CH218523A - Process for the preparation of 2-methyl-1,4-dioxy-naphthalene-diphosphoric acid ester. - Google Patents
Process for the preparation of 2-methyl-1,4-dioxy-naphthalene-diphosphoric acid ester.Info
- Publication number
- CH218523A CH218523A CH218523DA CH218523A CH 218523 A CH218523 A CH 218523A CH 218523D A CH218523D A CH 218523DA CH 218523 A CH218523 A CH 218523A
- Authority
- CH
- Switzerland
- Prior art keywords
- methyl
- water
- acid ester
- diphosphoric acid
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 230000002364 anti-haemorrhagic effect Effects 0.000 claims description 2
- 230000023555 blood coagulation Effects 0.000 claims description 2
- 230000006866 deterioration Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 235000016709 nutrition Nutrition 0.000 claims description 2
- 230000035764 nutrition Effects 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 8
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- -1 hydroquinone bis-phosphorus ester acids Chemical class 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 1
- 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 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PCILLCXFKWDRMK-UHFFFAOYSA-N naphthalene-1,4-diol Chemical compound C1=CC=C2C(O)=CC=C(O)C2=C1 PCILLCXFKWDRMK-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Description
Verfahren zur Darstellung von 2-Nethyl-1,4-diogy-naphthalin-dipbosphorsäureester. Es ist bekannt, dass Phosphorsäureester von Hydrochinonen nicht mit Phosphoroxy- chlorid hergestellt werden können, da die dabei entstehenden Bis-dichloro-phosphoryl- ester sich bei Zusatz von Wasser zersetzen, wobei ein Hydrochinon und Phosphorsäure entstehen:
(Knauer, Berichte der Deutschen Chemischen Gesellschaft, Bd. 27 [1894], S. 2565). Ferner ist bekannt, dass das Ver fahren für die Herstellung von lIydrochinon- bis-phosphorestersäuren (Genvresse, Compt. rend. [1927], S.
523) nicht für die Gewin nung von Diphosphorsäureestern substituier ter Hydrochinone angewendet werden kann, da bei der Behandlung solcher Hydrochinone mit Phosphorsäureanhydrid schwer zu be arbeitende, teerige Stoffe entstehen.
Es wurde nun gefunden, dass man alkyl- substituierte Phosphorsäureester des Hy dro- chinons und Naphthohydrochinons dadurch gewinnen kann, dass man auf das entspre- chende Hydrochinon Phosphoroxyhalogenid einwirken lässt und die gebildete Verbindung mit Wasser behandelt. Durch Umsetzung des so entstandenen Phosphorsäureesters mit anorganischen oder organischen Basen er hält man wasserlösliche Salze.
So kann man beispielsweise das Tetranatriumsalz des 2-Methyl-naphthohydrochinon-bis-phosphor- säureesters dadurch erhalten, da.ss man 2-Me- thyl-naphthohydrochinon mit. Phosphoroxy- chlorid umsetzt, das Reaktionsprodukt mit Wasser behandelt und auf den entstandenen 2 -Methyl-naphthohydrochinon-bis-phosphor- säureester Natriumalkoholat einwirken lässt.
Die als Ausgangsprodukte verwendeten substituierten Hydrochinone werden zweck mässig in einer wasserfreien Base, wie z. B. Pyridin, Dialkylanilin, Chinolin oder der gleichen, gelöst. Die Reaktion mit Phosphor- oxyhalogenid verläuft unter Wärmeentwick- lung; sie kann bei Temperaturen zwischen Zimmertemperatur und Siedepunkt der all fällig verwendeten Base vorgenommen wer den; besonders geeignet sind Temperaturen von 80 bis<B>150'</B> C.
Wässerige Lösungen der erhaltenen Diphosphorsäureester können un mittelbar neutralisiert oder die Ester daraus in trockenem Zustand isoliert und eventuell dann in andern Mitteln zur Reaktion ge bracht werden. So können zum Beispiel die wässerigen Lösungen der Diphosphorsäure- ester im Vakuum zur Trockne verdampft und dann die Ester in einem geeigneten organi schen Lösungsmittel, wie z. B. Äthylalkohol, aufgenommen werden.
Gegenstand des vorliegenden Patentes ist ein Verfahren zur Darstellung von 2-Methyl- 1, 4 - dioxynaphthalin - diphosphorsäureester, welches dadurch gekennzeichnet ist, dass' man auf 2-Methyl-naphthohydrochinon Phosphor- oxychlorid einwirken lässt und das Reaktions produkt mit Wasser behandelt.
Der 2-l@lethyl-1,4-dioxynaphthalin-di- phosphorsäureester schmilzt bei <B>209'.</B> In Wasser ist er leicht löslich, ebenso in Me- thyl-, Äthylalkohol und Aceton. Schwer löst Petroläther. Leicht löslich in Wasser ist das Tetranatriumsalz und das Dicalcium- salz, das 12 Moleküle Kristallwasser hat.
Der neue Phosphorsäureester besitzt eine starke antihämorrhagische Wirkung, so re duzieren seine Salze die Blutgerinnungszeit von nach Ansbacher (Journal Nutrition .1.7 <B>[</B>1939], S. 303) Vitamin-K-frei gehaltenen Kücken auf weniger als zehn Minuten bei Dosen von weniger als 4 gamma pro Kücken, wenn sie subkutan, intravenös oder intra muskulär angewandt werden.
Zufolge der aussergewöhnlichen Wasserlöslichkeit und der neutralen Reaktion eignen sich die Salze besonders für parenterale Anwendung, sie \werden vom Organismus leicht. aufgenommen, wodurch eine schnelle Wirkung erzielt. wird. Die wässerigen Lösungen sind stabil und können längere Zeit gekocht werden, ohne an Wirksamkeit zu verlieren oder Anzeichen von Zersetzung aufzuweisen.
Der 2-111ethyl-1,4-dioxynaphthalin-di- phosphorsäureester soll als solcher oder in Form seiner Salze als Arzneimittel verwen det werden.
Beispiel: 6,96 Gewichtsteile 2-Methyl-naphtho- hydrochinon werden in 20 Gewichtsteilen trockenem Pyridin gelöst und die Lösung tropfenweise unter Ausschluss von Feuch tigkeit zu 30 Gewichtsteilen eisgekühltem, ständig geschütteltem Phosphoroxychlorid gegeben. Die Mischung wird dann am Rück flusskühler 11/2 Stunden bei einer Bad temperatur von 120' erhitzt.
Nach Ent fernung .des Überschusses an Phosphoroxy- chlorid und Pyridin durch Destillation im Vakuum wird der Rückstand mit trockenem Äther extrahiert und der Ätherextrakt vom kristallinen Rückstand abgetrennt.
Nach Verdampfung der Ätherlösung verbleiben 14 Gewichtsteile eines gelben Ols, nämlich 2 - Methyl - naphthohydrochinon - bis - dichlor- phosphorylester von der Formel:
EMI0002.0051
9 Gewichtsteile 2-Methyl-naphthohydro- chinon -bis - dichlor-phosphorylester werden tropfenweise unter Eiskühlung mit 15 Ge wichtsteilen Wasser behandelt.
Es entsteht eine klare, gelbe Lösung, welche zweimal mit Äther geschüttelt. wird, wobei der Äther ab getrennt, die wässerige Schicht verdampft und im Vakuum getrocknet wird, bis die Salzsäure entfernt ist. Der kristalline Rück stand, der einen Schmelzpunkt von<B>209'</B> auf weist, besteht aus 2-Methyl-naphthohydro- chinon-bis-phosphorestersäure von folgender Formel:
EMI0003.0001
Process for the preparation of 2-methyl-1,4-diogy-naphthalene-dipbosphoric acid ester. It is known that phosphoric acid esters of hydroquinones cannot be produced with phosphorus oxychloride, since the bis-dichlorophosphoryl esters that are formed decompose when water is added, with hydroquinone and phosphoric acid being formed:
(Knauer, Reports of the German Chemical Society, Vol. 27 [1894], p. 2565). It is also known that the process for the production of hydroquinone bis-phosphorus ester acids (Genvresse, Compt. Rend. [1927], p.
523) cannot be used for the production of diphosphoric esters of substituted hydroquinones, since the treatment of such hydroquinones with phosphoric anhydride produces tarry substances that are difficult to process.
It has now been found that alkyl-substituted phosphoric acid esters of hydroquinone and naphthohydroquinone can be obtained by allowing phosphorus oxyhalide to act on the corresponding hydroquinone and treating the compound formed with water. By reacting the resulting phosphoric ester with inorganic or organic bases, water-soluble salts are obtained.
For example, the tetrasodium salt of 2-methyl-naphthohydroquinone-bis-phosphoric acid ester can be obtained by using 2-methyl-naphthohydroquinone. Reacts phosphorus oxychloride, treats the reaction product with water and allows the 2-methyl-naphthohydroquinone-bis-phosphoric acid ester sodium alcoholate to act.
The substituted hydroquinones used as starting materials are expediently in an anhydrous base, such as. B. pyridine, dialkylaniline, quinoline or the like, dissolved. The reaction with phosphorus oxyhalide takes place with the development of heat; it can be carried out at temperatures between room temperature and the boiling point of the base used all due; Temperatures of 80 to 150 ° C. are particularly suitable.
Aqueous solutions of the diphosphoric esters obtained can be neutralized directly or the esters isolated therefrom in the dry state and then possibly reacted in other agents. For example, the aqueous solutions of the diphosphoric acid ester can be evaporated to dryness in a vacuum and then the esters in a suitable organic solvent, such as. B. ethyl alcohol are added.
The subject of the present patent is a process for the preparation of 2-methyl-1, 4-dioxynaphthalene-diphosphoric acid ester, which is characterized in that 'phosphorus oxychloride is allowed to act on 2-methyl-naphthohydroquinone and the reaction product is treated with water.
The 2-lethyl-1,4-dioxynaphthalene-diphosphoric acid ester melts at <B> 209 '. </B> It is easily soluble in water, as well as in methyl, ethyl alcohol and acetone. Difficult to dissolve petroleum ether. The tetrasodium salt and the dicalcium salt, which have 12 molecules of crystal water, are easily soluble in water.
The new phosphoric acid ester has a strong antihemorrhagic effect, so its salts reduce the blood clotting time of chicks kept vitamin K-free according to Ansbacher (Journal Nutrition .1.7 <B> [</B> 1939], p. 303) to less than ten Minutes at doses less than 4 gamma per chicken when administered subcutaneously, intravenously, or intramuscularly.
As a result of the exceptional solubility in water and the neutral reaction, the salts are particularly suitable for parenteral use, they are easy for the body. added, which has a quick effect. becomes. The aqueous solutions are stable and can be boiled for long periods of time without losing their effectiveness or showing signs of deterioration.
The 2-111ethyl-1,4-dioxynaphthalene-diphosphoric acid ester should be used as such or in the form of its salts as a medicament.
Example: 6.96 parts by weight of 2-methyl-naphtho-hydroquinone are dissolved in 20 parts by weight of dry pyridine and the solution is added dropwise with exclusion of moisture to 30 parts by weight of ice-cold, constantly shaken phosphorus oxychloride. The mixture is then heated on the reflux condenser for 11/2 hours at a bath temperature of 120 '.
After removal of the excess phosphorus oxychloride and pyridine by distillation in vacuo, the residue is extracted with dry ether and the ether extract is separated off from the crystalline residue.
After evaporation of the ethereal solution, 14 parts by weight of a yellow oil remain, namely 2 - methyl - naphthohydroquinone - bis - dichlorophosphoryl ester of the formula:
EMI0002.0051
9 parts by weight of 2-methyl-naphthohydroquinone bis-dichlorophosphoryl ester are treated dropwise with 15 parts by weight of water while cooling with ice.
A clear, yellow solution is created, which is shaken twice with ether. is separated from the ether, the aqueous layer is evaporated and dried in vacuo until the hydrochloric acid is removed. The crystalline residue, which has a melting point of <B> 209 '</B>, consists of 2-methylnaphthohydroquinone-bis-phosphorus ester acid with the following formula:
EMI0003.0001
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US218523XA | 1940-01-10 | 1940-01-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH218523A true CH218523A (en) | 1941-12-15 |
Family
ID=21806510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH218523D CH218523A (en) | 1940-01-10 | 1940-11-29 | Process for the preparation of 2-methyl-1,4-dioxy-naphthalene-diphosphoric acid ester. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH218523A (en) |
-
1940
- 1940-11-29 CH CH218523D patent/CH218523A/en unknown
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