EP1494987A1 - Method for the production of 2,4,5-trimethylphenyl acetic acid - Google Patents
Method for the production of 2,4,5-trimethylphenyl acetic acidInfo
- Publication number
- EP1494987A1 EP1494987A1 EP03745691A EP03745691A EP1494987A1 EP 1494987 A1 EP1494987 A1 EP 1494987A1 EP 03745691 A EP03745691 A EP 03745691A EP 03745691 A EP03745691 A EP 03745691A EP 1494987 A1 EP1494987 A1 EP 1494987A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- trimethylphenyl
- isomeric
- ethanone
- pseudocumene
- 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.)
- Withdrawn
Links
- NGJKVDNPUSPLQE-UHFFFAOYSA-N 2-(2,4,5-trimethylphenyl)acetic acid Chemical compound CC1=CC(C)=C(CC(O)=O)C=C1C NGJKVDNPUSPLQE-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims description 36
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- GWHJZXXIDMPWGX-UHFFFAOYSA-N 1,2,4-trimethylbenzene Chemical compound CC1=CC=C(C)C(C)=C1 GWHJZXXIDMPWGX-UHFFFAOYSA-N 0.000 claims abstract description 52
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 claims abstract description 15
- MAJSNOZBSBVPOP-UHFFFAOYSA-N 2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone Chemical compound CC1=CC(C)=C(C(=O)C(Cl)Cl)C=C1C MAJSNOZBSBVPOP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 5
- MLIACTPSDQUOGE-UHFFFAOYSA-N 2-hydroxy-2-(2,4,5-trimethylphenyl)acetic acid Chemical compound CC1=CC(C)=C(C(O)C(O)=O)C=C1C MLIACTPSDQUOGE-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 abstract 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 abstract 2
- 229960002510 mandelic acid Drugs 0.000 abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- UOHMMEJUHBCKEE-UHFFFAOYSA-N prehnitene Chemical compound CC1=CC=C(C)C(C)=C1C UOHMMEJUHBCKEE-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- GENBEGZNCBFHSU-UHFFFAOYSA-N 1-(2,4,5-trimethylphenyl)ethanone Chemical compound CC(=O)C1=CC(C)=C(C)C=C1C GENBEGZNCBFHSU-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- ZHGUKHABIUDZDU-UHFFFAOYSA-N 1-(bromomethyl)-2,4,5-trimethylbenzene Chemical compound CC1=CC(C)=C(CBr)C=C1C ZHGUKHABIUDZDU-UHFFFAOYSA-N 0.000 description 2
- YHMFTAUOYLECGZ-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trimethylbenzene Chemical compound CC1=CC(C)=C(CCl)C=C1C YHMFTAUOYLECGZ-UHFFFAOYSA-N 0.000 description 2
- UCFWNQZOCNAHQD-UHFFFAOYSA-N 2-chloro-1-(2,4,5-trimethylphenyl)ethanone Chemical compound CC1=CC(C)=C(C(=O)CCl)C=C1C UCFWNQZOCNAHQD-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 2
- 238000007265 chloromethylation reaction Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 2
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical class C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- SQNZJJAZBFDUTD-UHFFFAOYSA-N durene Chemical compound CC1=CC(C)=C(C)C=C1C SQNZJJAZBFDUTD-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FILHLWJYWKVPEW-UHFFFAOYSA-N 1-phenyl-2-(2,4,5-trimethylphenyl)ethanone Chemical compound C1=C(C)C(C)=CC(C)=C1CC(=O)C1=CC=CC=C1 FILHLWJYWKVPEW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZGKUJEDKFKGCCL-UHFFFAOYSA-N 2-bromo-2-chloro-1-(2,4,5-trimethylphenyl)ethanone Chemical compound CC1=CC(C)=C(C(=O)C(Cl)Br)C=C1C ZGKUJEDKFKGCCL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 238000005659 Kindler reaction Methods 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- HKYGSMOFSFOEIP-UHFFFAOYSA-N dichloro(dichloromethoxy)methane Chemical compound ClC(Cl)OC(Cl)Cl HKYGSMOFSFOEIP-UHFFFAOYSA-N 0.000 description 1
- -1 etc. Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000010915 one-step procedure Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003464 sulfur compounds Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
Definitions
- the present invention relates to a new process for the preparation of 2,4,5-trimethylphenylacetic acid.
- 2,4,5-Trimethylphenylacetic acid is a well-known compound (for example from: J. Prakt. Chem. 80 (1909) 193; J. Amer. Chem. Soc. 58 (1936) 629-35).
- the preparation can be carried out, for example, starting from 2,4,5-trimethylphenyl acetophenone by an illgerodt-Kindler reaction.
- this method produces large amounts of sulfur-containing waste.
- highly odorous, volatile sulfur compounds can occur.
- Another method is based on 2,4,5-trimethylbenzyl bromide. It is used e.g. the corresponding nitrile with sodium cyanide, which is then saponified (J. Amer. Chem. Soc. 58 (1936) 629-35; DE-A 19 602 524).
- This nitrile can also be obtained by reacting durol (1,2,4,5-tetramemylbenzene) with cyanogen chloride at above 600 ° C. (DE-A 2 854210); however, the high toxicity of cyanogen chloride is disadvantageous.
- the 2,4,5-trimethylbenzyl bromide required can in turn be produced by bromination of durol with N-bromo-succmimide (see, for example, J. Amer. Chem. Soc. 92 (1970) 994-8).
- it is disadvantageous here that experience has shown that such brominations also lead to multi-brominated products, so that complex cleaning steps are necessary.
- 2,4,5-trimethylphenylacetic acid can be obtained in high yield and isomer purity by firstly producing pseudocumene with dichloroacetyl chloride in a Friedel-Crafts reaction to give 2,2-dichloro-l- (2,4,5 -trimethylphenyl) -ethanone is converted, the 2,4,5-trimethylmandelic acid is produced from it using an alkali metal hydroxide and is then finally used
- Dichlorinated acetophenones can also be prepared in a two-stage process by Friedel-Craf s acylation of the corresponding aromatics with acetyl chloride and subsequent chlorination.
- the present invention accordingly also relates to the new connection
- the 2,4,5-trimethylphenylacetic acid can be prepared in a simpler manner, in better selectivity and in a better yield than in the previously known processes by the process according to the invention.
- 2,2-dichloro-l- (2,4,5-trimethylphenyl) ethanone is prepared by the first step of the process according to the invention by reacting pseudocumene with dichloroacetyl chloride in the presence of a Friedel-Crafts catalyst.
- aluminum chloride, iron (III) chloride, tin tetrachloride or zeolites can be used as Friedel-Crafts catalysts in the process according to the invention.
- Aluminum chloride is preferably used as the Friedel-Crafts catalyst.
- the amount of Friedel-Crafts catalyst to be used in the process according to the invention is not critical. For example, 0.8 to 1.2 moles of catalyst can be used per dichloroacetyl chloride. 0.9 to 1.1 moles of dichloroacetyl chloride per mole of dichloroacetyl chloride are preferred.
- Solvents for the Friedel-Crafts reaction are largely inert solvents such as nitrobenzene, carbon disulfide, methylene chloride, 1,2-dichloroethane or pseudocumene itself are used in the process according to the invention. Carbon disulfide, 1,2-dichloroethane and pseudocumene are preferred.
- Pseudocumol is particularly preferred.
- the amount of dichloroacetyl chloride to be used by the process according to the invention is not critical and can be varied within wide limits.
- 0.8 to 1.2 moles of dichloroacetyl chloride can be used per mole of pseudocumene.
- 0.9 to 1.1 moles of dichloroacetyl chloride per mole of pseudocumol are preferred.
- the first step of the process according to the invention can be carried out at temperatures between -20 and + 60 ° C. Temperatures between - 10 and + 30 ° C are preferred.
- reaction times of the first step of the process according to the invention are between 1 and 24 hours.
- NaOH, KOH and CsOH can be used as alkali metal oxide in the second step of the process according to the invention.
- NaOH and KOH are preferred; NaOH is particularly preferred.
- the amount of alkali hydroxide is 3 to 7 moles per mole of 2,2-dichloro-1 - (2,4,5-trimethylphenyl) ethanone. 4 to 6 moles per mole of 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone are preferably used.
- Water is used as the solvent for the second step of the process according to the invention.
- the second step of the process according to the invention can be carried out at temperatures between -20 and + 120 ° C. Temperatures between +20 and + 110 ° C are preferred.
- reaction times of the second step of the process according to the invention are between 1 and 24 hours.
- the reduction of 2,4,5-trimethylmandelic acid in the third step of the process according to the invention can be carried out by various fundamentally known methods for reducing mandelic acids, for example using hydrogen on suitable catalysts or using red phosphorus.
- the reduction is preferably carried out with red phosphorus.
- the red phosphorus is in the third step of the process according to the invention in
- Amounts of 0.67 to 3 moles per mole of 2,4,5-trimethylmandelic acid are used. 1 to 2 moles per mole of 2,4,5-trimethylmandelic acid are preferred. Excess red phosphorus can be recovered and reused.
- hydrogen iodide, KJ or NaJ is used as the iodide source.
- iodine can also be used. NaJ or KJ is preferably used.
- the amount of iodide is 1 to 30 mole percent (based on 2,4,5-trimethylmandelic acid); 5 to 20 mole percent are preferably used.
- Suitable solvents in the third step of the process according to the invention are formic acid, acetic acid, propionic acid, etc., mixtures of these solvents, or 70 to 85% aqueous phosphoric acid. 70 to 85% aqueous phosphoric acid and acetic acid are preferred; acetic acid is particularly preferred.
- conc. Sulfuric acid, conc. Hydrochloric acid or 80 to 85% aqueous phosphoric acid are used.
- the third step of the method according to the invention can be carried out at temperatures between +20 and + 120 ° C. Temperatures between +60 and + 110 ° C are preferred.
- reaction times of the third step of the process according to the invention are between 1 and 24 hours.
- A1C1 3 146.6 g of A1C1 3 are introduced in portions into a mixture of 333 g of pseudocumene and 147.7 g of dichloroacetyl chloride at 0-5 ° C. in the course of 2-3 hours. The mixture is then stirred at 0-5 ° C for 2 hours and allowed to come to room temperature. The reaction mixture is concentrated in 3300 ml of ice water with 66.7 g. Hydrochloric acid stirred in. It is extracted with once 350 ml and twice 500 ml of ethyl acetate. The combined organic phases are first shaken with 165 ml of water and then 85 ml of saturated aqueous NaCl solution, dried and concentrated (up to 70 ° C. bath / 1 mbar).
- Target product isomers 5.32%; i.e. the ratio of ZP to isomers is approximately 94: 6.
- reaction mixture is mixed with 400 ml of water at 45 ° C. and with 400 ml of MTBE at room temperature, the phases are separated, the aqueous phase is shaken again with 300 ml of MTBE, then acidified with sulfuric acid and the precipitated solid is suctioned off. This is washed three times with 50 ml of water and then dried. This gives 102.4 g of white solid which, according to GC, is 91.9%
- Example 5 2,4,5-trimethylphenylacetic acid
- a mixture of 69.9 g of 2,4,5-trimethylmandelic acid, 38.3 g of 36% hydrochloric acid, 11.2 g of red phosphorus and 6 g of KJ in 270 ml of glacial acetic acid is heated to 100 ° C. for 16 hours. It is then diluted with 150 ml of glacial acetic acid at room temperature. The excess phosphorus is filtered off and washed with three times 50 ml of glacial acetic acid. The filtrate is mixed with 150 ml of water and the acetic acid at 50 ° C bath. / 60 mbar largely spun off. The remaining suspension is adjusted to pH 1 with 5 ml of 20% sulfuric acid and the solid is filtered off with suction.
- A1C1 3 are introduced in portions into a mixture of 60 g of pseudocumene and 7.85 g of acetyl chloride within 1-2 hours. The mixture is then stirred at 0-5 ° C for 2 hours and allowed to come to room temperature. The reaction mixture is concentrated in 340 ml of ice water with 7 g. Hydrochloric acid stirred in. It is extracted with 35 ml once and twice 50 ml of ethyl acetate. The combined organic phases are first shaken with 20 ml of water and then 10 ml of saturated aqueous ⁇ aCl solution, dried and concentrated (up to 70 ° C. bath / 1 mbar).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a novel method for producing 2,4,5-trimethylphenyl acetic acid, according to which pseudocumene is reacted with dichloroacetyl chloride in a Friedel-Crafts reaction so as to obtain 2,2-dichloro-1-(2,4,5-trimethylphenyl)-ethanone, from which trimethyl mandelic acid is produced by means of alkali metal hydroxide, and said trimethyl mandelic acid is reduced to 2,4,5-trimethylphenyl acetic acid.
Description
Verfahren zur Herstellung von 2,4,5 -TrimethylphenyϊessigsäureProcess for the preparation of 2,4,5-trimethylphenyϊacetic acid
Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung von 2,4,5- Trimethylphenylessigsäure.The present invention relates to a new process for the preparation of 2,4,5-trimethylphenylacetic acid.
2,4,5-Trimethylphenylessigsäure ist eine schon lange bekannte Verbindung (beispielsweise aus: J. prakt. Chem. 80 (1909) 193; J. Amer. Chem. Soc. 58 (1936) 629-35). Die Herstellung kann beispielsweise ausgehend von 2,4,5-Trimethylphenyl- acetophenon durch eine illgerodt-Kindler-Reaktion erfolgen. Bei dieser Methode fallen jedoch große Mengen schwefelhaltiger Abfälle an. Außerdem können stark geruchsbelästigende leichtflüchtige Schwefelverbindungen auftreten.2,4,5-Trimethylphenylacetic acid is a well-known compound (for example from: J. Prakt. Chem. 80 (1909) 193; J. Amer. Chem. Soc. 58 (1936) 629-35). The preparation can be carried out, for example, starting from 2,4,5-trimethylphenyl acetophenone by an illgerodt-Kindler reaction. However, this method produces large amounts of sulfur-containing waste. In addition, highly odorous, volatile sulfur compounds can occur.
Eine weitere Methode geht von 2,4,5 -Trimethylbenzylbromid aus. Man stellt daraus z.B. mit Natriumcyanid das entsprechende Nitril her, welches anschließend verseift wird (J. Amer. Chem. Soc. 58 (1936) 629-35; DE-A 19 602 524). Dieses Nitril lässt sich auch durch Umsetzung von Durol (l,2,4,5-Tetramemylbenzol) mit Chlorcyan bei über 600°C erhalten (DE-A 2 854210); hierbei ist jedoch die hohe Giftigkeit von Chlorcyan nachteilig. Das benötigte 2,4,5-Trimethylbenzylbromid wiederum kann durch Bromierung von Durol mit N-Brom-succmimid hergestellt werden (siehe beispielsweise J. Amer. Chem. Soc. 92 (1970) 994-8). Hierbei ist allerdings nachteilig, dass solche Bromierungen erfahrungsgemäß auch zu mehrfach bromierten Produkten führen, so dass aufwendige Reinigungsschritte notwendig werden.Another method is based on 2,4,5-trimethylbenzyl bromide. It is used e.g. the corresponding nitrile with sodium cyanide, which is then saponified (J. Amer. Chem. Soc. 58 (1936) 629-35; DE-A 19 602 524). This nitrile can also be obtained by reacting durol (1,2,4,5-tetramemylbenzene) with cyanogen chloride at above 600 ° C. (DE-A 2 854210); however, the high toxicity of cyanogen chloride is disadvantageous. The 2,4,5-trimethylbenzyl bromide required can in turn be produced by bromination of durol with N-bromo-succmimide (see, for example, J. Amer. Chem. Soc. 92 (1970) 994-8). However, it is disadvantageous here that experience has shown that such brominations also lead to multi-brominated products, so that complex cleaning steps are necessary.
Eine weitere bekannt gewordene Möglichkeit besteht darin, von 2,4,5-Trimethyl- benzylchlorid auszugehen, daraus das Nitril herzustellen (J. Amer. Chem. Soc. 58 (1936) 629-35; J. Org. Chem. 33 (1968) 2338-42) und dieses dann zu verseifen. 2,4,5-Trimethylbenzylchlorid ist bekannt und kann durch Chlormethylierung von Pseudocumol (1,2,4-Trimethylbenzol) hergestellt werden. Hierbei ist jedoch als ausgesprochen ungünstig anzusehen, dass die Chlormethylierung nur mit unbefriedigender Selektivität erfolgt. Es werden Selektivitäten von etwa 75-85 %
beschrieben (J. Org. Chem. 24 (1959) 1823-5; US 3,658,923). Außerdem ist die Chlormethylierung wegen der Möglichkeit, dass dabei der hochtoxische Bis-chlor- methyl-ether auftritt, eine nur mit hohem technischen Aufwand durchführbare Methode.Another possibility that has become known is to start from 2,4,5-trimethylbenzyl chloride and use it to produce the nitrile (J. Amer. Chem. Soc. 58 (1936) 629-35; J. Org. Chem. 33 (1968 ) 2338-42) and then to saponify it. 2,4,5-trimethylbenzyl chloride is known and can be prepared by chloromethylating pseudocumene (1,2,4-trimethylbenzene). However, it is to be regarded as extremely unfavorable that the chloromethylation only takes place with unsatisfactory selectivity. Selectivities of around 75-85% (J. Org. Chem. 24 (1959) 1823-5; US 3,658,923). In addition, because of the possibility that the highly toxic bis-chloromethyl ether occurs, chloromethylation is a method which can only be carried out with great technical outlay.
Eine weitere Möglichkeit zur Herstellung von 2,4,5-Trimethylphenylessigsäure besteht schließlich darin, zunächst Pseudocumol mit Glyoxylsäure zur 2,4,5-Trimethyl- mandelsäure umzusetzen (Atti Accad., Lettere Arti Palermo, Pt. I 24 (1965) 19-33) und diese dann zur 2,4,5-Trimethylphenylessigsäure zu reduzieren (J. Amer. Chem. Soc. 58 (1936) 629-35). Die Herstellung der 2,4,5-Trimethylmandelsäure nach dem genannten Verfahren hat jedoch den Nachteil, dass unter den üblichen Reaktionsbedingungen die bereits entstandene 2,4,5-Trimethylmandelsäure mit weiterem Pseudocumol reagiert und so erhebliche Anteile an 2.2',4,4',5,5'-Hexamethyldiphenylessig- säure entstehen (Atti Accad., Lettere Arti Palermo, Pt. I 24 (1965) 19-33), die natürlich die Ausbeute verringern und zusätzliche Reinigungsschritte notwendig machen.Another possibility for the preparation of 2,4,5-trimethylphenylacetic acid is finally to first react pseudocumene with glyoxylic acid to give 2,4,5-trimethylmandelic acid (Atti Accad., Lettere Arti Palermo, Pt. I 24 (1965) 19- 33) and then reduce it to 2,4,5-trimethylphenylacetic acid (J. Amer. Chem. Soc. 58 (1936) 629-35). The production of 2,4,5-trimethylmandelic acid by the process mentioned has the disadvantage, however, that under the usual reaction conditions the 2,4,5-trimethylmandelic acid which has already formed reacts with further pseudocumene and thus considerable amounts of 2 . 2 ', 4,4', 5,5'-hexamethyldiphenylacetic acid are formed (Atti Accad., Lettere Arti Palermo, Pt. I 24 (1965) 19-33), which of course reduce the yield and make additional cleaning steps necessary.
Alle bisher bekannt gewordenen Methoden zur Herstellung von 2,4,5-Trimethyl- phenylessigsäure weisen demnach z.T. erhebliche Mängel und Nachteile auf, die die Herstellung von 2,4,5 -Trimethylphenylessigsäure erschweren. Da Phenylessigsäuren, und unter ihnen auch die 2,4,5-Trimethylphenylessigsäure, wichtige Vorprodukte beispielsweise für Wirkstoffe im Pflanzenschutz sind (vgl. WO 97/36868), besteht Bedarf an einer technisch einfachen Methode zur Herstellung von 2,4,5-Trimethyl- phenylessigsäure.All of the methods for the preparation of 2,4,5-trimethylphenylacetic acid that have become known so far partly show. significant shortcomings and disadvantages that complicate the production of 2,4,5 -trimethylphenylacetic acid. Since phenylacetic acids, and among them 2,4,5-trimethylphenylacetic acid, are important precursors, for example for active substances in crop protection (cf. WO 97/36868), there is a need for a technically simple method for producing 2,4,5-trimethyl - phenylacetic acid.
Es wurde nun gefunden, dass man 2,4,5-Trimethylphenylessigsäure überraschenderweise in hoher Ausbeute und Isomerenreinheit erhält, indem man zunächst Pseudocumol mit Dichloracetylchlorid in einer Friedel-Crafts-Reaktion zu 2,2-Dichlor-l- (2,4,5-trimethylphenyl)-ethanon umsetzt, aus diesem mittels einem Alkalimetall- hydroxid die 2,4,5-Trimethylmandelsäure herstellt und diese dann schließlich zurIt has now been found that, surprisingly, 2,4,5-trimethylphenylacetic acid can be obtained in high yield and isomer purity by firstly producing pseudocumene with dichloroacetyl chloride in a Friedel-Crafts reaction to give 2,2-dichloro-l- (2,4,5 -trimethylphenyl) -ethanone is converted, the 2,4,5-trimethylmandelic acid is produced from it using an alkali metal hydroxide and is then finally used
2,4,5-Trimethylphenylessigsäure reduziert.
Die Herstellung von Mandelsäuren durch Umsetzung von Dihalogen-acetophenonen mit einem Alkalihydroxid ist eine bekannte Methode (siehe beispielsweise; Org. Syntheses 35 (1955) 11-14). Ebenfalls ist bereits bekannt, 2,4,5-Trimethylphenyl- ethanon (Acetyl-pseudocumol) bzw. 2-Chlor-l-(2,4,5-trimethylρhenyl)-ethanon2,4,5-trimethylphenylacetic acid reduced. The production of mandelic acids by reacting dihalo-acetophenones with an alkali hydroxide is a known method (see for example; Org. Syntheses 35 (1955) 11-14). Also known is 2,4,5-trimethylphenylethanone (acetyl-pseudocumol) or 2-chloro-l- (2,4,5-trimethylρhenyl) ethanone
(Chloracetyl-pseudocumol) zu bromieren, so 2,2-Dibrom-l-(2,4,5-tr-metiιylphenyl)- ethanon bzw. 2-Brom-2-chlor-l-(2,4,5-trimethylphenyl)-ethanon zu erhalten und diese dann mit wässriger Kaliumhydroxidlösung zur 2,4,5-Trimethylmandelsäure umzusetzen (J. Amer. Chem. Soc. 57 (1935) 1562-4). Diese Metliode hat jedoch den Nachteil, zweistufig und aufwendig zu sein.Brominate (chloroacetyl-pseudocumol), so 2,2-dibromo-l- (2,4,5-tr-methylphenyl) - ethanone or 2-bromo-2-chloro-l- (2,4,5-trimethylphenyl ) -ethanone and then converting it with aqueous potassium hydroxide solution to 2,4,5-trimethylmandelic acid (J. Amer. Chem. Soc. 57 (1935) 1562-4). However, this metliode has the disadvantage of being two-stage and complex.
Dichlorierten Acetophenone lassen sich in einem ebenfalls zweistufigen Verfahren durch Friedel-Craf s-Acylierung des entsprechenden Aromaten mit Acetylchlorid und .anschließende Chlorierung herstellen.Dichlorinated acetophenones can also be prepared in a two-stage process by Friedel-Craf s acylation of the corresponding aromatics with acetyl chloride and subsequent chlorination.
Vorteilhafter ist es jedoch, in einer einstufigen Verfahrensweise den betreffenden Aromaten direkt mit Dichloracetylchlorid in einer Friedel-Crafts-Acylierung zum dichlorierten Acetophenon umzusetzen.However, it is more advantageous to react the aromatics in question directly with dichloroacetyl chloride in a Friedel-Crafts acylation to give the dichlorinated acetophenone in a one-step procedure.
Während 2,4,5-Trimethylphenyl-ethanon (J. prakt. Chemie <2> 41 (1890) 509; J.While 2,4,5-trimethylphenylethanone (J. Prakt. Chemie <2> 41 (1890) 509; J.
Amer. Chem. Soc. 52 (1930) 2959-72) und 2-Chlor-l-(2,4,5-trimethylphenyl)- ethanon (J. Amer. Chem. Soc. 57 (1935) 1562) bereits seit langem bekannt sind, wurde das zur Herstellung der 2,4,5-Trimethylphenylessigsäure nach dem erfindungsgemäßen Verfahren benötigte 2,2-Dichlor-l-(2,4,5-trimethylphenyl)-ethanon bisher jedoch nicht beschrieben.Amer. Chem. Soc. 52 (1930) 2959-72) and 2-chloro-1- (2,4,5-trimethylphenyl) ethanone (J. Amer. Chem. Soc. 57 (1935) 1562) have been known for a long time However, the preparation of 2,2,5-dichloro-l- (2,4,5-trimethylphenyl) ethanone required by the process according to the invention of 2,4,5-trimethylphenylacetic acid has not previously been described.
Die Umsetzung von Pseudocumol mit Acetylchlorid unter Friedel-Crafts-Be- dingungen liefert 2,4,5-Trimethylphenyl-ethanon in hoher Selektivität (s. Vergleichsbeispiel 1). Die entsprechende Umsetzung mit Chloracetylchlorid ist dagegen deut- lieh weniger selektiv (s. Vergleichsbeispiel 2 ).
Es war daher nicht von vornherein zu erwarten, dass bei der Friedel-Crafts-Reaktion von Pseudocumol mit Dichloracetylchlorid das 2,2-Dichlor-l-(2,4,5-trimethyl- phenyl)-ethanon in genügend hoher Isomerenreinheit zu erhalten sein würde.The reaction of pseudocumene with acetyl chloride under Friedel-Crafts conditions provides 2,4,5-trimethylphenylethanone with high selectivity (see comparative example 1). The corresponding reaction with chloroacetyl chloride, on the other hand, is clearly less selective (see Comparative Example 2). It was therefore not to be expected from the outset that the Friedel-Crafts reaction of pseudocumol with dichloroacetyl chloride would give the 2,2-dichloro-l- (2,4,5-trimethylphenyl) ethanone in sufficiently high isomer purity would.
Das erfmdungsgemäße Verfahren kann durch folgendes Schema veranschaulicht werden:The method according to the invention can be illustrated by the following scheme:
CI2CHCOCI
CI 2 CHCOCI
Reduktionreduction
Ebenfalls Gegenstand der vorliegenden Erfindung ist demnach die neue VerbindungThe present invention accordingly also relates to the new connection
2,2-Dichlor- 1 -(2,4,5-trimethylphenyl)-ethanon.2,2-dichloro-1 - (2,4,5-trimethylphenyl) ethanone.
Überraschenderweise kann nach dem erfindungsgemäßen Verfahren die 2,4,5-Tri- methylphenylessigsäure auf einfachere Weise, in besserer Selektivität und in besserer Ausbeute als nach den früher bekannt gewordenen Verfahren hergestellt werden.Surprisingly, the 2,4,5-trimethylphenylacetic acid can be prepared in a simpler manner, in better selectivity and in a better yield than in the previously known processes by the process according to the invention.
Die Herstellung von 2,2-Dichlor-l-(2,4,5-trimethylphenyl)-ethanon nach dem ersten Schritt des erfindungsgemäßen Verfahrens erfolgt durch Umsetzung von Pseudocumol mit Dichloracetylchlorid in Gegenwart eine Friedel-Crafts-Katalysators.2,2-dichloro-l- (2,4,5-trimethylphenyl) ethanone is prepared by the first step of the process according to the invention by reacting pseudocumene with dichloroacetyl chloride in the presence of a Friedel-Crafts catalyst.
Als Friedel-Crafts-Katalysatoren nach dem erfindungsgemäßen Verfahren können beispielsweise Aluminiumchlorid, Eisen(III)-chlorid, Zinntetrachlorid oder Zeolithe eingesetzt werden. Bevorzugt wird als Friedel-Crafts-Kataylsator Aluminiumchlorid eingesetzt.
Die Menge an nach dem erfindungsgemäßen Verfahren einzusetzendem Friedel- Crafts-Katalysator ist nicht kritisch. So können beispielsweise 0,8 bis 1,2 Mol Katalysator pro Dichloracetylchlorid eingesetzt werden. Bevorzugt sind 0,9 bis 1,1 Mol Dichloracetylchlorid pro Mol Dichloracetylchlorid.For example, aluminum chloride, iron (III) chloride, tin tetrachloride or zeolites can be used as Friedel-Crafts catalysts in the process according to the invention. Aluminum chloride is preferably used as the Friedel-Crafts catalyst. The amount of Friedel-Crafts catalyst to be used in the process according to the invention is not critical. For example, 0.8 to 1.2 moles of catalyst can be used per dichloroacetyl chloride. 0.9 to 1.1 moles of dichloroacetyl chloride per mole of dichloroacetyl chloride are preferred.
Als Lösungsmittel für die Friedel-Crafts-Reaktion werden nach dem erfindungsgemäßen Verfahren weitgehend inerte Lösungsmittel wie beispielsweise Nitrobenzol, Schwefelkohlenstoff, Methylenchlorid, 1,2-Dichlorethan oder Pseudocumol selbst eingesetzt. Bevorzugt sind Schwefelkohlenstoff, 1,2-Dichlorethan und Pseudocumol.Solvents for the Friedel-Crafts reaction are largely inert solvents such as nitrobenzene, carbon disulfide, methylene chloride, 1,2-dichloroethane or pseudocumene itself are used in the process according to the invention. Carbon disulfide, 1,2-dichloroethane and pseudocumene are preferred.
Besonders bevorzugt ist Pseudocumol.Pseudocumol is particularly preferred.
Die Menge .an nach dem erfindungsgemäßen Verfahren einzusetzendem Dichloracetylchlorid ist nicht kritisch und kann in weiten Grenzen variiert werden. Bei Verwendung eines Lösungsmittels kann man beispielsweise 0,8 bis 1,2 Mol Dichloracetylchlorid pro Mol Pseudocumol einsetzen. Bevorzugt sind 0,9 bis 1,1 Mol Dichloracetylchlorid pro Mol Pseudocumol.The amount of dichloroacetyl chloride to be used by the process according to the invention is not critical and can be varied within wide limits. When using a solvent, for example, 0.8 to 1.2 moles of dichloroacetyl chloride can be used per mole of pseudocumene. 0.9 to 1.1 moles of dichloroacetyl chloride per mole of pseudocumol are preferred.
Verwendet man einen Überschuss an Pseudocumol als Lösungsmittel, wird das Verhältnis von Dichloracetylchlorid zu Pseudocumol naturgemäß deutlich kleiner sein.If an excess of pseudocumol is used as the solvent, the ratio of dichloroacetyl chloride to pseudocumol will naturally be significantly lower.
Der erste Schritt des erfindungsgemäßen Verfahrens kann bei Temperaturen zwischen -20 und +60°C durchgeführt werden. Bevorzugt sind Temperaturen zwischen - 10 und +30°C.The first step of the process according to the invention can be carried out at temperatures between -20 and + 60 ° C. Temperatures between - 10 and + 30 ° C are preferred.
Die Reaktionszeiten des ersten Schritts des erfmdungsgemäßen Verfahrens betragen zwischen 1 und 24 Stunden.The reaction times of the first step of the process according to the invention are between 1 and 24 hours.
Als Alkalihydoxid im zweiten Schritt des erfmdungsgemäßen Verfahrens kann beispielsweise NaOH, KOH und CsOH eingesetzt werden. Bevorzugt sind NaOH und KOH; besonders bevorzugt ist NaOH.
Die Menge an Alkalihydroxid beträgt 3 bis 7 Mol pro Mol 2,2-Dichlor-l -(2,4,5- trimethylphenyl)-ethanon. Bevorzugt werden 4 bis 6 Mol pro Mol 2,2-Dichlor-l- (2.4,5-trimethylphenyl)-ethanon eingesetzt.For example, NaOH, KOH and CsOH can be used as alkali metal oxide in the second step of the process according to the invention. NaOH and KOH are preferred; NaOH is particularly preferred. The amount of alkali hydroxide is 3 to 7 moles per mole of 2,2-dichloro-1 - (2,4,5-trimethylphenyl) ethanone. 4 to 6 moles per mole of 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone are preferably used.
Als Lösungsmittel des zweiten Schrittes des erfmdungsgemäßen Verfahrens wird Wasser verwendet.Water is used as the solvent for the second step of the process according to the invention.
Der zweite Schritt des erfmdungsgemäßen Verfahrens kann bei Temperaturen zwischen -20 und +120°C durchgeführt werden. Bevorzugt sind Temperaturen zwischen +20 und +110°C.The second step of the process according to the invention can be carried out at temperatures between -20 and + 120 ° C. Temperatures between +20 and + 110 ° C are preferred.
Die Reaktionszeiten des zweiten Schritts des erfindungsgemäßen Verfahrens betragen zwischen 1 und 24 Stunden.The reaction times of the second step of the process according to the invention are between 1 and 24 hours.
Die Reduktion der 2,4,5-Trimethylmandelsäure im dritten Schritt des erfindungsgemäßen Verfahrens kann nach verschiedenen grundsätzlich bekannten Methoden zur Reduktion von Mandelsäuren durchgeführt werden, so beispielsweise mittels Wasserstoff an geeigneten Katalysatoren, oder mittels rotem Phosphor. Bevorzugt wird die Reduktion mit rotem Phosphor durchgeführt.The reduction of 2,4,5-trimethylmandelic acid in the third step of the process according to the invention can be carried out by various fundamentally known methods for reducing mandelic acids, for example using hydrogen on suitable catalysts or using red phosphorus. The reduction is preferably carried out with red phosphorus.
Die Reduktion durch roten Phosphor erfolgt in Gegenwart katalytischer Mengen Jodid, eines Lösungsmittels und einer starken Säure.The reduction by red phosphorus takes place in the presence of catalytic amounts of iodide, a solvent and a strong acid.
Der rote Phosphor wird im dritten Schritt des erfindungsgemäßen Verfahrenes inThe red phosphorus is in the third step of the process according to the invention in
Mengen von 0,67 bis 3 Mol pro Mol 2,4.5-Trimethylmandelsäure eingesetzt. Bevorzugt sind 1 bis 2 Mol pro Mol 2,4,5-Trimethylmandelsäure. Überschüsse an rotem Phosphor können zurückgewonnen und wiederverwendet werden.
Als Jodidquelle wird im dritten Schritt des erfindungsgemäßen Verfahrens Jodwasserstoff, KJ oder NaJ verwendet. Grundsätzlich kann auch Jod eingesetzt werden. Bevorzugt wird NaJ oder KJ verwendet.Amounts of 0.67 to 3 moles per mole of 2,4,5-trimethylmandelic acid are used. 1 to 2 moles per mole of 2,4,5-trimethylmandelic acid are preferred. Excess red phosphorus can be recovered and reused. In the third step of the process according to the invention, hydrogen iodide, KJ or NaJ is used as the iodide source. In principle, iodine can also be used. NaJ or KJ is preferably used.
Die Menge an Jodid beträgt 1 bis 30 Molprozent (bezogen auf 2,4,5-Trimethyl- mandelsäure); bevorzugt werden 5 bis 20 Molprozent eingesetzt.The amount of iodide is 1 to 30 mole percent (based on 2,4,5-trimethylmandelic acid); 5 to 20 mole percent are preferably used.
Als Lösungsmittel im dritten Schritt des erfindungsgemäßen Verfahrenes kommen Ameisensäure, Essigsäure, Propionsäure usw., Gemische dieser Lösungsmittel, oder 70 bis 85 %ige wässrige Phosphorsäure in Frage. Bevorzugt sind 70 bis 85 %ige wässrige Phosphorsäure und Essigsäure; besonders bevorzugt ist Essigsäure.Suitable solvents in the third step of the process according to the invention are formic acid, acetic acid, propionic acid, etc., mixtures of these solvents, or 70 to 85% aqueous phosphoric acid. 70 to 85% aqueous phosphoric acid and acetic acid are preferred; acetic acid is particularly preferred.
Als starke Säure wird im dritten Schritt des erfindungsgemäßen Verfahrenes konz. Schwefelsäure, konz. Salzsäure oder 80 bis 85 %ige wässrige Phosphorsäure einge- setzt. Bevorzugt sind konz. Schwefelsäure und konz. Salzsäure. Besonders bevorzugt ist konz. Salzsäure.As a strong acid in the third step of the process according to the invention, conc. Sulfuric acid, conc. Hydrochloric acid or 80 to 85% aqueous phosphoric acid are used. Conc. Sulfuric acid and conc. Hydrochloric acid. Conc is particularly preferred. Hydrochloric acid.
Wenn als Lösungsmittel 80 bis 85%ige wässrige Phosphorsäure verwendet wird, kann auf den Zusatz einer weiteren Säure naturgemäß verzichtet werden.If 80 to 85% aqueous phosphoric acid is used as the solvent, the addition of another acid can of course be dispensed with.
Der dritte Schritt des erfmdungsgemäßen Verfahrens kann bei Temperaturen zwischen +20 und +120°C durchgeführt werden. Bevorzugt sind Temperaturen zwischen +60 und +110°C.The third step of the method according to the invention can be carried out at temperatures between +20 and + 120 ° C. Temperatures between +60 and + 110 ° C are preferred.
Die Reaktionszeiten des dritten Schritts des erfindungsgemäßen Verfahrens betragen zwischen 1 und 24 Stunden.The reaction times of the third step of the process according to the invention are between 1 and 24 hours.
Die Herstellung von 2,4,5-Trimethylphenylessigsäure nach dem erfindungsgemäßen Verfahren soll durch die folgenden Herstellungsbeispiele erläutert werden:
HerstellungsbeispieleThe preparation of 2,4,5-trimethylphenylacetic acid by the process according to the invention is illustrated by the following preparation examples: Preparation Examples
Beispiel 1: 2,2-Dichlor-l-(2,4,5-trimethylphenyl)-ethanonExample 1: 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone
Bei 0-5°C werden in eine Mischung aus 333 g Pseudocumol und 147,7 g Dichloracetylchlorid 146,6 g A1C13 innerhalb von 2-3 Stunden portionsweise eingetragen. Man rührt danach noch 2 Stunden bei 0-5 °C und lässt auf Raumtemperatur kommen. Das Reaktionsgemisch wird in 3300 ml Eiswasser mit 66,7 g konz. Salzsäure eingerührt. Man extrahiert mit einmal 350 ml und zweimal je 500 ml Essigester. Die vereinigten organischen Phasen werden mit zuerst 165 ml Wasser und dann 85 ml gesättigter wässriger NaCl-Lösung ausgeschüttelt, getrocknet und eingeengt (bis 70°C Badt. / 1 mbar). Man erhält 236,1 g Öl, das nach GC 85,57 % Zielprodukt (ZP) enthält = 202,0 g = 87,4 % der Theorie. Des weiteren sind enthalten: 2,8 % Pseudocumol; 2,6 % Tetramethylbenzol; 0,57 % isomeres ZP; 2,27 % isomeres ZP; 0,55 % isomeres ZP; 0,72 % isomeres ZP; 1,21 % isomeres ZP. Damit beträgt die Summe an146.6 g of A1C1 3 are introduced in portions into a mixture of 333 g of pseudocumene and 147.7 g of dichloroacetyl chloride at 0-5 ° C. in the course of 2-3 hours. The mixture is then stirred at 0-5 ° C for 2 hours and allowed to come to room temperature. The reaction mixture is concentrated in 3300 ml of ice water with 66.7 g. Hydrochloric acid stirred in. It is extracted with once 350 ml and twice 500 ml of ethyl acetate. The combined organic phases are first shaken with 165 ml of water and then 85 ml of saturated aqueous NaCl solution, dried and concentrated (up to 70 ° C. bath / 1 mbar). 236.1 g of oil are obtained which, according to GC, contains 85.57% of the target product (ZP) = 202.0 g = 87.4% of theory. It also contains: 2.8% pseudocumene; 2.6% tetramethylbenzene; 0.57% isomeric ZP; 2.27% isomeric ZP; 0.55% isomeric ZP; 0.72% isomeric ZP; 1.21% isomeric ZP. So the total is
Isomeren des Zielproduktes 5,32 %; d.h. das Verhältnis ZP zu Isomeren beträgt ca. 94 : 6.Target product isomers 5.32%; i.e. the ratio of ZP to isomers is approximately 94: 6.
1H-NMR (400 MHz, CDC13): δ = 2,29 (s; 6H), 2,48 (s; 3H), 6,71 (s., 1H), 7,09 (s; 1H), 7,50 (s; 1H) ppm. MS: m/e = 230 (M+ für 35C1; ca. 2% rel. Intensität), 147 (M-CHC12; 100%), 1191H-NMR (400 MHz, CDC1 3 ): δ = 2.29 (s; 6H), 2.48 (s; 3H), 6.71 (s., 1H), 7.09 (s; 1H), 7.50 (s; 1H) ppm. MS: m / e = 230 (M + for 35 C1; approx. 2% relative intensity), 147 (M-CHC1 2 ; 100%), 119
(Me3Ph; 28%).(Me 3 Ph; 28%).
Beispiel 2: 2,2-Dichlor-l-(2,4,5-trimethylphenyl)-ethanonExample 2: 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone
Bei 0-5°C werden in eine Lösung von 28,3 g Pseudocumol und 14,8 g Dichloracetylchlorid in 100 ml Schwefelkohlenstoff 14,7 g A1C13 innerhalb einer Stunde portionsweise eingetragen. Man rührt danach noch 2 Stunden bei 0-5°C, lässt auf Raumtemperatur kommen und rührt weitere 2 Stunden. Zum Reaktionsgemisch werden 50 ml 2 N Salzsäure getropft. Man extrahiert mit einmal 50 ml und zweimal je 25 ml Essigester. Die vereinigten organischen Phasen werden mit 50 ml gesättigter
wässriger NaCl-Lösung ausgeschüttelt, getrocknet und eingeengt (bis 50°C Badt. / 1 mbar).At 0-5 ° C in a solution of 28.3 g of pseudocumene and 14.8 g of dichloroacetyl chloride in 100 ml of carbon disulfide 14.7 g of A1C1 3 are added in portions within one hour. The mixture is then stirred for a further 2 hours at 0-5 ° C., allowed to come to room temperature and stirred for a further 2 hours. 50 ml of 2N hydrochloric acid are added dropwise to the reaction mixture. The mixture is extracted once with 50 ml and twice with 25 ml of ethyl acetate. The combined organic phases are saturated with 50 ml aqueous NaCl solution shaken out, dried and concentrated (up to 50 ° C bath / 1 mbar).
Man erhält 29,51 g Öl, das nach GC 61,49 % Zielprodukt (ZP) enthält = 18,1 g = 78,3 % der Theorie. Des weiteren sind enthalten: 28,9 % Pseudocumol; 3,2 % Tetramethylbenzol; 0,47 % isomeres ZP; 1,58 % isomeres ZP; 0,40 % isomeres ZP; 0,55 % isomeres ZP; 0,82 % isomeres ZP. Damit beträgt die Summe an Isomeren des Zielproduktes 3,82 %; d.h. das Verhältnis ZP zu Isomeren beträgt ca. 94 : 6.29.51 g of oil are obtained, which according to GC contains 61.49% of target product (ZP) = 18.1 g = 78.3% of theory. It also contains: 28.9% pseudocumene; 3.2% tetramethylbenzene; 0.47% isomeric ZP; 1.58% isomeric ZP; 0.40% isomeric ZP; 0.55% isomeric ZP; 0.82% isomeric ZP. The sum of isomers of the target product is 3.82%; i.e. the ratio of ZP to isomers is approximately 94: 6.
Beispiel 3: 2,2-Dichlor-l-(2,4,5-trimethyIphenyI)-ethanonExample 3: 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone
Es wird vorgegangen wie in Beispiel 2, mit dem Unterschied, dass in 1,2-Dichlor- ethan als Lösungsmittel gearbeitet wird.The procedure is as in Example 2, with the difference that the solvent used is 1,2-dichloroethane.
Man erhält 28,87 g Öl, das nach GC 59,15 % Zielprodukt (ZP) enthält = 17,1 g =28.87 g of oil are obtained, which according to GC contains 59.15% of target product (ZP) = 17.1 g =
74 % der Theorie. Des weiteren sind enthalten: 19,4 % Pseudocumol; 5,6 % Tetramethylbenzol; 0,96 % isomeres ZP; 2,71 % isomeres ZP; 0,42 % isomeres ZP; 0,52 % isomeres ZP; 0,90 % isomeres ZP. Damit beträgt die Summe an Isomeren des Zielproduktes 5,51 %; d.h. das Verhältnis ZP zu Isomeren beträgt ca. 91,5 : 8,5.74% of theory. It also contains: 19.4% pseudocumene; 5.6% tetramethylbenzene; 0.96% isomeric ZP; 2.71% isomeric ZP; 0.42% isomeric ZP; 0.52% isomeric ZP; 0.90% isomeric ZP. The sum of isomers of the target product is thus 5.51%; i.e. the ratio ZP to isomers is approximately 91.5: 8.5.
Beispiel 4: 2,4,5-TrimethylmandelsäureExample 4: 2,4,5-trimethylmandelic acid
222 g 45 %ige Natronlauge und 400 ml Wasser werden vorgelegt und zum Rückfluss erhitzt. Innerhalb von ca. 90 Minuten werden 115,6 g 2,2-Dichlor-l -(2,4,5- trimethylphenyl)-ethanon zugetropft. Anschließend kocht man noch eine weitere222 g of 45% sodium hydroxide solution and 400 ml of water are introduced and heated to reflux. 115.6 g of 2,2-dichloro-1 - (2,4,5-trimethylphenyl) ethanone are added dropwise within about 90 minutes. Then you cook another one
Stunde, versetzt dann das Reaktionsgemisch bei 45°C mit 400 ml Wasser und bei Raumtemperatur mit 400 ml MTBE, trennt die Phasen, schüttelt die wässrige Phase nochmals mit 300 ml MTBE aus, stellt sie dann mit Schwefelsäure sauer und saugt den ausgefallenen Feststoff ab. Dieser wird dreimal mit je 50 ml Wasser gewaschen und dann getrocknet. Man erhält 102,4 g weißen Feststoff, der laut GC 91,9 %Hour, then the reaction mixture is mixed with 400 ml of water at 45 ° C. and with 400 ml of MTBE at room temperature, the phases are separated, the aqueous phase is shaken again with 300 ml of MTBE, then acidified with sulfuric acid and the precipitated solid is suctioned off. This is washed three times with 50 ml of water and then dried. This gives 102.4 g of white solid which, according to GC, is 91.9%
Zielprodukt enthält = 94,1 g = 96,9 % der Theorie.
Beispiel 5: 2,4,5-TrimethylphenylessigsäureTarget product contains = 94.1 g = 96.9% of theory. Example 5: 2,4,5-trimethylphenylacetic acid
Eine Mischung aus 69,9 g 2,4,5-Trimethylmandelsäure, 38,3 g 36 %ige Salzsäure, 11,2 g rotem Phosphor und 6 g KJ in 270 ml Eisessig wird 16 Stunden auf 100°C erhitzt. Anschließend wird bei Raumtemperatur mit 150 ml Eisessig verdünnt. Der Überschuss an Phosphor wird abgesaugt und mit dreimal 50 ml Eisessig gewaschen. Das Filtrat wird mit 150 ml Wasser versetzt und die Essigsäure bei 50°C Badt. / 60 mbar weitgehend abrotiert. Die verbleibende Suspension wird mit 5 ml 20 %iger Schwefelsäure auf pH 1 gestellt und der Feststoff abgesaugt. Der Feststoff wird dreimal mit je 180 ml Wasser gewaschen, wobei dieses Wasser zum ersten Filtrat kommt. Dadurch fällt nochmals Feststoff aus, der über den schon vorhandenen Filterkuchen abgesaugt wird. Man wäscht nochmals mit 100 ml Wasser und trocknet bis zur Gewichtskonstanz. Es resultieren 64,46 g weißer Feststoff, der nach GC 95,8 % Zielprodukt enthält = 61,7 g = 96,2 % d.Th.A mixture of 69.9 g of 2,4,5-trimethylmandelic acid, 38.3 g of 36% hydrochloric acid, 11.2 g of red phosphorus and 6 g of KJ in 270 ml of glacial acetic acid is heated to 100 ° C. for 16 hours. It is then diluted with 150 ml of glacial acetic acid at room temperature. The excess phosphorus is filtered off and washed with three times 50 ml of glacial acetic acid. The filtrate is mixed with 150 ml of water and the acetic acid at 50 ° C bath. / 60 mbar largely spun off. The remaining suspension is adjusted to pH 1 with 5 ml of 20% sulfuric acid and the solid is filtered off with suction. The solid is washed three times with 180 ml of water, this water coming to the first filtrate. This again causes solid matter to precipitate, which is suctioned off over the filter cake already present. It is washed again with 100 ml of water and dried to constant weight. The result is 64.46 g of white solid, which according to GC contains 95.8% of the target product = 61.7 g = 96.2% of theory
NergleichsbeispieleNergleichsbeispiele
Nergleichsbeispiel 1: 2,4,5-Trimethylphenyl-ethanonComparative example 1: 2,4,5-trimethylphenylethanone
Bei 0-5°C werden in eine Mischung aus 60 g Pseudocumol und 7,85 g Acetylchlorid 14,7 g A1C13 innerhalb von 1-2 Stunden portionsweise eingetragen. Man rührt danach noch 2 Stunden bei 0-5°C und lässt auf Raumtemperatur kommen. Das Reaktionsgemisch wird in 340 ml Eiswasser mit 7 g konz. Salzsäure eingerührt. Man extrahiert mit einmal 35 ml und zweimal je 50 ml Essigester. Die vereinigten organischen Phasen werden mit zuerst 20 ml Wasser und dann 10 ml gesättigter wässriger ΝaCl-Lösung ausgeschüttelt, getrocknet und eingeengt (bis 70°C Badt. / 1 mbar).At 0-5 ° C, 14.7 g of A1C1 3 are introduced in portions into a mixture of 60 g of pseudocumene and 7.85 g of acetyl chloride within 1-2 hours. The mixture is then stirred at 0-5 ° C for 2 hours and allowed to come to room temperature. The reaction mixture is concentrated in 340 ml of ice water with 7 g. Hydrochloric acid stirred in. It is extracted with 35 ml once and twice 50 ml of ethyl acetate. The combined organic phases are first shaken with 20 ml of water and then 10 ml of saturated aqueous ΝaCl solution, dried and concentrated (up to 70 ° C. bath / 1 mbar).
Man erhält 14,44 g Öl, das nach GC 89,82 % Zielprodukt (ZP) enthält = 12,97 g = 80,0 % der Theorie. Des weiteren sind enthalten: 2,9 % Pseudocumol; 0,5 %14.44 g of oil are obtained, which according to GC contains 89.82% of target product (ZP) = 12.97 g = 80.0% of theory. It also contains: 2.9% pseudocumene; 0.5%
Tetramethylbenzol; 0,4 % isomeres ZP; 1,28 % isomeres ZP; 0,49 % isomeres ZP;
0,30 % isomeres ZP; 0,62 % isomeres ZP. Damit beträgt die Summe an Isomeren des Zielproduktes 3,09 %; d.h. das Verhältnis ZP zu Isomeren beträgt ca. 97 : 3.Tetramethylbenzene; 0.4% isomeric ZP; 1.28% isomeric ZP; 0.49% isomeric ZP; 0.30% isomeric ZP; 0.62% isomeric ZP. The sum of isomers of the target product is thus 3.09%; ie the ratio ZP to isomers is approximately 97: 3.
Nergleichsbeispiel 2: 2-ChIor-l-(2,4,5-trimethyIphenyl)-ethanonComparative example 2: 2-chloro-1- (2,4,5-trimethylphenyl) -ethanone
Bei 0-5°C werden in eine Mischung aus 170 g Pseudocumol und 67,7 g Chlor- acetylchlorid 88 g A1C13 innerhalb von 2-3 Stunden portionsweise eingetragen. Man rührt danach noch 2 Stunden bei 0;5°C und lässt auf Raumtemperatur kommen. Das Reaktionsgemisch wird in 1000 ml Eiswasser mit 20 g konz. Salzsäure eingerührt. Man extrahiert mit einmal 100 ml und zweimal je 75 ml Essigester. Die vereinigten organischen Phasen werden mit zuerst 100 ml Wasser und dann 50 ml gesättigter wässriger ΝaCl-Lösung ausgeschüttelt, getrocknet und eingeengt (bis 70°C Badt. / 1 mbar). Man erhält 125,77 g Öl, das nach GC 65,2 % Zielprodukt (ZP) enthält = 82,0 g = 69,5 % der Theorie. Des weiteren sind enthalten: 6,8 % Pseudocumol; 1,8 % Tetramethylbenzol; 16,1 % isomeres ZP; 8,0 % isomeres ZP. Damit beträgt dieAt 0-5 ° C, 88 g A1C1 3 are added in portions to a mixture of 170 g pseudocumene and 67.7 g chloroacetyl chloride within 2-3 hours. The mixture is then stirred at 0; 5 ° C for 2 hours and allowed to come to room temperature. The reaction mixture is concentrated in 1000 ml of ice water with 20 g. Hydrochloric acid stirred in. It is extracted with 100 ml once and twice with 75 ml ethyl acetate. The combined organic phases are shaken out with 100 ml of water and then 50 ml of saturated aqueous ΝaCl solution, dried and concentrated (up to 70 ° C bath / 1 mbar). This gives 125.77 g of oil which, according to GC, contains 65.2% of the target product (ZP) = 82.0 g = 69.5% of theory. It also contains: 6.8% pseudocumene; 1.8% tetramethylbenzene; 16.1% isomeric ZP; 8.0% isomeric ZP. So that is
Summe an Isomeren des Zielproduktes 24,7 %; d.h. das Verhältnis ZP zu Isomeren beträgt ca. 72,5 : 27,5.
Total isomers of the target product 24.7%; i.e. the ratio ZP to isomers is approximately 72.5: 27.5.
Claims
1. Verfahren zur Herstellung von 2,4,5-Trimethylphenylessigsäure dadurch gekennzeichnet, dass man Pseudocumol mit Dichloracetylchlorid in einer Friedel-Crafts-Reaktion zu 2.2-Dichlor-l-(2,4,5-trimethylphenyl)-ethanon umsetzt, aus diesem mittels einem Alkalimetallhydroxid die 2,4,5-Trimethyl- mandelsäure herstellt und diese zur 2,4,5-Trimethylphenylessigsäure reduziert.1. Process for the preparation of 2,4,5-trimethylphenylacetic acid, characterized in that pseudocumol is reacted with dichloroacetyl chloride in a Friedel-Crafts reaction to give 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone, from this produces 2,4,5-trimethylmandelic acid using an alkali metal hydroxide and reduces it to 2,4,5-trimethylphenylacetic acid.
2. 2,2-Dichlor-l-(2,4,5-trimethylphenyl)-ethanon. 2. 2,2-dichloro-1- (2,4,5-trimethylphenyl) ethanone.
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PCT/EP2003/003180 WO2003084914A1 (en) | 2002-04-08 | 2003-03-27 | Method for the production of 2,4,5-trimethylphenyl acetic acid |
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CN101353296B (en) * | 2008-09-02 | 2011-09-21 | 中国科学院广州化学研究所 | Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource |
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US3658923A (en) | 1969-12-29 | 1972-04-25 | Phillips Petroleum Co | Halomethylation of trimethylbenzenes |
DE2854210C2 (en) | 1978-12-15 | 1984-08-09 | Degussa Ag, 6000 Frankfurt | Process for the preparation of aromatically or heteroaromatically substituted acetonitriles |
BR9609250B1 (en) | 1995-06-28 | 2011-08-23 | Trisubstituted 2,4,5-phenylethoenols, process for their preparation, pest and herbicide control compositions, use of said compositions and method for pest control. | |
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