CN102381961B - 3-phenyl glutaric acid compound, preparation method and purpose thereof - Google Patents
3-phenyl glutaric acid compound, preparation method and purpose thereof Download PDFInfo
- Publication number
- CN102381961B CN102381961B CN201110258499.2A CN201110258499A CN102381961B CN 102381961 B CN102381961 B CN 102381961B CN 201110258499 A CN201110258499 A CN 201110258499A CN 102381961 B CN102381961 B CN 102381961B
- Authority
- CN
- China
- Prior art keywords
- reaction
- ether
- acid
- pentanedioic acid
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 Cc(cc1*)c(C(CC2OC2O)CC(CO)=O)c2c1[o]cc2 Chemical compound Cc(cc1*)c(C(CC2OC2O)CC(CO)=O)c2c1[o]cc2 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 pharmaceutical chemistry field, relate to 3-phenyl pentanedioic acid compounds (
i), its preparation method and prepare pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
iI) in application,
In formula: R
1, R
2represent independently of one another H, Cl, Br, I; R
1, R
2can be identical, also can be different; R
3represent CH (OR
4oR
5)
2, R
4, R
5represent C
1-12alkyl or R
4with R
5be connected to form ring-type; X
1-X
2represent 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 Japanese Wu Tian drugmaker, within 2005, in the U.S., go on the market first, be used for the treatment of the type insomnia that has difficulty in going to sleep, chronic insomnia and short-term insomnia are also had to definite curative effect; Due to ramelteon and MT
1and MT
2acceptor has higher avidity and selectivity, does not affect MT
3acceptor and other receptor signal path, thereby its toxic side effect is less, can not produce treatment behavior damage, long-term prescription does not produce the existing habituation of traditional sedative hypnotic drug and dependency.Document: Yong D.
et al.
cN 201110004916.0 described 1-indone-3-phenylacetic acid compound (
iI) preparation method; it is starting raw material that the method be take 4-aldehyde radical benzofuran compounds; under alkaline condition, through Knoevenagel condensation, Michael addition reaction, generate corresponding intermediate with acetylacetic ester; gained intermediate is hydrolyzed under alkaline condition, acid neutralization; obtain 3-(cumarone-4-yl) pentanedioic acid compounds; 3-(cumarone-4-yl) pentanedioic acid compounds in solvent-free or organic solvent through acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
iI), its chemical structure is as follows:
In formula:
a,
brepresent independently of one another H, halogen;
a,
bcan be identical, also can be different; X
1-X
2represent CH
2cH
2, HC=CH.
But the starting raw material of aforesaid method---though 4-aldehyde radical benzofuran compounds is available with Publication about Document (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) in prepared by disclosed method, but have that synthesis step is many, severe reaction conditions, operation and the drawback such as last handling process is loaded down with trivial details, environmental pollution is serious, yield is low, production cost is high, make 1-indone-3-phenylacetic acid compound (
iI) a large amount of preparations be restricted.Therefore, this area still need to develop 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 object 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) preparation method.
The 3rd object of the present invention be open 3-phenyl pentanedioic acid compounds (
i) prepare pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
iI) in application.
3-phenyl pentanedioic acid compounds disclosed in this invention (
i) chemical structure of general formula be:
In formula: R
1, R
2represent independently of one another H, Cl, Br, I; R
1, R
2can be identical, also can be different; R
3represent CH (OR
4oR
5)
2, R
4, R
5represent C
1-12alkyl or R
4with R
5be connected to form ring-type; X
1-X
2represent CH
2cH
2, HC=CH.
3-phenyl pentanedioic acid compounds proposed by the invention (
i) can prepare by following method, its chemical equation is as follows:
In formula: R
1, R
2represent independently of one another H, Cl, Br, I; R
1, R
2can be identical, also can be different; R
3represent CH (OR
4oR
5)
2, R
4, R
5represent C
1-12alkyl or R
4with R
5be connected to form ring-type; X represents Cl, Br, I.
Above-mentioned reaction formula provided 3-phenyl pentanedioic acid compounds (
i) synthetic method, its each reactions steps specifically describes as follows:
a)with 3-hydroxy benzaldehyde compound (
1) be starting raw material, under organic solvent and alkaline condition with the condensation of 2-halogen acetal, obtain 3-(2-oxygen oxyethyl group) compound of benzaldehyde category (
2); Wherein, reaction solvent is: C
1-6fatty alcohol, C
3-8aliphatic ketone,
n,N-dimethyl formamide,
n-methyl-2-pyrrolidone, ethers (as: ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether etc.), C
1-6lipid acid and C
1-6ester that fatty alcohol forms, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), benzene, toluene, chlorobenzene or acetonitrile, be preferably acetone,
n,N-dimethyl formamide,
n-methyl-2-pyrrolidone, ethanol or toluene; Reacting alkali used 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 and basic metal form or the combination of above-mentioned various alkali, preferred bases is: salt of wormwood, sodium bicarbonate, sodium ethylate; 2-halogen acetal is: 2-monochloroacetaldehyde or 2-bromoacetaldehyde and C
1-12fatty alcohol 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; 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-obtaining (2-oxygen oxyethyl group) compound of benzaldehyde category (
2) under organic solvent and alkaline condition with acetylacetic ester (
3) after Knoevenagel condensation, Michael addition reaction, generation intermediate (
4), then hydrolysis, acid neutralization under alkaline condition, obtain 3-phenyl pentanedioic acid compounds (
i),
In formula: R
1, R
2represent independently of one another H, Cl, Br, I; R
1, R
2can be identical, also can be different; R
3represent CH (OR
4oR
5)
2, R
4, R
5represent C
1-12alkyl or R
4with R
5be connected to form ring-type; R
6represent C
1-8alkyl;
Wherein, condensation reaction solvent is: C
1-6fatty alcohol, C
3-8aliphatic ketone,
n,N-dimethyl formamide, ethers (as: ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether etc.), C
1-6lipid acid and C
1-6the formed ester of fatty alcohol, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene etc.), benzene, toluene or acetonitrile, be preferably methylene dichloride, chloroform, tetrahydrofuran (THF), acetonitrile, methyl alcohol, ethanol; Condensation reaction alkali used 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) compound of benzaldehyde category (
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 hour ~ 7 days, is preferably 24 ~ 72 hours; Intermediate (
4) be hydrolyzed alkali used and be: basic metal or alkaline earth metal hydroxides, preferred bases is: sodium hydroxide, potassium hydroxide; Hydrolysis reaction solvent is: water, C
1-6fatty alcohol or water and C
1-6the solvent that fatty alcohol arbitrary proportion mixes; 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-obtaining (2-oxygen oxyethyl group) compound of benzaldehyde category (
2) in, work as R
1during=H, this compounds can be under suitable solvent and halogenating agent condition, by the ortho position halo of phenolic hydroxyl group, obtain 3-(2-oxygen oxyethyl group) compound of benzaldehyde category (
2 '), gained (
2 ') again according to step
b)can obtain 3-phenyl pentanedioic acid compounds (
i); Wherein, halogenating reaction solvent for use is: water, C
1-6fatty alcohol, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, dithiocarbonic anhydride, hexane, heptane, sherwood oil or acetonitrile, preferred solvent is: methyl alcohol, methylene dichloride, chloroform, ether, toluene, acetic acid or ethyl 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, preferably 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, preferably 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 obtaining (
i) in, work as R
1during=H, this compounds can be under suitable solvent and halogenating agent condition, by the ortho position halo of phenolic hydroxyl group, obtain 3-phenyl pentanedioic acid compounds (
i '); Wherein, reaction solvent for use is: water, C
1-6fatty alcohol, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, dithiocarbonic anhydride, hexane, heptane, sherwood oil or acetonitrile, preferred solvent is: methyl alcohol, methylene dichloride, chloroform, ether, toluene, acetic acid or ethyl 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, preferably 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, preferably 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 as follows:
(1) work as R
1for H, Cl, Br, I; R
2during for H,
In formula: R
3represent CH (OR
4oR
5)
2, R
4, R
5represent C
1-12alkyl or R
4with R
5be connected to form ring-type.
(2) work as R
1for H, Cl, Br, I; R
2during for Cl, Br, I,
In formula: R
3represent CH (OR
4oR
5)
2, R
4, R
5represent C
1-12alkyl or R
4with R
5be connected to form ring-type.
Above-mentioned reaction formula provided by 3-phenyl pentanedioic acid compounds (
i) prepare 1-indone-3-phenylacetic acid compound (
iI) synthetic method, its each reactions steps specifically describes as follows:
e)by step
b)or step
d)the 3-phenyl pentanedioic acid compounds obtaining (
i) (R
1for H, Cl, Br, I; R
2for H) in solvent-free or organic solvent through acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
iI); Wherein, 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, methyl tertiary butyl ether, tetrahydrofuran (THF) etc.), ethyl 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; Acidylate cyclization cyclizing agent used 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, preferably cyclizing agent is: P
2o
5, polyphosphoric acid, the vitriol oil; 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 obtaining (
i) (R
1for H, Cl, Br, I; R
2for Cl, Br, I) in solvent-free or organic solvent through acidylate cyclization, generate 3-(cumarone-4-yl) pentanedioic acid compounds (
5); Wherein, 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, methyl tertiary butyl ether, tetrahydrofuran (THF) etc.), ethyl 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; Acidylate cyclization cyclizing agent used 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, preferably cyclizing agent is: P
2o
5, polyphosphoric acid, the vitriol oil; 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-obtaining (cumarone-4-yl) pentanedioic acid compounds (
5), in organic solvent, through catalytic hydrogenation, furan nucleus is reduced to dihydrofuran ring, remove halogen atom simultaneously, obtain 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6); Wherein, hydrogenation solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol forms, ethers (as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether etc.), benzene, toluene, aliphatic hydrocarbon (as: hexane, heptane, octane etc.), be preferably toluene, ethanol, tetrahydrofuran (THF), acetic acid; Reaction can be carried out in single solvent, also can in mixed solvent, carry out, and mixed solvent volume ratio is 1:0.1 ~ 10; Catalytic hydrogenation used catalyst 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-obtaining (2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) in solvent-free or organic solvent through acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
iI); Wherein, 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, methyl tertiary butyl ether, tetrahydrofuran (THF) etc.), ethyl 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; Acidylate cyclization cyclizing agent used 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, preferably cyclizing agent is: P
2o
5, polyphosphoric acid, the vitriol oil; 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 the method has raw material, reactions steps reduces, and reaction conditions is gentle, reaction environment is friendly, does not need High Temperature High Pressure, easy and simple to handle, yield is high, and cost is low, is applicable to the features such as fairly large preparation 1-indone-3-phenylacetic acid compound.
Embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
IA6304 type melting point apparatus, thermometer is not calibrated; (solvent is CDCl to Varian INOVA-400 nuclear magnetic resonance analyser
3or DMSO-
d 6 , interior mark TMS); Agilent-6210 TOF LC/MS high-resolution mass spectrometer; Thin-layer chromatography silica-gel plate is that Yantai, Shandong chemical institute is produced, with ultraviolet lamp or iodine colour developing.
the preparation of embodiment 1 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2a)
In reaction flask, add successively 3-hydroxy benzaldehyde 12.21 g(0.1 mol), bromo second acetal 21.68 g(0.11 mol), anhydrous K
2cO
316.56 g(0.12 mol) and
n,N-dimethyl formamide 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 in chloroform 150 ml, with 10% aqueous sodium hydroxide solution 20 ml, the 25 ml washings of the saturated NaCl aqueous solution, organic layer is through anhydrous Na successively
2sO
4dry, filter, remove solvent under reduced pressure, obtain 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 the chloro-3-of embodiment 2 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2b)
Operating process, with embodiment 1, just substitutes 3-hydroxy benzaldehyde with 4-chloro-3-hydroxyl phenyl aldehyde,
n,N-dimethyl formamide substitutes with acetone, anhydrous K
2cO
3with sodium ethylate, substitute, temperature rising reflux stirring reaction 20 h, according to embodiment 1 aftertreatment, obtain the chloro-3-of 4-(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 embodiment 3～15 3-(2-oxygen oxyethyl group) compound of benzaldehyde category (2c ~ 2o)
Operating process is with embodiment 1, just by 3-respective compound for hydroxy benzaldehyde (
1) replace, bromo second acetal is replaced with corresponding 2-halogen acetal, and reaction conditions is carried out to corresponding change, obtain 3-(2-oxygen oxyethyl group) compound of benzaldehyde category (
2c ~ 2h), its chemical structure is as follows:
embodiment 16
the preparation of the bromo-3-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2g) and the bromo-5-of 2,4-bis-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2h)
By 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) 2.38 g(0.01 mol) be dissolved in ether 80 ml, be cooled to-10 ℃, drip bromine 0.013 mol, then be naturally warming up to stirring at room and react 25 h, after reaction finishes, reaction solution is successively with 5% sodium thiosulfate solution 25 ml, deionized water 25 ml, the 25 ml washings of the saturated NaCl aqueous solution, and organic layer is through anhydrous Na
2sO
4dry, filter, remove solvent under reduced pressure, resistates, through column chromatography purification (elutriant: chloroform/methanol=15:1 (v/v)), obtains respectively the bromo-3-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 68.0%, HR-TOFMS (+Q)
m/z: 317.0392) and the bromo-5-of 2,4-bis-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 25.0%, HR-TOFMS (+Q)
m/z: 394.9490).
embodiment 17
the preparation of the chloro-5-of the bromo-2-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2p)
The same embodiment of operating process
16, just by 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) the use chloro-5-of 2-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2o) replace, reaction solvent ether is replaced with acetic acid, and bromine is used
n-bromo-succinimide is replaced, and obtains the chloro-5-of the bromo-2-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde, yield 93.0%, HR-TOFMS (+Q)
m/z: 350.9995.
embodiment 18
the preparation of the chloro-3-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2b) and the chloro-5-of 2,4-bis-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2e)
The same embodiment of operating process
16, just reaction solvent ether to be replaced with acetic acid, bromine is used
n-chlorosuccinimide is replaced, and obtains respectively the chloro-3-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 60.0%, HR-TOFMS (+Q)
m/z: 273.0890) and the chloro-5-of 2,4-bis-(2,2-diethoxy oxyethyl group) phenyl aldehyde (yield 28.0%, HR-TOFMS (+Q)
m/z: 307.0506).
embodiment 19
the preparation of the iodo-5-of the bromo-2-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (2q)
The same embodiment of operating process
16, just by 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) the use iodo-5-of 2-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2k) replace, reaction solvent ether is replaced with chloroform, and bromine is replaced with pyridine hydrobromide perbromide, obtains the iodo-5-of the bromo-2-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde, yield 88.0%, HR-TOFMS (+Q)
m/z: 442.9359.
embodiment 20
3-[3-(2,2-diethoxy oxyethyl group) phenyl] preparation of 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 dehydrated alcohol 100 ml, stirring at room is reacted 48 h, after reaction finishes, removes solvent under reduced pressure, brown oily liquids, this be intermediate (
4a) crude product, without purifying, can be used for the next step.Gained intermediate (
4a) crude product and dehydrated alcohol 50 ml, sodium hydroxide 13.2 g(0.33mol) and deionized water 20 ml mix, 70 ℃ of stirring reaction 3 h, reaction finish after, remove ethanol under reduced pressure, residual solution is neutralized to strongly-acid with 10% hydrochloric acid, and ethyl acetate 2 ' 50 ml extract, and organic layer is through anhydrous Na
2sO
4dry, filter, remove solvent under reduced pressure, obtain 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid 14.6 g, yield 75.5 %, HR-TOFMS (Q)
m/z: 339.1438 ([C
17h
24o
7-H]
-calculated value: 339.1444).
embodiment 21
the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] preparation of pentanedioic acid (Ib)
Operating process is with embodiment 20, just by 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) the use chloro-3-of 4-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2b) substitute, methyl aceto acetate substitutes with methyl acetoacetate, and piperidines substitutes by piperidines and the pyridine mixtures of 1:1 volume ratio, obtains the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid, yield 72.9 %, HR-TOFMS (Q)
m/z: 373.1052 ([C
17h
23clO
7-H]
-calculated value: 373.1054).
embodiment 22～36 3-[3-(2-oxygen oxyethyl group) phenyl] preparation of pentanedioic acid compounds (Ic ~ Iq)
Operating process is with embodiment 20, just by 3-(2,2-diethoxy oxyethyl group) phenyl aldehyde (
2a) use respective compound (
2c ~ 2q) replace, obtain 3-[3-(2-oxygen oxyethyl group) phenyl] pentanedioic acid compounds (
ic ~ Iq), its chemical structure is as follows:
embodiment 37
the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ig) and 3-[2, the bromo-5-of 4-bis-(2,2-diethoxy oxyethyl group) phenyl] preparation of pentanedioic acid (Ih)
By 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ia) 3.40 g(0.01 mol) be dissolved in ether 80 ml, be cooled to-10 ℃, drip bromine 0.013 mol, then be naturally warming up to stirring at room and react 12 h, after reaction finishes, reaction solution is successively with 5% sodium thiosulfate solution 25 ml, deionized water 25 ml, the 25 ml washings of the saturated NaCl aqueous solution, and organic layer is through anhydrous Na
2sO
4dry, filter, remove solvent under reduced pressure, resistates is through column chromatography purification (elutriant: ethyl acetate/methanol=12:1 (v/v)), obtain respectively the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 71.0%, HR-TOFMS (+Q)
m/z: 417.0550) and 3-[2, the bromo-5-of 4-bis-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 18.0%, HR-TOFMS (+Q)
m/z: 494.9647).
embodiment 38
the chloro-5-of the bromo-2-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] preparation of pentanedioic acid (Ip)
The same embodiment of operating process
37, just by 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ia) the use chloro-5-of 3-[2-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
io) replace, reaction solvent ether is replaced with acetic acid, and bromine is used
n-bromo-succinimide is replaced, and obtains the chloro-5-of the bromo-2-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ip), yield 90.0%, HR-TOFMS (+Q)
m/z: 451.0158.
embodiment 39
the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (Ib) and 3-[2, the chloro-5-of 4-bis-(2,2-diethoxy oxyethyl group) phenyl] preparation of pentanedioic acid (Ie)
The same embodiment of operating process
37, just reaction solvent ether to be replaced with acetic acid, bromine is used
n-chlorosuccinimide is replaced, and obtains respectively the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 65.0%, HR-TOFMS (+Q)
m/z: 373.1052) and 3-[2, the chloro-5-of 4-bis-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (yield 23.0%, HR-TOFMS (+Q)
m/z: 407.0665).
embodiment 40
the iodo-5-of the chloro-2-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] preparation of pentanedioic acid (Iq)
The same embodiment of operating process
37, just by 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ia) the use iodo-5-of 3-[2-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ik) replace, reaction solvent ether is replaced with chloroform, and bromine is replaced with pyridine hydrobromide perbromide, obtains the iodo-5-of the chloro-2-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid, yield 85.0%, HR-TOFMS (+Q)
m/z: 542.9508.
embodiment 41
2-(the chloro-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IIb)
By the chloro-3-of 3-[4-(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 reaction flask, 60 ℃ of insulated and stirred are reacted 5.0 h, after reaction finishes, add frozen water 50 ml, after stirring, separate organic layer, with deionized water 50 ml, the 50 ml washings of the saturated NaCl aqueous solution, organic layer is through anhydrous Na successively
2sO
4dry, filter, remove solvent under reduced pressure, resistates ethyl acetate/hexane recrystallization, obtains 2-(the chloro-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) yellow solid 2.1 g of acetic acid, 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 acetic acid (IIa)
Operate same embodiment
41, just by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) use 3-[3-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ia) substitute, in reaction, without organic solvent, reaction finishes rear by ether extraction, and gained crude product, through column chromatography purification (elutriant: ethyl acetate/petroleum ether=10:1 (v/v)), obtains 2-(6-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) yellow solid of acetic acid, 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 acetic acid (IIa)
Operate same embodiment
41, just by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) use 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 gained crude product, through column chromatography purification (elutriant: ethyl acetate/petroleum ether=10:1 (v/v)), obtains 2-(6-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) yellow solid of acetic acid, yield 15.0 %; HR-TOFMS (Q)
m/z: 229.0495 ([C
13h
10o
4-H]
-calculated value: 229.0501).
embodiment 44
2-(the bromo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IIc)
In reaction flask, add methanesulfonic 30 g and Vanadium Pentoxide in FLAKES 3.0 g, stirring at room 2 h, add the bromo-3-of 3-[4-(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 extractions, merge organic layer, with deionized water 50 ml, the 50 ml washings of the saturated NaCl aqueous solution, organic layer is through anhydrous Na successively
2sO
4dry, filter, remove solvent under reduced pressure, resistates ethyl acetate/hexane recrystallization, obtains 2-(the bromo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) yellow solid of acetic acid, yield 75.0 %; HR-TOFMS (Q)
m/z: 306.9601 ([C
13h
9brO
4-H]
-calculated value: 306.9606).
embodiment 45
2-(the chloro-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IIb)
Operate same embodiment
41, just by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) the chloro-3-[(5 of use 3-[4-, 5-dimethyl-1,3-diox-2-yl) phenyl] pentanedioic acid (
id) substitute, 1,2-ethylene dichloride substitutes with benzene, obtains 2-(the chloro-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) yellow solid of acetic acid, yield 82.8 %; HR-TOFMS (Q)
m/z: 263.0105 ([C
13h
9clO
4-H]
-calculated value: 263.0111).
embodiment 46
2-(the bromo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IIc)
Operate same embodiment
41, just by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) the bromo-3-[(5 of use 3-[4-, 5-dimethyl-1,3-diox-2-yl) phenyl] pentanedioic acid (
ii) substitute, 1,2-ethylene dichloride substitutes with toluene, obtains 2-(the bromo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) acetic acid, yield 77.3 %; HR-TOFMS (Q)
m/z: 306.9607 ([C
13h
9brO
4-H]
-calculated value: 306.9606).
embodiment 47
2-(the iodo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IId)
Operate same embodiment
44, just by the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ig) the use iodo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
im) substitute, obtain 2-(the iodo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) acetic acid, yield 70.0 %; HR-TOFMS (Q)
m/z: 354.9464 ([C
13h
9iO
4-H]
-calculated value: 354.9467).
embodiment 48
2-(the iodo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IId)
Operate same embodiment
44, just by the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ig) the iodo-3-[(5 of use 3-[4-, 5-dimethyl-1,3-diox-2-yl) phenyl] pentanedioic acid (
in) substitute, obtain 2-(the iodo-6-of 4-oxygen-7,8-dihydro-6
h-indeno [5,4-b] furans-8-yl) acetic acid, 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 by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) use 3-[2, the chloro-5-of 4-bis-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ie) substitute, 1,2-ethylene dichloride substitutes with benzene, obtains 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 by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) use 3-[5-(1,3-dioxolane-2-yl) methoxyl group]-2,4 dichloro benzene base] pentanedioic acid (
if) substitute, 1,2-ethylene dichloride substitutes with benzene, and polyphosphoric acid substitutes with the vitriol oil, and temperature of reaction is room temperature, obtains 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 by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) use 3-[2, the bromo-5-of 4-bis-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ih) substitute, 1,2-ethylene dichloride substitutes with benzene, obtains 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 by the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ig) use 3-[2, the bromo-5-[(5 of 4-bis-, 5-dimethyl-1,3-diox-2-yl) phenyl] pentanedioic acid (
ij) substitute, obtain 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-(the chloro-7-bromine cumarone-4-of 4-yl) pentanedioic acid (5c)
Operate same embodiment
44, just by the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ig) the use bromo-5-of the chloro-4-of 3-[2-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ip) substitute, obtain 3-(the chloro-7-bromine cumarone-4-of 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-(the iodo-7-bromine cumarone-4-of 4-yl) pentanedioic acid (5d)
Operate same embodiment
44, just by the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ig) the use bromo-5-of the iodo-4-of 3-[2-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
iq) substitute, obtain 3-(the iodo-7-bromine cumarone-4-of 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 reactor, add 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) 3.16 g(0.01 mol), ethanol 50 ml, acetic acid 20 ml, anhydrous sodium acetate 0.02 mol, stirring at room to solid complete molten after, add 10%Pd-C 1.0 g, reactor is with after hydrogen exchange three times, in 50 ℃, 1.0 * 10
6under Pa pressure, insulated and stirred reaction is 15 hours; After reaction finishes, be cooled to room temperature, filter, a small amount of washing with alcohol filter cake, filtrate and washing lotion remove solvent under reduced pressure after merging, and obtain 3-(2,3-Dihydrobenzofuranes-4-yl) white, needle-shaped crystals 2.45 g of 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 by 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) use 3-(5,7-dibromo cumarone-4-yl) pentanedioic acid (
5b) substitute reaction solvent acetic acid, 10% Pd for 10%Pd-C (OH)
2-C substitutes, and obtains 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
55unanimously.
embodiment 57
the preparation of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (6)
Operate same embodiment
55, just by 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) use 3-(the chloro-7-bromine cumarone-4-of 4-yl) pentanedioic acid (
5c) substitute reaction solvent ethanol, 10% Pd for 10%Pd-C (OH)
2-C substitutes, and obtains 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
55unanimously.
embodiment 58
the preparation of 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (6)
Operate same embodiment
55, just by 3-(5,7-dichloro cumarone-4-yl) pentanedioic acid (
5a) use 3-(the iodo-7-bromine cumarone-4-of 4-yl) pentanedioic acid (
5d) substitute reaction solvent ethanol, 10% Pd for 10%Pd-C (OH)
2-C substitutes, and obtains 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
55unanimously.
embodiment 59
2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
h-indeno [5,4-b] furans-8-yl) preparation of acetic acid (IIe)
Operate same embodiment
41, just by the chloro-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ib) use 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) substitute, 1,2-ethylene dichloride substitutes with benzene, obtains 2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
h-indeno [5,4-b] furans-8-yl) the yellow needle-like solid of acetic acid, 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 acetic acid (IIe)
Operate same embodiment
44, just by the bromo-3-of 3-[4-(2,2-diethoxy oxyethyl group) phenyl] pentanedioic acid (
ig) use 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) substitute, obtain 2-(6-oxygen-2,6,7,8-tetrahydrochysene-1
h-indeno [5,4-b] furans-8-yl) the yellow needle-like solid of acetic acid, mp:180 ~ 182 ℃, yield 80.0 %.
1h NMR data and embodiment
59unanimously.
Claims (9)
1. a class 3-phenyl pentanedioic acid compounds, is characterized in that it is to have chemical structure of general formula
(I)shown compound:
In formula: R
1, R
2represent independently of one another H, Cl, Br, I; R
1, R
2can be identical, also can be different; R
3represent CH (OR
4oR
5), R
4, R
5represent C
1-12alkyl, or R
4with R
5be connected to form ring-type.
As claimed in claim 1 3-phenyl pentanedioic acid compounds (
i) preparation method, it is characterized in that comprising the steps:
a)with 3-hydroxy benzaldehyde compound (
1) be starting raw material, under organic solvent and alkaline condition with the condensation of 2-halogen acetal, obtain 3-(2-oxygen oxyethyl group) compound of benzaldehyde category (
2);
Each substituent definition and chemical structure of general formula in formula (
i) identical;
b)by step
a)the 3-obtaining (2-oxygen oxyethyl group) compound of benzaldehyde category (
2) under organic solvent and alkaline condition with acetylacetic ester (
3) after Knoevenagel condensation, Michael addition reaction, generation intermediate (
4), then hydrolysis, acid neutralization under alkaline condition, obtain 3-phenyl pentanedioic acid compounds (
i),
Each substituent definition and chemical structure of general formula in formula (
i) identical; R
6represent C
1-8alkyl;
Also can by following steps prepare 3-phenyl pentanedioic acid compounds (
i):
c)by step
a)the 3-obtaining (2-oxygen oxyethyl group) compound of benzaldehyde category (
2) in, work as R
1during=H, this compounds can be under suitable solvent and halogenating agent condition, by the ortho position halo of phenolic hydroxyl group, obtain 3-(2-oxygen oxyethyl group) compound of benzaldehyde category (
2 '), gained (
2 ') again according to step
b)can obtain 3-phenyl pentanedioic acid compounds (
i);
In formula: R
2represent H, Cl, Br, I; R
3represent CH (OR
4oR
5), R
4, R
5represent C
1-12alkyl, or R
4with R
5be connected to form ring-type; X represents 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 obtaining (
i) in, work as R
1during=H, this compounds can be under suitable solvent and halogenating agent condition, by the ortho position halo of phenolic hydroxyl group, obtain 3-phenyl pentanedioic acid compounds (
i ');
In formula: R
2represent H, Cl, Br, I; R
3represent CH (OR
4oR
5), R
4, R
5represent C
1-12alkyl, or R
4with R
5be connected to form ring-type; X represents Cl, Br, I.
3-phenyl pentanedioic acid compounds as claimed in claim 2 (
i) preparation method, it is characterized in that:
Described step
a)in, reaction solvent is: C
1-6fatty alcohol, C
3-8aliphatic ketone,
n,N-dimethyl formamide,
n-methyl-2-pyrrolidone, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C
1-6lipid acid and C
1-6the formed ester of fatty alcohol, methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene, benzene, toluene, chlorobenzene or acetonitrile; Reacting alkali used 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 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 or C
1-12the acetal that glycol forms; 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;
Described step
b)in, condensation reaction solvent is: C
1-6fatty alcohol, C
3-8aliphatic ketone,
n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, C
1-6lipid acid and C
1-6the formed ester of fatty alcohol, methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, benzene, toluene or acetonitrile; Condensation reaction alkali used is: piperidines, Pyrrolidine, alpha-amino group acids, triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl-α-phenylethylamine,
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) compound of benzaldehyde category (
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 hour ~ 7 days; Intermediate (
4) be hydrolyzed alkali used and be: basic metal or alkaline earth metal hydroxides; Hydrolysis reaction solvent is: water, C
1-6fatty alcohol or water and C
1-6the solvent that fatty alcohol arbitrary proportion mixes; Hydrolysising reacting temperature is 10 ℃ ~ 150 ℃; Hydrolysis time is 10 minutes ~ 24 hours.
3-phenyl pentanedioic acid compounds as claimed in claim 2 (
i) preparation method, it is characterized in that: described step
c)in, halogenating reaction solvent for use is: water, C
1-6fatty alcohol, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (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 as claimed in claim 2 (
i) preparation method, it is characterized in that: described step
d)in, halogenating reaction solvent for use is: water, C
1-6fatty alcohol, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol forms, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, orthodichlorobenzene, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (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.
6. utilize 3-phenyl pentanedioic acid compounds as claimed in claim 1 (
i) prepare pharmaceutical intermediate 1-indone-3-phenylacetic acid compound (
iI) method, it is characterized in that comprising the steps:
，
In formula: R
1represent H, Cl, Br, I; X
1-X
2represent CH
2cH
2or HC=CH;
e)3-phenyl pentanedioic acid compounds (
i) in, work as R
1for H, Cl, Br, I; R
2during for H, this compounds in solvent-free or organic solvent through acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
iI);
f)3-phenyl pentanedioic acid compounds (
i) in, work as R
1for H, Cl, Br, I; R
2during for Cl, Br, I, this compounds in solvent-free or organic solvent through acidylate cyclization, generate 3-(cumarone-4-yl) pentanedioic acid compounds (
5);
In formula: R
1represent H, Cl, Br, I; R
2represent Cl, Br, I;
g)by step
f)the 3-obtaining (cumarone-4-yl) pentanedioic acid compounds (
5), in organic solvent, through catalytic hydrogenation, furan nucleus is reduced to dihydrofuran ring, remove halogen atom simultaneously, obtain 3-(2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6);
h)by step
g)the 3-obtaining (2,3-Dihydrobenzofuranes-4-yl) pentanedioic acid (
6) in solvent-free or organic solvent through acidylate cyclization, generate 1-indone-3-phenylacetic acid compound (
iI).
1-indone-3-phenylacetic acid compound as claimed in claim 6 (
iI) preparation method, it is characterized in that,
Described step
e)in, reaction solvent for use is: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, hexane, heptane, octane, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), ethyl acetate, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; Acidylate cyclization cyclizing agent used 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; Ring-closure reaction temperature is-20 ℃ ~ 150 ℃; Reaction times is 30 minutes ~ 48 hours;
Described step
f)in, reaction solvent for use is: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, hexane, heptane, octane, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), ethyl acetate, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; Acidylate cyclization cyclizing agent used 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; Ring-closure reaction temperature is-20 ℃ ~ 150 ℃; Reaction times is 30 minutes ~ 48 hours;
Described step
g)in, hydrogenation solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol forms, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (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 mixed solvent volume ratio is 1:0.1 ~ 10; Catalytic hydrogenation used catalyst 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;
Described step
h)in, reaction solvent for use is: methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, orthodichlorobenzene, hexane, heptane, octane, benzene, toluene, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), ethyl acetate, dithiocarbonic anhydride, Nitromethane 99Min., oil of mirbane, sherwood oil or methanesulfonic; Acidylate cyclization cyclizing agent used 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; Ring-closure reaction temperature is-20 ℃ ~ 150 ℃; Reaction times is 30 minutes ~ 48 hours.
8. a class 3-(2-oxygen oxyethyl group) compound of benzaldehyde category, is characterized in that it is to have chemical structure of general formula
(2)shown compound:
In formula: R
1, R
2represent independently of one another H, Cl, Br, I; R
1, R
2can be identical, also can be different; R
3represent CH (OR
4oR
5), R
4, R
5represent C
1-12alkyl, or R
4with R
5be connected to form ring-type.
As described in claim 1 or 8 any compound preparation 1-indone-3-phenylacetic acid compound (
iI) in application,
In formula: R
1represent H, Cl, Br, I; X
1-X
2represent CH
2cH
2or HC=CH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110258499.2A CN102381961B (en) | 2011-09-03 | 2011-09-03 | 3-phenyl glutaric acid compound, preparation method and purpose thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110258499.2A CN102381961B (en) | 2011-09-03 | 2011-09-03 | 3-phenyl glutaric acid compound, preparation method and purpose thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102381961A CN102381961A (en) | 2012-03-21 |
| CN102381961B true CN102381961B (en) | 2014-01-15 |
Family
ID=45821857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110258499.2A Expired - Fee Related CN102381961B (en) | 2011-09-03 | 2011-09-03 | 3-phenyl glutaric acid compound, preparation method and purpose thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102381961B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964263B (en) * | 2012-11-29 | 2014-12-03 | 太仓市茜泾化工有限公司 | Process for preparing (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid |
| CN108821966B (en) * | 2018-06-04 | 2021-08-24 | 江苏理工学院 | Method for synthesizing 3,3' - (1,4-phenylene) bis-glutaric acid |
| CN113061084B (en) * | 2020-12-31 | 2024-01-12 | 成都亨达药业有限公司 | Novel method for preparing ferulic acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3703529A (en) * | 1969-03-31 | 1972-11-21 | Wyeth John & Brother Ltd | Nitrogen-containing tricyclic compounds |
| GB1351754A (en) * | 1970-07-02 | 1974-05-01 | Allen & Hanburys Ltd | Indenopyrrole derivatives |
| US4259338A (en) * | 1978-06-22 | 1981-03-31 | Ciba-Geigy Corporation | Benzofuranyl-tetrahydropyridines and -piperidines, their acid addition salts and antidepressant preparations thereof |
| CN101993426A (en) * | 2009-08-31 | 2011-03-30 | 四川大学 | 3-aryl glutaric acid mono-amide compound as well as preparation method and application thereof |
| CN102070576A (en) * | 2011-01-12 | 2011-05-25 | 四川大学 | 1-indanone-3-acetic acid compound as well as preparation method and application of 1-indanone-3-acetic acid compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2507699A1 (en) * | 2002-12-20 | 2004-07-15 | Pharmacia Corporation | Heteroarylalkanoic acids as integrin receptor antagonists |
-
2011
- 2011-09-03 CN CN201110258499.2A patent/CN102381961B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3703529A (en) * | 1969-03-31 | 1972-11-21 | Wyeth John & Brother Ltd | Nitrogen-containing tricyclic compounds |
| GB1351754A (en) * | 1970-07-02 | 1974-05-01 | Allen & Hanburys Ltd | Indenopyrrole derivatives |
| US4259338A (en) * | 1978-06-22 | 1981-03-31 | Ciba-Geigy Corporation | Benzofuranyl-tetrahydropyridines and -piperidines, their acid addition salts and antidepressant preparations thereof |
| CN101993426A (en) * | 2009-08-31 | 2011-03-30 | 四川大学 | 3-aryl glutaric acid mono-amide compound as well as preparation method and application thereof |
| CN102070576A (en) * | 2011-01-12 | 2011-05-25 | 四川大学 | 1-indanone-3-acetic acid compound as well as preparation method and application of 1-indanone-3-acetic acid compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102381961A (en) | 2012-03-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101993407A (en) | Indoline compound for preparing silodosin and preparation method thereof | |
| CN102381961B (en) | 3-phenyl glutaric acid compound, preparation method and purpose thereof | |
| US20120029179A1 (en) | Process for the synthesis of cleistanthin | |
| CN104230853A (en) | Preparation method of (p-methylphenyl) methylamine-N-morpholinoethyl hydrochloride | |
| CN109896943A (en) | A kind of chemical preparation process of cajanin and its analogue | |
| CN102070576A (en) | 1-indanone-3-acetic acid compound as well as preparation method and application of 1-indanone-3-acetic acid compound | |
| CN101967096B (en) | 3-[4-(alkoxy) phenyl] propionate compound and preparation method and application thereof | |
| Meshram et al. | Bismuthtriflate-catalyzed Reaction of N-Alkylisatins with Allyltrimethylsilane | |
| CN102491953A (en) | Method for synthesizing florfenicol midbody RT0131 | |
| CN100436441C (en) | Method for preparing 3-formacyl chromone derivative | |
| CN103360352B (en) | Total synthesis method for 4-methoxy-2,6-dihydroxy-2-benzyl-3(2H)-benzofuranone | |
| CN103435490B (en) | Synthesis method for 2,2,4,4,6,6-hexanitro-adamantane | |
| CN102627563B (en) | Phthalic acid compound, its preparation method and application | |
| CN101648931B (en) | Method for preparing 3-(2,3-dihydrobenzfuran-5-radical)-metacetonic acid | |
| CN103420962B (en) | 3-aryl glutaric acid monoester class compound, Preparation Method And The Use | |
| CN113173908A (en) | Preparation method of thiophene compound | |
| CN102358733B (en) | 2-(1-oxy-1H-indene-3-radical) acetic acid compound and preparation method and application thereof | |
| CN102408337B (en) | (E)-3-[4-(alkoxy)phenyl]acrylate compounds and preparation method and applications thereof | |
| CN101397278B (en) | Method for synthesizing 3-aryl-5-alkenyl oxazoline-2-one | |
| CN108290877A (en) | The method for preparing thiophene -2- formyl chlorides with oxalyl chloride | |
| CN102020615B (en) | Morpholone derivative and preparation method thereof | |
| CN102070427B (en) | Synthesis methods of flocumafen and flocumafen intermediate | |
| Shah | Phase Transfer Catalysis Assisted Thorpe Reaction for the Synthesis of 3‐Aminothiophene‐2‐carboxylates | |
| CN102838609B (en) | Azabicyclo [3.3.0] octane derivative, as well as preparation method and application thereof | |
| CN101657411B (en) | Preparation methods of 4-acetyl-2,3,4,5-tetrahydro- benzo[1,4]diazepine and their intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140115 Termination date: 20170903 |