phenylpropionic acid, other operations are identical, obtain 7-hydroxyl-2,3-bihydrogen-1-indenone, productive rate 50%.
3) 7-benzyloxy-2,3-bihydrogen-1-indenone (compound 4, R=CH 2C 6H 5)
According to preparation method 3 among the embodiment 1) described method, 7-hydroxyl-2, the 3-bihydrogen-1-indenone is in anhydrous K 2CO 3Lower and the cylite reaction of effect obtains 7-benzyloxy-2,3-bihydrogen-1-indenone, productive rate 90%.
4) 7-benzyloxy-1-heptyl-3H-indenes (compound 5, R=CH 2C 6H 5, R 2=n-C 7H 15)
According to preparation method 4 among the embodiment 1) described method, 7-benzyloxy-2,3-bihydrogen-1-indenone and Grignard reagent n-C 7H 15The MgCl reaction, then acidic hydrolysis obtains 7-benzyloxy-1-heptyl-3H-indenes 5, productive rate 75%.
5) 3-benzyloxy-2-capryloyl-toluylic acid (compound 6, R=CH 2C 6H 5, R 2=n-C 7H 15)
According to preparation method 5 among the embodiment 1) described method, with 7-benzyloxy-1-heptyl-acid potassium dichromate oxidation of 3H-indenes, obtain 3-benzyloxy-2-capryloyl-toluylic acid 6, productive rate 52%.
6) 3-benzyloxy-2-capryloyl-Phenylacetic acid ethylester (compound 6, R=CH 2C 6H 5, R 1=C 2H 5, R 2=n-C 7H 15)
According to preparation method 6 among the embodiment 1) described method, under the sulfur oxychloride effect, 3-benzyloxy-2-capryloyl-toluylic acid dehydrated alcohol esterification obtains 3-benzyloxy-2-capryloyl-Phenylacetic acid ethylester, productive rate 85%.
7) 3-hydroxyl-2-capryloyl-Phenylacetic acid ethylester (Compound C sM1, R 1=C 2H 5, R 2=n-C 7H 15)
According to preparation method 7 among the embodiment 1) described method, 3-benzyloxy-2-capryloyl-Phenylacetic acid ethylester with 10%Pd/C catalysis Deprotection, obtains 3-hydroxyl-2-capryloyl-Phenylacetic acid ethylester CsM1, productive rate 83% in methyl alcohol/formic acid medium.
Embodiment 5
3-hydroxyl-2-nonanoyl-Phenylacetic acid ethylester (Compound C sM2, R 1=C 2H 5, R 2=n-C 8H 17)
The preparation method of 3-hydroxyl-2-nonanoyl-Phenylacetic acid ethylester CsM2 is with identical described in the embodiment 4, and difference only is step
4) employed Grignard reagent is n-C in 8H 17MgCl.
1) 7-benzyloxy-1-octyl group-3H-indenes (compound 5, R=CH 2C 6H 5, R 2=n-C 8H 17)
According to preparation method 4 among the embodiment 4) described method, 7-benzyloxy-2,3-bihydrogen-1-indenone and Grignard reagent n-C 8H 17The MgCl reaction, then acidic hydrolysis obtains 7-benzyloxy-1-octyl group-3H-indenes 5, productive rate 73%.
2) 3-benzyloxy-2-nonanoyl-toluylic acid (compound 6, R=CH 2C 6H 5, R 2=n-C 8H 17)
According to preparation method 5 among the embodiment 4) described method, with 7-benzyloxy-1-octyl group-acid potassium dichromate oxidation of 3H-indenes, obtain 3-benzyloxy-2-nonanoyl-toluylic acid 6, productive rate 55%.
3) 3-benzyloxy-2-nonanoyl-Phenylacetic acid ethylester (compound 6, R=CH 2C 6H 5, R 1=C 2H 5, R 2=n-C 8H 17)
According to preparation method 6 among the embodiment 4) described method, under the sulfur oxychloride effect, 3-benzyloxy-2-nonanoyl-toluylic acid dehydrated alcohol esterification obtains 3-benzyloxy-2-nonanoyl-Phenylacetic acid ethylester, productive rate 82%.
4) 3-hydroxyl-2-nonanoyl-Phenylacetic acid ethylester (Compound C sM2, R 1=C 2H 5, R 2=n-C 8H 17)
According to preparation method 7 among the embodiment 4) described method, 3-benzyloxy-2-nonanoyl-Phenylacetic acid ethylester with 10%Pd/C catalysis Deprotection, obtains 3-hydroxyl-2-nonanoyl-Phenylacetic acid ethylester CsM2, productive rate 85% in methyl alcohol/formic acid medium.
Embodiment 6
3-hydroxyl-2-tridecanoyl-Phenylacetic acid ethylester (Compound C sM3, R 1=C 2H 5, R 2=n-C 12H 25)
The preparation method of 3-hydroxyl-2-tridecanoyl-Phenylacetic acid ethylester CsM3 is with identical described in the embodiment 4, and difference only is step 4) in employed Grignard reagent be n-C 12H 25MgCl.
1) 7-benzyloxy-1-dodecyl-3H-indenes (compound 5, R=CH 2C 6H 5, R 2=n-C 12H 25)
According to preparation method 4 among the embodiment 4) described method, 7-benzyloxy-2,3-bihydrogen-1-indenone and Grignard reagent n-C 12H 25The MgCl reaction, then acidic hydrolysis obtains 7-benzyloxy-1-dodecyl-3H-indenes 5, productive rate 70%.
2) 3-benzyloxy-2-tridecanoyl-toluylic acid (compound 6, R=CH 2C 6H 5, R 2=n-C 12H 25)
According to preparation method 5 among the embodiment 4) described method, with 7-benzyloxy-1-dodecyl-acid potassium dichromate oxidation of 3H-indenes, obtain 3-benzyloxy-2-tridecanoyl-toluylic acid 6, productive rate 51%.
3) 3-benzyloxy-2-tridecanoyl-Phenylacetic acid ethylester (compound 6, R=CH 2C 6H 5, R 1=C 2H 5, R 2=n-C 12H 25)
According to preparation method 6 among the embodiment 4) described method, under the sulfur oxychloride effect, 3-benzyloxy-2-tridecanoyl-toluylic acid dehydrated alcohol esterification obtains 3-benzyloxy-2-tridecanoyl-Phenylacetic acid ethylester, productive rate 82%.
4) 3-hydroxyl-2-tridecanoyl-Phenylacetic acid ethylester (Compound C sM3, R 1=C 2H 5, R 2=n-C 12H 25)
According to preparation method 7 among the embodiment 4) described method, 3-benzyloxy-2-tridecanoyl-Phenylacetic acid ethylester with 10%Pd/C catalysis protecting group, obtains 3-hydroxyl-2-tridecanoyl-Phenylacetic acid ethylester CsM3, productive rate 82% in methyl alcohol/formic acid medium.

Claims (8)

1. the preparation method of monohydroxy-2-acyl phenylacetate is characterized in that the structural formula of described monohydroxy-2-acyl phenylacetate is:
Figure FFW00000069948500011
Wherein, R 1=C 1～C 10Alkyl or alkenyl, R 2=C 2～C 20Alkyl or alkenyl, OH are positioned at phenyl ring C3, C4 or C6;
The preparation method of described monohydroxy-2-acyl phenylacetate may further comprise the steps:
1) preparation hydroxy phenylpropionic acid
In hydroxy benzaldehyde, add 2,2-dimethyl-1,3-diox-4,6-diketone, stir, add again triethylammonium formate solution, become the solution of 0.5～1.2mol/L, or adding DMF and triethylammonium formate mixing solutions, heating is stirred to reaction and finishes, add frozen water, be adjusted to pH=1～2 with 6N hydrochloric acid, use again ethyl acetate extraction, united extraction liquid is with saturated nacl aqueous solution washing, drying, concentrating under reduced pressure, residue rapid column chromatography purifying obtains hydroxy phenylpropionic acid;
2) preparation indone
In hydroxy phenylpropionic acid, add sodium-chlor and anhydrous AlCl 3, stir, finish to reaction, add HCl solution, use dichloromethane extraction, united extraction liquid, through washing, drying, concentrating under reduced pressure, residue rapid column chromatography purifying obtains indone;
3) preparation alcoxyl indone
Indone is dissolved in acetone, makes the solution of 0.3～0.6mol/L, add powdered anhydrous salt of wormwood, stir the lower halohydrocarbon RX that adds, wherein, R=CH 3, CH 2C 6H 5, X=Cl, Br, I, heating refluxes, and the elimination solids adds entry to filtrate, uses ethyl acetate extraction, united extraction liquid, washing, drying, decompression is lower concentrated, and rapid column chromatography separates, and obtains the alcoxyl indone;
4) preparation hydrogenation indenes
The alcoxyl indone is dissolved in methylene dichloride, makes the solution of 0.1～0.2mol/L, add Grignard reagent R 2MgX, wherein, R 2=C 2-C 20Alkane or alkene, X=Cl, Br, I is stirred to reaction and finishes, and adds hydrochloric acid, stirs, and use dichloromethane extraction, united extraction liquid, washing, drying, decompression is lower concentrated, the rapid column chromatography separation obtains the hydrogenation indenes;
5) preparation 2-acyl group-Arylacetic acids
Add the solution that the hydrogenation indenes is dissolved in acetone in potassium dichromate aqueous solution, add sulfuric acid again, heating is stirred, until reaction is finished, add acetone and hydrochloric acid, use ethyl acetate extraction, united extraction liquid, drying, decompression is lower concentrated, and rapid column chromatography separates, and obtains 2-acyl group-Arylacetic acids;
6) preparation 2-acyl group-aryl acetate
2-acyl group-Arylacetic acids is dissolved in pure R 1Among the OH, make the solution of 0.1～0.3mol/L, stir the lower sulfur oxychloride that adds, stir, until reaction is finished, concentrating under reduced pressure, residue separate through rapid column chromatography, obtain 2-acyl group-aryl acetate, wherein, and R 1=C 1-C 10Alkyl, thiazolinyl;
7) preparation Compound C sM
For R=CH 2C 6H 5Compound: corresponding 2-acyl group-aryl acetate is dissolved in the methyl alcohol, make the solution of 0.1～0.3mol/L, stir lower being added in the methanol suspension of 10%Pd/C, add again formic acid, be stirred to reaction and finish, filtering Pd/C catalyzer, filtrate is concentrated, rapid column chromatography separates, and obtains Compound C sM; Or
For R=CH 3Compound: corresponding 2-acyl group-aryl acetate is dissolved in the methylene dichloride, makes the solution of 0.1～0.3mol/L, add anhydrous AlCl 3, stir until reaction is finished, add hydrochloric acid, use ethyl acetate extraction, united extraction liquid, washing, drying, decompression is lower concentrated, and rapid column chromatography separates, and obtains Compound C sM.
2. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate; it is characterized in that in step 1) in; 2; 2-dimethyl-1; 3-diox-4, the add-on of 6-diketone are 1.0～1.2 moles of hydroxy benzaldehyde, by volume; DMF in DMF and the triethylammonium formate mixing solutions: triethylammonium formate=1: 1, the temperature of heating are 95～100 ℃.
3. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate is characterized in that in step 2) in, the add-on of sodium-chlor is 10 times of mole numbers of hydroxy phenylpropionic acid, anhydrous AlCl 3Add-on be 4 times of mole numbers of hydroxy phenylpropionic acid, the temperature of stirring is 150 ℃.
4. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate is characterized in that in step 3) in, the add-on of powdered anhydrous salt of wormwood is 2 times of mole numbers of indone, the add-on of halohydrocarbon RX is 2 times of mole numbers of indone, wherein, R=CH 3, CH 2C 6H 5, X=Cl, Br, I.
5. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate is characterized in that in step 4) in, add Grignard reagent R 2Temperature during MgX is 0 ℃, Grignard reagent R 2The add-on of MgX is 1～5 times of mole number of alcoxyl indone, and the time of stirring is 1～2h, wherein, and R 2=C 2-C 20Alkane or alkene, X=Cl, Br, I.
6. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate; it is characterized in that in step 5) in, the concentration of potassium dichromate aqueous solution is 0.4～0.8mol/L, in molar ratio; the hydrogenation indenes: potassium bichromate=1: 1.2～1.6, the temperature of heating are 50～60 ℃.
7. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate is characterized in that in step 6) in, 2-acyl group-Arylacetic acids is dissolved in pure R 1Temperature among the OH is 0 ℃, and the add-on of sulfur oxychloride is 2～3 times of mole numbers of 2-acyl group-Arylacetic acids, wherein, and R 1=C 1-C 10Alkyl, thiazolinyl.
8. the preparation method of monohydroxy as claimed in claim 1-2-acyl phenylacetate is characterized in that in step 7) in, by mass percentage, the consumption of Pd/C is 5%～20% of compound; Anhydrous AlCl 3Consumption be 5～10 times of mole numbers of compound.
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