DE819696C - Process for the production of nuclear-substituted phenylacetic acids - Google Patents
Process for the production of nuclear-substituted phenylacetic acidsInfo
- Publication number
- DE819696C DE819696C DEK3175D DEK0003175D DE819696C DE 819696 C DE819696 C DE 819696C DE K3175 D DEK3175 D DE K3175D DE K0003175 D DEK0003175 D DE K0003175D DE 819696 C DE819696 C DE 819696C
- Authority
- DE
- Germany
- Prior art keywords
- fluoro
- acid
- phenylacetic acids
- production
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- NKIJBSVPDYIEAT-UHFFFAOYSA-N 1,4,7,10-tetrazacyclododec-10-ene Chemical compound C1CNCCN=CCNCCN1 NKIJBSVPDYIEAT-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 230000003113 alkalizing effect Effects 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- VURNBRZIFABCRU-UHFFFAOYSA-N 2-(3-fluoro-4-methoxyphenyl)acetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1F VURNBRZIFABCRU-UHFFFAOYSA-N 0.000 description 2
- OFCMGCZEFVKTAN-UHFFFAOYSA-N 2-(3-fluoro-4-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1F OFCMGCZEFVKTAN-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- DKPMAQFMVLAJQS-UHFFFAOYSA-N methyl 2-(3-fluoro-4-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(OC)C(F)=C1 DKPMAQFMVLAJQS-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung kernsubstituierter Phenylessigsäuren 1?s wurde gefunden, daß die 3-Fluor-4-oxyphenylessigsäure und ihre O-Alkylderivate bzw. deren Salze die Erscheinungen der Schilddrüsenüberfunktion sehr günstig beeinflussen. Die Stoffe sind wegen ihrer Ungiftigkeit ausgezeichnet verträglich und wirken auf Grundumsatz und Pulsfrequenz in günstigster Weise ein.Process for the production of ring-substituted phenylacetic acids 1? S it was found that 3-fluoro-4-oxyphenylacetic acid and its O-alkyl derivatives or the salts of which have a very beneficial effect on the symptoms of hyperthyroidism. Because of their non-toxicity, the substances are extremely well tolerated and have an effect Basal metabolic rate and pulse rate in the most favorable way.
Man gelangt zu den neuen Verbindungen, die zweckmäßig in der Therapie in Form ihrer Alkalisalze angewendet werden, auf verschiedenen Wegen. So läßt sich das 3-Fluor-4-alkoxybenzylcyanid mit Schwefelsäure zur Fluoralkoxyphenylessigsäure verseifen, und in einer zweiten Stufe kann gegebenenfalls die Alkoxygruppe durch Behandlung mit Bromwasserstoffsäure aufgespalten werden. Verwendet man von vornherein zu der Verseifung z. B. 13romwasserstoffsäureeisessig, dann erhält man die 3-Fluor-4-oxyl>heuvlessigsäure in einem Arbeitsgang. Man kann weiterhin von den entsprechenden, an der alkoholischen Hydroxylgruppe unsubstituierten oder substituierten 3-Fluor-4-oxy- bzw. -alkoxymandelsäuren bzw. -mandelsäurecyaniden ausgehen, die nach bekannten Methoden, z. B. mit jodwasserstoffsäure, in einer Stufe reduziert und zur 3-Fluor-4-oxyphenylessigsÄure verseift werden. Die Reduktion kann auch an einem O-acylierten :@landelsäurecyanid durchgeführt werden, z. B. durch katalytische Hydrierung.One arrives at the new compounds that are useful in therapy in the form of their alkali salts are applied in various ways. So can 3-fluoro-4-alkoxybenzyl cyanide with sulfuric acid to form fluoroalkoxyphenylacetic acid saponify, and in a second stage, the alkoxy group can optionally through Treatment with hydrobromic acid. Used from the start to the saponification z. B. hydrochloric acid acetic acid, then 3-fluoro-4-oxyl> heuvlacetic acid is obtained in one operation. One can continue from the appropriate, at the alcoholic Hydroxyl group unsubstituted or substituted 3-fluoro-4-oxy- or alkoxymandelic acids or go out mandelsäurecyaniden, which by known methods, for. B. with hydriodic acid, reduced in one stage and saponified to 3-fluoro-4-oxyphenyl acetic acid. The reduction can also be carried out on an O-acylated: @ landelsäurecyanid, z. B. by catalytic hydrogenation.
Ein weiterer Weg zur Herstellung der neuen Verbindungen geht von den 3-Fluor-4-oxy- bzw. -alkoxy-a-halogenphenylessigsäuren aus, die leicht zu den halogenfreien substituierten Phenylessigsäuren reduziert und verseift werden können.Another way of making the new compounds is from the 3-fluoro-4-oxy- or -alkoxy-a-halophenylacetic acids, which easily become halogen-free substituted phenylacetic acids can be reduced and saponified.
Dabei kann die Reihenfolge der einzelnen Maßnahmen verschieden sein; man kann zunächst unter Erhaltung der C N-Gruppe die Reduktion an dem der C N-Gruppe benachbarten Kohlenstoffatom einsetzen lassen (z. B. Ersatz von Cl, O H oder O-Acyl durch H), worauf dann Verseifung der C N-Gruppe zu CO OH erfolgt; oder die oben erwähnten Reduktionen werden ausgeführt, wenn die Carboxylgruppe bereits ausgebildet ist.The order of the individual measures can be different; one can first start the reduction at the carbon atom adjacent to the C N group while retaining the C N group (e.g. replacement of Cl, OH or O-acyl by H), which then leads to saponification of the C N group CO OH takes place; or the above-mentioned reductions are carried out when the carboxyl group is already formed.
Eine weitere Möglichkeit zur Darstellung der erfindungsgemäßen Verbindungen besteht in der Behandlung der aus 3-Fluor-4-oxv- bzw. -alkoxybenzaldehyden mit Hippursäuren erhaltenen :\zlactone mit Alkalilauge und Wasserstoffsuperoxyd. Diese Reaktion verläuft nach folgendem Formelschema Beispiele 1. 50 g 3-Fluor-4-methoxybenzylcyanid werden mit einem Gemisch von 36 ccm konzentrierter Schwefelsäure, 36 ccm Wasser und 36 ccm Eisessig etwa 45 Minuten unter Rückfluß gekocht. Dabei löst sich das Nitril mit orangeroter Farbe. Die Mischung wird dann abkühlen gelassen und in etwa 200 ccm Eiswassergegossen. Dabei scheidet sich die3-Fluor-4-methoxyphenylessigsäure in gelblichweißen Kristallen ab, die nach dem Umlösen aus Wasser, gegebenenfalls unter Behandlung mit Tierkohle, bei 115"' schmelzen; Ausbeute: 850% der Theorie.Another possibility for preparing the compounds according to the invention consists in treating the lactones obtained from 3-fluoro-4-oxybenzaldehydes or -alkoxybenzaldehydes with hippuric acids with alkali lye and hydrogen peroxide. This reaction takes place according to the following equation EXAMPLES 1. 50 g of 3-fluoro-4-methoxybenzyl cyanide are refluxed for about 45 minutes with a mixture of 36 cc of concentrated sulfuric acid, 36 cc of water and 36 cc of glacial acetic acid. The nitrile dissolves with an orange-red color. The mixture is then allowed to cool and poured into about 200 cc of ice water. The 3-fluoro-4-methoxyphenylacetic acid separates out in yellowish-white crystals which, after dissolving from water, possibly with treatment with animal charcoal, melt at 115 "'; Yield: 850% of theory.
2. 35,5 g 3 - Fluor - 4 - methoxyphenylessigsäure werden mit 200 ccm 48%iger Bromwasserstoffsäure 4 Stunden unter Rückfluß gekocht. Hierauf wird die Bromwasserstoffsäure bis auf etwa 25 ccm eingedampft, dann der Kolben bis zur Hälfte mit Wasser nachgefüllt und abermals abdestilliert. Der aus braunen Kristallen von 3-Fluor-4-oxyphenylegsigsäure bestehende Rückstand wird in wenig heißem Wasser gelöst, mit Tierkohle behandelt und im Eisschrank auskristallisieren gelassen. Die Kristalle werden abgesaugt, mit wenig Eiswasser nachgewaschen und aus Wasser nochmals umgelöst. F. 132°, Ausbeute 30,5 g = 93 % der Theorie.2. 35.5 g of 3 - fluoro - 4 - methoxyphenylacetic acid are added with 200 ccm 48% hydrobromic acid refluxed for 4 hours. Then the Hydrobromic acid evaporated to about 25 cc, then the flask up to halfway topped up with water and distilled off again. The one made of brown crystals from 3-fluoro-4-oxyphenylegetic acid existing residue is dissolved in a little hot water, Treated with animal charcoal and left to crystallize in the refrigerator. The crystals are suctioned off, washed with a little ice water and redissolved from water. M.p. 132 °, yield 30.5 g = 93% of theory.
3. 200 g 3-Fluor-4-methoxybenzylcyanid werden mit 6oo ccm Bromwasserstoffsäure
(48%ig) und 400 ccm Eisessig 1:1 Stunden unter Rückfluß gekocht. Hierauf wird die
Mischung auf etwa 1/s des Volumens eingedampft und mehrere Stunden in Eis stehengelassen.
Die abgeschiedenen Kristalle von 3-Fluor-4-oxy-phenylessigsäure werden abgesaugt,
mit wenig Eiswasser nachgewaschen und aus wenig heißem Wasser nochmals umkristallisiert;
F. 129 bis 131°. Die Mutterlaugen werden eingedampft und die erhaltenen Kristalle
mehrmals umkristallisiert, bis der F. 132° erreicht ist. Ausbeute: 8o 0/0 der Theorie.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEK3175D DE819696C (en) | 1943-02-03 | 1943-02-03 | Process for the production of nuclear-substituted phenylacetic acids |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEK3175D DE819696C (en) | 1943-02-03 | 1943-02-03 | Process for the production of nuclear-substituted phenylacetic acids |
Publications (1)
Publication Number | Publication Date |
---|---|
DE819696C true DE819696C (en) | 1951-11-05 |
Family
ID=7209755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DEK3175D Expired DE819696C (en) | 1943-02-03 | 1943-02-03 | Process for the production of nuclear-substituted phenylacetic acids |
Country Status (1)
Country | Link |
---|---|
DE (1) | DE819696C (en) |
-
1943
- 1943-02-03 DE DEK3175D patent/DE819696C/en not_active Expired
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