CN101648931B - Method for preparing 3-(2,3-dihydrobenzfuran-5-radical)-metacetonic acid - Google Patents
Method for preparing 3-(2,3-dihydrobenzfuran-5-radical)-metacetonic acid Download PDFInfo
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Abstract
The invention discloses a method for preparing 3-(2,3-dihydrobenzfuran-5-radical)-metacetonic acid (I), which comprises the following steps: condensing cresol (1) used as starting raw material with 2-halogen acetaldehyde or 2-halogenated acetaldehyde under an alkaline condition to obtain 2-(4-methylphenoxyl) acetaldehyde or an acetal compound (2); carrying out Friedel-Crafts reaction on the compound (2) to obtain 5-methylbenzfuran (3); further oxidizing (3) after halo to obtain benzfuran-5-formaldehyde (5); condensing the benzfuran-5-formaldehyde (5) with malonic acid or malonic ester under the alkaline condition to obtain (E)-3-(benzfuran-5-radical) acrylic acid (6); finally catalyzing, hydrogenating and reducing to obtain the 3-(2,3-dihydrobenzfuran-5-radical)-metacetonic acid (I).
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the preparation method of a kind of selectivity melatonin receptor agonist ramelteon (Ramelteon) synthetic important intermediate 3-(2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I).
Background technology
3-(2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I) is a synthesis of selective melatonin receptor agonist---the important intermediate of ramelteon (Ramelteon), and document: J Med Chem 2002,45 (19), 4222; WO2006030739; WO 2008150953; WO 2008151170 etc.; Described the preparation method of this compound, these methods all are with 2, and 3-Dihydrobenzofuranes-5-formaldehyde is starting raw material; Prolong carbochain after further reduction through diverse ways; And obtain 3-(2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I), its reaction formula is following:
Method one:
This method is with 2; 3-Dihydrobenzofuranes-5-formaldehyde is starting raw material, in piperidines, pyridine mixed solvent, with propanedioic acid the Knoevenagel condensation reaction takes place, and gets 3-(2; 3-Dihydrobenzofuranes-5-yl)-vinylformic acid; Through Pd/C or Raney Ni reduction, get 3-(2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I) then.
Method two:
This method is with 2; 3-Dihydrobenzofuranes-5-formaldehyde is starting raw material, under strong basicity (NaH, NaOBu-t) condition, with 2-(diethoxy phosphonate group) ETHYLE ACETATE the Wittig-Horner condensation reaction takes place, and gets 3-(2; 3-Dihydrobenzofuranes-5-yl)-ethyl propenoate; Hydrolysis again after Pd/C or Raney Ni reduction gets 3-(2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I).
Above-mentioned synthetic 3-(2; 3-Dihydrobenzofuranes-5-yl)-method of propionic acid (I); Exist to use raw material high price, severe reaction conditions, operation and last handling process is loaded down with trivial details, total recovery is on the low side, the serious deficiency that waits of " three wastes " discharging in the preparation process; Make the synthetic cost of compound (I) higher, a large amount of preparations are restricted.Therefore, this area need develop still that raw material is cheap and easy to get, reaction conditions is gentle, easy and simple to handle, chemical yield is high, the 3-of " environmental protection " (2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I) novel preparation method.
Summary of the invention
The objective of the invention is to be to avoid the deficiency of existing method, the new synthetic method of (2,3-Dihydrobenzofuranes-5-the yl)-propionic acid (I) that provides that a kind of reaction conditions is gentle, aftertreatment is easy, reaction environment is friendly, yield is high, cost is low, can prepare 3-in a large number.
3-proposed by the invention (2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I) novel preparation method is to be starting raw material with p-cresol cheap and easy to get and 2-halogen acetaldehyde or 2-halogen acetal, and its synthetic route is following:
(in the formula: R
1, R
2Expression H, C
1-12Straight chained alkyl or branched-chain alkyl or naphthenic base or R
1, R
2Link to each other and form ring-type; X representes Cl, Br, I).
For said synthesis route, its concrete steps are:
A) be starting raw material with p-cresol (1), under alkaline condition,, get 2-(4-methylphenoxy) acetaldehyde or acetal compounds (2) with 2-halogen acetaldehyde or the condensation of 2-halogen acetal;
B) by steps A) 2-(4-methylphenoxy) acetaldehyde that obtains or acetal compounds (2) under protonic acid or Lewis acid catalysis, through the Friedel-Crafts reaction, 5-methyl cumarone (3);
C) by step B) the 5-methyl cumarone (3) that obtains in the presence of halogenating agent, the halogenating reaction through the benzyl position, 5-monochloromethyl cumarone (4);
D) by step C) the 5-monochloromethyl cumarone (4) that obtains is through oxidizing reaction, cumarone-5-formaldehyde (5);
E) by step D) cumarone-5-formaldehyde (5) alkaline condition of obtaining down with propanedioic acid or malonic ester through Knoevenagel condensation, hydrolysis decarboxylation, must (E)-3-(cumarone-5-yl) vinylformic acid (6);
F) by step e) (E)-3-(cumarone-5-yl) vinylformic acid (6) of obtaining is through the catalytic hydrogenation reduction, 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid (I).
The method of above-mentioned synthetic 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid specifically describes as follows:
Steps A): p-cresol (1) under organic solvent and alkaline condition with 2-halogen acetaldehyde or the condensation of 2-halogen acetal, 2-(4-methylphenoxy) acetaldehyde or acetal compounds (2); Wherein, reaction solvent is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone, N, dinethylformamide, ethers (as: ether, isopropyl ether, MTBE, THF, glycol dimethyl ether etc.), C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, acetonitrile are preferably methylene dichloride, chloroform, THF, acetonitrile, acetone; Reacting used alkali is: basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, piperidines, Pyrrolidine, trimethylamine class (as: triethylamine, Tributylamine, trioctylamine, pyridine, N; N-dimethyl--α-Ben Yian, N-methylmorpholine, N-methyl piperidine, triethylene diamine, 1; 8-diazabicyclo [5; 4; 0] 11 carbon-7-alkene etc.) or the combination of above-mentioned various alkali, preferred bases is: salt of wormwood, yellow soda ash, sodium hydrogencarbonate, pyridine, triethylamine, N-methylmorpholine; 2-halogen acetaldehyde is selected from: 2-monochloroacetaldehyde, 2-bromoacetaldehyde; 2-halogen acetal is: 2-monochloroacetaldehyde or 2-bromoacetaldehyde and C
1-12Fatty Alcohol(C12-C14 and C12-C18) or C
1-12The acetal that glycol forms is preferably: bromo second acetal, 2-(brooethyl)-1,3-diox; P-cresol (1): 2-halogen acetaldehyde or 2-halogen acetal: the molar feed ratio of alkali is 1.0: 1.0～4.0: 0.5～4.0, be preferably 1.0: 1.0～2.0: 1.0～and 2.0; Temperature of reaction is room temperature～160 ℃, is preferably 50 ℃～80 ℃; Reaction times is 1～48 hour, is preferably 2～18 hours.
Step B): by steps A the 2-that) obtains (4-methylphenoxy) acetaldehyde or acetal compounds (2) through the Friedel-Crafts reaction, get 5-methyl cumarone (3) in organic solvent and under protonic acid or the Lewis acid catalysis; Wherein, The reaction solvent for use is: halohydrocarbon (as: methylene dichloride, chloroform, 1; 2-ethylene dichloride, orthodichlorobenzene etc.), aliphatic hydrocarbon (as: hexane, heptane, octane etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, ethers (as: ether, isopropyl ether, MTBE, THF etc.), ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., nitro aromatic compound, sherwood oil; Preferred solvent is: benzene, dithiocarbonic anhydride, 1,2-ethylene dichloride, toluene, Nitromethane 99Min.; Bronsted acid catalyst is: polyphosphoric acid (PPA), H
3PO
4/ P
2O
5Mixture, the vitriol oil are preferably polyphosphoric acid (PPA); The Lewis acid catalyst is: ZnCl
2, TiCl
4, SnCl
4, AlCl
3, FeCl
3, BF
3Diethyl ether solution is preferably AlCl
3, ZnCl
2, BF
3Compound (2) is 1.0: 1.0～10.0 with the molar feed ratio of protonic acid or Lewis acid, and preferred molar feed ratio is 1.0: 1.0～3.0; Temperature of reaction is-20 ℃～150 ℃, is preferably 50 ℃～100 ℃; Reaction times is 0.5～48 hour, is preferably 2～8 hours.
Step C): by step B the 5-methyl cumarone (3) that) obtains reacts with halogenating agent in organic solvent, gets 5-monochloromethyl cumarone (4); Wherein, the reaction solvent for use is: halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), aliphatic hydrocarbon (as: hexane, heptane, octane etc.), dithiocarbonic anhydride, sherwood oil, and preferred solvent is: tetracol phenixin, benzene, hexane; Halogenating agent is: halogen, N-halogen acid amide (as: N-chlorosuccinimide, N-bromo-succinimide, N-chloro-acetamide, N-bromo ethanamide, trichloroisocyanuric acid, tribromo tricarbimide), sulfonyl halide, hypohalite (as: t-butyl hypochlorate), and preferred halogenating agent is: N-bromo-succinimide, trichloroisocyanuric acid, sulfuryl chloride, t-butyl hypochlorate; Compound (3) is 1.0: 1.0～10.0 with the molar feed ratio of halogenating agent, and preferred molar feed ratio is 1.0: 1.0～3.0; Temperature of reaction is 20 ℃～150 ℃, is preferably 30 ℃～80 ℃; Reaction times is 1～24 hour, is preferably 3～10 hours.
Step D): by step C the 5-monochloromethyl cumarone (4) that) obtains through the oxygenant oxidation, gets cumarone-5-formaldehyde (5) in organic solvent; Wherein, Reaction solvent is: halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, acetonitrile, ethers (as: ether, isopropyl ether, MTBE, THF, glycol dimethyl ether etc.), C
3-8Alkanone, N, dinethylformamide, C
2-8Aliphatic carboxylic acid is preferably methylene dichloride, chloroform, toluene, acetonitrile, acetone, acetate; Oxygenant is preferably: methyl-sulphoxide, hexamethylenetetramine (urotropine), four positive fourth ammonium dichromates, Manganse Dioxide; Compound (4) is 1.0: 1.0～10.0 with the molar feed ratio of oxygenant, and preferred molar feed ratio is 1.0: 1.0～3.0; Temperature of reaction is 0 ℃～150 ℃, is preferably 40～120 ℃; Reaction times is 1～24 hour, is preferably 1～10 hour.
Step e): by step D the cumarone that) obtains-5-formaldehyde (5) alkaline condition down with propanedioic acid or malonic ester through Knoevenagel condensation, hydrolysis decarboxylation, must (E)-3-(cumarone-5-yl) vinylformic acid (6); Wherein, the condensation reaction solvent is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone, N, dinethylformamide, pyridine, ethers (as: ether, isopropyl ether, MTBE, THF, glycol dimethyl ether etc.), C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, acetonitrile are preferably methylene dichloride, chloroform, THF, acetonitrile, methyl alcohol, ethanol; The used alkali of condensation reaction is: piperidines, Pyrrolidine, alpha-amino group acids, trimethylamine class (as: triethylamine, Tributylamine, trioctylamine, pyridine, N; N-dimethyl--α-Ben Yian, N-methylmorpholine, N-methyl piperidine, triethylene diamine, 1; 8-diazabicyclo [5; 4; 0] 11 carbon-7-alkene etc.), the combination of basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates or above-mentioned various alkali, preferred bases is: piperidines, Pyrrolidine, piperidines/pyridine (1: 1) mixture, N-methylmorpholine; Compound (5): propanedioic acid or malonic ester: the molar feed ratio of alkali is 1.0: 1.0～4.0: 0.1～4.0, be preferably 1.0: 1.3～2.6: 0.1～and 2.0; Setting-up point is room temperature～150 ℃, is preferably 30 ℃～120 ℃; Condensation reaction time is 1～24 hour, is preferably 2～12 hours.
Step F): by step e (the E)-3-that) obtains (cumarone-5-yl) vinylformic acid (6) through the catalytic hydrogenation reduction, gets 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid (I) in organic solvent; Wherein, the hydrogenation solvent for use is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone, C
1-6Lipid acid, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, ethers (like ether, isopropyl ether, MTBE, THF, glycol dimethyl ether etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, aliphatic hydrocarbon (as: hexane, heptane, octane etc.), preferred solvent is toluene, Virahol, THF, acetate; Reaction can be carried out in single solvent, also can in mixed solvent, carry out, and the mixed solvent volume ratio is 1: 0.1～10; The catalytic hydrogenation catalyst system therefor is: the palladium of 1%～30%Pd-C, palladium black, polymer carrier load (as: D61-Pd, D72-Pd, D153-Pd, D261-Pd, D290-Pd etc.), 1%～30%Pd (OH)
2-C, palladium, palladium chloride, Raney-Ni, Rh-Al
2O
3, PtO
2, a kind of or its compsn among the Ni-Al, preferred catalyst is: Raney-Ni, 5%～20%Pd-C, 5%～20%Pd (OH)
2-C; Compound (6) is 1.0: 0.01～1.0 with the mass ratio of catalyzer; Reaction pressure is normal pressure～10.0MPa, preferred normal pressure～2.0MPa; Temperature of reaction is room temperature～150 ℃, is preferably room temperature～80 ℃; Reaction times is 1～48 hour, is preferably 1～24 hour.
The invention has the advantages that: compared with prior art; This method raw materials used cheap and easy to get, reaction conditions is gentle, the reaction required solvent need not have water treatment; Easy and simple to handle, cost is low, yield is high, " three wastes " pollute few; Be fit to characteristics such as a large amount of preparation 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid.
Embodiment
Can further describe the present invention through following embodiment, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
Embodiment 1
The preparation of 2-(4-methylphenoxy)-diethyl acetal (2a)
In reaction flask, add p-cresol 10.81g (0.1mol), bromo ethylidene ether 21.68g (0.11mol), anhydrous K successively
2CO
316.56g (0.12mol) with acetone 80ml, temperature rising reflux stirring reaction 12h is after reaction finishes; Filter, filtrate decompression is steamed and is desolventized, and remaining oily matter is dissolved among the chloroform 100ml; With 10% aqueous sodium hydroxide solution 20ml, saturated NaCl aqueous solution 25ml washing, organic layer is through anhydrous Na successively
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets 2-(4-methylphenoxy)-diethyl acetal 21.31g, yield 95.0%.
Embodiment 2
The preparation of 2-(4-methylphenoxy)-acetaldehyde (2b)
Operating process just substitutes the bromo ethylidene ether with embodiment 1 with the 40% chloroethanal aqueous solution, acetone is used N, and dinethylformamide substitutes, and gets 2-(4-methylphenoxy)-acetaldehyde, yield 88.5%.
Embodiment 3
The preparation of 5-methyl cumarone (3)
With 2-(4-methylphenoxy)-diethyl acetal 17.95g (0.08mol), polyphosphoric acid 20.0g, 1,2-ethylene dichloride 200ml adds in the reaction flask, temperature rising reflux stirring reaction 2h; After reaction finishes; Add frozen water 100ml, after stirring, tell organic layer; With 10% aqueous sodium carbonate 50ml, saturated NaCl aqueous solution 25ml washing, organic layer is through anhydrous Na successively
2SO
4Drying is filtered, and underpressure distillation gets colourless 5-methyl cumarone liquid 9.16g, yield 86.6%.
1H?NMR(CDCl
3，400MHz)δ：7.57(d，J＝1.8Hz，1H，Ar-H
2)，7.38(d，J＝7.2Hz，1H，Ar-H
7)，7.37(s，1H，Ar-H
4)，7.10(d，J＝7.2Hz，1H，Ar-H
6)，6.69(d，J＝1.8Hz，1H，Ar-H
3)，2.44(s，1H，Ar-CH
3)。
Embodiment 4
The preparation of 5-methyl cumarone (3)
Operating process just substitutes polyphosphoric acid with embodiment 3 with boron trifluoride ether solution, get colourless 5-methyl cumarone liquid, yield 79.2%.
Embodiment 5
The preparation of 5-brooethyl cumarone (4a)
In reaction flask, add 5-methyl cumarone 13.22g (0.1mol), N-bromo-succinimide 35.60g (0.2mol), catalytic amount Lucidol and tetracol phenixin 150ml, temperature rising reflux stirring reaction 6h is after reaction finishes; Cooling; Filter, filtrate decompression is steamed and is desolventized, and remaining oily matter is dissolved among the chloroform 100ml; With 10% aqueous sodium carbonate 20ml, saturated NaCl aqueous solution 25ml washing, organic layer is through anhydrous Na successively
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets 5-brooethyl cumarone 20.73g, yield 98.2%.
Embodiment 6
The preparation of 5-chloromethyl benzo furans (4b)
Operating process just substitutes the N-bromo-succinimide with embodiment 5 with trichloroisocyanuric acid, tetracol phenixin substitutes with hexanaphthene, gets 5-chloromethyl benzo furans, yield 95.0%.
Embodiment 7
The preparation of cumarone-5-formaldehyde (5)
In reaction flask, add 5-brooethyl cumarone 16.89g (0.08mol), sodium hydrogencarbonate 13.44g (0.16mol) and methyl-sulphoxide 100ml, be warming up to 90～100 ℃ of insulated and stirred reaction 30min, after reaction finishes; Cooling; Add frozen water 150ml, extract, after organic layer merges with ether 50ml * 2; Successively with 10% aqueous sodium carbonate 25ml, saturated NaCl aqueous solution 25ml washing, through anhydrous Na
2SO
4Drying is filtered, and underpressure distillation gets colorless benzofuryl-5-formaldehyde liquid 5.55g, yield 56.0%.
1H?NMR(CDCl
3，600MHz)δ：10.08(s，1H，CHO)，8.16(d，J＝1.2Hz，1H，Ar-H
4)，7.87(dd，J
1＝1.2Hz，J
2＝8.4Hz，1H，Ar-H
6)，7.73(d，J＝2.4Hz，1H，Ar-H
2)，7.63(d，J＝8.4Hz，1H，Ar-H
7)，6.91(d，J＝1.8Hz，1H，Ar-H
3)；
13C?NMR(CDCl
3，100MHz)δ：192.0(C＝O)，158.8(Ar-C
7a)，147.1(Ar-C
2)，132.5(Ar-C
3a)，128.5(Ar-C
5)，126.2(Ar-C
6)，125.1(Ar-C
4)，112.5(Ar-C
7)，107.7(Ar-C
3)。
Embodiment 8
The preparation of cumarone-5-formaldehyde (5)
5-chloromethyl benzo furans 13.33g (0.08mol), hexamethylenetetramine 14.02g (0.10mol), acetate 50ml and deionized water 50ml are mixed, behind the temperature rising reflux stirring reaction 1h, add concentrated hydrochloric acid 40ml; Continue refluxing and stirring reaction 20min, after reaction finishes, cooling; Extract with ether 50ml * 2; After organic layer merges, successively with 10% aqueous sodium carbonate 25ml, saturated NaCl aqueous solution 25ml washing, through anhydrous Na
2SO
4Drying is filtered, and underpressure distillation gets colorless benzofuryl-5-formaldehyde liquid 9.19g, yield 78.6%;
1H NMR spectrum is consistent with embodiment 7.
Embodiment 9
(E)-preparation of 3-(cumarone-5-yl) vinylformic acid (6)
In reaction flask, add cumarone-5-formaldehyde 14.62g (0.1mol), propanedioic acid 15.62g (0.15mol), piperidines 2.0ml and pyridine 60ml, behind the temperature rising reflux stirring reaction 4h, remove solvent under reduced pressure; Resistates is poured among the deionized water 100ml, regulates pH to strongly-acid with 10% aqueous hydrochloric acid, suction filtration; The gained bullion is used re-crystallizing in ethyl acetate; The acrylic acid white crystals 14.53g of (E)-3-(cumarone-5-yl), mp:175～176 ℃, yield 77.2%.
1H?NMR(CDCl
3，400MHz)δ：11.2(brs，1H，COOH)，7.91(d，J＝15.6Hz，1H，ArCH＝)，7.85(s，1H，Ar-H
4)，7.66(d，J＝2.0Hz，1H，Ar-H
2)，7.54(d，J＝8.8Hz，1H，Ar-H
7)，7.51(d，J＝8.8Hz，1H，Ar-H
6)，6.81(d，J＝2.0Hz，1H，Ar-H
3)，6.46(d，J＝15.6Hz，1H，＝CHCOOH)。
Embodiment 10
(E)-preparation of 3-(cumarone-5-yl) vinylformic acid (6)
In reaction flask, add cumarone-5-formaldehyde 7.31g (0.05mol), ethyl malonate 8.81g (0.055mol), piperidines 0.48g (0.0057mol) and absolute ethyl alcohol 50ml, 50 ℃ of stirring reaction 12h are after reaction finishes; Remove solvent under reduced pressure, add 10% aqueous sodium hydroxide solution 30ml, stirring at room 3h in the resistates; Regulate pH to strongly-acid with 10% aqueous hydrochloric acid; Suction filtration, the gained bullion is used re-crystallizing in ethyl acetate, gets the acrylic acid white crystals 7.90g of (E)-3-(cumarone-5-yl); Mp:174～176 ℃, yield 83.9%;
1The HNMR spectrum is consistent with embodiment 9.
Embodiment 11
The preparation of 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid (I)
In reaction flask, add (E)-3-(cumarone-5-yl) vinylformic acid 18.82g (0.1mol), ethanol 80ml, acetate 20ml; After stirring at room to solid dissolves entirely; Add 10%Pd-C catalyzer 1.5g, reaction flask with hydrogen exchange three times after, stirring reaction is 12 hours under normal temperature, normal pressure; After reaction finishes, filter, the small amount of ethanol washing leaching cake, filtrating and washing lotion remove solvent under reduced pressure after merging, the white crystals 19.03g of 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid, mp:94～96 ℃, yield 99.0%.
1H?NMR(CDCl
3，400MHz)δ：7.05(s，1H，Ar-H
4)，6.94(d，J＝8.0Hz，1H，Ar-H
6)，6.71(d，J＝8.0Hz，1H，Ar-H
7)，4.55(t，J＝8.8Hz，2H，OCH
2)，3.18(t，J＝8.8Hz，2H，ArCH
2CH
2O)，2.89(t，J＝6.4Hz，2H，ArCH
2)，2.66(t，J＝6.4Hz，2H，CH
2COOH)，hidden(COOH)。
Embodiment 12
The preparation of 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid (I)
Operating process is with embodiment 11, just the 10%Pd-C catalyzer substituted with Raney Ni, and reduction reaction is carried out under the 0.1MPa hydrogen pressure, white crystals that must 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid, mp:94～96 ℃, yield 97.5%;
1The HNMR spectrum is consistent with embodiment 11.
The invention is not restricted to the foregoing description.
Claims (1)
1. the preparation method of a 3-(2,3-Dihydrobenzofuranes-5-yl)-propionic acid (I),
It is characterized in that:
A) be starting raw material with p-cresol (1), under organic solvent and alkaline condition,, get 2-(4-methylphenoxy) acetaldehyde or acetal compounds (2) with 2-halogen acetaldehyde or the condensation of 2-halogen acetal,
In the formula: R
1, R
2Expression C
1-12Straight chained alkyl;
B) by steps A) 2-(4-methylphenoxy) acetaldehyde that obtains or acetal compounds (2) in organic solvent with polyphosphoric acid or BF
3Under the ether catalysis,, get 5-methyl cumarone (3) through the Friedel-Crafts reaction,
C) by step B) the 5-methyl cumarone (3) that obtains in organic solvent with the halogenating agent reaction, 5-monochloromethyl cumarone (4), used halogenating agent is: N-chlorosuccinimide, N-bromo-succinimide, trichloroisocyanuric acid or tribromo tricarbimide,
In the formula: X representes Cl, Br;
D) by step C) the 5-monochloromethyl cumarone (4) that obtains in organic solvent through the oxygenant oxidation, cumarone-5-formaldehyde (5), used oxygenant is: methyl-sulphoxide, hexamethylenetetramine or Manganse Dioxide,
E) by step D) cumarone-5-formaldehyde (5) of obtaining under alkaline condition with propanedioic acid through Knoevenagel condensation, hydrolysis decarboxylation, (E)-3-(cumarone-5-yl) vinylformic acid (6),
F) by step e) (E)-3-(cumarone-5-yl) vinylformic acid (6) of obtaining, in organic solvent through the catalytic hydrogenation reduction, 3-(2,3-Dihydrobenzofuranes-5-yl) propionic acid (I), catalyzer is Raney-Ni or 5%-20%Pd-C.
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| CN104370865A (en) * | 2014-11-24 | 2015-02-25 | 苏州乔纳森新材料科技有限公司 | Method for synthesizing 3-(2,3-dihydrobenzofuran-5-yl) propionic acid through Heck reaction |
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| CN101056867A (en) * | 2004-09-13 | 2007-10-17 | 武田药品工业株式会社 | Process for production of optically active amine derivatives |
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| CN101056867A (en) * | 2004-09-13 | 2007-10-17 | 武田药品工业株式会社 | Process for production of optically active amine derivatives |
Non-Patent Citations (1)
| Title |
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| Hung-Yi Huang,et al.Constituents of the Root Wood of Zanthoxylum wutaiense with Antitubercular Activity.《Journal of Natural Products》.2008,第71卷(第7期),1146-1151. * |
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