Back to results
US 5,962,675 AGranted
Chemical syntheses of 2'-O-methoxy purine nucleosides
AssigneeRibozyme Pharmaceuticals, Inc.
InventorsLeonid Beigelman, David Sweedler, Peter Haeberli, Alexander Karpeisky
Life of this patent
Estimating the term…
Abstract
Several processes for the chemical synthesis of 2'-O-methoxy purine nucleosides are herein disclosed.
Claims12
A process for the synthesis of a 2'-O-methyl adenosine nucleoside, comprising the step of contacting a solution of N.sup.4 -acetyl-5',3'-di-O-acetyl-2'-O-methyl cytidine with a Lewis acid under conditions suitable for the formation of said nucleoside.
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) methylating 2-amino-6-chloropurine riboside by contacting said 2amino-6-chloropurine riboside with sodium hydride, dimethylformamide and methyl iodide under conditions suitable for the formation of 2'-O-methyl-2amino-6-chloropurine riboside;
- b) contacting said 2'-O-methyl-2-amino-6-chloropurine riboside with 1,4-diazabicyclo(2.2.2) octane and water under conditions suitable for the formation of said 2'-O-methyl guanosine nucleoside in a crude form;
- and
- c) purifying said 2'-O-methyl guanosine nucleoside from said crude form.
1 more element
A process for the synthesis of 2'-O-methyl adenosine nucleoside, comprising the steps of:
- a) methylating 2-amino-6-chloropurine riboside by contacting said 2amino-6-chloropurine riboside with sodium hydride, dimethylformamide and methyl iodide under conditions suitable for the formation of 2'-O-methyl-2amino-6-chloropurine riboside;
- b) contacting said 2'-O-methyl-2-amino-6-chloropurine riboside with acetic anhydride, 4-dimethylaminopyridine and triethylamine under conditions suitable for the formation of 3',5'-di-O-acetyl-2'-O-methyl-6-chloro-2-aminopurine riboside;
- c) deaminating said 3',5'-di-O-acetyl-2'-O-methyl-6-chloro-2-aminopurine riboside with isoamyl nitrite and tetrahydrofuran to form 3',5'-di-O-acetyl-2'-O-methyl-6'-chloropurine;
- d) aminating said 3',5'-di-O-acetyl-2'-O-methyl-6-chloropurine with ammonia to form 2'-O-methyl adenosine nucleoside in a crude form;
- and
- e) purifying said 2'-O-methyl adenosine nucleoside from said crude form.
3 more elements
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) contacting 2,6-diaminopurine nucleoside with anhydrous pyridine and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane under conditions suitable for the formation of 2,6-diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine;
- b) methylating said 2,6-Diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine by contacting said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine with anhydrous DMF and methyl iodide under conditions suitable for the formation of 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2'-O-methyl-.beta. -D-ribofuranosyl) purine;
- c) acylating said 2,6-Diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine by contacting said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine with anhydrous pyridine and isobutyryl chloride under conditions suitable for the formation of 2,6-Diamino-N.sup.2 -isobutyryl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2'-O-methyl-.beta. -D-ribofuranosyl) purine;
- d) deaminating and desilylating said 2,6-Diamino-N.sup.2 -isobutyryl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine under conditions suitable for the formation of N.sup.2 -isobutyryl-2'-O-methyl guanosine nucleoside in a crude form;
- e) purifying said N.sup.2 -isobutyryl-2'-O-methyl guanosine nucleoside from said crude form;
- and
- f) deblocking said N.sup.2 -isobutyryl-2'-O-methyl guanosine nucleoside under suitable conditions to form said 2'-O-methyl guanosine nucleoside.
4 more elements
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) contacting 2,6-diaminopurine nucleoside with anhydrous pyridine and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPSCI) under conditions suitable for the formation of 2,6-Diamino-9-(3',5'-O-tetraisopropyidisiloxan-(1,3-diyl)-.beta.-D-ribofur anosyl) purine;
- b) methylating said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine by contacting said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine with anhydrous DMF and methyl iodide under conditions suitable for the formation of 2,6-Diamino-9-(3',5'-O-tetraisopropyldisiloxan-(1,3-diyl)-2'-O-methyl-.bet a.-D-ribofuranosyl) purine;
- c) acylating said 2,6-Diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine by contacting said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine with anhydrous pyridine and isopropylphenoxyacetyl chloride under conditions suitable for the formation of 2,6-Diamino-N.sup.2 -isopropylphenoxyacetyl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-me thyl-.beta.-D-ribofuranosyl) purine;
- d) deaminating and desilylating said 2,6-Diamino-N.sup.2 -isopropylphenoxyacetyl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-me thyl-.beta.-D-ribofuranosyl) purine under conditions suitable for the formation of N.sup.2 -isopropylphenoxyacetyl-2'-O-methyl guanosine nucleoside in a crude form;
- e) purifying said N.sup.2 -isopropylphenoxyacetyl-2'-O-methyl guanosine nucleoside from said crude form;
- and
- f) deblocking said N.sup.2 -isopropylphenoxyacetyl-2'-O-methyl guanosine nucleoside under suitable conditions to form said 2'-O-methyl guanosine nucleoside.
4 more elements
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) contacting guanosine with N,N-dimethylformamide dibenzyl acetal under conditions suitable for the formation of N1-benzyl guanosine;
- b) methylating said N1-benzyl guanosine by contacting said N1-benzyl guanosine with silver acetylacetonate, trimethylsulphonium hydroxide and dimethylformamide under conditions suitable for the formation of N1-benzyl-2'-O-methyl guanosine in a crude form;
- c) purifying said N1-benzyl-2'-O-methyl guanosine from said crude form;
- d) removing the N1-benzyl protection from said N1-benzyl-2'-O-methyl guanosine by contacting said N1-benzyl-2'-O-methyl guanosine with sodium naphthalene under conditions suitable for the formation of 2'-O-methyl guanosine nucleoside in a crude form;
- and
- e) purifying said 2'-O-methyl guanosine from said crude form.
3 more elements
A process for the synthesis of 2'-O-methyl adenosine nucleoside, comprising the steps of:
- a) methylating adenosine by contacting said adenosine with dimethylformamide, silver acetylacetonate and trimethylsulphonium hydroxide under conditions suitable for the formation of 2'-O-methyl adenosine in a crude form;
- and
- b) purifying said 2'-O-methyl adenosine from said crude form.
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) contacting guanosine with N,N-dimethylformamide dibenzyl acetal under conditions suitable for the formation of N1-benzyl guanosine;
- b) methylating said N1-benzyl guanosine by contacting said N1-benzyl guanosine with magnesium acetylacetonate, trimethylsulphonium hydroxide and dimethylformamide under conditions suitable for the formation of N1-benzyl-2'-O-methyl guanosine in a crude form;
- c) purifying said N1-benzyl-2'-O-methyl guanosine from said crude form;
- d) removing the N1-benzyl protection from said N1-benzyl-2'-O-methyl guanosine by contacting said N1-benzyl-2'-O-methyl guanosine with sodium naphthalene under conditions suitable for the formation of 2'-O-methyl guanosine nucleoside in a crude form;
- and
- e) purifying said 2'-O-methyl guanosine nucleoside from said crude form.
3 more elements
A process for the synthesis of 2'-O-methyl adenosine nucleoside, comprising the steps of:
- a) methylating adenosine by contacting said adenosine with dimethylformamide, magnesium acetylacetonate and trimethylsulphonium hydroxide under conditions suitable for the formation of 2'-O-methyl adenosine in a crude form;
- and
- b) purifying said 2'-O-methyl adenosine from said crude form.
A process for the synthesis of 2'-O-methyl adenosine nucleoside, comprising the steps of:
- a) methylating adenosine by contacting said adenosine with dimethylformamide, strontium acetylacetonate and trimethylsulphonium hydroxide under conditions suitable for the formation of 2'-O-methyl adenosine in a crude form;
- and
- b) purifying said 2'-O-methyl adenosine from said crude form.
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) contacting 2,6-diaminopurine nucleoside with anhydrous pyridine and TIPSCI under conditions suitable for the formation of 2,6-diamino-9-(3',5'-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofur anosyl) purine;
- b) methylating said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine by contacting said 2,6-Diamino-9-(3',5'-O-tetraisopropyidisiloxan-(1,3-diyl)-.beta.-D-ribofur anosyl) purine with anhydrous DMF and methyl iodide under conditions suitable for the formation of 2,6-Diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine;
- c) acylating said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine by contacting said 2,6-Diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine with anhydrous pyridine and isobutyryl chloride under conditions suitable for the formation of 2,6-Diamino-N.sup.2 -isobutyryl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine;
- d) deaminating and desilylating said 2,6-Diamino-N.sup.2 -isobutyryl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2'-O-methyl-.beta. -D-ribofuranosyl) purine under conditions suitable for the formation of N.sup.2 -isobutyryl-2'-O-methyl guanosine nucleoside in a crude form;
- and
- e) purifying said N.sup.2 -isobutyryl-2'-O-methyl guanosine nucleoside from said crude form.
3 more elements
A process for the synthesis of 2'-O-methyl guanosine nucleoside, comprising the steps of:
- a) contacting 2,6-diaminopurine nucleoside with anhydrous pyridine and TIPSCI under conditions suitable for the formation of 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine;
- b) methylating said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine by contacting said 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-.beta.-D-ribofuran osyl) purine with anhydrous DMF and methyl iodide under conditions suitable for the formation of 2,6-Diamino-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine;
- c) acylating said 2,6-Diamino-9-(3,5-O-tetraisopropyidisiloxan-(1,3-diyl)-2-O-methyl-.beta.- D-ribofuranosyl) purine by contacting said 2,6-Diamino9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2'-O-methyl-.beta.- D-ribofuranosyl) purine with anhydrous pyridine and isopropylphenoxyacetyl chloride under conditions suitable for the formation of 2,6-Diamino-N.sup.2 -isopropylphenoxyacetyl-9-(3',5'-O-tetraisopropyldisiloxan-(1,3-diyl)-2'-O -methyl-.beta.-D-ribofuranosyl) purine;
- d) deaminating and desilylating said 2,6-Diamino-N.sup.2 -isopropylphenoxyacetyl-9-(3,5-O-tetraisopropyldisiloxan-(1,3-diyl)-2-O-me thyl-.beta.-D-ribofuranosyl) purine under conditions suitable for the formation of N.sup.2 -isopropylphenoxyacetyl-2'-O-methyl guanosine nucleoside in a crude form;
- and
- e) purifying said N.sup.2 -isopropylphenoxyacetyl-2'-O-methyl guanosine nucleoside from said crude form.
3 more elements
Dependencies are inferred from the claim text.