US2951838A - Novel method of preparing nucleotide imidazoles - Google Patents

Novel method of preparing nucleotide imidazoles Download PDF

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US2951838A
US2951838A US862788A US86278859A US2951838A US 2951838 A US2951838 A US 2951838A US 862788 A US862788 A US 862788A US 86278859 A US86278859 A US 86278859A US 2951838 A US2951838 A US 2951838A
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nucleotide
adenosine
imidazoles
novel method
imidazole
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US862788A
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Goldman Leon
Marsico Joseph William
Anderson George Washington
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Wyeth Holdings LLC
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • nucleoside is used herein to include deoxynucleosides.
  • nucleoside within the meaning of the present invention includes:
  • Thymidine or thymine deoxyriboside
  • a nucleotide is a phosphate ester of a nucleoside and maybe a nucleoside monophosphate gor a nucleoside polyphosphate.
  • nucleoside monophosphates are:
  • Adenosine-5' phosphate or muscle adenylic acid or adenosine monophosphate, the latter hereinafter termed AMP: "i
  • nucleoside polyphosphates are: (1) Adenosine-S diphosphate (hereinafter termed ADP):
  • ATP Adenosine-S' 'triphosphate
  • a nucleotide coenzyme is a compound including in its structure at least one simple nucleotide moiety.
  • the term nucleotide coenzyme is applied to a large and growing group of substances which are vital components of many enzyme systems involved in metabolic processes. Nucleotide coenzymes functionin association with specific proteins or apoenzymes, the complete enzyme system being made up of the combination ajpoenzyme plus coenzyme. Historically, the first nucleotide coenzyme discovered was cozymase, or diphosphopyridine nucleotide, discovered by Harden and Young in 1904. Examples ofi nucleotide coenzymes are:
  • Cozymase or diphosphopyridine nucleotide
  • phosphate may condense, giving the undesired symmetrical pyrophosphate
  • nucleotide imidazoles may be prepared in good yield by the treatment of a salt of a nucleotide with a 1,1-carbonyldiimidazole as set forth in the following reaction scheme:
  • H R R wherein the Base is either a purine or a pyrimidine moiety, the Sugar is either a pentose or a hexose moiety such as, for example, D-ribose, D-glucose, or 2-deoxy-D- ribose, R is vinylene, substituted-vinylene, o-phenylene, or substituted-o-phenylene, R is hydrogen or lower alkyl, and B is an organic base such as, for example, imidazole, pyridine, or trioctyl amine.
  • the Base is either a purine or a pyrimidine moiety
  • the Sugar is either a pentose or a hexose moiety such as, for example, D-ribose, D-glucose, or 2-deoxy-D- ribose
  • R is vinylene, substituted-vinylene, o-phenylene, or substituted-o-phenylene
  • R
  • the 1,1-carbonyldiimidazole reagent employed may be, for example, 1,1-carbonyldiimidazole, 1,1-carbonyldi(2-methyl) -imidazole, 1,1 carbonyldi(4 methyl)imidazole, 1,1 carbonyldibenzimidazole, 1,1 carbonyldi(4-nitro)benzirnidaziole, 1,1' carbonyldi(6 nitro) benzimidazole, and the like.
  • the reaction may be carried out in nonaqueous solvents such as, for example, formamide N,N-dimethylformamide, dimethyl sulfoxide, acetontitrile, pyridine, diethyl phosphite, morpholine, dioxane, 1,2-dimethoxyethane, and the like.
  • the reaction is ordinarily carried out at temperatures not substantially exceeding room temperature and over periods of time ranging from less than one minute to an hour or more.
  • Carbon dioxide and an imidazole are the only by-products of the reaction, and it is an advantage of the novel method of the present invention that both by-products are easily separated from the final reaction mixture.
  • the principal advantage of the novel method of the present invention is that it is superior to the previously known method of preparing nucleotide imidazoles insofar as facility of manipulation is concerned.
  • nucleotide coenzymes and related compounds such as the linear and cyclic oligonucleotides from the nucleotide imidazoles in the presence of water as a solvent without the starting material reacting with that solvent.
  • Ultraviolet absorbing spots were observed corresponding to a major amount of adenosine-S' phosphoroimidazole and a very minor amount of unchanged adenosine-5' phosphate.
  • An additional spot corresponding to adenosine-S' phosphoroamidate was observed, this having been formed by the action of ammonia on adenosine-S' phosphoroimidazole during the chromatographic process.
  • spots appeared corresponding to adenosine-S phosphoroimidazole and imidazole.
  • EXAMPLE 2 Preparation of adenosine-S' phosphoroimidazole To a stirred solution of 1 mole of adenosine-S' phosphate hydrate and 3.14 moles of imidazole in anhydrous dimethylforrnamide, cooled to 0' C. to 5 C., was added 2 moles of 1,1-carbony1diimidazole. After 5 minutes the mixture was cooled to -10 C. to --20 C. and stirred for an additional 10 minutes.
  • Paper chromatography in isopropyl alcohol-1% ammonium sulfate (21) showed the reaction mixture to contain mainly adenosine-S' phosphoroimidazole along with a small amount of unreacted adenosine-S' phosphate.
  • Chromatography in isopropyl alcohol-ammonia-water (7--1-2) confirmed the above.
  • EXAMPLE 3 Preparation of adenosine-S' phosphoroimidazole To a stirred solution of 1.00 g. of adenosine-S' phosphate hydrate and 0.586 g. of imidazole in 7.5 ml. of anhydrous dimethylformarnide at room temperature was added 1.486 g. of 93% 1,1-carbonyldiimidazole, and after 15 minutes the resulting solution was analyzed by paper chromatography in isopropyl alcohol-ammonia-water (7-1-2), showing complete conversion of adenosine-S' phosphate to adenosine-S' phosphoroimidazole.
  • nucleotide imidazoles which comprises treating a salt of a nucleotide and an organic base with a compound of the formula:
  • R is selected from the group consisting of vinylene, lower alkyl substituted vinylene, o-phenylene and mono-nitro substituted o-phenylene, and R is selected 2,951,838 .r 7 a from the group consisting of hydrogen and lower alkyl. benzimidazole and 1,1'-carbonyldi(6-nitro)benzimidazole.
  • the method of preparing nucleotide imidazoles 3.
  • the method of preparing adenosine-Yphosphoro which comprises treating a salt of a nucleotide and an imidazole which comprises treating the salt imidazole organic base with a compound selected from the group adenosine-S phosphate with 1,1-carbonyldi-imidazole in consisting of 1,1-carbonyldiimidazo1e, 1,1'-carbonyldi(2- 5 an inert solvent at a temperature between -20 C. and methyDimidazole, 1,1'-carbonyldi(4 methyl)irnidazole, +30 C. 1,1 carbonyldibenzimidazole, 1,1 carbonyldi(4-nitro) No references cited.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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Description

NOVEL METHOD OF PREPARING NUCLEOTIDE IMIDAZOLES Leon Goldman and Joseph William Marsico, Nanuet,
N.Y.,yand George Washington Anderson, Upper Saddle River,vN.J., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed Dec. 30, 1959, Ser. No. 862,788
3 Claims. (Cl. 260 211.5)
IfNTN\ CHnOH (2) Guanosine (or guanine riboside):
(3) Cytidine (or cytosine riboside):
CHzOH The termnucleoside is used herein to include deoxynucleosides. Thus, nucleoside within the meaning of the present invention includes:
' i United States Patent O Patented Sept. 6, 1960 ice 2 (4) Thymidine (or thymine deoxyriboside):
N CHzOH 0 f N OH;
A nucleotide is a phosphate ester of a nucleoside and maybe a nucleoside monophosphate gor a nucleoside polyphosphate. Examples of nucleoside monophosphates are:
(1) Adenosine-5' phosphate (or muscle adenylic acid or adenosine monophosphate, the latter hereinafter termed AMP): "i
l H H t N N omo-r-oi'z 1/ (2) Guanosine-S' phosphate:
N N- CH O] -OH Hm i T 2 l (3) Cytidine-S' phosphate:
n r N 01110-1 -011 f y H (4) Thymidine-S phosphate:
, omo-r-on 3 Examples of nucleoside polyphosphates are: (1) Adenosine-S diphosphate (hereinafter termed ADP):
II II cmo-r-o-r-on '(2) Adenosine-S' 'triphosphate (hereinafter termed ATP):
A nucleotide coenzyme is a compound including in its structure at least one simple nucleotide moiety. The term nucleotide coenzyme is applied to a large and growing group of substances which are vital components of many enzyme systems involved in metabolic processes. Nucleotide coenzymes functionin association with specific proteins or apoenzymes, the complete enzyme system being made up of the combination ajpoenzyme plus coenzyme. Historically, the first nucleotide coenzyme discovered was cozymase, or diphosphopyridine nucleotide, discovered by Harden and Young in 1904. Examples ofi nucleotide coenzymes are:
(1) Cozymase (or diphosphopyridine nucleotide):
on OH 4 (3) Uridine diphosphate glucose:
u l N O-H'zOP-'O--'PO OH r I OH H t N (4) Coenzyme A:
II H OK i N N H10-P-0-P-0oHrb-( JH- -NH I OH H H: H: N N/ H: v HS-CH2CHPHN-3=D The reaction of adenosine-S' phosphate, dicyclo-hexylcarbodiimide and imidazole was recently examined by R. W. Chambers and I. G. Molfatt [J. Am. Chem. Soc.
80, 3752 (1958)]. There are obtained 1,3-dicyclohexylurea and adenosine-S' phosphoroimidazole as set forth in the following reaction scheme:
phosphate may condense, giving the undesired symmetrical pyrophosphate;
The following examples illustrate the novel method of preparing nucleotide imidazoles of the present invention.
thus wasting starting material and complicating the isolation procedure: and (b) the incidentally formed dialkyl urea must be removed, an additional isolation requirement.
Our invention is based upon the discovery that nucleotide imidazoles may be prepared in good yield by the treatment of a salt of a nucleotide with a 1,1-carbonyldiimidazole as set forth in the following reaction scheme:
H R R wherein the Base is either a purine or a pyrimidine moiety, the Sugar is either a pentose or a hexose moiety such as, for example, D-ribose, D-glucose, or 2-deoxy-D- ribose, R is vinylene, substituted-vinylene, o-phenylene, or substituted-o-phenylene, R is hydrogen or lower alkyl, and B is an organic base such as, for example, imidazole, pyridine, or trioctyl amine.
In carrying out the novel method of the present invention for preparing nucleotide imidazoles, the 1,1-carbonyldiimidazole reagent employed may be, for example, 1,1-carbonyldiimidazole, 1,1-carbonyldi(2-methyl) -imidazole, 1,1 carbonyldi(4 methyl)imidazole, 1,1 carbonyldibenzimidazole, 1,1 carbonyldi(4-nitro)benzirnidaziole, 1,1' carbonyldi(6 nitro) benzimidazole, and the like. The reaction may be carried out in nonaqueous solvents such as, for example, formamide N,N-dimethylformamide, dimethyl sulfoxide, acetontitrile, pyridine, diethyl phosphite, morpholine, dioxane, 1,2-dimethoxyethane, and the like. The reaction is ordinarily carried out at temperatures not substantially exceeding room temperature and over periods of time ranging from less than one minute to an hour or more. Carbon dioxide and an imidazole are the only by-products of the reaction, and it is an advantage of the novel method of the present invention that both by-products are easily separated from the final reaction mixture. The principal advantage of the novel method of the present invention, however, is that it is superior to the previously known method of preparing nucleotide imidazoles insofar as facility of manipulation is concerned.
The reactivity of phosphorylated imidazoles is much greater than that of the ordinary phosphoramidates which also contain a phosphorus-nitrogen linkage. Surprising- 1y, however, although the phosphorus-nitrogen bond in the nucleotide imidazoles is thus generally activated, it is nevertheless resistant to reaction with water. Hence, it is possible to prepare nucleotide coenzymes and related compounds such as the linear and cyclic oligonucleotides from the nucleotide imidazoles in the presence of water as a solvent without the starting material reacting with that solvent. This circumstance is of critical importance because water is the most convenient solvent for nucleo- EXAMPLE 1 Preparation of adenosine-5' phosphor-oimidazole To a solution of 1 mole of adenosine-S" phosphate hydrate and 3 moles of imidazole in anhydrous dimethylformamide at room temperature Was added 2 moles of 1,1-carbonyldiimidazole with stirring. Carbon dioxide was immediately evolved, with the formation of adenosine-5 phosphoroimidazole in solution. This was shown by paper chromatography in isopropyl alcohol-ammonia water (7l--2) of aliquots taken after 2,5, and 20 minutes. Ultraviolet absorbing spots were observed corresponding to a major amount of adenosine-S' phosphoroimidazole and a very minor amount of unchanged adenosine-5' phosphate. An additional spot corresponding to adenosine-S' phosphoroamidate was observed, this having been formed by the action of ammonia on adenosine-S' phosphoroimidazole during the chromatographic process. When the chromatogram was sprayed with imidazole detecting reagent, spots appeared corresponding to adenosine-S phosphoroimidazole and imidazole.
EXAMPLE 2 Preparation of adenosine-S' phosphoroimidazole To a stirred solution of 1 mole of adenosine-S' phosphate hydrate and 3.14 moles of imidazole in anhydrous dimethylforrnamide, cooled to 0' C. to 5 C., was added 2 moles of 1,1-carbony1diimidazole. After 5 minutes the mixture was cooled to -10 C. to --20 C. and stirred for an additional 10 minutes. Paper chromatography in isopropyl alcohol-1% ammonium sulfate (21) showed the reaction mixture to contain mainly adenosine-S' phosphoroimidazole along with a small amount of unreacted adenosine-S' phosphate. Chromatography in isopropyl alcohol-ammonia-water (7--1-2) confirmed the above. An additional spot corresponding to adenosine-S phosphoroamidate arose from ammonolysis of adenosine-S' phosphoroimidazole during the chromatographic process.
EXAMPLE 3 Preparation of adenosine-S' phosphoroimidazole To a stirred solution of 1.00 g. of adenosine-S' phosphate hydrate and 0.586 g. of imidazole in 7.5 ml. of anhydrous dimethylformarnide at room temperature was added 1.486 g. of 93% 1,1-carbonyldiimidazole, and after 15 minutes the resulting solution was analyzed by paper chromatography in isopropyl alcohol-ammonia-water (7-1-2), showing complete conversion of adenosine-S' phosphate to adenosine-S' phosphoroimidazole.
We claim:
1. The method of preparing nucleotide imidazoles which comprises treating a salt of a nucleotide and an organic base with a compound of the formula:
wherein R is selected from the group consisting of vinylene, lower alkyl substituted vinylene, o-phenylene and mono-nitro substituted o-phenylene, and R is selected 2,951,838 .r 7 a from the group consisting of hydrogen and lower alkyl. benzimidazole and 1,1'-carbonyldi(6-nitro)benzimidazole.
2. The method of preparing nucleotide imidazoles 3. The method of preparing adenosine-Yphosphorowhich comprises treating a salt of a nucleotide and an imidazole which comprises treating the salt imidazole organic base with a compound selected from the group adenosine-S phosphate with 1,1-carbonyldi-imidazole in consisting of 1,1-carbonyldiimidazo1e, 1,1'-carbonyldi(2- 5 an inert solvent at a temperature between -20 C. and methyDimidazole, 1,1'-carbonyldi(4 methyl)irnidazole, +30 C. 1,1 carbonyldibenzimidazole, 1,1 carbonyldi(4-nitro) No references cited.

Claims (1)

1. THE METHOD OF PREPARING NUCLEOTIDE IMIDAZOLES WHICH COMPRISES TREATING A SALT OF A NUCLEOTIDE AND AN ORGANIC BASE WITH A COMPOUND OF THE FORMULA:
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4544741A (en) * 1982-03-29 1985-10-01 Robins Roland K Azole dinucleotide compounds and methods for their production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4544741A (en) * 1982-03-29 1985-10-01 Robins Roland K Azole dinucleotide compounds and methods for their production

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