Process for 5'-phosphorylation of nucleic acids
First Claim
1. A process for the preparation of compounds of the formula I ##STR19## in which Kat represents one molar equivalent of a cation,R is an organic radical which carries no further phosphorylatable hydrogen atoms,X represents oxygen, sulfur or selenium,X represents oxygen, sulfur or --NH-- and n is 1 to 6,which comprises reacting in the presence of weak acid, a compound of the formula II
with at least n moles of the phosphorylating reagent of the formula III ##STR20## in which R1 represents a group of the formula IIIa or IIIb ##STR21## R5, R6 and R7, which can be identical or different, denote hydrogen or methyl,R8 denotes of the formula IIIc, IIId, or IIIe or cyano or Ar, ##STR22## R10 denotes lower alkyl or Ar, G, which can be identical or different, denotes C or N, but at least one G represents N,Ar denotes phenyl which can be substituted by 1 to 5 identical or different substituents belonging to the series chlorine, fluorine, nitro and cyano or, in addition to the election-withdrawing substituents, can be substituted by branched or unbranched alkyl with 8 to 24 carbon atomsy is 0, 1 or 2,R9 denotes a group of the formula IIIf or IIIg ##STR23## Y denotes identical or different substituents belonging to the series chlorine, bromine or iodine,R2 can have a meaning of R1 and is then identical or different, or denotes lower alkyl, a group of the formula IIIh
space="preserve" listing-type="equation">--CH.sub.z --Ar IIIh or Ar, if the latter can be removed by alkaline hydrolysis at a higher rate, under alkaline conditions, than R1 by alkalis, R5 and R8 together represent a group of the formula IIIi ##STR24## and R1 also represents methyl if R2 is also methyl, and R3 and R4, which can be identical or different, denote alkyl having 1 to 8 carbon atoms, cycloalkyl having 5 to 12 carbon atoms, benzyl or phenyl or, together with the nitrogen atom to which they are attached, denote a saturated or unsaturated heterocyclic ring which can contain further heteroatoms and substituents,oxidizing the resulting compound of the formula IV ##STR25## in which R1, R2, R, Z and n have the meanings mentioned and liberating the compound of the formula I by means of bases from the oxidized compounds of the formula V ##STR26## in which n, R1, R2, X, Z and R have the meanings mentioned.
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Abstract
Compounds of the formula ##STR1## are phosphorylating reagents which react with acylatable hydrogen atoms with elimination of the amine HNR3 R4. The resulting compounds are oxidized to give the corresponding phosphate, thiophosphate or selenophosphate derivatives, and the radicals R1 and R2 are then split off by means of bases. The chemical nature of the radicals R1, R2, R3 and R4 accordingly depends on the requirements for these cleavage reactions.
21 Citations
3 Claims
- 1. A process for the preparation of compounds of the formula I ##STR19## in which Kat represents one molar equivalent of a cation,
R is an organic radical which carries no further phosphorylatable hydrogen atoms, X represents oxygen, sulfur or selenium, X represents oxygen, sulfur or --NH-- and n is 1 to 6, which comprises reacting in the presence of weak acid, a compound of the formula II - space="preserve" listing-type="equation">R--(Z--H).sub.n II
with at least n moles of the phosphorylating reagent of the formula III ##STR20## in which R1 represents a group of the formula IIIa or IIIb ##STR21## R5, R6 and R7, which can be identical or different, denote hydrogen or methyl, R8 denotes of the formula IIIc, IIId, or IIIe or cyano or Ar, ##STR22## R10 denotes lower alkyl or Ar, G, which can be identical or different, denotes C or N, but at least one G represents N, Ar denotes phenyl which can be substituted by 1 to 5 identical or different substituents belonging to the series chlorine, fluorine, nitro and cyano or, in addition to the election-withdrawing substituents, can be substituted by branched or unbranched alkyl with 8 to 24 carbon atoms y is 0, 1 or 2, R9 denotes a group of the formula IIIf or IIIg ##STR23## Y denotes identical or different substituents belonging to the series chlorine, bromine or iodine, R2 can have a meaning of R1 and is then identical or different, or denotes lower alkyl, a group of the formula IIIh
space="preserve" listing-type="equation">--CH.sub.z --Ar IIIhor Ar, if the latter can be removed by alkaline hydrolysis at a higher rate, under alkaline conditions, than R1 by alkalis, R5 and R8 together represent a group of the formula IIIi ##STR24## and R1 also represents methyl if R2 is also methyl, and R3 and R4, which can be identical or different, denote alkyl having 1 to 8 carbon atoms, cycloalkyl having 5 to 12 carbon atoms, benzyl or phenyl or, together with the nitrogen atom to which they are attached, denote a saturated or unsaturated heterocyclic ring which can contain further heteroatoms and substituents, oxidizing the resulting compound of the formula IV ##STR25## in which R1, R2, R, Z and n have the meanings mentioned and liberating the compound of the formula I by means of bases from the oxidized compounds of the formula V ##STR26## in which n, R1, R2, X, Z and R have the meanings mentioned. - View Dependent Claims (2, 3)
Specification
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- Resources
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Current AssigneeHoechst Aktiengesellschaft (Sanofi )
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Original AssigneeHoechst Aktiengesellschaft (Sanofi )
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InventorsUhlmann, Eugen, Engels, Joachim
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Primary Examiner(s)Brown, Johnnie R.
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Assistant Examiner(s)Crane, L. Eric
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Application NumberUS07/396,803Time in Patent Office722 DaysField of Search536/27-29US Class Current536/25.34CPC Class CodesC07F 9/146 containing P-halide groupsC07F 9/2408 of hydroxyalkyl compoundsC07F 9/2429 of arylalkanolsC07F 9/26 containing P-halide groupsC07H 21/00 Compounds containing two or...
