CH443350A - Process for the production of new salicylic acid derivatives - Google Patents
Process for the production of new salicylic acid derivativesInfo
- Publication number
- CH443350A CH443350A CH348263A CH348263A CH443350A CH 443350 A CH443350 A CH 443350A CH 348263 A CH348263 A CH 348263A CH 348263 A CH348263 A CH 348263A CH 443350 A CH443350 A CH 443350A
- Authority
- CH
- Switzerland
- Prior art keywords
- salicylic acid
- methyl
- acid derivatives
- production
- xylene
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 title claims description 5
- 150000003872 salicylic acid derivatives Chemical class 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000001569 carbon dioxide Substances 0.000 claims description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002989 phenols Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 23
- 229960004889 salicylic acid Drugs 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 11
- 239000008096 xylene Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- -1 salicylic acid derivatives Salicylic acids Chemical class 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 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 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- DZZPJWJPJJNWHM-UHFFFAOYSA-N 2-hydroxy-3-(1-phenylethyl)benzoic acid Chemical compound C=1C=CC(C(O)=O)=C(O)C=1C(C)C1=CC=CC=C1 DZZPJWJPJJNWHM-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GVZMSQZBRPXEGK-UHFFFAOYSA-N 2-hydroxy-3-(1-phenylprop-2-enyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(C=C)C2=CC=CC=C2)=C1O GVZMSQZBRPXEGK-UHFFFAOYSA-N 0.000 description 2
- VAYMEJTVMQWPBZ-UHFFFAOYSA-N 3-[1-(4-chlorophenyl)ethyl]-2-hydroxybenzoic acid Chemical compound C=1C=CC(C(O)=O)=C(O)C=1C(C)C1=CC=C(Cl)C=C1 VAYMEJTVMQWPBZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HKNDKNUNEABACI-UHFFFAOYSA-N CC(C(C=CC=C1)=C1OC)C(C=CC=C1C(O)=O)=C1O Chemical compound CC(C(C=CC=C1)=C1OC)C(C=CC=C1C(O)=O)=C1O HKNDKNUNEABACI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000021523 carboxylation Effects 0.000 description 2
- 238000006473 carboxylation reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QYPBOXRMLFPDEQ-UHFFFAOYSA-N 2-(1-phenylethenyl)phenol Chemical compound OC1=CC=CC=C1C(=C)C1=CC=CC=C1 QYPBOXRMLFPDEQ-UHFFFAOYSA-N 0.000 description 1
- CPIXGYKQJSHWGS-UHFFFAOYSA-N 2-[1-(4-chlorophenyl)ethyl]phenol Chemical compound C=1C=CC=C(O)C=1C(C)C1=CC=C(Cl)C=C1 CPIXGYKQJSHWGS-UHFFFAOYSA-N 0.000 description 1
- VPTXPMBNBZLRET-UHFFFAOYSA-N 2-hydroxy-3-(3-phenylpropyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(CCCC=2C=CC=CC=2)=C1O VPTXPMBNBZLRET-UHFFFAOYSA-N 0.000 description 1
- BXQSMDCMQRISEC-UHFFFAOYSA-N 2-hydroxy-5-methyl-3-(1-phenylethyl)benzoic acid Chemical compound C=1C(C)=CC(C(O)=O)=C(O)C=1C(C)C1=CC=CC=C1 BXQSMDCMQRISEC-UHFFFAOYSA-N 0.000 description 1
- CKDMFIHYMJZAIL-UHFFFAOYSA-N 2-hydroxy-6-methyl-3-(1-phenylethyl)benzoic acid Chemical compound C=1C=C(C)C(C(O)=O)=C(O)C=1C(C)C1=CC=CC=C1 CKDMFIHYMJZAIL-UHFFFAOYSA-N 0.000 description 1
- IIVWHGMLFGNMOW-UHFFFAOYSA-N 2-methylpropane Chemical compound C[C](C)C IIVWHGMLFGNMOW-UHFFFAOYSA-N 0.000 description 1
- LHSIUQJHRFFBPW-UHFFFAOYSA-N CC(C1=C(C)C=CC=C1)C(C=CC=C1C(O)=O)=C1O Chemical compound CC(C1=C(C)C=CC=C1)C(C=CC=C1C(O)=O)=C1O LHSIUQJHRFFBPW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
-
- 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
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
- C07C47/57—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
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)
Description
Verfahren zur Herstellung von neuen Salicylsäure-Derivaten
In 3-Stellung durch einen Aralkylrest substituierte Salicylsäuren der Formel
EMI1.1
in welcher X und Y Wasserstoff, Halogen, Hydroxyl- oder niedrige Alkyl-bzw. Alkoxygruppen bedeuten und A einen geradkettigen oder verzweigten, gesättigten oder ungesÏttigten aliphatischen Kohlenwasserstoffrest von 2-4 Kohlenstoffatomen vorstellt, sind in der Literatur bislang nicht beschrieben.
Es wurde gefunden, da¯ diese neuen Verbindungen eine sbarke Wirkung auf den Kohlehydratistoffwochsel baiben, die sich in ihrer Fähigkeit zur Senkung des nor- mayen Blutzuckerspiegels und insbesondere des phatologisch erh¯hten Blutzuckerspiegels zeigt. Eine im Prinzip eicharbige Wirkung besitzt auch-wie bereits be- ekannt-die Salicylsäure sowie einige ihrer Substitutions. produkte (vgl. z. B. J. Pharm. a. Pharmacol, 11/1959, S. 705 ; Biochem. J. 75/1060, S. 298).
Die Wirkung g der neuen Verbinduumgen : ist jedoch wesentlich höher (etwa das 5-bis lOfache und mehr) ; dabei ist gleich- zeitig die akute ToxizitÏt nur wenig höhler als die der Salicylsäure selbst. Die Verbindungen besitzen somit hohes Interesse, insbesondere zur Behandlung von dia betischen Zuständen, wofür sie entweder allein oder in n Kombination mit anderen, gleichfalls auf den Kohle- hydratstoffwechsel einwirkenden Substanzen geeignet sind.
Die Erfindung betrifft ein Verfahren f r Herstellung der neuen Aralkylsalicylsäuren, bei welchem man ein substituiertes Phenol der Formel
EMI1.2
bzw. dessen Alkalisalze mit Koblendioxyd behandelt.
Diese Carboxylierung wird vorzugsweise unter den Reaktionsbedingungen der Kolbe-Schmitt-Synth ! ese odler einer der bekannten Variationen dieses Verfahrens vor- genommen (vgl. Chem. Reviews 57/1957, S. 583). Anstelle der freien Phenole kann man auch o-metallierte Derivate der Carboxylierung unterwerfen.
Bei der oben genannten Reaktion ist es mitunter wünschenswert oder erforderlich, dass man dile p-Sbellung zur OH-Gruppe zwischenzeitlich durch eine nach eirfolgter Umse, tzung leicht abspaltbare Gruppe blockiert.
Hierfür kommen Halogen, Nibro-oder Aminognuppen in Frage, die man z. B. durch reduktive Verfahren wieder entfernen kann ; eine weitere Möglichkeit ist die Blok kierung der p-Stellung mit einem tert.-Butylrest, welcher mit Aluminiumchlorid abspaltbar ist. Die Herstellung der ungesättigten SalicylsÏure-Derivate (A = ungesÏttigter, geradkettiger oder verzweigter aJiphajtischer Kohlen- wasserstoffrest) erfolgt prinzipiell in analoger Weise wie die der gesättigten Verbindungen, wobei allerdings diejenigen Methoden weniger geeignet sind, bei dene die ungesättigte Aralkylgruppe in Mitleidenschaft gezogen wird.
Die ungesättigten Salicylsäure-Derivatie besitzen selbst eine starke blutzuckersenkende Wirkung. Sie sind aber auch wichtige Zwischenprodukte zur Herstellung der Verbindungen obiger Formel, in welcher A einen Alkylenrest bedeutet ; denn sie lassen sich durch Hydrierung in einfacher Weise in die Aralkyl-salicylsäuren überführen.
Beispiele
1. 3- (a-Methyl-benzyl)-salicylsäure
In eine Lösung von 38 g 2- (a-Methyl-benzyl)- phenol in 500 cm3 Xylol werden unter Rückfluss und ständigem Durchleiten von Kohlendioxyd 8, 8 g Natrium in kleinen Stücken innerhalb von 2 Stunden eingetragen.
Anschliessend wird noch weitere 4 Stunden unterDurch- leiten von Kohlendioxyd erhitzt. Nach dem Abkühlen l¯st man nichtumgesetzte Natriumreste mit Alkohol und engt die Lösung im Vakuum ein. Der Rückstand wird in Wasser aufgenommen, angesäuert und mit Ather extrahiert. Der ätherischen Lösung entzieht man die gebildete SÏure mit Sodal¯sung, wÏhrend nichtumgesetztes Ausgangs-Phenol im Ather verbleibt und zurückgewonnen wird. Die Sadalösung wird nun angesäuert, erneut mit Au-heur extrahiert und der Ather nach dem Trocknen eingeengt. Als Rückstand erhält man 29, 5 g (= 63,6 % d. Th.) 3-(α-Methyl-benzyl)-salicylsÏure vom Fp. 132-134 .
Der Schmelzpunkt steigt nach Umkristallisieren aus Benzol-Ligroin (5 : 1) oder aus 50 % wϯ rigem Alkohol auf 136-138 .
In analoger Weise erhält man die folgenden Verbindungen :
3- Fp. 199-200
3-(α-Methyl-2'-methylbenzyl)-salicylsÏureFp. 186-187¯
3-(¯-Phenyl-Ïthyl)-salicylsÏure Fp. 145-147¯ 3-(α-¯thyl-benzyl)-salicylsÏure Fp. 114-116
2. 3-(α-Methyl-2'-methoxybenzyl)-salicylsÏure
12, 2 g 2-(α-Methyl-2'-methoxybenzyl)-phenol-Na- triumsalz werden in 35 cm3 Diäthylenglykol-dimethyl- äther gelöst und im 200 cm3-Autoklav 10 Stunden bei 200 unter 105 atü Kohlendioxyd erhitzt. Die Aufarbei- tung erfolgt wie im Beispiel l. Ausbeute 60% d. Th.
3- (a-Methyl-2'-methoxybenzyl)-salicylsäure vom Fp. 176 .
3. 3-(α-Methyl-4'-chlorbenzyl)-salicylsÏure
2,77 g Natrium werden in 50 cm3 abs. Methanol gel¯st und 27 g 2-(α-Methyl-4'-chlorbenzyl)-phenol (Kp0,2 159-160¯) zugegeben. Das Methanol wird im Vakuum verdampft. Den R ckstand nimmt man zweimal in je 20 cm3 abs. Xylol auf und engt wieder im Vakuum ein. Schliesslich gibt man nochmails 30 cm3 Xylol zu und destilliert das Xylol ohne Vakuum unter Einleiten von Stickstoff ab. Nach Zugabe von 100 cm3 Xylol wird bei 130-140 unter Rühren 9 Stunden trockenes Kohlendioxyd eingeleitet. Die Aufarbeitung erfolgt wie im Beispiel 1 Ausbeute: 15,6 g 3-(α-Methyl- 4'-chlorbenzyl)-salicylsÏure vom Fp. 189¯.
4. Nach der in Beispiel 1 beschriebenen Methode erhält man die folgenden Verbindungen : 3-(γ-Phenyl-propyl)-salicylsÏure F. 128-130 3-(α-Methyl-benzyl)-6-methyl-salicylsÏure F. 129-131 3-(α-Methyl-benzyl)-5-methyl-salicylsÏure F. 160-161¯ 3- (a-Methyl-m-methylbenzyl)-salicylsäure F. 106-108 3-(α-Methyl-¯-phenÏthyl)-salicylsÏure F. 125-127 3-(¯-o-Hydroxy-phenÏthyl)-salicylsÏure F. 160-162 3-(a-Methyl-benzyl)-y-resorcylsäure F. 167 3-(α-Methyl-p-methylbenzyl)-salicylsÏure F. 160¯
5.
In analoger Weise wie im Beispiel 2 beschriebenjedoch unter Verwendung von Xylol als Lösungsmittel erhÏlt man die 3-(α-Methyl-o-fluorbenzyl)-salicylsÏure vom F. 157-158 .
6. Nach der in Beispiel 3 beschriebenen Methode erhält man folgende Verbindungen : 3-(a-Methyl-m-chlorbenzyl)-salicylsäure F. 95¯
3-(¯-o-Chlor-phenÏthyl)-salicylsÏure F. 163
7. 3-(α-Vinyl-benzyl)-salicylsÏure
11 g Natrium werden in 400 ml trockenem Xylol geschmolzen. Dann lässt man 50 g 2-(α-Phenyl-allyl)- phenol (hergestellt nach B. 58/1925, S. 275) in 100 ml Xylol zulaufen. Anschliessend leitet man in die Lösung unter Rühren und Rückfluss 9 Stunden Kohlendioxyd ein. Nach Abkühlen gibt man etwas Alkohol zu und @ destilliert das Lösungsmibbel im Vakuum ab. Der R ckstand wird in Sodalösung aufgenommen und diese mehrmals mit Ligroin extrahiert.
Aus dem Ligroinextrakt t können 12 g nichtumgesetztes Ausgangsphenol zurück- erhalten werden. Die wässrige Lösung wird mit Tierkohle erhitzt und in das Filtrat Schwefeldioxyd eingeleitet. Das ausgefallene Produkt wird bei Raumtemperatur abgesaugt, mehrmals mit Wasser gewaschen und getrocknet.
Auf diese Weise erhält man 40, 2 g 3-(α-Vinyl-benzyl)- salicylsäure vom F. 119-122 . Nach Umkristallisieren aus Benzol/Ligroin schmilzt die Verbindung bei 124 bis 125¯; ; Ausbaute an reinem Produkt : 28, 2 g (= 61 % d. Th., bezagen auf umgesetztes Ausgangs- phenol).
Durch katalytische Hydrierung der 3- (a-Vinyl benzyl)-salicylsäure unter Verwendung von Palladium Kohle als Katalysator erhält man in 93 % iger Ausbeute die im Beispiel 1 beschriebene 3-(α-¯thyl-benzyl)- salicylsäure vom F. 114-116 .
8. 3- (P-Styryl)-salicylsiiure
11, 8 g o-Oxystilben (Fp. 145-146 ; A. 433/1923, S. 240) werden mit molaren Mengen Natriummethylat (13, 8 g Natrium in 40 ml absol. Methanol) in das Natriumsalz übergeführt. Zur Entfernung des Methanols wird Xylol zugesetzt und so lange destilliert, bis nur noch reines Xylol übergeht. Anschlie¯end versetzt man die Xylol-Lösung des Natriumsalzes mit 4, 2 g Kaliumcarbonat und carboxyliert 7 Stunden im Autoklav bei 130 unter 56 atü Kohlendioxyd-Druck.
Das Reaktions- gemisch wird dann mit Wasser extrahiert, der erhaltene Extrakt angesäuert und ausgeäthert. Der Atherextrakt wird mit verdünnter Natriumbicarbonat-Lösung ausgeschüttelt, die erhaltene Lösung angesäuert und der Niederschlag abfiltriert. Nach dem Umkristallisieren aus Toluol erhält man 4, 9 g 3-(¯-Styryl)-salicylsÏure vom F. 201-203 ; Ausbeute 34%d. Th.
In analoger Weise erhält man die folgenden Ver- bindungen : 3-(α-Methyl-¯-styryl)-salicylsÏure F. 155-158
Das als Ausgangsprodukt verwendete o-(α-Methyl-¯- -styryl)-phenol siedet bei Kpo. i 123-129 . Die Reini gung des Endprodukts erfolgt ber das Natriumsalz,
3-[¯-(2'-Chlor-styryl)]-salicylsÏure F. 220-222¯
Das als Auagangsprodukt verweindete o-Chlor-o' oxystilben schmilzt bei 133 . Die Reinigung des Endprodukts erfolgt ber das Natriumsalz.
3-(α-Styryl)-salicylsÏure F. 143-145
Das als Ausgangsprodukt verwendete 2-(α-Methy- len-benzyl)-phenol wird nach B 36/1903, S. 4002 hergestellt. Die Reinigung des Endprodukts erfolgt durch Umkristallisation aus Benzol/Ligroin.
Durch katalytische Hydrierung der letztgenannten Verbindung unter Verwendung von Palladium-Kohle als Katalysator erhält man in 96 % iger Ausbeute die im Beispiel beschriebene 3-(α-Methyl-benzyl)-salicyl- sÏure vom F. 136-138¯.
Process for the production of new salicylic acid derivatives
Salicylic acids, substituted in the 3-position by an aralkyl radical, of the formula
EMI1.1
in which X and Y are hydrogen, halogen, hydroxyl or lower alkyl or. Alkoxy groups and A represents a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical of 2-4 carbon atoms, have not yet been described in the literature.
It has been found that these new compounds have a strong effect on the carbohydrate week, which manifests itself in their ability to lower normal blood sugar levels and in particular the pathologically elevated blood sugar level. As already known, salicylic acid as well as some of its substitutions also have an effect that is essentially calibrated. products (cf. e.g. J. Pharm. a. Pharmacol, 11/1959, p. 705; Biochem. J. 75/1060, p. 298).
The effect of the new compounds: is, however, much higher (about 5 to 10 times and more); At the same time, the acute toxicity is only slightly higher than that of salicylic acid itself. The compounds are therefore of great interest, especially for the treatment of diabetic conditions, for which they either alone or in combination with others, which also have an effect on the carbohydrate metabolism Substances are suitable.
The invention relates to a process for the preparation of the new aralkylsalicylic acids, in which a substituted phenol of the formula
EMI1.2
or its alkali salts treated with coblene dioxide.
This carboxylation is preferably carried out under the reaction conditions of the Kolbe-Schmitt-Synth! ese or one of the known variations of this process was carried out (cf. Chem. Reviews 57/1957, p. 583). Instead of the free phenols, o-metalated derivatives can also be subjected to carboxylation.
In the above-mentioned reaction it is sometimes desirable or necessary that the p-bond to the OH group is blocked in the meantime by a group which can easily be split off after the reaction has taken place.
For this purpose halogen, nibro or amino groups come into question, which one z. B. can be removed again by reductive processes; Another possibility is to block the p-position with a tert-butyl radical, which can be split off with aluminum chloride. The production of the unsaturated salicylic acid derivatives (A = unsaturated, straight-chain or branched aliphatic hydrocarbon radical) is in principle carried out in a manner analogous to that of the saturated compounds, although those methods are less suitable in which the unsaturated aralkyl group is affected.
The unsaturated salicylic acid derivatives themselves have a strong blood sugar lowering effect. But they are also important intermediates for the preparation of the compounds of the above formula in which A is an alkylene radical; because they can be converted into the aralkyl salicylic acids in a simple manner by hydrogenation.
Examples
1. 3- (α-Methyl-benzyl) -salicylic acid
In a solution of 38 g of 2- (a-methyl-benzyl) phenol in 500 cm3 of xylene, 8.8 g of sodium are introduced in small pieces within 2 hours under reflux and with constant passage of carbon dioxide.
The mixture is then heated for a further 4 hours while passing through carbon dioxide. After cooling, unreacted residual sodium is dissolved with alcohol and the solution is concentrated in vacuo. The residue is taken up in water, acidified and extracted with ether. The acid formed is removed from the ethereal solution with soda solution, while unreacted starting phenol remains in the ether and is recovered. The Soda solution is now acidified, extracted again with Au-heur and the ether is concentrated after drying. The residue obtained is 29.5 g (= 63.6% of theory) of 3 - (α-methylbenzyl) salicylic acid of melting point 132-134.
After recrystallization from benzene-ligroin (5: 1) or from 50% aqueous alcohol, the melting point rises to 136-138.
The following compounds are obtained in an analogous manner:
3 m.p. 199-200
3 - (α-Methyl-2'-methylbenzyl) -salicylic acid FP. 186-187¯
3- (¯-Phenyl-ethyl) salicylic acid, m.p. 145-147¯ 3 - (α-¯-ethyl-benzyl) -salicylic acid, m.p. 114-116
2. 3 - (α-Methyl-2'-methoxybenzyl) salicylic acid
12.2 g of 2 - (α-methyl-2'-methoxybenzyl) phenol sodium salt are dissolved in 35 cm3 of diethylene glycol dimethyl ether and heated in a 200 cm3 autoclave for 10 hours at 200 under 105 atmospheres of carbon dioxide. The processing takes place as in example 1. Yield 60% of theory Th.
3- (α-Methyl-2'-methoxybenzyl) salicylic acid, m.p. 176.
3. 3 - (α-Methyl-4'-chlorobenzyl) salicylic acid
2.77 g of sodium are in 50 cm3 abs. Dissolved methanol and added 27 g of 2 - (α-methyl-4'-chlorobenzyl) phenol (boiling point 0.2 159-160¯). The methanol is evaporated in vacuo. The residue is taken twice in 20 cm3 abs. Xylene and concentrated again in vacuo. Finally, another 30 cm3 of xylene is added and the xylene is distilled off without a vacuum while passing in nitrogen. After adding 100 cm3 of xylene, dry carbon dioxide is passed in at 130-140 for 9 hours while stirring. Working up is as in Example 1. Yield: 15.6 g of 3 - (α-methyl-4'-chlorobenzyl) salicylic acid with a melting point of 189¯.
4. The following compounds are obtained according to the method described in Example 1: 3 - (γ-phenyl-propyl) -salicylic acid F. 128-130 3 - (α-methyl-benzyl) -6-methyl-salicylic acid F. 129-131 3 - (α-methyl-benzyl) -5-methyl-salicylic acid F. 160-161¯ 3- (a-methyl-m-methylbenzyl) -salicylic acid F. 106-108 3 - (α-methyl -¯-phenÏthyl) -salicylic acid F. 125-127 3- (¯-o-Hydroxyphenyl) -salicylic acid F. 160-162 3- (a-methyl-benzyl) -y-resorcylic acid F. 167 3 - (? ; -Methyl-p-methylbenzyl) salicylic acid F. 160¯
5.
In a manner analogous to that described in Example 2, however, using xylene as the solvent, 3 - (α-methyl-o-fluorobenzyl) salicylic acid with a melting point of 157-158 is obtained.
6. The following compounds are obtained by the method described in Example 3: 3- (a-Methyl-m-chlorobenzyl) salicylic acid F. 95¯
3- (¯-o-chlorophenÏthyl) salicylic acid F. 163
7. 3 - (α-Vinyl-benzyl) -salicylic acid
11 g of sodium are melted in 400 ml of dry xylene. Then 50 g of 2 - (α-phenyl-allyl) phenol (prepared according to B. 58/1925, p. 275) in 100 ml of xylene are run in. Carbon dioxide is then passed into the solution with stirring and reflux for 9 hours. After cooling, a little alcohol is added and the liquid solution is distilled off in vacuo. The residue is taken up in soda solution and this extracted several times with ligroin.
12 g of unreacted starting phenol can be recovered from the ligroin extract t. The aqueous solution is heated with animal charcoal and sulfur dioxide is introduced into the filtrate. The precipitated product is filtered off with suction at room temperature, washed several times with water and dried.
In this way 40.2 g of 3 - (α-vinyl-benzyl) -salicylic acid of m.p. 119-122 are obtained. After recrystallization from benzene / ligroin, the compound melts at 124 to 125¯; ; Expansion of pure product: 28.2 g (= 61% of theory, based on converted starting phenol).
Catalytic hydrogenation of 3- (a-vinylbenzyl) salicylic acid using palladium carbon as a catalyst gives the 3 - (α-¯thyl-benzyl) salicylic acid with a melting point of 114 described in Example 1 in 93% yield -116.
8. 3- (P-styryl) salicylic acid
11.8 g of o-oxystilbene (mp. 145-146; A. 433/1923, p. 240) are converted into the sodium salt with molar amounts of sodium methylate (13.8 g of sodium in 40 ml of absolute methanol). Xylene is added to remove the methanol and the mixture is distilled until only pure xylene passes over. The xylene solution of the sodium salt is then mixed with 4.2 g of potassium carbonate and carboxylated for 7 hours in an autoclave at 130 under 56 atmospheres of carbon dioxide pressure.
The reaction mixture is then extracted with water, and the extract obtained is acidified and extracted with ether. The ether extract is extracted with dilute sodium bicarbonate solution, the resulting solution is acidified and the precipitate is filtered off. After recrystallization from toluene, 4.9 g of 3- (¯-styryl) salicylic acid with a melting point of 201-203 are obtained; Yield 34% of theory Th.
The following compounds are obtained in an analogous manner: 3 - (α-methyl-¯-styryl) -salicylic acid F. 155-158
The o- (α-methyl-¯- -styryl) -phenol used as the starting product boils at Kpo. i 123-129. The final product is cleaned using the sodium salt,
3- [¯- (2'-chlorostyryl)] - salicylic acid F. 220-222¯
The o-chloro-o 'oxystilbene, used as an initial product, melts at 133. The final product is purified using the sodium salt.
3 - (α-Styryl) salicylic acid F. 143-145
The 2 - (α-methylene-benzyl) -phenol used as the starting product is prepared according to B 36/1903, p. 4002. The final product is purified by recrystallization from benzene / ligroin.
Catalytic hydrogenation of the last-mentioned compound using palladium-carbon as a catalyst gives the 3 - (α-methyl-benzyl) -salicylic acid with a melting point of 136-138¯ described in the example in 96% yield.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB66450A DE1198831B (en) | 1962-03-21 | 1962-03-21 | Process for the preparation of 3-aralkylsalicylic acids |
| DEB69969A DE1216293B (en) | 1962-12-13 | 1962-12-13 | Process for the preparation of 3-phenylalkenyl-salicylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH443350A true CH443350A (en) | 1967-09-15 |
Family
ID=25966191
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH348263A CH443350A (en) | 1962-03-21 | 1963-03-19 | Process for the production of new salicylic acid derivatives |
| CH1253966A CH479526A (en) | 1962-03-21 | 1963-03-19 | Process for the preparation of substituted salicylic acids |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1253966A CH479526A (en) | 1962-03-21 | 1963-03-19 | Process for the preparation of substituted salicylic acids |
Country Status (7)
| Country | Link |
|---|---|
| AT (1) | AT243785B (en) |
| CH (2) | CH443350A (en) |
| DK (2) | DK109782C (en) |
| FI (2) | FI40720B (en) |
| GB (1) | GB966479A (en) |
| LU (1) | LU43384A1 (en) |
| SE (1) | SE312142B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004058679A3 (en) * | 2002-12-20 | 2004-08-26 | Mitokor Inc | Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4687869A (en) * | 1984-10-22 | 1987-08-18 | Ciba-Geigy Corporation | Metal salicylates, process for their preparation and use thereof as color developers in pressure-sensitive or heat-sensitive recording materials |
-
1963
- 1963-03-01 GB GB830463A patent/GB966479A/en not_active Expired
- 1963-03-14 FI FI49763A patent/FI40720B/fi active
- 1963-03-19 CH CH348263A patent/CH443350A/en unknown
- 1963-03-19 CH CH1253966A patent/CH479526A/en not_active IP Right Cessation
- 1963-03-19 LU LU43384D patent/LU43384A1/xx unknown
- 1963-03-20 AT AT220563A patent/AT243785B/en active
- 1963-03-20 DK DK560965A patent/DK109782C/en active
- 1963-03-20 DK DK127363A patent/DK109147C/en active
-
1965
- 1965-06-15 SE SE787865A patent/SE312142B/xx unknown
-
1968
- 1968-08-15 FI FI231568A patent/FI42093C/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004058679A3 (en) * | 2002-12-20 | 2004-08-26 | Mitokor Inc | Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto |
Also Published As
| Publication number | Publication date |
|---|---|
| FI40720B (en) | 1969-01-31 |
| DK109147C (en) | 1968-03-25 |
| FI42093C (en) | 1970-05-11 |
| CH479526A (en) | 1969-10-15 |
| FI42093B (en) | 1970-02-02 |
| DK109782C (en) | 1968-07-01 |
| GB966479A (en) | 1964-08-12 |
| LU43384A1 (en) | 1963-05-20 |
| AT243785B (en) | 1965-11-25 |
| SE312142B (en) | 1969-07-07 |
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