CN101417947A - Method for preparing alkoxyl benzoic acids compounds - Google Patents
Method for preparing alkoxyl benzoic acids compounds Download PDFInfo
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- CN101417947A CN101417947A CNA200810162638XA CN200810162638A CN101417947A CN 101417947 A CN101417947 A CN 101417947A CN A200810162638X A CNA200810162638X A CN A200810162638XA CN 200810162638 A CN200810162638 A CN 200810162638A CN 101417947 A CN101417947 A CN 101417947A
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- China
- Prior art keywords
- phenol
- alkyloyl
- derivative
- methyl
- benzoic acids
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- -1 alkoxyl benzoic acids compounds Chemical class 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000000460 chlorine Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000002841 Lewis acid Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005618 Fries rearrangement reaction Methods 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000012022 methylating agents Substances 0.000 claims abstract description 3
- 150000002989 phenols Chemical class 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 230000001035 methylating effect Effects 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical group [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 238000006266 etherification reaction Methods 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- SATVIFGJTRRDQU-UHFFFAOYSA-N potassium hypochlorite Chemical compound [K+].Cl[O-] SATVIFGJTRRDQU-UHFFFAOYSA-N 0.000 claims description 2
- ORQYPOUSZINNCB-UHFFFAOYSA-N potassium;hypobromite Chemical compound [K+].Br[O-] ORQYPOUSZINNCB-UHFFFAOYSA-N 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- 235000010233 benzoic acid Nutrition 0.000 abstract 2
- 230000010933 acylation Effects 0.000 abstract 1
- 150000008064 anhydrides Chemical class 0.000 abstract 1
- 229940027987 antiseptic and disinfectant phenol and derivative Drugs 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 239000006184 cosolvent Substances 0.000 abstract 1
- 238000011112 process operation Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 230000002194 synthesizing effect Effects 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- IBCQUQXCTOPJOD-UHFFFAOYSA-N 3-chloro-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1Cl IBCQUQXCTOPJOD-UHFFFAOYSA-N 0.000 description 6
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 6
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 6
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 4
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 4
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 4
- ABXFXDSGHDZAEV-UHFFFAOYSA-N OC1=C(C(=O)C=NO)C=C(C=C1)C Chemical compound OC1=C(C(=O)C=NO)C=C(C=C1)C ABXFXDSGHDZAEV-UHFFFAOYSA-N 0.000 description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 4
- 229940090668 parachlorophenol Drugs 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- SRTOCDALRUBACC-UHFFFAOYSA-N 1-(3-chloro-4-hydroxyphenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(O)C(Cl)=C1 SRTOCDALRUBACC-UHFFFAOYSA-N 0.000 description 3
- YVAACGXAZGGQSM-UHFFFAOYSA-N 2,2-dimethylpropaneperoxoic acid Chemical compound CC(C)(C)C(=O)OO YVAACGXAZGGQSM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 3
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000010813 municipal solid waste Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- 150000005224 alkoxybenzenes Chemical class 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- QILWOKAXHOAFOF-UHFFFAOYSA-N 1-(3-chloro-4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(C)=O)C=C1Cl QILWOKAXHOAFOF-UHFFFAOYSA-N 0.000 description 1
- DNMUMZLKDOZMEY-UHFFFAOYSA-N 4-methoxy-3-methylbenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1C DNMUMZLKDOZMEY-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of alkoxy benzoic acids, which comprises the following steps in sequence: phenol, or phenol derivatives with the ortho position or the para position as methyl or chlorine is used as the raw material; at first, correspondent phenolic ester and derivatives are prepared after single anhydride acylation; in a solvent or a cosolvent, the phenolic ester and derivatives performs Fries rearrangement reaction under the catalysis of Lewis acid to prepare 2- acyl alkyl phenol, 4-acyl alkyl phenol and derivatives; then in the presence of alkali, acyl alkyl phenol is etherified by a methylating agent, and 2-n-acyl-phenyl methyl ether, 4-n-acyl-phenyl methyl ether and derivatives are obtained; finally, in the presence of hypohalous acid salt, 2-n-acyl-phenyl methyl ether, 4-n-acyl-phenyl methyl ether and derivatives are oxidized to alkoxy benzoic acids. The preparation method has the advantages of simple process operation, easy control of reaction conditions, easy acquirement of raw materials, high yield and low manufacture cost.
Description
Technical field
The present invention relates to the preparation method of alkoxyl benzoic acids compounds.
Background technology
The important chemical intermediate that fields such as alkoxyl benzoic acids compounds is a plants antimicrobial, and medicine is synthetic, and dyestuff is synthetic, and agricultural chemicals is synthetic are widely used.
The main preparation methods of existing alkoxyl benzoic acids compounds has three kinds: (J.Organomet.Chem.1973 is that the halogeno-benzene methyl ether is a raw material 51:381) to method one, is catalyzer with the transition metal, carries out carbonyl with carbon monoxide and makes; Method two (T.L2008,49,15, be to be raw material 2457-2460) with alkoxy benzene methyl alcohol, with the cuprous chloride catalyzer, make with the t-butyl peroxy formic acid oxidation; Method three (T.L.2008,49,6, be to be raw material 1083-1086) with alkoxy benzene formaldehyde, use cuprous salt to be catalyzer equally, make with the t-butyl peroxy formic acid oxidation.
Method one uses transition metal to be catalyzer, reacts with carbon monoxide, needs High Temperature High Pressure, the equipment requirements height, and also catalyzer costs an arm and a leg; Method two and method three not only raw material are difficult to obtain, and all need use expensive t-butyl peroxy formic acid as oxygenant, are unfavorable for suitability for industrialized production.
Summary of the invention
The method for preparing alkoxyl benzoic acids compounds that the purpose of this invention is to provide a kind of high yield, simple to operate and constant product quality.
The preparation method of alkoxyl benzoic acids compounds of the present invention in turn includes the following steps:
The first step is that the phenol derivatives of methyl or chlorine is a raw material with phenol or ortho position, contraposition, with be solvent be again that the single acid anhydrides of reaction reagent under refluxad carries out acylation reaction, make corresponding phenol ester and derivative thereof, phenol or ortho position, contraposition are that the phenol of methyl or chlorine and the mol ratio of single acid anhydrides are 1:2～6;
The second step phenol ester and derivative thereof are in solvent or solubility promoter; under the Lewis acid catalysis; carry out the Fries rearrangement reaction make the neighbour, to alkyloyl phenol derivmives blend biology; the weight ratio of used phenol ester and derivative thereof and solvent for use is 1:4～10; the weight ratio of used phenol ester and derivative thereof and used solubility promoter is 1:5～10, and used Lewis acid is 1:1.2～4 with the mol ratio of phenol ester and derivative thereof.
The 3rd step is adjacent, to alkyloyl phenol derivmives blend biology in the presence of alkali; by methylating reagent phenolic hydroxyl group is carried out methyl-etherified; make the neighbour, to alkyloyl phenyl methyl ether and derivative thereof; used neighbour, mol ratio biological to the alkyloyl phenol derivmives blend and alkali are: 1:1.5～5, used neighbour, mol ratio biological to the alkyloyl phenol derivmives blend and methylating reagent are: 1:1.5～5.
The 4th step is adjacent, to alkyloyl phenyl methyl ether and derivative thereof in the presence of hypohalite, be oxidized to alkoxyl benzoic acids compounds, the neighbour, be: 1:2～6 to the mol ratio of alkyloyl phenyl methyl ether and derivative and hypohalous acid sodium.
Concrete synthetic route is as follows:
The R of the compound in the said synthesis route
1, R
2, R
3Represent following group respectively:
1) works as R
1During=H; R
2=CH
3Or Cl; R
3=CH
3, CH
3CH
2Or CH
3CH
2CH
2
2) work as R
1=CH
3Or during Cl; R
2=H; R
3=CH
3, CH
3CH
2Or CH
3CH
2CH
2
The used single acid anhydrides of the first step acylation reaction be solvent be again reaction reagent, can adopt diacetyl oxide, propionic anhydride or butyryl oxide.
The used solvent of the second step Fries rearrangement reaction can be oil of mirbane or dithiocarbonic anhydride, and used solubility promoter can be sodium-chlor or Repone K, and used Lewis acid can be iron trichloride, aluminum chloride or zinc chloride.
The used alkali of the 3rd step etherification reaction can be sodium hydroxide or potassium hydroxide, and used methylating agent can be methyl iodide or methyl-sulfate.
The used hypohalous acid sodium of the 4th step oxidizing reaction can be clorox, potassium hypochlorite, sodium hypobromite or potassium hypobromite.
The method technological operation for preparing alkoxyl benzoic acids compounds of the present invention is simple, and reaction conditions is easy to control, and raw material is easy to get, yield height, low cost of manufacture.
Embodiment
Embodiment 1
Synthesizing of the first step phenol acetic ester
28.2g (0.3mol) phenol is added in 170mL (1.8mol) diacetyl oxide, stirs and slowly be heated to backflow down, reaction 3h, TLC analyzes and determines reaction end, after reaction finishes, steams the acetate that removes excessive acetic anhydride via and generation, reduce to room temperature, slowly add the saturated NaHCO of 100ml
3Solution is used CH
2Cl
2Organic phase is told in (100ml * 2) extraction, uses anhydrous Na
2SO
4Drying, suction filtration, concentrate phenol acetic ester 39.1g, yield 95.8% need not to make with extra care, and is directly used in the next step.
Synthesizing of the second step parahydroxyacet-ophenone
Phenol acetic ester 20.4g (0.15mol) adds the anhydrous AlCl of 50g (0.375mol) with 204g dithiocarbonic anhydride in batches under vigorous stirring
3, keep reacting liquid temperature to be no more than 20 ℃ in the reinforced process, finish, stirring reaction 11～12h at room temperature, vapor detection is determined reaction end, reaction finishes reactant is poured in 300g trash ice+30ml concentrated hydrochloric acid mixture, tells organic phase, water CH
2Cl
2Extraction (100ml * 2) merges organic phase, adds the sodium hydroxide solution vigorous stirring of 30ml 20%, separatory is got organic phase and is repeated aforesaid operations 2 times, merges water, under water-bath, add concentrated hydrochloric acid to pH=1, the ice bath cooling is separated out white needle-like crystals, suction filtration, oven dry, get parahydroxyacet-ophenone 15.3g, yield 75%, content 97.5% (HPLC), m.p.109～110 ℃.
Synthesizing of the 3rd step p-methoxy-acetophenone
Parahydroxyacet-ophenone 13.6g (0.1mol) dissolves with 20% KOH solution 140ml (0.5mol), stirs, and slowly drips methyl-sulfate (0.5mol), be warming up to 40 ℃ after dropwising, reaction 1h, TLC analyze and determine reaction end, reaction finishes, and reduces to room temperature, suction filtration, filter cake is washed twice with 5%NaOH, again with the saturated common salt washing once, drying gets p-methoxy-acetophenone 13.2g, yield 88% can be directly used in the next step.
Synthesizing of the 4th step anisic acid
NaBrO (0.15mol) solution of p-methoxy-acetophenone 7.5g (0.05mol) and 162ml10% is mixed and heated to 80 ℃, backflow stirring reaction 8h, reaction process reaction solution pH〉10, react to the organic phase disappearance, be cooled to room temperature, use CH
2Cl
2Extraction (100ml * 2), water is acidified to pH＜3 with 36% concentrated hydrochloric acid.Ice bath spends the night, and separates out needle-like crystal, filters, and recrystallization gets the 7g anisic acid, yield 92.1%, content 99.0% (HPLC), m.p.187～188 ℃.
Embodiment 2
Synthesizing of the first step ortho-methyl phenol acetic ester
27g (0.25mol) ortho-cresol is added in 118mL (1.25mol) diacetyl oxide, stirs and slowly be heated to backflow down, reaction 3h, TLC analyzes and determines reaction end, after reaction finishes, steams the acetate that removes excessive acetic anhydride via and generation, reduce to room temperature, slowly add the saturated NaHCO of 100ml
3Solution is used CH
2Cl
2Organic phase is told in (100ml * 2) extraction, uses anhydrous Na
2SO
4Drying, suction filtration, concentrate ortho-methyl phenol acetic ester 35.8g, yield 95.5% need not to make with extra care, and is directly used in the next step.Synthesizing of second step 3-methyl-4-hydroxy acetophenone
Ortho-methyl phenol phenol acetic ester 30g (0.2mol) adds the anhydrous AlCl of 48g (0.36mol) with 210g dithiocarbonic anhydride in batches under vigorous stirring
3, keep reacting liquid temperature to be no more than 20 ℃ in the reinforced process, finish, stirring reaction 11～12h at room temperature, vapor detection is determined reaction end, reaction finishes reactant is poured in 320g trash ice+35ml concentrated hydrochloric acid mixture, tells organic phase, water CH
2Cl
2Extraction (100ml * 2) merges organic phase, adds the sodium hydroxide solution vigorous stirring of 30ml 20%, separatory is got organic phase and is repeated aforesaid operations 2 times, merges water, under water-bath, add concentrated hydrochloric acid to pH=1, the ice bath cooling is separated out white needle-like crystals, suction filtration, oven dry, get 3-methyl-4-hydroxy acetophenone 21.7g, yield 72.3%, content 98.3% (HPLC), m.p.107～109 ℃.
Synthesizing of the 3rd step 3-methyl-4-methoxyacetophenone
3-methyl-4-hydroxy acetophenone 22.5g (0.15mol) dissolves with 20% NaOH solution 120ml (0.6mol), stirs, and slowly drips methyl-sulfate (0.6mol), be warming up to 35～40 ℃ after dropwising, reaction 1h, TLC analyze and determine reaction end, reaction finishes, and reduces to room temperature, suction filtration, filter cake is washed twice with 5%NaOH, again with the saturated common salt washing once, drying gets 3-methyl-4-methoxyacetophenone 19.2g, yield 85.3% is directly used in the next step.
Synthesizing of the 4th step 3-methyl-4-methoxybenzoic acid
KBrO (0.2mol) solution of 3-methyl-4-methoxyacetophenone 16.4g (0.1mol) and 245ml 10% is mixed and heated to 80 ℃, backflow stirring reaction 8h, reaction process reaction solution pH〉10, react to the organic phase disappearance, be cooled to room temperature, use CH
2Cl
2Extraction (100ml * 2), water is acidified to pH＜3 with 36% concentrated hydrochloric acid.Ice bath spends the night, and separates out needle-like crystal, filter, the 14.1g anisic acid, yield 84.9%, content 99.0% (HPLC), m.p.192.5～194 ℃.
Embodiment 3
Synthesizing of the first step p-methyl phenol acetic ester
27g (0.25mol) p-cresol is added in 95mL (1.0mol) diacetyl oxide, stirs and slowly be heated to backflow down, reaction 3.5h, TLC analyzes and determines reaction end, after reaction finishes, steams the acetate that removes excessive acetic anhydride via and generation, reduce to room temperature, slowly add the saturated NaHCO of 100ml
3Solution is used CH
2Cl
2Organic phase is told in (100ml * 2) extraction, uses anhydrous Na
2SO
4Drying, suction filtration, concentrate p-methyl phenol acetic ester 35.7g, yield 95.2% is directly used in the next step.
Synthesizing of the second step 2-hydroxy-5-methyl benzoylformaldoxime
P-methyl phenol acetic ester 30g (0.2mol) and 120g add anhydrous AlCl through the oil of mirbane that anhydrous sodium sulfate drying is crossed in batches under vigorous stirring
332g (0.24mol) finishes, and is warming up to 130～140 ℃, reaction 1.5～2h, and vapor detection is determined reaction end, reaction finishes reactant is poured in 320g trash ice+35ml concentrated hydrochloric acid mixture, tells organic phase, water CH
2Cl
2Extraction (100ml * 2) merges organic phase, adds the sodium hydroxide solution vigorous stirring of 30ml20%, separatory is got organic phase and is repeated aforesaid operations 2 times, merges water, under water-bath, add concentrated hydrochloric acid to pH=1, the ice bath cooling is separated out white needle-like crystals, suction filtration, oven dry, get 2-hydroxy-5-methyl benzoylformaldoxime 26.3g, yield 87.7%, content 98.2% (HPLC), m.p.46～49 ℃.
Synthesizing of the 3rd step 2-methoxyl group-5-methyl acetophenone
2-hydroxy-5-methyl benzoylformaldoxime 22.5g (0.15mol) dissolves with 20% NaOH solution 90ml (0.45mol), stirs, and slowly drips methyl-sulfate (0.45mol), be warming up to 60 ℃ after dropwising, reaction 1h, TLC analyze and determine reaction end, reaction finishes, and reduces to room temperature, suction filtration, filter cake is washed twice with 5%NaOH, again with the saturated common salt washing once, drying gets 2-methoxyl group-5-methyl acetophenone 23.1g, yield 86.5% is directly used in the next step.
Synthesizing of the 4th step 2-methoxyl group-5-tolyl acid
KBrO (0.2mol) solution of 2-methoxyl group-5-methyl acetophenone 16.4g (0.1mol) and 245ml 10% is mixed and heated to 80 ℃, backflow stirring reaction 8h, reaction process reaction solution pH〉10, react to the organic phase disappearance, be cooled to room temperature, use CH
2Cl
2Extraction (100ml * 2), water is acidified to pH＜3 with 36% concentrated hydrochloric acid.Ice bath spends the night, and separates out needle-like crystal, filter, 14.3g2-methoxyl group-5-tolyl acid, yield 86.0%, content 99.2% (HPLC), m.p.78～79 ℃.
Embodiment 4
Synthesizing of the first step ortho chloro phenol propionic ester
With reference to embodiment 2 the first steps, 32.13g (0.25mol) replaces ortho-cresol with ortho chloro phenol, and 96.5ml (0.75mol) propionic anhydride replaces diacetyl oxide, back flow reaction 4h gets adjacent chloro-phenol propionic ester 45.1g, yield 97.8%, need not to make with extra care, be directly used in the next step.
Synthesizing of the second step 3-chloro-4-hydroxypropiophenone
With reference to 2 second steps of embodiment, replace the ortho-methyl phenol acetic ester with the adjacent chloro-phenol propionic ester of 36.9g (0.2mol), replace solvent with solubility promoter NaCl (369g), in 70 ℃ of reaction 1.5～2h, with the anhydrous FeCl of 64.8g (0.4mol)
3Replace anhydrous AlCl
3, 3-chloro-4-hydroxypropiophenone 29.4g, yield 79.7%, content 97.3% (HPLC), m.p.114～115 ℃.
Synthesizing of the 3rd step 3-chloro-4-p-methoxy-phenyl ethyl ketone
With reference to the 3rd step of embodiment 2, replace 3-methyl-4-hydroxy acetophenone with 26.7g (0.15mol) 3-chloro-4-hydroxypropiophenone, replace methyl-sulfate with 42.6g (0.3mol) methyl iodide, back flow reaction 6h, get 3-chloro-4-p-methoxy-phenyl ethyl ketone 28.1g, yield 94.4% need not to make with extra care, and is directly used in the next step.Synthesizing of the 4th step 3-chloro-4-methoxybenzoic acid
With reference to the 4th step of embodiment 2, replace 3-methyl-4-methoxyacetophenone with 19.85g (0.1mol) 3-chloro-4-p-methoxy-phenyl ethyl ketone, replace KBrO to get 3-chloro-4-methoxybenzoic acid 15.0g with 410ml (0.5mol) KClO, yield 80.4%, content 99.2% (HPLC), m.p.212～213 ℃.
Embodiment 5
Synthesizing of the first step para-chlorophenol butyric ester
With reference to embodiment 3 the first steps, replace methyl cresols with 32.13g (0.25mol) para-chlorophenol, 82ml (0.5mol) butyryl oxide replaces diacetyl oxide, back flow reaction 4h gets para-chlorophenol butyric ester 48.7g, yield 98.1%, need not to make with extra care, be directly used in the next step.
Synthesizing of second step 2-hydroxyl-5-chloro-phenyl-propyl group ketone
With reference to 3 second steps of embodiment, replace the p-methyl phenol acetic ester with 39.7g (0.2mol) para-chlorophenol butyric ester, replace solvent with solubility promoter KCl (198.5g), with the anhydrous ZnCl of 108.8g (0.8mol)
2Replace anhydrous AlCl
3, in 160 ℃ of reaction 1.5～2h, 2-hydroxyl-5-chloro-phenyl-propyl group ketone 35.0g, yield 88.2%, content 98.1% (HPLC), m.p.49～50 ℃.
Synthesizing of the 3rd step 2-methoxyl group-5-chloro-phenyl-propyl group ketone
With reference to the 3rd step of embodiment 3, replace 2-hydroxy-5-methyl benzoylformaldoxime with 29.8g (0.15mol) 2-hydroxyl-5-chloro-phenyl-propyl group ketone, replace methyl-sulfate with 32g (0.225mol) methyl iodide, back flow reaction 5h, get 3-chloro-4-methoxyacetophenone and get 2-methoxyl group-5-chloro-phenyl-propyl group ketone 29.4g, yield 92.2% need not to make with extra care, and is directly used in the next step.
Synthesizing of the 4th step 2-methoxyl group-5-chloro-benzoic acid
With reference to the 4th step of embodiment 3, replace 3-methyl-4-methoxyacetophenone with 21.25g (0.1mol) 2-methoxyl group-5-chloro-phenyl-propyl group ketone, replace KBrO with NaClO 406ml (0.6mol), get 3-chloro-4-methoxybenzoic acid and get 15.4g 2-methoxyl group-5-chloro-benzoic acid, yield 82.5%, content 99.6% (HPLC), m.p.80～81 ℃.
Claims (5)
1. the preparation method of alkoxyl benzoic acids compounds in turn includes the following steps:
The first step is that the phenol derivatives of methyl or chlorine is a raw material with phenol or ortho position, contraposition, under refluxad carry out acylation reaction with single acid anhydrides, make corresponding phenol ester and derivative thereof, phenol or ortho position, contraposition are that the phenol of methyl or chlorine and the mol ratio of single acid anhydrides are 1:2～6;
The second step phenol ester and derivative thereof are in solvent or solubility promoter; under the Lewis acid catalysis; carry out the Fries rearrangement reaction make the neighbour, to alkyloyl phenol derivmives blend biology; the weight ratio of used phenol ester and derivative thereof and solvent for use is 1: 4～10; the weight ratio of used phenol ester and derivative thereof and used solubility promoter is 1:5～10, and used Lewis acid is 1:1.2～4 with the mol ratio of phenol ester and derivative thereof.
The 3rd step is adjacent, to alkyloyl phenol derivmives blend biology in the presence of alkali; by methylating reagent alkyloyl phenol is carried out methyl-etherified; make the neighbour, to alkyloyl phenyl methyl ether and derivative thereof; used neighbour, mol ratio biological to the alkyloyl phenol derivmives blend and alkali are: 1:1.5～5, used neighbour, mol ratio biological to the alkyloyl phenol derivmives blend and methylating reagent are: 1:1.5～5.
The 4th step is adjacent, to alkyloyl phenyl methyl ether and derivative thereof in the presence of hypohalite, be oxidized to alkoxyl benzoic acids compounds, the neighbour, be: 1:2～6 to the mol ratio of alkyloyl phenyl methyl ether and derivative and hypohalous acid sodium.
2. by the preparation method of the described alkoxyl benzoic acids compounds of claim 1, it is characterized in that the used single acid anhydrides of the first step acylation reaction is diacetyl oxide, propionic anhydride or butyryl oxide.
3. press the preparation method of the described alkoxyl benzoic acids compounds of claim 1, it is characterized in that the used solvent of the second step Fries rearrangement reaction is oil of mirbane or dithiocarbonic anhydride, used solubility promoter is sodium-chlor or Repone K, and used Lewis acid is iron trichloride, aluminum chloride or zinc chloride.
4. by the preparation method of the described alkoxyl benzoic acids compounds of claim 1, it is characterized in that the used alkali of the 3rd step etherification reaction is sodium hydroxide or potassium hydroxide, used methylating agent is methyl iodide or methyl-sulfate.
5. by the preparation method of the described alkoxyl benzoic acids compounds of claim 1, it is characterized in that the used hypohalous acid sodium of the 4th step oxidizing reaction is clorox, potassium hypochlorite, sodium hypobromite or potassium hypobromite.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516072A (en) * | 2011-12-13 | 2012-06-27 | 江苏长青农化股份有限公司 | Preparation method of benzoic acid herbicide dicamba |
| CN106928147A (en) * | 2017-03-14 | 2017-07-07 | 华东师范大学 | Tricyclic diterpene analog and preparation method thereof and its application in antiprostate cancer is prepared |
| CN109369359A (en) * | 2018-12-24 | 2019-02-22 | 浙江工业大学 | A method of preparing parahydroxyacet-ophenone |
| CN111807954B (en) * | 2019-04-10 | 2024-04-05 | 广东东阳光药业股份有限公司 | Preparation method of simmond intermediate |
-
2008
- 2008-12-08 CN CNA200810162638XA patent/CN101417947A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516072A (en) * | 2011-12-13 | 2012-06-27 | 江苏长青农化股份有限公司 | Preparation method of benzoic acid herbicide dicamba |
| CN106928147A (en) * | 2017-03-14 | 2017-07-07 | 华东师范大学 | Tricyclic diterpene analog and preparation method thereof and its application in antiprostate cancer is prepared |
| CN109369359A (en) * | 2018-12-24 | 2019-02-22 | 浙江工业大学 | A method of preparing parahydroxyacet-ophenone |
| CN111807954B (en) * | 2019-04-10 | 2024-04-05 | 广东东阳光药业股份有限公司 | Preparation method of simmond intermediate |
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