Method for preparing oligonucleotides

A solution phase synthesis method for preparing an oligonucleotide, wherein at least some of the reagents are solid supported. The method suitable for large-scale synthesis comprises coupling a protected compound with a nucleotide derivative having a protection group in the presence of a solid supported activator to give an elongated oligonucleotide with a P(III)-internucleotide bond; optionally processing the elongated oligonucleotide by capping by reaction with a solid supported capping agent and/or by oxidizing or sulfurizing by reaction of the oligonucleotide with a solid supported oxidizing or sulfurization reagent; and removing the protection group. The coupling may include reacting a 3-protected compound of formula: with a nucleotide derivative having a 5-protection group, or reacting a 5-protected compound of formula with a nucleotide derivative having a 3-protection group.

PURIFICATION OF OLIGONUCLEOTIDES

A method for purifying a protected oligonucleotide comprising the steps of: 118-. (canceled)19. A method for purifying a protected oligonucleotide comprising:a1) providing a solution of said protected oligonucleotide in at least one solvent (A) having a boiling point below the boiling point of a solvent (B);a2) heating said solution of said protected oligonucleotide in at least one solvent (A) at a temperature of at least 30° C. and below the boiling point of said at least one solvent (A);a3) adding solvent (B) to said solution until precipitation of a material is visible, said solvent (B) being an alcohol having 1 to 6 carbon atoms or a diol having 2 to 6 carbon atoms;a4) allowing said solution to cool down under stirring until formation of a supernatant and a residue; anda5) removing said supernatant; orb1) providing solvent (B), said solvent (B) being an alcohol having 1 to 6 carbon atoms or a diol having 2 to 6 carbon atoms;b2) heating said solvent (B) at a temperature above 30° C. and below the boiling point of said solvent (B);b3) adding a solution of a protected oligonucleotide in at least one solvent (A) to said solvent (B) until precipitation of a material is visible in the solution;b4) allowing said solution to cool down under stirring until formation of a supernatant and a residue; andb5) removing said supernatant.20. The method of claim 19 , wherein said protected oligonucleotide comprises from 2 to 30 nucleotides.21. The method of claim 19 , wherein said protected oligonucleotide comprises a 3′ and 5′protection group claim 19 , a 5′ protection group and no 3′ protection group claim 19 , or a 3′ protection group and no 5′ protection group.22. The method of claim 21 , wherein said 5′protection group is DMTr claim 21 , MMTr claim 21 , tert-butyl dimethylsilyl claim 21 , levulinyl claim 21 , benzoyl claim 21 , fluorenemethoxycarbonyl claim 21 , or 9-phenylthioxanthen-9-yl.23. The method of claim 19 , wherein said solvent A is CHCl claim 19 , CHCl claim 19 , ...

Method for the Production of a-(Alpha-Hydroxyalkyl)-1,3 Dioxan-5-Ones

A process for the synthesis of compounds of general formulas comprising the step of reacting in the presence of wherein: R=substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; R 1 and R 2 independently represent H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; R′═H, OH, OR or OSiX 3 , wherein X independently represent alkyl or aryl.

SYNTHESIS OF PHOSPHITYLATED COMPOUNDS USING A QUATERNARY HETEROCYCLIC ACTIVATOR

A method for preparing a phosphitylated compound comprising the step of:reacting a hydroxyl containing compound with a phosphitylating agent in the presence of an activator having the formula (I) wherein R=alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl R1, R2=either H or form a 5 to 6-membered ring together. X1, X2=independently either N or CH YH or Si(R4)3, with R4=alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl B=deprotonated acid. The hydroxyl containing compound is preferably a sugar moiety or a nucleoside or an oligomer derived therefrom.

PURIFICATION OF OLIGONUCLEOTIDES

A method for purifying a protected oligonucleotide comprising the steps of: a) providing a solution of the protected oligonucleotide in at least one solvent A having a boiling point below the boiling point of a solvent B, heating the solution at a temperature of at least 30° C. and below the boiling point of the at least solvent A, adding solvent B until precipitation of a material is visible in the solution, said solvent B being an alcohol having 1 to 6 C-atoms or a diol having 2 to 6 C-atoms, allowing the solution to cool down under stirring until formation of a supernatant and a residue, removing the supernatant or b) providing solvent B, said solvent B being an alcohol having 1 to 6 C-atoms or a diol having 2 to 6 C-atoms, heating solvent B at a temperature above 30° C. and below the boiling point of solvent B, adding a solution of a protected oligonucleotide in at least one solvent A until precipitation of a material is visible in the solution, allowing the solution to cool down under ...

SYNTHESIS OF OLIGONUCLEOTIDES

A method for preparing an oligonucleotide comprising the steps of a) providing a hydroxyl containing compound having the formula (A), b) reacting said compound with a phosphitylating agent in the presence of an activator (activator I) having the formula (I) to prepare a phosphitylated compound; and c) reacting said phosphitylated compound without isolation with a second compound having the formula (A) wherein R 5 , R 3 , R 2 , B are independently selected, but have the same definition as above in the presence of an activator II different from activator I.

Method for preparing oligonucleotides

A solution phase synthesis method for preparing an oligonucleotide, wherein at least some of the reagents are solid supported. The method suitable for large-scale synthesis comprises coupling a protected compound with a nucleotide derivative having a protection group in the presence of a solid supported activator to give an elongated oligonucleotide with a P(III)-internucleotide bond; optionally processing the elongated oligonucleotide by capping by reaction with a solid supported capping agent and/or by oxidizing or sulfurizing by reaction of the oligonucleotide with a solid supported oxidizing or sulfurization reagent; and removing the protection group. The coupling may include reacting a 3-protected compound of formula: with a nucleotide derivative having a 5-protection group, or reacting a 5-protected compound of formula with a nucleotide derivative having a 3-protection group.

SYNTHESIS OF OLIGONUCLEOTIDES

A method for preparing an oligonucleotide comprising the steps of a) providing a hydroxyl containing compound having the formula (A), b) reacting said compound with a phosphitylating agent in the presence of an activator (activator I) having the formula (I) to prepare a phosphitylated compound; and c) reacting said phosphitylated compound without isolation with a second compound having the formula (A) wherein R5, R3, R2, B are independently selected, but have the same definition as above in the presence of an activator II different from activator I.

Method for the production of a-(alpha-hydroxyalkyl)-1,3 dioxan-5-ones

A process for the synthesis of compounds of general formulas comprising the step of reacting in the presence of wherein: R=substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; R1 and R2 independently represent H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; R=H, OH, OR or OSiX3, wherein X independently represent alkyl or aryl.

Method for preparing oligonucleotides

A method for preparing an oligonucleotide comprising the steps of a) providing a 3-protected compound having the formula: wherein B is a heterocyclic base R2 is H, a protected 2-hydroxyl group, F, a protected amino group, an O-alkyl group, an O-substituted alkyl, a substituted alkylamino or a C4′-O2′methylen linkage R3 is OR′3, NHR″3, NR″3R′″3, a 3′-protected nucleotide or a 3′-protected oligonucleotide, R′3 is a hydroxyl protecting group, R″3, R′″3 are independently an amine protecting group, b) reacting said compound with a nucleotide derivative having a 5-proctection group in the presence of a solid supported activator to give an elongated oligonucleotide with a P(III)-internucleotide bond c) optionally processing the elongated oligonucleotide with a P(III)-internucleotide bond by either or both of steps c1) and c2) in any sequence c1) capping preferably by reacting with a solid supported capping agent c2) oxidizing preferably by reacting the oligonucleotide with a solid supported oxidizing ...

Synthesis of oligonucleotides

A method for preparing an oligonucleotide comprising the steps of synthesizing a phosphoramidite by reacting a hydroxyl-containing compound of formula (A) with a phosphitylating agent in the presence of an activator compound of formula (I), to prepare a phosphitylated compound, then coupling the phosphitylated compound without isolation with a second compound having the formula (A), wherein R, R, R, B are independently selected, but have the same definition as above in the presence of an activator II selected from the group of imidazole, imidazolium salts, and mixtures thereof, which are improved activators over activators disclosed in related art. 4. The method of claim 1 , wherein the phosphitylating agent is 2-cyanoethyl-N claim 1 ,N claim 1 ,N′ claim 1 ,N′-tetraisopropylphosphorodiamidite.5. The method of claim 1 , wherein the deprotonated acid is selected from the group consisting of trifluoroacetic acid claim 1 , dichloroacetic acid claim 1 , methanesulfonic acid claim 1 , trifluoromethanesulfonic acid claim 1 , and o-chlorophenolic acid.6. The method of claim 1 , wherein the reacting is in the presence of acetone.7. The method of claim 1 , wherein the concentration of phosphitylating agent in step b) is from 1.0 to 1.2 mol/mol of hydroxyl groups in the hydroxyl containing compound.8. The method of claim 1 , wherein the concentration of phosphitylating agent in step b) is from 3 to 5 mol/mol of hydroxyl groups in the hydroxyl containing compound.9. The method of claim 1 , further comprising adding a polymeric alcohol after step b).10. The method of claim 9 , wherein the polymeric alcohol is polyvinyl alcohol.11. The method of claim 1 , wherein the deprotonated acid is selected from the group consisting of trifluoroacetic acid claim 1 , dichloroacetic acid claim 1 , methanesulfonic acid claim 1 , trifluormethanesulfonic acid (triflate) claim 1 , o-chlorophenolate claim 1 , and mixtures thereof.12. The method of claim 9 , wherein the reacting is in the presence ...

Synthesis of oligonucleotides

A method for preparing an oligonucleotide comprising the steps of a) providing a hydroxyl containing compound having the formula (1), wherein B is a heterocyclic base and the radicals R2, R3 and R5 are as defined in the description; b) reacting said compound with a phosphitylating agent in the presence of an activator having the formula (I) (activator I)), wherein R = alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; R1, R2 = either H or form a 5 to 6-membered ring together; X1, X2 = independently either N or CH; Y = H or Si(R4)3, with R4= alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; B = deprotonated acid; to prepare a phosphitylated compound; c) reacting said phosphitylated compound without isolation with a second compound having the formula (1), wherein R5, R3, R2, B are independently selected, but have the same definition as above in the presence of an activator II selected from the group of imidazole imidazolium salts and mixtures thereof.

Synthesis of phosphitylated compounds using a quaternary heterocyclic activator

A method for preparing a phosphitylated compound comprising the step of: -reacting a hydroxy! containing compound with a phosphitylating agent in the presence of an activator having the formula (I) wherein R = alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl R1, R2 = either H or form a 5 to 6-membered ring together. X1, X2 = independently either N or CH Y = H or Si(R4)3, with R4 = alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl B = deprotonated acid. The hydroxyl containing compound is preferably a sugar moiety or a nucleoside or an oligomer derived therefrom.

Method for preparing oligonucleotides

Synthesis of oligonucleotides

A method for preparing an oligonucleotide comprising the steps of a) providing a hydroxyl containing compound having the formula (A), wherein B is a heterocyclic base and i) R2 is H, a protected 2'-hydroxyl group, F, a protected amino group, an O-alkyl group, an O-substituted alkyl, a substituted alkylamino or a C4 '-O2 ' methylen linkage; R3 is OR'3, NHR"3, NR"3R'3, wherein R3 is a hydroxyl protecting group, a protected nucleotide or a protected oligonucleotide, R"3, R"3 are independently amine protecting groups, and R5 is OH or ii) R2 is H, a protected 2'-hydroxyl group, F, a protected amino group, an O-alkyl group, an O-substituted alkyl, a substituted alkylamino or a C4'-O2 'methylen linkage; R3 is OH and R5 is OR'5 and R'5 is a hydroxyl protecting group, a protected nucleotide or a protected oligonucleotide or iii) R2 is OH, R3 is OR'3, NHR"3, NR"3R'"3, wherein R3 is a hydroxyl protecting group, a protected nucleotide or a protected oligonucleotide, R"3, R"3 are independently amine protecting groups, and R5 is OR'5 and R'5 is a hydroxyl protecting group, a protected nucleotide or a protected oligonucleotide b) reacting said compound with a phosphitylating agent in the presence of an activator having the formula (I) (activator I) wherein R = alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; R1, R2 = either H or form a 5 to 6-membered ring together; X1, X2 = independently either N or CH; Y = H or Si(R4)3, with R4= alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; B = deprotonated acid to prepare a phosphitylated compound; c) reacting said phosphitylated compound without isolation with a second compound having the formula (A) wherein R5, R3, R2, B are independently selected, but have the same definition as above in the presence of an activator II different from activator I.

Process for the preparation of dipeptides with c-terminal non-proteinogenous amino acids

Process for producing dipeptides from non-proteinogenic amino acids with terminal carbon atoms.

Purification of oligonucleotides

A method for purifying a protected oligonucleotide comprising the steps of: a) - providing a solution of the protected oligonucleotide in at least one solvent A having a boiling point below the boiling point of a solvent B, - heating the solution at a temperature of at least 30°C and below the boiling point of the at least solvent A, - adding solvent B until precipitation of a material is visible in the solution, said solvent B being an alcohol having 1 to 6 C-atoms or a diol having 2 to 6 C-atoms, - allowing the solution to cool down under stirring until formation of a supernatant and a residue, - removing the supernatant or b) - providing solvent B, said solvent B being an alcohol having 1 to 6 C- atoms or a diol having 2 to 6 C-atoms, - heating solvent B at a temperature above 30°C and below the boiling point of solvent B, - adding a solution of a protected oligonucleotide in at least one solvent A until precipitation of a material is visible in the solution, - allowing the solution to cool down under stirring until formation of a supernatant and a residue, - removing the supernatant.

Process for preparing peptides with n-terminal non-proteinogenous amino acids

A process for preparing dipeptides with N-terminal non-proteinogenous amino acids of the formula ##STR1## in which R 1 to R 6 have the meaning stated in the description, from compounds of the formula ##STR2## is described.

Peptide compounds, method for the preparation and use thereof

Process for producing dipeptides from non-proteinogenic amino acids with terminal carbon atoms

Process for preparing dipeptides of formula (I), from non-proteinogenic amino acids with terminal carbon atoms, in which R1 to R5 have the meaning given in the description, from compounds of formula (II).

Method for preparing oligonucleotides

Method for preparing oligonucleotides

Synthesis of oligonucleotides.

Un método para preparar un oligonucleótido que comprende los pasos de: (ver fórmula) proveer un compuesto que contiene hidroxilo, que tiene la fórmula: en donde: B es una base heterocíclica; Y i) R2 es H, un grupo 2´-hidroxilo protegido, F, un grupo amino protegido, un grupo O-alquilo, un alquilo O-sustituido, un alquilamino sustituido o un enlace C4´- O2´metileno, R3 es 0R´3, NHR"3, NR"3R"'3, en donde R´3 es un grupo protector de hidroxilo, un nucleótido protegido o un oligonucleótido protegido, R"3, R'''3 son independientemente grupos protectores de amina, y R5 es OH, o ii) R2 es H, un grupo 2´-hidroxilo protegido, F, un grupo amino protegido, un grupo O-alquilo, un alquilo O-sustituido, un alquilamino sustituido o un enlace C4´- O2´metileno, R3 es OH y R5 es OR´5 y R´5 es un grupo protector de hidroxilo, un nucleótido protegido o un oligonucleótido protegido; o iii) R2 es OH, R3 es OR´3, NHR"3, NR"3R'''3, en donde R´3 es un grupo protector de hidroxilo, un nucleótido protegido o un oligonucleótido protegido, R"3, R'''3 son independientemente grupos protectores de amina, y R5 es OR´5 y R´5 es un grupo protector de hidroxilo, un nucleótido protegido o un oligonucleótido protegido; hacer reaccionar dicho compuesto con un agente de fosfitilación en presencia de un activador que tiene la fórmula I (activador I) (ver fórmula) donde: R = alquilo, cicloalquilo, arilo, aralquilo, heteroalquilo, heteroarilo, R1, R2 = ya sea H, o forman un anillo de 5 a 6 miembros de manera conjunta, X1, X2 = independientemente, ya sea N o CH Y = H o Si(R4)3, con R4= alquilo, cicloalquilo, arilo, aralquilo, heteroalquilo, heteroarilo, B = ácido desprotonado, para preparar un compuesto fosfitilado; hacer reaccionar dicho compuesto fosfitilado sin aislamiento con un segundo compuesto que tiene la fórmula: (ver fórmula) en donde R5, R3, R2, B se seleccionan independientemente, pero tienen la misma definición que la dada con ...

Double-chain hemoregulatory peptides

The invention relates to peptide compounds comprising two single-chain hemoregulatory, for example haemopoiesis-inhibiting, peptides linked by a bridging group terminally attached to the Cα atoms of non-terminal amino acids wherein at least one of said Cα atoms is independently substituted by an alkyl group. The bridged dipeptide compounds disclosed have a stimulating activity on cell division, especially in myelopoietic and bone marrow cells.

Dobbeltkjedede hemoregulatoriske peptider

Denne oppfinnelsen relaterer dl peptidforbindelser som omfatter to enkeltkjedede hemoregulatoriske, for eksempel hemopoeseinhiberende, peptider bundet sammen med en brogruppe terminalt knyttet til Ca atomer til ikke-terminale aminosyrer hvor minst et av de nevnte Ca atomene er uavhengig substituert med en alkylgruppe. De brokoblede dipeptidene som er beskrevet har en stimulerende aktivitet på celledeling, spesielt i myelopoetiske- og benmargsceller.

Double-chain hemoregulatory peptides

Dobbeltkjedete peptidforbindelser med hemoregulatorisk aktivitet

Oppfinnelsen angår dipeptidforbindelser med to peptidkjeder bundet sammen ved et C,,,,^- atom i en ikke-terminal aminosyre med en di valent brogruppe -A-. C^-atomene bundet til gruppen -A- er lokalisert i ekvivalente posisjoner i hver peptidkjede og begge mangler sin native alpha-sidekjede. Gruppen -A- er definert i krav l. De bro- inneholdende dipeptidforbindelsene som er beskrevet har stimulerende effekt på celledeling, særlig på myelopoetiske - og benmargceller.

Dobbeltkjedete peptidforbindelser med hemoregulatorisk aktivitet

Verfahren zur herstellung von 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-onen

Verfahren zur Synthese von Verbindungen der allgemeinen Formel (1), (2), (3), (4) umfassend den Schritt der Umsetzung von Formeln (5) und (6) in Gegenwart von Formel (7) wobei R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B; R1 und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B, R' = H, OH, OR oder OSiX3 wobei X unabhängig voneinander Alkyl oder Aryl sind.

Verfahren zur herstellung von 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-onen

Verfahren zur Synthese von Verbindungen der allgemeinen Formel (1), (2), (3), (4) umfassend den Schritt der Umsetzung von Formeln (5) und (6) in Gegenwart von Formel (7) wobei R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B; R1 und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B, R' = H, OH, OR oder OSiX3 wobei X unabhängig voneinander Alkyl oder Aryl sind.

Verfahren zur herstellung von dipeptiden mit cterminalen nicht-proteinogenen aminosaeuren.