Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-07-29
1998-03-31
Ambrose, Michael G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 2672, 536 268, 558118, 558119, C07H 102, C07H 1910, C07H 19207, C07F 909
Patent
active
057340420
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/00219 filed Jan. 21, 1995.
The present invention concerns a process for the production of phosphoric acid diesters with two non-identical organic residues.
The process according to the invention for the production of phosphoric acid diesters is characterized in that alcohol of formula II sparingly soluble salt by the addition of a solution containing alkaline-earth ions and it is isolated, solvent by suspension in a water-immiscible organic solvent and a dilute aqueous mineral acid.
The product that is formed is subsequently purified further. This can for by preparative chromatography on an appropriate column, for example a compound obtained in the form of its free acid is subsequently converted
In certain cases in which the alcohol of formula II has for example further secondary OH groups in addition to a primary OH group, it may be advantageous to react the phosphoric acid ester of formula I with the arylsulfonic acid chloride in the presence of an organic base (producing the mixed anhydride) and only afterwards add the alcohol of formula II.
The process claimed is particularly suitable for the production of liponucleotides in which R.sup.2 represents a nucleosidic residue.
Three different processes for the production of lipid derivatives of nucleosides are shown in WO 92/03462: presence of an organic base. monocholine ester with the nucleoside (phospholipase D from Streptomyces). of DCC (dicyclohexylcarbodiimide).
All three variants are suitable for making internucleotidic bonds as well as for condensing nucleosides with lipid phosphates and are described in the literature.
The condensation of a lipid phosphate and of a nucleoside using DCC is described in J. Med. Chem. 34, 1408 (1991), Biochem. Biophys. Res. Commun. 171, 451 (1990) and U.S. Pat. No. 5,149,794. The enzymatically catalyzed condensation of a phosphocholine with a nucleoside in the presence of phospholipase D from Streptomyces is described in Biochem. 31, 4757 (1992), EP 0 457 570, EP 0 262 876 and WO 92/17487. In addition the use of arylsulfonic acid chlorides for the synthesis of the internucleotidic J. Am. Chem. Soc. 88, 829 (1966), dto. 86, 1630 (1964)! and especially the sterically hindered 2,4,6-triisopropylbenzenesulfonic acid chloride. This reagent was used by Hostetler et.al. for the condensation of phospholipids with nucleosides and is described inter alia in J. Biol. Chem. 265, 6112 (1990), dto. 266, 11714 (1991). Analogously it was possible to condense nucleoside monophosphates with primary lipid alcohols as described in J. Biol. Chem. 267, 20288 (1992).
However, the described methods have the disadvantage that the production of lipid derivatives is only possible in unsatisfactory yields. Further disadvantages are in addition inadequate product purities and complicated purification procedures which impede mechanization on a large technical scale of for example amounts of several kilograms. It was not even possible to reproduce the published processes in the described yields with larger process batches.
It was possible to eliminate these difficulties with the process according to the invention.
A particular subject matter of the present invention is a process for the production of lipid derivatives which is characterized in that organic residue, such as e.g. a special lipid moiety, is condensed with a 5' unprotected nucleoside in the presence of an arylsulfonic acid chloride and an organic base such as e.g. pyridine, organic solvent (e.g. DIPE, MTB), the arylsulfonic acid pyridine salt which is formed is almost completely crystallized and recycled, addition of e.g. aqueous calcium acetate solution and isolated, solvent by suspension in a water-immiscible organic solvent and a dilute aqueous mineral acid (residue of evaporation >95% area after HPLC).
The crude product is subsequently purified by preparative chromatography on a RP phase and the free acid is converted into any desired salt.
If desired an intermediate isolation is possible after HPLC from the fractions containing product by p
REFERENCES:
patent: 4239905 (1980-12-01), Kodama et al.
patent: 4605645 (1986-08-01), Watanabe et al.
Kiegel Einhard
Zilch Harald
Ambrose Michael G.
Boehringer Mannheim GmbH
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