DD238978A1 - PROCESS FOR THE PREPARATION OF 2-O-ALKYL-I-DES OXY-1 HALOGENGLYCERO-3-PHOSPHO-L-SERINES - Google Patents
PROCESS FOR THE PREPARATION OF 2-O-ALKYL-I-DES OXY-1 HALOGENGLYCERO-3-PHOSPHO-L-SERINES Download PDFInfo
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- DD238978A1 DD238978A1 DD27823085A DD27823085A DD238978A1 DD 238978 A1 DD238978 A1 DD 238978A1 DD 27823085 A DD27823085 A DD 27823085A DD 27823085 A DD27823085 A DD 27823085A DD 238978 A1 DD238978 A1 DD 238978A1
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- alkyl
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- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 14
- 102000011420 Phospholipase D Human genes 0.000 claims abstract description 9
- 108090000553 Phospholipase D Proteins 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 229960001153 serine Drugs 0.000 claims abstract description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims abstract 2
- 150000008106 phosphatidylserines Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 241000251730 Chondrichthyes Species 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 230000031018 biological processes and functions Effects 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 150000003278 haem Chemical class 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 2
- 244000178937 Brassica oleracea var. capitata Species 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 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
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000003468 Ehrlich Tumor Carcinoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000008103 phosphatidic acids Chemical class 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Ziel der Erfindung ist es, ein Verfahren zur Herstellung von 2-0-Alkyl-1-desoxy-1-halogen-3-phospho-L-serinen zu entwickeln. Erfindungsgemaess werden diese Verbindungen durch Umsetzung von 2-0-Alkyl-1-desoxy-1-halogenglycero-3-phosphorsaeurealkylestern bzw. analogen Verbindungen wie 2-0-Alkyl-1-desoxycholin mit L-Serin in Gegenwart von Phospholipase D hergestellt. Anwendungsgebiet der Erfindung ist die chemische bzw. pharmazeutische Industrie.The aim of the invention is to develop a process for the preparation of 2-0-alkyl-1-deoxy-1-halo-3-phospho-L-serines. According to the invention, these compounds are prepared by reacting 2-0-alkyl-1-deoxy-1-halo-glycero-3-phosphoric acid alkyl esters or analogous compounds such as 2-0-alkyl-1-deoxycholine with L-serine in the presence of phospholipase D. Field of application of the invention is the chemical or pharmaceutical industry.
Description
Es ist bekannt, daß Glycerophospholipde mit Serinhaltiger Kopfgruppe sich durch Kondensation von Glycerophosphorsäurederivaten mit Serinderivaten herstellen lassen. In diesen Fällen werden die Carboxyl- und die Aminogruppe des Serins durch die Einführung von Schutzgruppen blockiert, um Nebenreaktionen zu vermeiden. Nach erfolgter Kondensation werden diese Schutzgruppen in zusätzlichen Syntheseschritten wieder abgespalten. Nach dieser Methode sind z. B. Diacyl-, Dialkyl- sowie auch Acylalkylglycerophosphoserine synthetisiert worden (A. J. Slotboom et al., Chem. Phys. Lipids, 5 [1970] 301-379; H. Eibl, Chem. Phys. Lipids, 26 [1980] 405-429; A. Hermetter et al., Chem. Phys. Lipids, 30 [1982] 35-45). Phosphatidylserine, die zwei Acylgruppen im Molekül enthalten sind auch durch eine enzymatisch katalysierte Umesterung mit Hilfe der Phospholipase D ausgehend von Phosphatidylcholinen hergestellt worden (P.Comfuriusetal., Biochim.Biophys.Acta, 488 [1977] 36-42). Verfahren zur Synthese von halogenhaltigen O-Alkylglycerophosphoserin-Analogen des Typs I sind bisher nicht beschrieben worden. Andere Phospholipide sind bereits mit Hilfe von Phospholipase D hergestellt worden (H. Eibl et al.. Methods in Enzymology, 72 [1981] 632-639), wobei teilweise auch nicht natürlich vorkommende Glycerophosphorsäurealkylester und Analoge als Substrate in die Reaktion eingesetzt wurden. Über die Synthese von Phosphatidylserinen mit Hilfe von Phospholipase D ist hingegen bisher wenig bekannt. P.Comfuriusetal. (vgl. oben) beschreiben die enzymatische Synthese von Phosphatidylserinen aus natürlichen Phosphatidycholinen, wobei allerdings die Ausbeuten an Phosphatidylserinen vergleichsweise gering waren, und vornehmlich Hydrolyse unter Bildung von Phosphatidsäuren eintrat. Andere als natürliche Substrate sind bisher zur Herstellung von Phosphatidylserinen durch Umesterung mittels Phospholipase D nicht eingesetzt worden.It is known that glycerophospholipde with Serinhaltiger head group can be prepared by condensation of Glycerophosphorsäurederivaten with serine derivatives. In these cases, the carboxyl and amino groups of the serine are blocked by the introduction of protecting groups to avoid side reactions. After condensation, these protective groups are split off again in additional synthesis steps. By this method z. For example, diacyl, dialkyl, and also acylalkylglycerophosphoserins have been synthesized (AJ Slotboom et al., Chem. Phys. Lipids, 5 [1970] 301-379, H. Eibl, Chem. Phys. Lipids, 26 [1980] 405-429 A. Hermetter et al., Chem. Phys. Lipids, 30 [1982] 35-45). Phosphatidylserines containing two acyl groups in the molecule have also been prepared by enzymatically catalyzed transesterification with the aid of phospholipase D starting from phosphatidylcholines (P. Comfurius et al., Biochim. Biophys. Acta, 488 (1977) 36-42). Methods for the synthesis of halogen-containing O-alkyl glycerophosphoserine type I analogues have not previously been described. Other phospholipids have already been prepared with the aid of phospholipase D (H. Eibl et al .. Methods in Enzymology, 72 [1981] 632-639), wherein partially non-naturally occurring Glycerophosphorsäurealkylester and analogues were used as substrates in the reaction. By contrast, little is known about the synthesis of phosphatidylserines with the aid of phospholipase D. P.Comfuriusetal. (see above) describe the enzymatic synthesis of phosphatidylserines from natural phosphatidycholines, although the yields of phosphatidylserines were comparatively low, and predominantly hydrolysis with formation of phosphatidic acids occurred. Other than natural substrates have not been used for the production of phosphatidylserines by transesterification by means of phospholipase D.
Ziel der Erfindung ist es, ein Verfahren zu entwickeln, nach dem sich die 2-0-Alkyl-1-desoxy-1-halogen-3-phospho-L-serine der allgemeinen Formel I herstellen lassen.The aim of the invention is to develop a process by which the 2-0-alkyl-1-deoxy-1-halo-3-phospho-L-serines of general formula I can be prepared.
Erfindungsgemäß werden die Verbindungen der allgemeinen Formel I hergestellt, indem man 2-O-Alkyl-1-desoxy-1-halogenglycero-3-phosphorsäurealkylesteroder2-0-Alkyl-1-desoxy-1-halogenglycerophosphocholine, -N-methylalkanolamine, -Ν,Ν-dimethylalkanolamine, O-(2-O-Alkyl-1-desoxy-1-halogenglycer-3-yl)-O'-^-N,N,N-trimethylammonio)alkyl]phosphate der allgemeinen Formel II,According to the invention, the compounds of the general formula I are prepared by reacting alkyl 2-O-alkyl-1-deoxy-1-halogenoglycero-3-phosphorates or 2-O-alkyl-1-deoxy-1-halo-glycerophosphoquines, -N-methylalkanolamines, -Ν, Ν-dimethylalkanolamines, O- (2-O-alkyl-1-deoxy-1-halo-glycer-3-yl) -O '- ^ - N, N, N-trimethylammonio) alkyl] phosphates of the general formula II,
CH2-HaI CH-O-RCH 2 -HaI CH-OR
CH2-O-P(O)-O-R16"CH 2 -OP (O) -OR 1 6 "
II .II.
in der Hai und R die bereits genannten Bedeutungen besitzen und R1 einen Alkylrest mit 1 bis 6 C-Atomen, der auch durch OH, Cl oder Br substituiert sein kann, falls 2 bis 6 C-Atome vorliegen, bzw. die Gruppierungin the shark and R have the meanings already mentioned and R 1 is an alkyl radical having 1 to 6 carbon atoms, which may also be substituted by OH, Cl or Br, if 2 to 6 carbon atoms, or the grouping
X ) -U - YX) -U - Y
bedeutet, wobei X, Y und Zfür Methylgruppen oder Wasserstoffatome stehen und η = 1 bis 6 sein kann, mit L-Serin in Gegenwart von Phospholipase D zur Umsetzung bringt und die entstandenen Alkyldesoxyhalogenglycerophosphoserine nach üblichen Verfahren isoliert. Im wesentlichen erfolgt die Herstellung der Verbindungen vom Typ !,indem man eine Verbindung der allgemeinen Formel Il in wäßriger Lösung oder Suspension unter Zusatz von organischen Lösungsmitteln, z. B. Ether und/oder Chloroform, und eines Puffers, z. B. Natriumacetat- oder Tris-Puffer, bei einem pH-Wert zwischen 4,8 bis 8, in Gegenwart eines Calciumsalzes (Molarität vorzugsweise zwischen 0,01 und 0,1) mit L-Serin in Anwesenheit von Phospholipase D bei Temperaturen zwischen 10 und 500C reagieren läßt.where X, Y and Z are methyl groups or hydrogen atoms and η = 1 to 6, with L-serine brings in the presence of phospholipase D for reaction and the resulting Alkyldeoxyhalogenglycerophosphoserine isolated by conventional methods. Essentially, the preparation of compounds of the type carried out by reacting a compound of general formula II in aqueous solution or suspension with the addition of organic solvents, for. For example, ether and / or chloroform, and a buffer, for. As sodium acetate or Tris buffer, at a pH of 4.8 to 8, in the presence of a calcium salt (molarity preferably between 0.01 and 0.1) with L-serine in the presence of phospholipase D at temperatures between 10th and 50 0 C react.
Es ist ein besonderer Vorteil dieses Verfahren, daß man das Serin ohne Schutzgruppen, deren Einführung oft präparativ aufwendig ist, zur Reaktion einsetzen kann. Nach erfolgtem Umsatz, der dünnschichtchromatographisch verfolgt wird, wird zur Inaktivierung des Enzyms eine 0,1 M EDTA-Lösung zum Reaktionsgemisch zugesetzt und anschließend das entstandene Phosphatidylserin-Analoge auf üblichem Wege, z. B. mit Hilfe chromatographischer Methoden, isoliert und gereinigt. Es war überraschend und keineswegs vorauszusehen, daß sich die halogenhaltigen synthetischen Phospholipide vom Typ II, die keine natürlichen Verbindungen darstellen, für die enzymatisch katalysierte Synthese der Verbindungen I eignen.It is a particular advantage of this process that one can use the serine without protecting groups, the introduction of which is often preparatively expensive to react. After the conversion, which is monitored by thin layer chromatography, a 0.1 M EDTA solution is added to the reaction mixture to inactivate the enzyme and then the resulting phosphatidylserine analogues in the usual way, for. B. using chromatographic methods, isolated and purified. It was surprising and by no means foreseeable that the halogen-containing synthetic phospholipids of type II, which are not natural compounds, are suitable for the enzymatically catalyzed synthesis of the compounds I.
Das Verfahren erlaubt die Herstellung sowohl der Recemate als auch der optischen Stereoisomeren.The method allows the preparation of both the recemates and the optical stereoisomers.
Die verwendete Phospholipase D wird in Anlehnung an bereits bekannte Methoden in einfacher Weise aus Weißkohl erhalten, indem man diesen homogenisiert, das Homogenisat filtriert und die wäßrige Phase 45 Minuten bei 25000g zentrifugiert. Der klare Überstand wird mit 2 Volumen Aceton versetzt. Vom entstandenen Niederschlag wird unter Benutzung einer Tauchfritte dekantiert und der Rückstand 20 Minuten bei 13000g (5°C) zentrifugiert. Dasacetonfeuchteenzymhaltige Präparat wird über Phosphorpentoxid im Vakuum getrocknet.The phospholipase D used is obtained in a simple manner from white cabbage, based on previously known methods, by homogenizing it, filtering the homogenate and centrifuging the aqueous phase at 25,000 g for 45 minutes. The clear supernatant is mixed with 2 volumes of acetone. The resulting precipitate is decanted using a dip frit and the residue is centrifuged for 20 minutes at 13000g (5 ° C). Dasacetonfeuchteenzymhaltige preparation is dried over phosphorus pentoxide in a vacuum.
Die erfindungsgemäß erhaltenen Verbindungen stellen physiologisch hochaktive Verbindungen dar. Sie besitzen z. B. eine ausgeprägte cytostatische Wirksamkeit. So bewirkt das i-ChloM-desoxy^-O-hexadecylglycero-S-phospho-L-serin bei Konzentrationen <10~4M eine mehr als 50%ige Hemmung des Zellwachstums von Ehrlich-Ascites-Tumorzellen in vitro.The compounds obtained according to the invention are physiologically highly active compounds. B. a pronounced cytostatic activity. Thus, the i-ChloM-deoxy ^ -O-hexadecylglycero-S-phospho-L-serine at concentrations <10 ~ 4 M causes more than 50% inhibition of the cell growth of Ehrlich ascites tumor cells in vitro.
Die Erfindung wird an nachstehendem Beispiel erläutert:The invention is illustrated by the following example:
Beispiel 1 i-Chlor-i-desoxy^-O-hexadecylglycero-S-phospho-L-serinExample 1 i-Chloro-i-deoxy ^ -O-hexadecylglycero-S-phospho-L-serine
(Formel I : R = C16H33, Hai = Cl)(Formula I: R = C 16 H 33 , Hai = Cl)
1 g L-Serin wird in 1,9ml 0,1 M Acetatpuffer (pH 5,6), der 0,1 M an CaCI2 ist, bei 450C gelöst. Zu dieser Lösung werden 40mg i-Chlor-i-desoxy^-O-hexadecylglycero-S-phosphocholin (Il : R = C16H33, Hai = Cl, X = Y = Z = CH3, η = 2), 2ml Ether/ Chloroform (9:1, v/v, ethanolfrei) und 100mg des Enzympräparates (erhalten aus etwa 500g Weißkohl) gegeben. Das Gemisch wird unter starkem Rühren 4 Stunden auf 400C gehalten. Nach dem Abkühlen auf Raumtemperatur werden 4,35 ml 0,1 M EDTA-Lösung hinzugegeben und die organischen Lösungsmittel durch Ein leiten von Stickstoff entfernt. Die zurückbleibende wäßrige Phase wird mit dem 4,3fachen Volumen Chloroform/Methanol (5:8, v/v) 30 Minuten gerührt und darauf vom Ungelösten (L-Serin) abgesaugt. Das Filtrat wird mit 1 Volumen Wasser und 3,7 Volumen Chloroform versetzt, die Mischung 10 Minuten gerührt, die organische Phase abgetrennt, im Vakuum eingeengt und der erhaltene Rückstand an Carboxymethylcellulose (Servacel CM52) säulenchromatographisch getrennt. Die Elution erfolgt nacheinander mit 75ml Chloroform (Fraktion 1), je 500ml Chloroform/Methanol, 9:1,8:2,7:3,1:1, v/v (Fraktionen 2 bis 5). Aus Fraktion 5 werden 15mg reines i-Chlor-i-desoxy-2-O-hexadecylglycero-3-phospho-L-serin erhalten. DC (Merck Kieselgel 60, Fertigplatte): Rf 0,13 (CHCIg/CHaOH/HjO, 50:25:4, v/v/v); Rf 0,04 (CHCI3ZCH3OHZ25% NH3, 65:25:4, \/NN). 1 g L-serine is dissolved in 1,9ml 0.1 M acetate buffer (pH 5.6) containing 0.1 M of CaCl 2 at 45 0 C. To this solution, 40 mg of i-chloro-i-deoxy ^ -O-hexadecylglycero-S-phosphocholine (II: R = C 16 H 33 , Hai = Cl, X = Y = Z = CH 3 , η = 2), 2ml Ether / chloroform (9: 1, v / v, ethanol free) and 100 mg of the enzyme preparation (obtained from about 500 g of white cabbage). The mixture is kept at 40 ° C. with vigorous stirring for 4 hours. After cooling to room temperature, 4.35 ml of 0.1 M EDTA solution are added and the organic solvents are removed by introducing nitrogen. The remaining aqueous phase is stirred with 4.3 times the volume of chloroform / methanol (5: 8, v / v) for 30 minutes and then aspirated from the undissolved (L-serine). The filtrate is treated with 1 volume of water and 3.7 volumes of chloroform, the mixture stirred for 10 minutes, the organic phase separated, concentrated in vacuo and the residue obtained on carboxymethylcellulose (Servacel CM52) separated by column chromatography. The elution is carried out successively with 75 ml of chloroform (fraction 1), 500 ml of chloroform / methanol, 9: 1.8: 2.7: 3.1: 1, v / v (fractions 2 to 5). From fraction 5, 15 mg of pure i-chloro-i-deoxy-2-O-hexadecylglycero-3-phospho-L-serine are obtained. TLC (Merck Kieselgel 60, finished plate): Rf 0.13 (CHClg / CHaOH / HjO, 50: 25: 4, v / v / v); Rf 0.04 (CHCl 3 ZCH 3 OH 25% NH 3 , 65: 25: 4, \ / NN).
Claims (2)
CH-O-Ri
CHOIR
CH0-O-P(O)-O-CH0-CH-COOHi
CH 0 -OP (O) -O-CH 0 -CH-COOH
CH-O-RCHp-Hal
CHOIR
0"CH 0 -OP (O) -OR 1
0 "
N Z- (CH 2 JK - Y
N Z
CH-O-RCH 2 -HaI
CHOIR
OHCH 2 -OP (O) -O-GH 2 -CH-COOH
OH
Anwendungsgebiet der Erfindung ist die chemische bzw. pharmazeutische Industrie.The compounds have a close structural relationship with naturally occurring phosphatidylserines, which are very important in biological processes.
Field of application of the invention is the chemical or pharmaceutical industry.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD27823085A DD238978A1 (en) | 1985-07-03 | 1985-07-03 | PROCESS FOR THE PREPARATION OF 2-O-ALKYL-I-DES OXY-1 HALOGENGLYCERO-3-PHOSPHO-L-SERINES |
| EP86904150A EP0229128B1 (en) | 1985-07-03 | 1986-07-02 | Derivatives of glycero-3(2)-phospho-l-serine and pharmaceutical preparations containing them |
| JP61503925A JPH0751588B2 (en) | 1985-07-03 | 1986-07-02 | Glycero-3 (2) -phospho-L-serine derivative or salt thereof and pharmaceutical preparation containing the same |
| DE8686904150T DE3671630D1 (en) | 1985-07-03 | 1986-07-02 | GLYCERO-3 (2) -PHOSPHO-L-SERINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
| PCT/EP1986/000390 WO1987000173A1 (en) | 1985-07-03 | 1986-07-02 | Derivatives of glycero-3(2)-phospho-l-serine and pharmaceutical preparations containing them |
| AT86904150T ATE53214T1 (en) | 1985-07-03 | 1986-07-02 | GLYCERO-3(2)-PHOSPHO-L-SERINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
| HU862805A HU198076B (en) | 1985-07-03 | 1986-07-03 | Process for producing o-alkylated glycerophospho- and deoxyglycerophosphorine derivatives and pharmaceutical compositions comprising these compounds as active ingredient |
| FI870732A FI82473C (en) | 1985-07-03 | 1987-02-20 | Process for the preparation of pharmacologically valuable glycero-3 (2) -phospho-L-cerine derivatives |
| NO87870834A NO169171C (en) | 1985-07-03 | 1987-02-27 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE GLYCERO-3 (2) -PHOSPHO-L SERIN DERIVATIVES |
| DK106287A DK167978B1 (en) | 1985-07-03 | 1987-03-02 | GLYCERO-3 (2) -PHOSPHO-L-SERINE DERIVATIVES AND SALTS THEREOF, PROCEDURE FOR PREPARING SUCH COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE |
| US07/376,161 US4916249A (en) | 1985-07-03 | 1989-07-07 | Glycero-3(2)-phospho-L-serine derivatives and salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD27823085A DD238978A1 (en) | 1985-07-03 | 1985-07-03 | PROCESS FOR THE PREPARATION OF 2-O-ALKYL-I-DES OXY-1 HALOGENGLYCERO-3-PHOSPHO-L-SERINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD238978A1 true DD238978A1 (en) | 1986-09-10 |
Family
ID=5569330
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD27823085A DD238978A1 (en) | 1985-07-03 | 1985-07-03 | PROCESS FOR THE PREPARATION OF 2-O-ALKYL-I-DES OXY-1 HALOGENGLYCERO-3-PHOSPHO-L-SERINES |
Country Status (1)
| Country | Link |
|---|---|
| DD (1) | DD238978A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0338407A1 (en) * | 1988-04-19 | 1989-10-25 | Hafslund Nycomed Pharma Aktiengesellschaft | New alkylphosphonoserines, methods for preparing them, and pharmaceutical substances containing them |
| WO1991015494A1 (en) * | 1990-03-30 | 1991-10-17 | Istituto Chemioterapico Italiano Fine Chemicals S.P.A. | Process for separating the main components of a mixture of raw deacylated phospholipids |
-
1985
- 1985-07-03 DD DD27823085A patent/DD238978A1/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0338407A1 (en) * | 1988-04-19 | 1989-10-25 | Hafslund Nycomed Pharma Aktiengesellschaft | New alkylphosphonoserines, methods for preparing them, and pharmaceutical substances containing them |
| WO1989010370A1 (en) * | 1988-04-19 | 1989-11-02 | Cl-Pharma Aktiengesellschaft | New alkylphosphono- and phosphoserines, method for preparing them, and pharmaceutical substances containing them |
| WO1991015494A1 (en) * | 1990-03-30 | 1991-10-17 | Istituto Chemioterapico Italiano Fine Chemicals S.P.A. | Process for separating the main components of a mixture of raw deacylated phospholipids |
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