CN102381961A - 3-phenyl glutaric acid compound, preparation method and purpose thereof - Google Patents
3-phenyl glutaric acid compound, preparation method and purpose thereof Download PDFInfo
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- CN102381961A CN102381961A CN2011102584992A CN201110258499A CN102381961A CN 102381961 A CN102381961 A CN 102381961A CN 2011102584992 A CN2011102584992 A CN 2011102584992A CN 201110258499 A CN201110258499 A CN 201110258499A CN 102381961 A CN102381961 A CN 102381961A
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- 0 Cc1c(*)cc(*)c(O)c1 Chemical compound Cc1c(*)cc(*)c(O)c1 0.000 description 7
- UZDGLTFZLPRGPJ-NHSZFOGYSA-N CC1C=CC[C@H]1C1CC1 Chemical compound CC1C=CC[C@H]1C1CC1 UZDGLTFZLPRGPJ-NHSZFOGYSA-N 0.000 description 1
Abstract
The invention discloses a 3-phenyl glutaric acid compound (I), and a preparation method thereof and application thereof to preparation of 1- indenone-3acetate compounds. In the formula, R1 and R2 respectively represent H, Cl, Br and I; R1 and R2 can be the same or not; R3 represents CH(OR4OR5)2; R4 and R5 represent C1-12 alkyl, or R4 and R5 are connected to form a ring.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to 3-phenyl pentanedioic acid compounds (
I), its preparation method and preparation pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
II) in application,
In the formula: R
1, R
2Represent H, Cl, Br, I independently of one another; R
1, R
2Can be identical, also can be different; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type; X
1-X
2Expression CH
2CH
2, HC=CH.
Background technology
1-indone-3-phenylacetic acid compound (
II) be the important intermediate of synthetic ramelteon (Ramelteon); Ramelteon is the selectivity melatonin receptor agonist by the development of Japan military field drugmaker; Went on the market in the U.S. first in 2005; Be used for treating the type insomnia that has difficulty in going to sleep, chronic insomnia and short-term insomnia are also had definite curative effect; Because ramelteon and MT
1And MT
2Acceptor has higher avidity and selectivity, does not influence MT
3Acceptor and other receptor signal path, thereby its toxic side effect is less, can not produce the treatment behavior damage, long-term prescription does not produce existing habituation property of traditional sedative hypnotic drug and dependency.Document: Yong D.
Et al.
CN 201110004916.0 described 1-indone-3-phenylacetic acid compound (
II) the preparation method; This method is a starting raw material with 4-aldehyde radical benzofuran compounds; Under alkaline condition, generate corresponding midbody with acetylacetic ester through Knoevenagel condensation, Michael addition reaction, the hydrolysis under alkaline condition of gained midbody, acid neutralization get 3-(cumarone-4-yl) pentanedioic acid compounds; 3-(cumarone-4-yl) pentanedioic acid compounds in solvent-free or organic solvent through the acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
II), its chemical structure is following:
In the formula:
A,
BRepresent H, halogen independently of one another;
A,
BCan be identical, also can be different; X
1-X
2Expression CH
2CH
2, HC=CH.
Though but the starting raw material of aforesaid method---the available following document of 4-aldehyde radical benzofuran compounds (1. Rois B.
Et al.
J Chem Soc Perkin Trans 2 1984, (9): 1479-1485; 2. Willem AL.
Et al.
Tetrahedron 2005, 61 (32): 7746-7755; 3. Curt DH.
Et al.
WO 2003027090; 4. Bruce FM.
Et al.
US 2006111385; 5. Frank E.
Et al.
WO 9743272) disclosed method prepares in, but have that synthesis step is many, severe reaction conditions, operation and drawbacks such as last handling process is loaded down with trivial details, environmental pollution is serious, yield is low, production cost height, make 1-indone-3-phenylacetic acid compound (
II) a large amount of preparations be restricted.Therefore, this area need develop still that raw material is cheap and easy to get, step is brief, reaction conditions is gentle, easy and simple to handle, yield is high, the 1-of " environmental protection " indone-3-phenylacetic acid compound (
II) novel preparation method.
Summary of the invention
The objective of the invention is to open 3-phenyl pentanedioic acid compounds (
I).
Another object of the present invention is to open 3-phenyl pentanedioic acid compounds (
I) the preparation method.
The 3rd purpose of the present invention be open 3-phenyl pentanedioic acid compounds (
I) preparation pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
II) in application.
The disclosed 3-phenyl of the present invention pentanedioic acid compounds (
I) chemical structure of general formula be:
In the formula: R
1, R
2Represent H, Cl, Br, I independently of one another; R
1, R
2Can be identical, also can be different; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type; X
1-X
2Expression CH
2CH
2, HC=CH.
3-phenyl pentanedioic acid compounds proposed by the invention (
I) can prepare through following method, its reaction formula is following:
In the formula: R
1, R
2Represent H, Cl, Br, I independently of one another; R
1, R
2Can be identical, also can be different; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type; X representes Cl, Br, I.
Above-mentioned reaction formula provided 3-phenyl pentanedioic acid compounds (
I) compound method, its each reactions step specifically describes as follows:
A)With the 3-hydroxy benzaldehyde compound (
1) be starting raw material, under organic solvent and alkaline condition with the condensation of 2-halogen acetal, 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2); Wherein, reaction solvent is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone,
N, N-N,
N-SL 1332, 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.), benzene, toluene, chlorobenzene or acetonitrile, be preferably acetone,
N, N-N,
N-SL 1332, ethanol or toluene; Reacting used alkali is: basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, C
1-6The salt that Fatty Alcohol(C12-C14 and C12-C18) and basic metal form or the combination of above-mentioned various alkali, preferred bases is: salt of wormwood, sodium hydrogencarbonate, sodium ethylate; 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-dioxolanes, 2-(chloromethyl)-5,5-dimethyl--1,3-diox; The 3-hydroxy benzaldehyde compound (
1): 2-halogen acetal: the molar feed ratio of alkali is 1.0:1.0 ~ 4.0:0.5 ~ 4.0, is preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5; Temperature of reaction is room temperature ~ 200 ℃, is preferably 50 ℃ ~ 160 ℃; Reaction times is 1 ~ 48 hour, is preferably 2 ~ 24 hours.
By step
A)The 3-that obtains (2-oxygen oxyethyl group) phenyl aldehyde compounds (
2) under organic solvent and alkaline condition with acetylacetic ester (
3) after Knoevenagel condensation, Michael addition reaction, the generation midbody (
4), hydrolysis under alkaline condition then, acid neutralization, 3-phenyl pentanedioic acid compounds (
I),
In the formula: R
1, R
2Represent H, Cl, Br, I independently of one another; R
1, R
2Can be identical, also can be different; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type; R
6Expression C
1-8Alkyl;
Wherein, the condensation reaction solvent is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone,
N, N-N, ethers (as: ether, isopropyl ether, MTBE, THF, glycol dimethyl ether etc.), C
1-6Lipid acid and C
1-6The formed ester of Fatty Alcohol(C12-C14 and C12-C18), halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene etc.), benzene, toluene or acetonitrile are preferably methylene dichloride, chloroform, THF, acetonitrile, methyl alcohol, ethanol; The used alkali of condensation reaction is: piperidines, Pyrrolidine, a-amino acids, trimethylamine class (as: triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl--a-phenylethylamine,
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: the piperidines of piperidines, Pyrrolidine, 1:1 volume ratio and pyridine mixtures, N-methylmorpholine; 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2): acetylacetic ester (
3): the molar feed ratio of alkali is 1.0:2.0 ~ 4.0:0.01 ~ 1.0, is preferably 1.0:2.0 ~ 3.0:0.01 ~ 0.50; Setting-up point is 0 ℃ ~ 120 ℃, is preferably 20 ℃ ~ 80 ℃; Condensation reaction time is 1 h ~ 7 days, is preferably 24 ~ 72 hours; Midbody (
4) the used alkali of hydrolysis is: basic metal or alkaline earth metal hydroxides, preferred bases is: sodium hydroxide, Pottasium Hydroxide; The hydrolysis reaction solvent is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18) or water and C
1-6Fatty Alcohol(C12-C14 and C12-C18) arbitrary proportion blended solvent; Hydrolysising reacting temperature is 10 ℃ ~ 150 ℃, is preferably 20 ℃ ~ 100 ℃; Hydrolysis time is 10 minutes ~ 24 hours, is preferably 30 minutes ~ 4 hours.
By step
A)The 3-that obtains (2-oxygen oxyethyl group) phenyl aldehyde compounds (
2) in, work as R
1During=H, this compounds can be under suitable solvent and halogenating agent condition, with the ortho position halo of phenolic hydroxyl group, 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2 '), gained (
2 ') again according to step
B)Can obtain 3-phenyl pentanedioic acid compounds (
I); Wherein, the halogenating reaction solvent for use is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
1-6Lipid acid, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1; 2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, dithiocarbonic anhydride, hexane, heptane, sherwood oil or acetonitrile, preferred solvent is: methyl alcohol, methylene dichloride, chloroform, ether, toluene, acetate or ETHYLE ACETATE; Halogenating agent is: Cl
2, Br
2, NaBrO
3/ NaHSO
3, I
2/ HIO
3, I
2/ KI,
N-halogen acid amide (as:
N-chlorosuccinimide,
N-bromo-succinimide,
N-chloro-acetamide,
N-bromo ethanamide, trichloroisocyanuric acid, tribromo tricarbimide), hypohalite (as: t-butyl hypochlorate), tetrabutylammonium tribromide or pyridine hydrobromide perbromide, preferred halogenating agent is: Cl
2, Br
2, I
2/ HIO
3,
N-chlorosuccinimide,
N-bromo-succinimide or pyridine hydrobromide perbromide; Compound (
2) with the molar feed ratio of halogenating agent be 1.0:1.0 ~ 10.0, preferred molar feed ratio is 1.0:1.0 ~ 3.0; Temperature of reaction is-80 ℃ ~ 150 ℃, is preferably-20 ℃ ~ 80 ℃; Reaction times is 0.2 ~ 96 hour, is preferably 0.5 ~ 72 hour.
By step
B)The 3-phenyl pentanedioic acid compounds that obtains (
I) in, work as R
1During=H, this compounds can be under suitable solvent and halogenating agent condition, with the ortho position halo of phenolic hydroxyl group, 3-phenyl pentanedioic acid compounds (
I '); Wherein, the reaction solvent for use is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
1-6Lipid acid, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1; 2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, dithiocarbonic anhydride, hexane, heptane, sherwood oil or acetonitrile, preferred solvent is: methyl alcohol, methylene dichloride, chloroform, ether, toluene, acetate or ETHYLE ACETATE; Halogenating agent is: Cl
2, Br
2, NaBrO
3/ NaHSO
3, I
2/ HIO
3, I
2/ KI,
N-halogen acid amide (as:
N-chlorosuccinimide,
N-bromo-succinimide,
N-chloro-acetamide,
N-bromo ethanamide, trichloroisocyanuric acid, tribromo tricarbimide), hypohalite (as: t-butyl hypochlorate), tetrabutylammonium tribromide or pyridine hydrobromide perbromide, preferred halogenating agent is: Cl
2, Br
2, I
2/ HIO
3,
N-chlorosuccinimide,
N-bromo-succinimide or pyridine hydrobromide perbromide; R
1Compound during=H (
I) with the molar feed ratio of halogenating agent be 1.0:1.0 ~ 10.0, preferred molar feed ratio is 1.0:1.0 ~ 3.0; Temperature of reaction is-80 ℃ ~ 150 ℃, is preferably-20 ℃ ~ 80 ℃; Reaction times is 0.2 ~ 96 hour, is preferably 0.5 ~ 72 hour.
Utilize the 3-phenyl pentanedioic acid compounds that aforesaid method makes (
I), can be used for preparing pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
II), its synthetic route is following:
(1) works as R
1Be H, Cl, Br, I; R
2During for H,
In the formula: R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type.
(2) work as R
1Be H, Cl, Br, I; R
2During for Cl, Br, I,
In the formula: R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type.
Above-mentioned reaction formula provided by 3-phenyl pentanedioic acid compounds (
I) preparation 1-indone-3-phenylacetic acid compound (
II) compound method, its each reactions step specifically describes as follows:
E)By step
B)Or step
D)The 3-phenyl pentanedioic acid compounds that obtains (
I) (R
1Be H, Cl, Br, I; R
2Be H) in solvent-free or organic solvent through the acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
II); Wherein, The reaction solvent for use is: halohydrocarbon (as: methylene dichloride, chloroform, 1; 2-ethylene dichloride, chlorobenzene, orthodichlorobenzene etc.), aliphatic hydrocarbon (as: hexane, heptane, octane etc.), benzene, toluene, ethers (as: ether, isopropyl ether, MTBE, THF etc.), ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; Preferred solvent is: benzene, dithiocarbonic anhydride, 1,2-ethylene dichloride, toluene, Nitromethane 99Min., methanesulfonic; The used cyclizing agent of acidylate cyclization is: hydrofluoric acid, pyrophosphoryl chloride, P
2O
5, polyphosphoric acid (PPA), 1:1 mol ratio H
3PO
4With P
2O
5Mixture, chlorsulfonic acid, the vitriol oil, BF
3Diethyl ether solution, preferred cyclizing agent is: P
2O
5, polyphosphoric acid, the vitriol oil; The ring-closure reaction temperature is-20 ℃ ~ 150 ℃, and preferable reaction temperature is 0 ~ 100 ℃; Reaction times is 30 minutes ~ 48 hours, and the preferred reaction time is 1 ~ 24 hour.
By step
B)Or step
D)The 3-phenyl pentanedioic acid compounds that obtains (
I) (R
1Be H, Cl, Br, I; R
2Be Cl, Br, I) in solvent-free or organic solvent through the acidylate cyclization, generate 3-(cumarone-4-yl) pentanedioic acid compounds (
5); Wherein, The reaction solvent for use is: halohydrocarbon (as: methylene dichloride, chloroform, 1; 2-ethylene dichloride, chlorobenzene, orthodichlorobenzene etc.), aliphatic hydrocarbon (as: hexane, heptane, octane etc.), benzene, toluene, ethers (as: ether, isopropyl ether, MTBE, THF etc.), ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; Preferred solvent is: benzene, dithiocarbonic anhydride, 1,2-ethylene dichloride, toluene, Nitromethane 99Min., methanesulfonic; The used cyclizing agent of acidylate cyclization is: hydrofluoric acid, pyrophosphoryl chloride, P
2O
5, polyphosphoric acid (PPA), 1:1 mol ratio H
3PO
4With P
2O
5Mixture, chlorsulfonic acid, the vitriol oil, BF
3Diethyl ether solution, preferred cyclizing agent is: P
2O
5, polyphosphoric acid, the vitriol oil; The ring-closure reaction temperature is-20 ℃ ~ 150 ℃, and preferable reaction temperature is 0 ~ 100 ℃; Reaction times is 30 minutes ~ 48 hours, and the preferred reaction time is 1 ~ 24 hour.
By step
F)The 3-that obtains (cumarone-4-yl) pentanedioic acid compounds (
5), in organic solvent,, furan nucleus is reduced to the dihydrofuran-ring through catalytic hydrogenation, remove halogen atom simultaneously, 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6); 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.), benzene, toluene, aliphatic hydrocarbon (as: hexane, heptane, octane etc.) are preferably toluene, ethanol, 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, preferred catalyst is: 5% ~ 20%Pd-C, 5% ~ 20% Pd (OH)
2-C; Compound (
5) with the mass ratio of catalyzer be 1.0:0.01 ~ 1.0; Reaction pressure is normal pressure ~ 10.0 MPa, is preferably normal pressure ~ 2.0 MPa; Temperature of reaction is room temperature ~ 150 ℃, is preferably room temperature ~ 80 ℃; Reaction times is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
By step
G)The 3-that obtains (2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) in solvent-free or organic solvent through the acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
II); Wherein, The reaction solvent for use is: halohydrocarbon (as: methylene dichloride, chloroform, 1; 2-ethylene dichloride, chlorobenzene, orthodichlorobenzene etc.), aliphatic hydrocarbon (as: hexane, heptane, octane etc.), benzene, toluene, ethers (as: ether, isopropyl ether, MTBE, THF etc.), ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; Preferred solvent is: benzene, dithiocarbonic anhydride, 1,2-ethylene dichloride, toluene, Nitromethane 99Min., methanesulfonic; The used cyclizing agent of acidylate cyclization is: hydrofluoric acid, pyrophosphoryl chloride, P
2O
5, polyphosphoric acid (PPA), 1:1 mol ratio H
3PO
4With P
2O
5Mixture, chlorsulfonic acid, the vitriol oil, BF
3Diethyl ether solution, preferred cyclizing agent is: P
2O
5, polyphosphoric acid, the vitriol oil; The ring-closure reaction temperature is-20 ℃ ~ 150 ℃, and preferable reaction temperature is 0 ~ 100 ℃; Reaction times is 30 minutes ~ 48 hours, and the preferred reaction time is 1 ~ 24 hour.
The invention has the advantages that: compared with prior art, it is cheap and easy to get that this method has raw material, and reactions step reduces, and reaction conditions is gentle; Reaction environment is friendly, does not need HTHP, and is easy and simple to handle; Yield is high, and cost is low, is fit to fairly large preparation 1-indone-characteristics such as 3-phenylacetic acid compound.
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.
IA6304 type fusing point appearance, TM is not calibrated; (solvent is CDCl to Varian INOVA-400 NMR
3Or DMSO-
d 6 , interior mark TMS); Agilent-6210 TOF LC/MS high-resolution mass spectrometer; Thin-layer chromatography uses silica-gel plate to produce as Yantai, Shandong chemical institute, with uv lamp or iodine colour developing.
The preparation of embodiment 1 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2a)
In reaction flask, add 3-hydroxy benzaldehyde 12.21 g (0.1 mol), bromo second acetal 21.68 g (0.11 mol), anhydrous K successively
2CO
316.56 g (0.12 mol) and
N, N-N 80 ml are warming up to 120 ℃ of stirring reaction 10 h, after reaction finishes; Filter, filtrate decompression is steamed and is desolventized, and remaining oily matter is dissolved among chloroform 150 ml; With 10% aqueous sodium hydroxide solution 20 ml, the saturated NaCl aqueous solution 25 ml washing, organic layer is through anhydrous Na successively
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde 22.87 g, yield 96.0%; HR-TOFMS (+Q)
M/z: 239.1280 ([C
13H
18O
4+ H]
+Calculated value: 239.1283).
The preparation of embodiment 2 4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2b)
Operating process just substitutes the 3-hydroxy benzaldehyde with embodiment 1 with 4-chloro-3-hydroxy benzaldehyde,
N, N-N substitutes with acetone, anhydrous K
2CO
3Substitute with sodium ethylate, temperature rising reflux stirring reaction 20 h according to embodiment 1 aftertreatment, get 4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde, yield 95.0%; HR-TOFMS (+Q)
M/z: 273.0898 ([C
13H
17ClO
4+ H]
+Calculated value: 273.0894).
(the preparation of 2c ~ 2o) of embodiment 3～15 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds
Operating process is with embodiment 1, just with the 3-hydroxy benzaldehyde with respective compound (
1) replacement, bromo second acetal is replaced with corresponding 2-halogen acetal, and reaction conditions is carried out corresponding change, must 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2c ~ 2h), its chemical structure is following:
Embodiment 16
4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2g) and 2, the preparation of 4-two bromo-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2h)
With 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) 2.38 g (0.01 mol) are dissolved among ether 80 ml; Be cooled to-10 ℃; Dripping bromine 0.013 mol is warming up to stirring at room then naturally and reacts 25 h, after reaction finishes; With 5% sodium thiosulfate solution, 25 ml, deionized water 25 ml, the saturated NaCl aqueous solution 25 ml washing, organic layer is through anhydrous Na successively for reaction solution
2SO
4Drying is filtered, and removes solvent under reduced pressure, and resistates is through column chromatography purification (elutriant: chloroform/methanol=15:1 (v/v)), obtain respectively 4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 68.0%, HR-TOFMS (+Q)
M/z: 317.0392) and 2,4-two bromo-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 25.0%, HR-TOFMS (+Q)
M/z: 394.9490).
Embodiment 17
The preparation of 4-bromo-2-chloro-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2p)
The same embodiment of operating process
16, just with 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) with 2-chloro-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2o) replacement, the reaction solvent ether is replaced with acetate, and bromine is used
NThe replacement of-bromo-succinimide gets 4-bromo-2-chloro-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde, yield 93.0%, HR-TOFMS (+Q)
M/z: 350.9995.
Embodiment 18
4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2b) and 2, the preparation of 4-two chloro-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2e)
The same embodiment of operating process
16, just the reaction solvent ether to be replaced with acetate, bromine is used
N-chlorosuccinimide replacement, obtain respectively 4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 60.0%, HR-TOFMS (+Q)
M/z: 273.0890) and 2,4-two chloro-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 28.0%, HR-TOFMS (+Q)
M/z: 307.0506).
Embodiment 19
The preparation of 4-bromo-2-iodo-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2q)
The same embodiment of operating process
16, just with 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) with 2-iodo-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2k) replacement, the reaction solvent ether is replaced with chloroform, and bromine gets 4-bromo-2-iodo-5-(2,2-diethoxy oxyethyl group) phenyl aldehyde with the replacement of pyridine hydrobromide perbromide, yield 88.0%, HR-TOFMS (+Q)
M/z: 442.9359.
Embodiment 20
The preparation of 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ia)
In reaction flask, add successively 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) 13.6 g (0.0567mol), methyl aceto acetate 17.4 g (0.134mol), piperidines 0.24 g (0.00284mol) and absolute ethyl alcohol 100 ml; Stirring at room is reacted 48 h, and reaction removes solvent under reduced pressure after finishing; Brown oily liquids, this be midbody (
4a) bullion, need not purifying and promptly can be used for step reaction down.The gained midbody (
4a) bullion mixes with absolute ethyl alcohol 50 ml, sodium hydroxide 13.2 g (0.33mol) and deionized water 20 ml, 70 ℃ of stirring reaction 3 h are after reaction finishes; Remove ethanol under reduced pressure; Residual solution is neutralized to strongly-acid with 10% hydrochloric acid, and ETHYLE ACETATE 2 ' 50 ml extract, and organic layer is through anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid 14.6 g, yield 75.5 %, and HR-TOFMS is (Q)
M/z: 339.1438 ([C
17H
24O
7-H]
-Calculated value: 339.1444).
Embodiment 21
The preparation of 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ib)
Operating process is with embodiment 20, just with 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) with 4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2b) substitute, methyl aceto acetate substitutes with methyl acetoacetate, and piperidines substitutes with the piperidines and the pyridine mixtures of 1:1 volume ratio, gets 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid, yield 72.9 %, HR-TOFMS is (Q)
M/z: 373.1052 ([C
17H
23ClO
7-H]
-Calculated value: 373.1054).
(the preparation of Ic ~ Iq) of embodiment 22～36 3-[3-(2-oxygen oxyethyl group) phenyl] pentanedioic acid compounds
Operating process is with embodiment 20, just with 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) with respective compound (
2c ~ 2q) replacement, 3-[3-(2-oxygen oxyethyl group) phenyl] pentanedioic acid compounds (
Ic ~ Iq), its chemical structure is following:
Embodiment 37
The preparation of 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ig) and 3-[2,4-two bromo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ih)
With 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ia) 3.40 g (0.01 mol) are dissolved among ether 80 ml; Be cooled to-10 ℃; Dripping bromine 0.013 mol is warming up to stirring at room then naturally and reacts 12 h, after reaction finishes; With 5% sodium thiosulfate solution, 25 ml, deionized water 25 ml, the saturated NaCl aqueous solution 25 ml washing, organic layer is through anhydrous Na successively for reaction solution
2SO
4Drying is filtered, and removes solvent under reduced pressure, and resistates is through column chromatography purification (elutriant: ethyl acetate/methanol=12:1 (v/v)), obtain respectively 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 71.0%, HR-TOFMS (+Q)
M/z: 417.0550) and 3-[2,4-two bromo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 18.0%, HR-TOFMS (+Q)
M/z: 494.9647).
Embodiment 38
The preparation of 3-[4-bromo-2-chloro-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ip)
The same embodiment of operating process
37, just with 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ia) with 3-[2-chloro-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Io) replacement, the reaction solvent ether is replaced with acetate, and bromine is used
N-bromo-succinimide replacement, 3-[4-bromo-2-chloro-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ip), yield 90.0%, HR-TOFMS (+Q)
M/z: 451.0158.
Embodiment 39
The preparation of 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ib) and 3-[2,4-two chloro-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ie)
The same embodiment of operating process
37, just the reaction solvent ether to be replaced with acetate, bromine is used
N-chlorosuccinimide replacement, obtain respectively 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 65.0%, HR-TOFMS (+Q)
M/z: 373.1052) and 3-[2,4-two chloro-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 23.0%, HR-TOFMS (+Q)
M/z: 407.0665).
Embodiment 40
The preparation of 3-[4-chloro-2-iodo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Iq)
The same embodiment of operating process
37, just with 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ia) with 3-[2-iodo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ik) replacement, the reaction solvent ether is replaced with chloroform, and bromine gets 3-[4-chloro-2-iodo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid with the replacement of pyridine hydrobromide perbromide, yield 85.0%, HR-TOFMS (+Q)
M/z: 542.9508.
Embodiment 41
2-(4-chloro-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIb)
With 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) 3.74 g (0.01 mol), polyphosphoric acid 15.0 g, 1,2-ethylene dichloride 50 ml add in the reaction flask, and 60 ℃ of insulated and stirred are reacted 5.0 h; After reaction finishes; Add frozen water 50 ml, after stirring, tell organic layer; With deionized water 50 ml, the saturated NaCl aqueous solution 50 ml washing, organic layer is through anhydrous Na successively
2SO
4Drying is filtered, and removes solvent under reduced pressure, and resistates is used the ethyl acetate/hexane recrystallization, gets 2-(4-chloro-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) yellow solid 2.1 g of acetate, mp:192 ~ 195 ℃, yield 78.5 %.
1H NMR (DMSO-
d 6 , 400 MHz)
d: 12.31 (brs, 1H, COOH), 8.33 (d,
J=2.4Hz, 1H, Furanyl-H), 7.62 (s, 1H, Ar-H), 7.52 (d,
J=2.4Hz, 1H, Furanyl-H), 3.96 ~ 3.90 (m, 1H, CH), 3.09 (dd,
J 1 =3.6Hz,
J 2 =16.8Hz, 1H, CH
2CO), 3.02 (dd,
J 1 =9.6Hz,
J 2 =19.2Hz, 1H, CH
2COOH), 2.62 (dd,
J 1 =9.6Hz,
J 2 =16.8Hz, 1H, CH
2CO), 2.51 (dd,
J 1 =2.8Hz,
J 2 =19.2Hz, 1H, CH
2COOH); HR-TOFMS (Q)
M/z: 263.0115 ([C
13H
9ClO
4-H]
-Calculated value: 263.0111).
Embodiment 42
2-(6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIa)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ia) substitute, need not organic solvent in the reaction, reaction finishes the back and uses ether extraction, and the gained bullion gets 2-(6-oxygen-7,8-dihydro-6 through column chromatography purification (elutriant: ethyl acetate/petroleum ether=10:1 (v/v))
H-indeno [5,4-b] furans-8-yl) yellow solid of acetate, yield 20.0 %; HR-TOFMS (Q)
M/z: 229.0498 ([C
13H
10O
4-H]
-Calculated value: 229.0501).
Embodiment 43
2-(6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIa)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[3-[(5,5-dimethyl--1,3-diox-2-yl) phenyl] pentanedioic acid (
Ic) substitute, polyphosphoric acid substitutes with the vitriol oil, and temperature of reaction is 0～5 ℃, and the gained bullion gets 2-(6-oxygen-7,8-dihydro-6 through column chromatography purification (elutriant: ethyl acetate/petroleum ether=10:1 (v/v))
H-indeno [5,4-b] furans-8-yl) yellow solid of acetate, yield 15.0 %; HR-TOFMS (Q)
M/z: 229.0495 ([C
13H
10O
4-H]
-Calculated value: 229.0501).
Embodiment 44
2-(4-bromo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIc)
In reaction flask, add methanesulfonic 30 g and Vanadium Pentoxide in FLAKES 3.0 g, stirring at room 2 h, adding 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) 4.18 g (0.01 mol), 60 ℃ of insulated and stirred are reacted 5.0 h, after reaction finishes; Add frozen water 150 ml, stirring at room 20 min, methylene dichloride 2 ' 50 ml extraction; Merge organic layer, with deionized water 50 ml, the saturated NaCl aqueous solution 50 ml washing, organic layer is through anhydrous Na successively
2SO
4Drying is filtered, and removes solvent under reduced pressure, and resistates is used the ethyl acetate/hexane recrystallization, gets 2-(4-bromo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) yellow solid of acetate, yield 75.0 %; HR-TOFMS (Q)
M/z: 306.9601 ([C
13H
9BrO
4-H]
-Calculated value: 306.9606).
Embodiment 45
2-(4-chloro-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIb)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[4-chloro-3-[(5,5-dimethyl--1,3-diox-2-yl) phenyl] pentanedioic acid (
Id) substitute, 1, the 2-ethylene dichloride substitutes with benzene, gets 2-(4-chloro-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) yellow solid of acetate, yield 82.8 %; HR-TOFMS (Q)
M/z: 263.0105 ([C
13H
9ClO
4-H]
-Calculated value: 263.0111).
Embodiment 46
2-(4-bromo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIc)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[4-bromo-3-[(5,5-dimethyl--1,3-diox-2-yl) phenyl] pentanedioic acid (
Ii) substitute, 1, the 2-ethylene dichloride substitutes with toluene, gets 2-(4-bromo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) acetate, yield 77.3 %; HR-TOFMS (Q)
M/z: 306.9607 ([C
13H
9BrO
4-H]
-Calculated value: 306.9606).
Embodiment 47
2-(4-iodo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IId)
Operate same embodiment
44, just with 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) with 3-[4-iodo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Im) substitute, get 2-(4-iodo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) acetate, yield 70.0 %; HR-TOFMS (Q)
M/z: 354.9464 ([C
13H
9IO
4-H]
-Calculated value: 354.9467).
Embodiment 48
2-(4-iodo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IId)
Operate same embodiment
44, just with 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) with 3-[4-iodo-3-[(5,5-dimethyl--1,3-diox-2-yl) phenyl] pentanedioic acid (
In) substitute, get 2-(4-iodo-6-oxygen-7,8-dihydro-6
H-indeno [5,4-b] furans-8-yl) acetate, yield 74.9 %; HR-TOFMS (Q)
M/z: 354.9470 ([C
13H
9IO
4-H]
-Calculated value: 354.9467).
Embodiment 49
The preparation of 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (5a)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[2,4-two chloro-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ie) substitute, 1, the 2-ethylene dichloride substitutes with benzene, gets 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid, yield 85.0%; HR-TOFMS (Q)
M/z: 314.9830 ([C
13H
10Cl
2O
5-H]
-Calculated value: 314.9827).
Embodiment 50
The preparation of 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (5a)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[5-(1,3-dioxolane-2-yl) methoxyl group]-2,4 dichloro benzene base] pentanedioic acid (
If) substitute, 1, the 2-ethylene dichloride substitutes with benzene, and polyphosphoric acid substitutes with the vitriol oil, and temperature of reaction is a room temperature, gets 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid, yield 78.0%; HR-TOFMS (Q)
M/z: 314.9825 ([C
13H
10Cl
2O
5-H]
-Calculated value: 314.9827).
Embodiment 51
The preparation of 3-(5,7-dibromo cumarone-4-yl) pentanedioic acid (5b)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-[2,4-two bromo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ih) substitute, 1, the 2-ethylene dichloride substitutes with benzene, gets 3-(5,7-dibromo cumarone-4-yl) pentanedioic acid, yield 85.0%; HR-TOFMS (Q)
M/z: 402.8814 ([C
13H
10Br
2O
5-H]
-Calculated value: 402.8817).
Embodiment 52
The preparation of 3-(5,7-dibromo cumarone-4-yl) pentanedioic acid (5b)
Operate same embodiment
44, just with 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) with 3-[2,4-two bromo-5-[(5,5-dimethyl--1,3-diox-2-yl) phenyl] pentanedioic acid (
Ij) substitute, get 3-(5,7-dibromo cumarone-4-yl) pentanedioic acid, yield 86.9%; HR-TOFMS (Q)
M/z: 402.8819 ([C
13H
10Br
2O
5-H]
-Calculated value: 402.8817).
Embodiment 53
The preparation of 3-(4-chloro-7-bromobenzene and furans-4-yl) pentanedioic acid (5c)
Operate same embodiment
44, just with 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) with 3-[2-chloro-4-bromo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ip) substitute, get 3-(4-chloro-7-bromobenzene and furans-4-yl) pentanedioic acid, yield 80.2%; HR-TOFMS (Q)
M/z: 358.9327 ([C
13H
10BrClO
5-H]
-Calculated value: 358.9322).
Embodiment 54
The preparation of 3-(4-iodo-7-bromobenzene and furans-4-yl) pentanedioic acid (5d)
Operate same embodiment
44, just with 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) with 3-[2-iodo-4-bromo-5-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Iq) substitute, get 3-(4-iodo-7-bromobenzene and furans-4-yl) pentanedioic acid, yield 83.5%; HR-TOFMS (Q)
M/z: 450.8680 ([C
13H
10BrIO
5-H]
-Calculated value: 450.8678).
Embodiment 55
The preparation of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (6)
In reaction kettle, add 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) 3.16 g (0.01 mol), ethanol 50 ml, acetate 20 ml, anhydrous sodium acetate 0.02 mol, stirring at room to solid add 10%Pd-C 1.0 g after dissolving entirely, reaction kettle with hydrogen exchange three times after, in 50 ℃, 1.0 * 10
6The insulated and stirred reaction is 15 hours under the Pa pressure; After reaction finishes, be cooled to room temperature, filter, the small amount of ethanol washing leaching cake, filtrating and washing lotion remove solvent under reduced pressure after merging, white, needle-shaped crystals 2.45 g of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid, mp:188 ~ 190 ℃, yield 98.0 %.
1H NMR (DMSO-
d 6 , 400 MHz)
d: 12.06 (brs, 2H, 2 ' COOH), 7.02 (t,
J=8.0Hz, 1H, Ar-H
6), 6.75 (d,
J=8.0Hz, 1H, Ar-H
5), 6.56 (d,
J=8.0Hz, 1H, Ar-H
7), 4.48 (t,
J=8.8Hz, 2H, CH
2O), 3.46 ~ 3.41 (m, 1H, CH), 3.22 (t,
J=8.8Hz, 2H, ArCH
2), 2.62 (q,
J 1 =6.4Hz,
J 2 =16.0Hz, 2H, 2 ' CH
2-H
a), 2.53 (d,
J=16.0Hz, 2H, 2 ' CH
2-H
b); HR-TOFMS (Q)
M/z: 249.0766 ([C
13H
14O
5-H]
-Calculated value: 249.0763).
Embodiment 56
The preparation of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (6)
Operate same embodiment
55, just with 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) with 3-(5,7-dibromo cumarone-4-yl) pentanedioic acid (
5b) substitute, reaction solvent is used acetate, and 10%Pd-C is with 10% Pd (OH)
2-C substitutes, the white, needle-shaped crystals of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid, mp:188 ~ 190 ℃, yield 95.0 %.
1H NMR data and embodiment
55Consistent.
Embodiment 57
The preparation of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (6)
Operate same embodiment
55, just with 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) with 3-(4-chloro-7-bromobenzene and furans-4-yl) pentanedioic acid (
5c) substitute, reaction solvent is used ethanol, and 10%Pd-C is with 10% Pd (OH)
2-C substitutes, the white, needle-shaped crystals of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid, mp:188 ~ 190 ℃, yield 97.0 %.
1H NMR data and embodiment
55Consistent.
Embodiment 58
The preparation of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (6)
Operate same embodiment
55, just with 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) with 3-(4-iodo-7-bromobenzene and furans-4-yl) pentanedioic acid (
5d) substitute, reaction solvent is used ethanol, and 10%Pd-C is with 10% Pd (OH)
2-C substitutes, the white, needle-shaped crystals of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid, mp:188 ~ 190 ℃, yield 85.0 %.
1H NMR data and embodiment
55Consistent.
Embodiment 59
2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIe)
Operate same embodiment
41, just with 3-[4-chloro-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ib) with 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) substitute, 1, the 2-ethylene dichloride substitutes with benzene, gets 2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
H-indeno [5,4-b] furans-8-yl) the yellow needle-like solid of acetate, mp:180 ~ 182 ℃, yield 83.0 %.
1H NMR (DMSO-
d 6 , 400 MHz)
d: 12.29 (brs, 1H, COOH), 7.44 (d,
J=8.0Hz, 1H, Ar-H
4), 6.85 (d,
J=8.0Hz, 1H, Ar-H
5), 4.70 ~ 4.64 (m, 2H, CH
2O), 3.68 ~ 3.64 (m, 1H, CH), 3.28 (t,
J=8.8Hz, 2H, ArCH
2), 2.91 ~ 2.82 (m, 2H, ArCOCH
2), 2.44 ~ 2.38 (m, 2H, CH
2COOH); HR-TOFMS (Q)
M/z: 231.0650 ([C
13H
12O
4-H]
-Calculated value: 231.0657).
Embodiment 60
2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
H-indeno [5,4-b] furans-8-yl) preparation of acetate (IIe)
Operate same embodiment
44, just with 3-[4-bromo-3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
Ig) with 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) substitute, get 2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
H-indeno [5,4-b] furans-8-yl) the yellow needle-like solid of acetate, mp:180 ~ 182 ℃, yield 80.0 %.
1H NMR data and embodiment
59Consistent.
Claims (10)
1. one type of 3-phenyl pentanedioic acid compounds is characterized in that it is to have chemical structure of general formula
(I)Shown compound:
In the formula: R
1, R
2Represent H, Cl, Br, I independently of one another; R
1, R
2Can be identical, also can be different; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type.
According to claim 1 3-phenyl pentanedioic acid compounds (
I) the preparation method, it is characterized in that comprising the steps:
A)With the 3-hydroxy benzaldehyde compound (
1) be starting raw material, under organic solvent and alkaline condition with the condensation of 2-halogen acetal, 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2);
Each substituent definition and chemical structure of general formula in the formula (
I) identical;
B)By step
A)The 3-that obtains (2-oxygen oxyethyl group) phenyl aldehyde compounds (
2) under organic solvent and alkaline condition with acetylacetic ester (
3) after Knoevenagel condensation, Michael addition reaction, the generation midbody (
4), hydrolysis under alkaline condition then, acid neutralization, 3-phenyl pentanedioic acid compounds (
I),
Each substituent definition and chemical structure of general formula in the formula (
I) identical; R
6Expression C
1-8Alkyl;
Also can by following steps prepare 3-phenyl pentanedioic acid compounds (
I):
C)By step
A)The 3-that obtains (2-oxygen oxyethyl group) phenyl aldehyde compounds (
2) in, work as R
1During=H, this compounds can be under suitable solvent and halogenating agent condition, with the ortho position halo of phenolic hydroxyl group, 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2 '), gained (
2 ') again according to step
B)Can obtain 3-phenyl pentanedioic acid compounds (
I);
In the formula: R
2Expression H, Cl, Br, I; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type; X representes Cl, Br, I;
Also can by following steps prepare 3-phenyl pentanedioic acid compounds (
I):
D)By step
B)The 3-phenyl pentanedioic acid compounds that obtains (
I) in, work as R
1During=H, this compounds can be under suitable solvent and halogenating agent condition, with the ortho position halo of phenolic hydroxyl group, 3-phenyl pentanedioic acid compounds (
I ');
In the formula: R
2Expression H, Cl, Br, I; R
3Expression CH (OR
4OR
5)
2, R
4, R
5Expression C
1-12Alkyl or R
4With R
5Link to each other and form ring-type; X representes Cl, Br, I.
3-phenyl pentanedioic acid compounds 3. as claimed in claim 2 (
I) the preparation method, it is characterized in that:
Said step
A)In, reaction solvent is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone,
N, N-N,
N-SL 1332, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, C
1-6Lipid acid and C
1-6The formed ester of Fatty Alcohol(C12-C14 and C12-C18), methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene, benzene, toluene, chlorobenzene or acetonitrile; Reacting used alkali is: basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, C
1-6The salt that Fatty Alcohol(C12-C14 and C12-C18) and basic metal form or the combination of above-mentioned various alkali; 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; The 3-hydroxy benzaldehyde compound (
1): 2-halogen acetal: the molar feed ratio of alkali is 1.0:1.0 ~ 4.0:0.5 ~ 4.0; Temperature of reaction is room temperature ~ 200 ℃; Reaction times is 1 ~ 48 hour;
Said step
B)In, the condensation reaction solvent is: C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Alkanone,
N, N-N, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, C
1-6Lipid acid and C
1-6The formed ester of Fatty Alcohol(C12-C14 and C12-C18), methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, benzene, toluene or acetonitrile; The used alkali of condensation reaction is: piperidines, Pyrrolidine, alpha-amino group acids, triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl--α-Ben Yian,
N-methylmorpholine,
N-methyl piperidine, triethylene diamine, 1, the combination of 8-diazabicyclo [5,4,0] 11 carbon-7-alkene, 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; 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds (
2): acetylacetic ester (
3): the molar feed ratio of alkali is 1.0:2.0 ~ 4.0:0.01 ~ 1.0; Setting-up point is 0 ℃ ~ 120 ℃; Condensation reaction time is 1 h ~ 7 days; Midbody (
4) the used alkali of hydrolysis is: basic metal or alkaline earth metal hydroxides; The hydrolysis reaction solvent is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18) or water and C
1-6Fatty Alcohol(C12-C14 and C12-C18) arbitrary proportion blended solvent; Hydrolysising reacting temperature is 10 ℃ ~ 150 ℃; Hydrolysis time is 10 minutes ~ 24 hours.
3-phenyl pentanedioic acid compounds 4. as claimed in claim 2 (
I) the preparation method, it is characterized in that: said step
C)In, the halogenating reaction solvent for use is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
1-6Lipid acid, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, dithiocarbonic anhydride, hexane, heptane, sherwood oil or acetonitrile; Halogenating agent is: Cl
2, Br
2, NaBrO
3/ NaHSO
3, I
2/ HIO
3, I
2/ KI,
N-chlorosuccinimide,
N-bromo-succinimide,
N-chloro-acetamide,
N-bromo ethanamide, trichloroisocyanuric acid, tribromo tricarbimide, t-butyl hypochlorate, tetrabutylammonium tribromide or pyridine hydrobromide perbromide; Compound (
2) with the molar feed ratio of halogenating agent be 1.0:1.0 ~ 10.0; Temperature of reaction is-80 ℃ ~ 150 ℃; Reaction times is 0.2 ~ 96 hour.
3-phenyl pentanedioic acid compounds 5. as claimed in claim 2 (
I) the preparation method, it is characterized in that: said step
D)In, the halogenating reaction solvent for use is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
1-6Lipid acid, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, dithiocarbonic anhydride, hexane, heptane, sherwood oil or acetonitrile; Halogenating agent is: Cl
2, Br
2, NaBrO
3/ NaHSO
3, I
2/ HIO
3, I
2/ KI,
N-chlorosuccinimide,
N-bromo-succinimide,
N-chloro-acetamide,
N-bromo ethanamide, trichloroisocyanuric acid, tribromo tricarbimide, t-butyl hypochlorate, tetrabutylammonium tribromide or pyridine hydrobromide perbromide; R
1Compound during=H (
I) with the molar feed ratio of halogenating agent be 1.0:1.0 ~ 10.0; Temperature of reaction is-80 ℃ ~ 150 ℃; Reaction times is 0.2 ~ 96 hour.
3-phenyl pentanedioic acid compounds 6. as claimed in claim 1 (
I) be used to prepare pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
II) method, it is characterized in that comprising the steps:
E)By step
B)Or step
D)The 3-phenyl pentanedioic acid compounds that obtains (
I) in, work as R
1Be H, Cl, Br, I; R
2During for H, this compounds in solvent-free or organic solvent through the acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
II);
In the formula: R
1Expression H, Cl, Br, I; X
1-X
2Expression HC=CH;
F)By step
B)Or step
D)The 3-phenyl pentanedioic acid compounds that obtains (
I) in, work as R
1Be H, Cl, Br, I; R
2During for Cl, Br, I, this compounds in solvent-free or organic solvent through the acidylate cyclization, generate 3-(cumarone-4-yl) pentanedioic acid compounds (
5);
In the formula: R
1Expression H, Cl, Br, I; R
2Expression Cl, Br, I;
G)By step
F)The 3-that obtains (cumarone-4-yl) pentanedioic acid compounds (
5), in organic solvent,, furan nucleus is reduced to the dihydrofuran-ring through catalytic hydrogenation, remove halogen atom simultaneously, 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6);
H)By step
G)The 3-that obtains (2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) in solvent-free or organic solvent through the acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
II);
1-indone 7. as claimed in claim 6-3-phenylacetic acid compound (
II) the preparation method, it is characterized in that,
Said step
E)In; The reaction solvent for use is: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, hexane, heptane, octane, benzene, toluene, ether, isopropyl ether, MTBE, THF, ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; The used cyclizing agent of acidylate cyclization is: hydrofluoric acid, pyrophosphoryl chloride, P
2O
5, polyphosphoric acid, 1:1 mol ratio H
3PO
4With P
2O
5Mixture, chlorsulfonic acid, the vitriol oil or BF
3Diethyl ether solution; The ring-closure reaction temperature is-20 ℃ ~ 150 ℃; Reaction times is 30 minutes ~ 48 hours;
Said step
F)In; The reaction solvent for use is: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, hexane, heptane, octane, benzene, toluene, ether, isopropyl ether, MTBE, THF, ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; The used cyclizing agent of acidylate cyclization is: hydrofluoric acid, pyrophosphoryl chloride, P
2O
5, polyphosphoric acid, 1:1 mol ratio H
3PO
4With P
2O
5Mixture, chlorsulfonic acid, the vitriol oil, BF
3Diethyl ether solution; The ring-closure reaction temperature is-20 ℃ ~ 150 ℃; Reaction times is 30 minutes ~ 48 hours;
Said step
G)In, 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, ether, isopropyl ether, MTBE, THF, glycol dimethyl ether, benzene, toluene, hexane, heptane, octane; 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: 1% ~ 30%Pd-C, palladium black, D61-Pd, D72-Pd, D153-Pd, D261-Pd, D290-Pd, 1% ~ 30% Pd (OH)
2-C, palladium, palladium chloride; Compound (
5) with the mass ratio of catalyzer be 1.0:0.01 ~ 1.0; Reaction pressure is normal pressure ~ 10.0 MPa; Temperature of reaction is room temperature ~ 150 ℃; Reaction times is 1 ~ 48 hour;
Said step
H)In; The reaction solvent for use is: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, hexane, heptane, octane, benzene, toluene, ether, isopropyl ether, MTBE, THF, ETHYLE ACETATE, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; The used cyclizing agent of acidylate cyclization is: hydrofluoric acid, pyrophosphoryl chloride, P
2O
5, polyphosphoric acid, 1:1 mol ratio H
3PO
4With P
2O
5Mixture, chlorsulfonic acid, the vitriol oil, BF
3Diethyl ether solution; The ring-closure reaction temperature is-20 ℃ ~ 150 ℃; Reaction times is 30 minutes ~ 48 hours.
8. one type of 3-(2-oxygen oxyethyl group) phenyl aldehyde compounds is characterized in that it is to have chemical structure of general formula
(2)Shown compound:
Each substituent definition and chemical structure of general formula in the formula (
I) identical.
9. one type of 3-(cumarone-4-yl) pentanedioic acid compounds, it is characterized in that it be have chemical structure of general formula (
5) shown in compound:
In the formula: R
1Expression H, Cl, Br, I; R
2Expression Cl, Br, I.
As claim 1,8 and 9 said any compound preparation 1-indone-3-phenylacetic acid compound (
II) in application.
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| CN102964263A (en) * | 2012-11-29 | 2013-03-13 | 太仓市茜泾化工有限公司 | Process for preparing (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid |
| CN108821966A (en) * | 2018-06-04 | 2018-11-16 | 江苏理工学院 | A method of synthesis 3,3`- (1,4- phenylene) double glutaric acids |
| CN113061084A (en) * | 2020-12-31 | 2021-07-02 | 成都亨达药业有限公司 | Novel method for preparing ferulic acid |
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