DE2033357B2 - Palmitoyl-propanediol- (13) -phosphoric acid-5-trimethylaminophenyl ester and process for its preparation - Google Patents

Palmitoyl-propanediol- (13) -phosphoric acid-5-trimethylaminophenyl ester and process for its preparation

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Publication number
DE2033357B2
DE2033357B2 DE19702033357 DE2033357A DE2033357B2 DE 2033357 B2 DE2033357 B2 DE 2033357B2 DE 19702033357 DE19702033357 DE 19702033357 DE 2033357 A DE2033357 A DE 2033357A DE 2033357 B2 DE2033357 B2 DE 2033357B2
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Germany
Prior art keywords
ester
propanediol
palmitoyl
phosphoric acid
preparation
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.)
Granted
Application number
DE19702033357
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German (de)
Other versions
DE2033357C3 (en
DE2033357A1 (en
Inventor
Auf Nichtnennung Antrag
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Priority to DE19702033357 priority Critical patent/DE2033357C3/en
Publication of DE2033357A1 publication Critical patent/DE2033357A1/en
Publication of DE2033357B2 publication Critical patent/DE2033357B2/en
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Publication of DE2033357C3 publication Critical patent/DE2033357C3/en
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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 System
    • 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
    • C07F9/14—Esters of phosphoric acids containing P(=O)-halide groups
    • 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 System
    • 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
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • 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 System
    • 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
    • C07F9/10—Phosphatides, e.g. lecithin

Description

-(CH2J14—CH3 umsetzt, mit Trimethylamin aminiert und durch- (CH 2 J 14 —CH 3 reacted, aminated with trimethylamine and through

I Entfernung der Bromidionen in das innere Salz derI Removal of the bromide ions in the inner salt of the CH2 (II) Formel I überführt.CH 2 (II) formula I transferred. I 25 Die erfindungsgemäße Substanz ist ein amorphesI 25 The substance according to the invention is an amorphous one CH2OH Pulver mit einem ulicharakteristischen SchmelzverhalCH 2 OH powder with a characteristic melting ratio

ten. Die Charakterisierung erfolgt daher durch die Dünnschichtchromatographie (RF-Wert) und durch Elementaranalyse.The characterization is therefore carried out by thin layer chromatography (RF value) and by Elemental analysis.

Die erfindungsgemäße Substanz weist grenzflächenaktive Eigenschaften auf und führt bei Verabreichung an den tierischen Organismus zu einer Veränderung der Grenzflächenaktivität von Zellmembranen. Höhere Konzentrationen verursachen Zytolyse z. B. Hämolyse, in sublytischen Dosen ist dagegen eine dosisabhängige Veränderung der Membrangrenzflächenaktivität zu beobachten. Die erfindungsgemäße neue Verbindung ist besonders als immunologisches Adjuvans zu verwenden.The substance according to the invention has surface-active properties and is effective when administered the animal organism to a change in the surface activity of cell membranes. Higher Concentrations cause cytolysis e.g. B. hemolysis, in sublytic doses, on the other hand, there is a dose-dependent change in the membrane interface activity watch. The novel compound of the invention is particularly useful as an immunological adjuvant.

Herstellungsbeispiel aJS-BrompentylphosphorsäuredichloridManufacturing example aJS-bromopentylphosphoric acid dichloride

Zu 100 g (0,65 Mol) Phosphoroxychlorid und 25 ml Chloroform tropft man unter Rühren bei 0°C eine Lösung von 25 g (0,15 Mol)5-Brompentanol-(l)in 25 ml Chloroform. Man entfernt das Eisbad und läßt das Reaktionsgemisch 12 Stunden bei Raumtemperatur stehen. Man erwärmt nun für etwa zwei Stunden auf 100° C, bis die Chlorwasserstoff ent wicklung aufhört, destilliert das Reaktionsgemisch nach Abzug des Lösungsmittels im Vakuum und erhält 15 g (35%) 5-BiOmpentylphosphorsäurechlorid (Kpo,M mmA solution of 25 g (0.15 mol) of 5-bromopentanol- (l) in 25 ml of chloroform is added dropwise to 100 g (0.65 mol) of phosphorus oxychloride and 25 ml of chloroform while stirring at 0 ° C. The ice bath is removed and the reaction mixture is left to stand at room temperature for 12 hours. The mixture is then heated to 100 ° C. for about two hours until the development of hydrogen chloride ceases. After the solvent has been removed, the reaction mixture is distilled in vacuo and 15 g (35%) of 5-biopentylphosphoric acid chloride (bp o , M mm) are obtained

124-125° C; η % 1.4750). Das Phosphorylierungsmittel ist eine farblose, ölige Flüssigkeit, die sich über 150°C zersetzt.124-125 ° C; η% 1.4750). The phosphorylating agent is a colorless, oily liquid that decomposes above 150 ° C.

b) Propandiol-(l,3)-monopalmitinsäureesterb) Propanediol (1,3) monopalmitic acid ester

Zu 5 g (66 mMol) Propandiol-(13), 5 ml Pyridin und 5 ml Chloroform tropft man unter Rühren bei 0°C 5 g (18 mMol) Palmitinsäurechlorid in 20 ml absolutem Chloroform. Nach 30 min wird das Eisbad entfernt und bei Raumtemperatur 12 Stunden weitergerührt. Man dampft bei 40 bis 50°C (Bad) im Vakuum ein und gießt den öligen Rückstand auf 800 ml eisgekühlte 0,2 n-Schwefelsäure. Der weiße Niederschlag wird abgesaugt, gut mit Wasser gewaschen und im Vakuum über Blaugel getrocknet.To 5 g (66 mmol) of propanediol- (13), 5 ml of pyridine and 5 ml of chloroform are added dropwise with stirring at 0 ° C. 5 g (18 mmol) of palmitic acid chloride in 20 ml of absolute Chloroform. After 30 minutes, the ice bath is removed and stirring is continued for 12 hours at room temperature. Man evaporated at 40 to 50 ° C (bath) in a vacuum and poured the oily residue onto 800 ml of ice-cold 0.2 N sulfuric acid. The white precipitate is sucked off, washed well with water and dried in vacuo over blue gel.

umsetzt, den Ester mit Phosphorsäure-mono-5-brompentylesterdichlorid zum Palmitoyl-propandiol-( 13)-phosphorsäure-5-brompentylester der Formelconverts the ester with phosphoric acid mono-5-bromopentyl ester dichloride to the palmitoyl propanediol (13) phosphoric acid 5-bromopentyl ester formula

CH2—O—CO—(CH,)14—CH, CH2 (III)CH 2 —O — CO— (CH,) 14 —CH, CH 2 (III)

CH2-O-PO2-(CH2J5-Br i OHCH 2 -O-PO 2 - (CH 2 J 5 -Br i OH

umwandelt, mit Trimethylamin aminiert und durch Entfernung der Bromidionen in das innere Salz der Formel I überführt.converts, aminated with trimethylamine and by removing the bromide ions in the inner salt of the Formula I transferred.

3. Verwendung von Palmitoyl-propandiol-(t,3)-phosphorsäure-5-trimethylaminopentylester als immunologisches Adjuvans.3. Use of palmitoyl-propanediol- (t, 3) -phosphoric acid-5-trimethylaminopentyl ester as an immunological adjuvant.

Die Erfindung betrifft den pharmakologisch wertvollen Palmitoyl-propandiol-(l,3)-phosphorsäure-5-trimethylaminopentylesterder FormelThe invention relates to the pharmacologically valuable palmitoyl-propanediol- (1,3) -phosphoric acid-5-trimethylaminopentyl ester of the formula

CH2-O-CO-(CH2J14-CHjCH 2 -O-CO- (CH 2 J 14 -CHj

CH2 CH 2

CH2-O- PO2-(CH2),-N(CH3J3 CH 2 -O- PO 2 - (CH 2 ), - N (CH 3 J 3

(I)(I)

sowie dessen Herstellung.as well as its manufacture.

Die erfindungsgemäße neue Verbindung der Formel I wird hergestellt, indem man Propandiol-(1,3) mitThe novel compound of the formula I according to the invention is prepared by using propanediol- (1,3) with

Umkristallisation aus Petroläther (40 bis 60° C) ergibt 4 g Rohprodukt Nach Chromatographie an Kieselgel und Umkristallisation aus Petroläther erhält man 3 g weiße Blättchen, die bei 43 bis 44° C schmelzen.Recrystallization from petroleum ether (40 to 60 ° C) results 4 g of crude product After chromatography on silica gel and recrystallization from petroleum ether, 3 g are obtained white flakes that melt at 43 to 44 ° C.

c)PaImitoy!-propandioI-(l,3)-phosphorsäure-5-trimethylaminopentylester c) Palmitoy! -propandioI- (1,3) -phosphoric acid-5-trimethylaminopentyl ester

Man gibt zu 15 ml absolutem Chloroform bei 0cC 4,5 g (45 mMol) wasserfreies Triäthylamin und 5,1 g (18 mMol) 5-Brompentylphosphorsäuredichlorid. Unter Rühren und Eiskühlung IaBt man eine Lösung von 2 g (6,5 pMol) Propandiol-(l,3)-monopalmitinsäureester in 15 ml absolutem Chloroform zutropfen. Man bringt 6 Stunden auf Raumtemperatur und 12 Stunden auf 400C. Dann kühlt man die dunkelgefärbte Lösung auf 00C und gibt zur Hydrolyse der Phosphorsäurechloride 15 ml 0,1 n-KCI zu. Nach einstündigem Rühren und Zugabe von 25 ml Methanol stellt man mit konzentrierter Salzsäure auf etwa pH 3 ein und schüttelt Der Rückstand der organischen Phase wird im Hochvakuum über Phosphorpentoxyd getrocknetAre added to 15 ml of absolute chloroform at 0 c C 4.5 g (45 mmol) of anhydrous triethylamine and 5.1 g (18 mmol) of 5-Brompentylphosphorsäuredichlorid. A solution of 2 g (6.5 pmol) of propanediol (1.3) monopalmitic acid ester in 15 ml of absolute chloroform is added dropwise with stirring and cooling with ice. It is brought to room temperature for 6 hours and to 40 ° C. for 12 hours. The dark-colored solution is then cooled to 0 ° C. and 15 ml of 0.1 N KCl are added to hydrolyze the phosphoric acid chlorides. After stirring for one hour and adding 25 ml of methanol, the pH is adjusted to about 3 with concentrated hydrochloric acid and the mixture is shaken. The residue of the organic phase is dried over phosphorus pentoxide in a high vacuum

Das Phosphorylierungsprodukt wird in 50 ml Butanol mit 10 ml Trimethylamin für 12 Stunden auf 55°C erwärmt dann auf 0°C abgekühlt, das ausgefällte kristalline Produkt abgesaugt, mit Aceton, Wasser und wiederum Aceton gewaschen. Zur vollständigen Reinigung wird nach Behandlung mit 1 g Silberacetat in 9O°/oigem Methanol (30 Min. Rühren) an Kieselgel Chromatographien und danach aus Butanon umkriitallisiert Man erhält 1,4 g (41% der Theorie) Palmitoyl-pro-The phosphorylation product is in 50 ml of butanol with 10 ml of trimethylamine for 12 hours at 55 ° C warmed then cooled to 0 ° C, the precipitated crystalline product filtered off with suction, with acetone, water and again acetone washed. For complete cleaning, after treatment with 1 g of silver acetate in 90% methanol (stirring for 30 minutes) chromatographed on silica gel and then crystallized from butanone 1.4 g (41% of theory) of palmitoyl-pro-

pandiol-(1,3)-phosphorsäure-5-trimethylaminopentylester. 5-trimethylaminopentyl pandiol (1,3) phosphoric acid.

Rf-Wert 0,15
65:30:4.Rf value 0.15
65: 30: 4.

inin

Chloroform/Methanol/WasserChloroform / methanol / water

C27H58NO7P (539.8)C 27 H 58 NO 7 P (539.8)

Ber.: C 60,0, H 10,83, N 2,59, P 5,74,
gef.: C 59,1, H 1039, N 2^8, P 5,51.Calc .: C 60.0, H 10.83, N 2.59, P 5.74,
Found: C 59.1, H 1039, N 2-8, P 5.51.

Claims (2)

Patentansprüche:Patent claims: 1. Palmitoyl-propandiol-( 1,3)-phosphorsäure-5-trimethylaminopentylesterder Formel1. Palmitoyl-propanediol- (1,3) -phosphoric acid-5-trimethylaminopentyl ester of the formula CH2-O-CO-(CHj)14-CH,CH 2 -O-CO- (CHj) 14 -CH, CH, (I)CH, (I) I "I " CH2—O—PO,—(CH2)5—N(CH3)3 O«CH 2 —O — PO, - (CH 2 ) 5 —N (CH 3 ) 3 O « 2. Verfahren zur Herstellung von Palmitoyl-propandiol-( 1,3)-phosphorsäure-5-trimethylaminopenty!ester nach Anspruch 1, dadurch gekennzeichnet, daß man Propandiol-(13) mit Palmitoylchlorid zum Propandiol-(13)-mono-palmitinsäureester der Formel2. Process for the preparation of palmitoyl-propanediol- (1,3) -phosphoric acid-5-trimethylaminopenty! Ester according to claim 1, characterized in that that one propanediol (13) with palmitoyl chloride to propanediol (13) mono-palmitic acid ester of the formula Palmitoylchlorid zum Propandiol-(l,3)-manopalmit!n-■säureester der FormelPalmitoyl chloride to propanediol- (1,3) -manopalmit! N- ■ acid ester of the formula CH2-O-CO-(CH2J14-CH3 CH 2 -O-CO- (CH 2 J 14 -CH 3 CH2 (II)CH 2 (II) CH2OHCH 2 OH acyliert, den Ester mit Phosphorsäure-mono-5-brompentylesterdichlorid zum l-Palmitoyl-propandiol-(13)-phosphorsäure-5-brompentylester der Formelacylated, the ester with phosphoric acid mono-5-bromopentyl ester dichloride to l-palmitoyl-propanediol- (13) -phosphoric acid-5-bromopentyl ester of the formula CH3- O—CO-(CH2J14-CH3 CH2 (III)CH 3 - O — CO- (CH 2 J 14 -CH 3 CH 2 (III) CH2-O-PO2-(CH2J5-Br OHCH 2 -O-PO 2 - (CH 2 J 5 -Br OH
DE19702033357 1970-07-06 1970-07-06 Palmitoyl-propandioKl 3) -phosphoric acid-S-trimethylaminophenyl ester and process for its preparation Expired DE2033357C3 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19702033357 DE2033357C3 (en) 1970-07-06 1970-07-06 Palmitoyl-propandioKl 3) -phosphoric acid-S-trimethylaminophenyl ester and process for its preparation

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Application Number Priority Date Filing Date Title
DE19702033357 DE2033357C3 (en) 1970-07-06 1970-07-06 Palmitoyl-propandioKl 3) -phosphoric acid-S-trimethylaminophenyl ester and process for its preparation

Publications (3)

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DE2033357A1 DE2033357A1 (en) 1972-01-20
DE2033357B2 true DE2033357B2 (en) 1979-06-07
DE2033357C3 DE2033357C3 (en) 1980-02-14

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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2752553C2 (en) * 1977-11-24 1985-07-25 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Novel phospholipid-like compounds, their use in the manufacture of plant hybrids and processes for their manufacture
DE3011738A1 (en) 1980-03-26 1981-10-01 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen NEW GLYCERIN-3-PHOSPHORIC ACID HALOGYL ALTER
US5030733A (en) * 1987-07-23 1991-07-09 Hoechst-Roussel Pharmaceticals Incorporated Hydroxy-, alkoxy- and benzyloxy-substituted phospholipids
US5145844A (en) * 1987-07-23 1992-09-08 Hoechst-Roussel Pharmaceuticals Incorporated Methods of using hydroxy-, alkoxy- and benzyloxy-substituted phospholipids to treat phospholipase A2 -mediated conditions and to alleviate pain
US5036152A (en) * 1988-03-10 1991-07-30 Hoechst-Roussel Pharmaceuticals Incorporated Alkoxycarbonylalkylphospholipids and alkylaminocarbonylalkylphospholipids
ATE226210T1 (en) 1997-08-18 2002-11-15 Max Planck Gesellschaft PHOSPHOLIPIDE ANALOGOUS COMPOUNDS
WO2021195555A1 (en) * 2020-03-27 2021-09-30 Travecta Therapeutics, Pte. Ltd. Palmitoylethanolamide compounds

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DE2033357A1 (en) 1972-01-20

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