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DE2033357A1 - Palmitoyl-propandiol-(1,3)-phosphoric acid-5-trimethylaminopentyl - ester, immunological adjuvant affecting cell membrane surface activity - Google Patents

Palmitoyl-propandiol-(1,3)-phosphoric acid-5-trimethylaminopentyl - ester, immunological adjuvant affecting cell membrane surface activity

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Publication number
DE2033357A1
DE2033357A1 DE19702033357 DE2033357A DE2033357A1 DE 2033357 A1 DE2033357 A1 DE 2033357A1 DE 19702033357 DE19702033357 DE 19702033357 DE 2033357 A DE2033357 A DE 2033357A DE 2033357 A1 DE2033357 A1 DE 2033357A1
Authority
DE
Germany
Prior art keywords
ester
phosphoric acid
palmitoyl
propanediol
trimethylaminopentyl
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
DE2033357B2 (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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Priority to DE19702033357 priority Critical patent/DE2033357C3/en
Publication of DE2033357A1 publication Critical patent/DE2033357A1/en
Publication of DE2033357B2 publication Critical patent/DE2033357B2/en
Application granted granted Critical
Publication of DE2033357C3 publication Critical patent/DE2033357C3/en
Expired legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/06Phosphorus compounds without P—C bonds
    • C07F9/08Esters of oxyacids of phosphorus
    • C07F9/09Esters of phosphoric acids
    • C07F9/14Esters of phosphoric acids containing P(=O)-halide groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/06Phosphorus compounds without P—C bonds
    • C07F9/08Esters of oxyacids of phosphorus
    • C07F9/09Esters of phosphoric acids
    • C07F9/091Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/06Phosphorus compounds without P—C bonds
    • C07F9/08Esters of oxyacids of phosphorus
    • C07F9/09Esters of phosphoric acids
    • C07F9/10Phosphatides, e.g. lecithin

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  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Title cpd. has formula: Prepn. is (a) by reaction of propan-1,3-diol with palmitoyl chloride to give the monopalmitic acid ester (III); (b) (III) is then reacted with phosphoric acid mono-5-Br-pentyl ester dichloride to give propanediol-1-palmitic acid ester-3-phosphoric acid chloride-5-Br-pentyl ester (V); (c) V is reacted with NMe3 to replace the 5-Br and the acid chloride hydrolysed.

Description

Palmitoyl-propandiol-(1,3)-phosphorsäure-5-trimethylaminopentylester und Verfahren zu dessen Herstellung Die Erfindung betrifft den pharmakologisch wertvollen Palmitoyl-propandiol-(1,;phosphorsäurew5-trimethylaminopentylester der Formel sowie dessen Herstellung.Palmitoyl-propanediol- (1,3) -phosphoric acid-5-trimethylaminopentyl ester and process for its preparation The invention relates to the pharmacologically valuable palmitoyl-propanediol- (1,; phosphoric acid w5-trimethylaminopentyl ester of the formula as well as its manufacture.

Die erfindungsgemäße neue Verbindung der Formel I wird hergestellt, indem man Propandiol-(l,3) mit Palmitoylchlorid zum Propandiol-(1,3)-monopalmitinsäureester der Formel acyliert, den Ester mit Phosphorsäure-mono-5-brompentylesterdichlorid zum l-ralmitoyl-propandiol-(l, 3)-phosphorsäure-5-brompentylester der Formel umsetzt, mit Trimethylamin aminiert und durch Entfernung er Bromidionen in das innere Salz der Formel I überführt.The novel compound of the formula I according to the invention is prepared by converting propanediol (1,3) with palmitoyl chloride to give the propanediol (1,3) monopalmitic acid ester of the formula acylated, the ester with phosphoric acid mono-5-bromopentyl ester dichloride to l-ralmitoyl-propanediol- (1,3) -phosphoric acid-5-bromopentyl ester of the formula reacted, aminated with trimethylamine and converted into the inner salt of the formula I by removing it.

Die erfindungsgemäße Substanz ist ein amorphes Pulver mit einem uncharakteristischen Schmelzverhalten. Die Charakterisierung erfolgt daher durch die DEnnschichtchromatographie (RF-Wert) und durch Elementaranalyse.The substance of the present invention is an amorphous powder with an uncharacteristic one Melting behavior. Characterization is therefore carried out using 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.losen ist dagegen eine dosisabhängige Veränderung der Nembrangrenzflächenaktivität zu beobachten. Die erfindungsgemäße neue Verbindung ist besonders als immunologisches Adjuvans zu verwenden.The substance according to the invention has surface-active properties and leads to a change when administered to the animal organism the interfacial activity of cell membranes. Cause higher concentrations On the other hand, cytolysis, e.g. hemolysis, in sublytic lots is a dose-dependent change to observe the membrane interface activity. The new compound according to the invention is particularly to be used as an immunological adjuvant.

Herstellungsbeispiel a) 5-Brompentylphosphorsäuredichlorid Zu 100 g (0,65 Mol) Phosphoroxychlorid und 25 ml Chloroform tropft man unter Rühren bei 000 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 Raumtemwratur stehen. Man erwärmt nun für etwa zwei Stunden auf 10000, bis die Chlorwasserstoffentwicklung aufhört, destilliert das Reaktionsgemisch nach Abzug des Lösungsmittels im Vakuum und erhält 15 g (35 %) 5-Brompentylphosphorsäurechlorid (Kp0,05 mm 124-125°C; n20 1.4750). Das Phosphorylierungsmittel ist eine farblose, olige Flüssigkeit, die sich über 15000 zersetzt.Preparation example a) 5-bromopentylphosphoric acid dichloride To 100 g (0.65 mol) of phosphorus oxychloride and 25 ml of chloroform are added dropwise with stirring 000 a solution of 25 g (0.15 mol) of 5-bromopentanol- (l) in 25 ml of chloroform. Man removed the ice bath and left the reaction mixture to stand for 12 hours at room temperature. The mixture is then heated to 10,000 for about two hours until the evolution of hydrogen chloride ends, the reaction mixture is distilled after the solvent has been removed in vacuo and receives 15 g (35%) 5-bromopentylphosphoric acid chloride (boiling point 0.05 mm 124-125 ° C; n20 1.4750). The phosphorylating agent is a colorless, oily liquid that over 15000 decomposed.

b) Propandiol-(1,3)-monopalmitinsäureester Zu 5 g (66 mMol) Propandiol-(1,33, 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.b) Propanediol (1,3) monopalmitic acid ester To 5 g (66 mmol) of propanediol (1,33, 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 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 iber Blaugel getrocknet.the ice bath is removed and the mixture is stirred for a further 12 hours at room temperature. It is evaporated at 40 to 50 ° C (bath) in vacuo and the oily residue is poured on 800 ml ice-cold 0.2N sulfuric acid. The white precipitate is filtered off with suction, good washed with water and dried in vacuo over blue gel.

Umkristallisation aus Petroläther (40 bis 600C) ergibt 4 g Rohprodukt. Nach Chromatographie an Kieselgel und Umkristallisation aus Petroläther erhält man 3 g weiße Blättchen, die bei 43 bis 440 C schmelzen.Recrystallization from petroleum ether (40 to 60 ° C.) gives 4 g of crude product. After chromatography on silica gel and recrystallization from petroleum ether, one obtains 3 g of white flakes that melt at 43 to 440 C.

c) Pa1mitoyl-roandiol-(l' 3)-hoshorsäure-5-trimethvIaminonentylester Man gibt zu 15 ml absolutem Chloroform bei 0°C 4,5 g (4 mMol) wasserfreies Triäthylamin und 5,1 g (18 mMol) 5-Brompentylphosphorsäuredichlorid. Unter Rühren und Eiskühlung läßt man eine Lösung von 2 g (6,5 mMol) Propandiol-(l,3)-monopalmitinsäureester in 15 ml absolutem Chloroform zutropfen. Man bringt 6 Stunden auf Raumtemperatur und 12 Stunden auf 40QC.c) Palmitoyl-roanediol- (l '3) -horosic acid-5-trimethvinylaminonentyl ester 4.5 g (4 mmol) of anhydrous triethylamine are added to 15 ml of absolute chloroform at 0 ° C and 5.1 g (18 mmol) of 5-bromopentylphosphoric acid dichloride. While stirring and cooling with ice a solution of 2 g (6.5 mmol) of propanediol (l, 3) monopalmitic acid ester is left add dropwise in 15 ml of absolute chloroform. It is brought to room temperature for 6 hours and 12 hours on 40QC.

Dann kühlt man die dunkelgefärbte Lösung auf 0 0C und gibt zur Hydrolyse der Phosphorsäurechloride 15 ml 0,1 n KCl zu.The dark-colored solution is then cooled to 0 ° C. and added to hydrolysis 15 ml of 0.1 N KCl of the phosphoric acid chlorides.

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 getrocknet.After stirring for one hour and adding 25 ml of methanol, one sets with concentrated hydrochloric acid to about pH 3 and shake. 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 OOC abgekühlt, das ausgefällte kristalline Produkt abgesaugt, mit Aceton, Wasser und wiederum Aceton gewaschen. Zur vollständigen Reinigung wird nach Behandlung mit 1 g Silberacetat in 90 igem Methanol (30 Min. Rühren) an Kieselgel chromatographiert und danach aus Butanon umkristallisiert. Man erhält 1,4 g (41 Vo der Theorie) Palmitoyl-propandiol-(1,3)-phosphorsäure-5-trimethylaminopentylester.The phosphorylation product is dissolved in 50 ml of butanol with 10 ml of trimethylamine heated to 55 ° C for 12 hours, then cooled to OOC, the precipitated crystalline Sucked off product, washed with acetone, water and again acetone. To complete After treatment with 1 g of silver acetate in 90% methanol (30 min. Stirring) chromatographed on silica gel and then recrystallized from butanone. 1.4 g (41 vol of theory) of 5-trimethylaminopentyl palmitoyl-propanediol (1,3) -phosphoric acid are obtained.

Rf-Wert 0,15 in Chloroform/Methanol/Wasser 65:30:4 C27H58N07P (539.8) Ber.: C 60,0 H 10,83 N 2,59 P 5,74 Gef.: C 59,1 H 10,99 N 2,58 P 5,51Rf value 0.15 in chloroform / methanol / water 65: 30: 4 C27H58N07P (539.8) Calc .: C 60.0 H 10.83 N 2.59 P 5.74 Found: C 59.1 H 10.99 N 2.58 P 5.51

Claims (1)

Patentansprüche 1. Palmitoyl-propandiol-(1,3 )-pho sphorsäure-5-trimethylaminopentylester der Formel 2. Verfahren zur Herstellung von Palmitoyl-propandiol-(1,3) phosphorsäure-5-trimethylaminopentylester nach Anspruch 1, dadurch gekennzeichnet, daß man Propandiol-(1,3)-mit Palmitoylchlorid zum Propandiol-(1,3)-mono-palmitinsäureester der Formel umsetzt, den EsterniLt Phosphorsäure-mono-5-brompentylesterdichlorid zum Palmitoyl-propandiol-(1,3)-phosphorsäure-5-brompentylester der Formel umwandelt, mit Trimethylamin aminiert und durch Entfernung der Bromidionen in das innere Salz der Formel I überführt.Claims 1. Palmitoyl-propanediol- (1,3) -phosphoric acid-5-trimethylaminopentyl ester of the formula 2. A process for the preparation of palmitoyl-propanediol (1,3) phosphoric acid-5-trimethylaminopentyl ester according to claim 1, characterized in that propanediol (1,3) -with palmitoyl chloride to propanediol- (1,3) -mono- palmitic acid ester of the formula converts the EsterniLt phosphoric acid mono-5-bromopentyl ester dichloride to the palmitoyl-propanediol- (1,3) -phosphoric acid-5-bromopentyl ester of the formula converted, aminated with trimethylamine and converted into the inner salt of formula I by removing the bromide ions. 3. Verwendung von Palmitoyl-propandiol-(1,3)-phosphorsäure-5-trimethylaminopentylester als immunologisches Adjuvans.3. Use of palmitoyl-propanediol- (1,3) -phosphoric acid-5-trimethylaminopentyl ester as an immunological adjuvant.
DE19702033357 1970-07-06 1970-07-06 Palmitoyl-propandioKl 3) -phosphoric acid-S-trimethylaminophenyl ester and process for its preparation Expired DE2033357C3 (en)

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

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002202A3 (en) * 1977-11-24 1979-10-31 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Phospholipid compounds and process for their preparation; process of peralkylation of organic nitrogen compounds
EP0036583A3 (en) * 1980-03-26 1982-01-13 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Glycerine-3-phosphoric acid halogenalkyl ester, process for its preparation and further processing
US5030733A (en) * 1987-07-23 1991-07-09 Hoechst-Roussel Pharmaceticals Incorporated Hydroxy-, alkoxy- and benzyloxy-substituted phospholipids
US5036152A (en) * 1988-03-10 1991-07-30 Hoechst-Roussel Pharmaceuticals Incorporated Alkoxycarbonylalkylphospholipids and alkylaminocarbonylalkylphospholipids
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
US7595411B2 (en) 1997-08-18 2009-09-29 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Phospholipid-analogous compounds
WO2021195555A1 (en) * 2020-03-27 2021-09-30 Travecta Therapeutics, Pte. Ltd. Palmitoylethanolamide compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002202A3 (en) * 1977-11-24 1979-10-31 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Phospholipid compounds and process for their preparation; process of peralkylation of organic nitrogen compounds
EP0036583A3 (en) * 1980-03-26 1982-01-13 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Glycerine-3-phosphoric acid halogenalkyl ester, process for its preparation and further processing
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
US7595411B2 (en) 1997-08-18 2009-09-29 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Phospholipid-analogous compounds
US7939683B2 (en) 1997-08-18 2011-05-10 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Phospholipid-analogous compounds
US8497388B2 (en) 1997-08-18 2013-07-30 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften. E.V. Phospholipid-analogous compounds
WO2021195555A1 (en) * 2020-03-27 2021-09-30 Travecta Therapeutics, Pte. Ltd. Palmitoylethanolamide compounds

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DE2033357C3 (en) 1980-02-14
DE2033357B2 (en) 1979-06-07

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