Intermediates for oligonucleotide synthesis

Details Intermediates for oligonucleotide synthesis Intermediates for oligonucleotide synthesis

1999-03-15

2001-12-11

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S026710, C536S026720, C536S026730, C536S026740, C536S026800

Reexamination Certificate

active

06329519

ABSTRACT:

This invention relates to chemical compounds which are intermediates for oligonucleotides and the use of such compounds in the preparation of oligonucleotides.
Accordingly, the present invention provides, in one aspect, a compound of formula
where B
1
is a radical of a nucleoside base, R
1
is hydrogen or a hydroxy-protecting group, R
2
is hydrogen, hydroxy or a 2′ nucleoside-modifying atom or group, R
3
is an unsubstituted or substituted C
1
to C
10
alkyl, C
2
to C
10
alkenyl, C
4
to C
10
cycloalkylalkyl, C
6
to C
10
aryl or C
7
to C
13
aralkyl group, and Z is halogen or a group of formula
where R
4
and R
5
are each independently an unsubstituted or substituted C
1
to C
10
alkyl, C
2
to C
10
alkenyl, C
4
to C
10
cycloalkylalkyl, C
6
to C
10
aryl or C
7
to C
13
aralkyl group, or R
4
is said group and R
5
is hydrogen, or R
4
and R
5
together with the nitrogen atom to which they are attached denote a five- to thirteen- membered heterocyclic ring; or Z is a group of formula
where Nuc is the residue of a natural or synthetic nucleoside or oligonucleotide after removal of a 5′ hydroxyl group therefrom attached through a 5′ methylene thereof to the indicated oxygen atom.
When R
3
, R
4
or R
5
denote a substituted alkyl, alkenyl, cycloalkylalkyl, aryl or aralkyl group, the group is preferably substituted by halogen, hydroxy, C
1
-C
4
alkoxy, cyano, nitro or tri(C
1
-C
15
hydrocarbyl)silyl or, in the case of R
3
, by C
1
-C
4
alkylsulphonyl or C
6
-C
10
arylsulphonyl.
When a tri(C
1
-C
15
hydrocarbyl)silyl group is present in compounds of formula I, it may be, for example, trialkylsilyl such as trimethylsilyl, triethysilyl, tri-n-propylsilyl, tri-isopropylsilyl, tri-n-butylsilyl, tri-isobutysilyl, isopropyldimethylsilyl, ter.butyldimethylsilyl or 1,1,2,2-tetramethylethyldimethylsilyl (thexyldimethylsilyl), triarylsilyl such as triphenylsilyl, triarylalkylsilyl such as tribenzylsilyl, aryldialkylsilyl such as phenyldimethylsilyl, phenyldiethylsilyl, phenyldiisopropylsilyl or phenyl di-tert-butylsilyl, or alkyldiarylsilyl such as methyldiphenylsilyl, isopropyldiphenylsilyl or tert-butyldiphenylsilyl. Where R
3
, R
4
or R
5
has a tri(C
1
-C
15
hydrocarbyl)silyl substituent, it is preferably tri(C
1
-C
4
hydrocarbyl)silyl, especially trimethylsilyl. R
1
as tri(C
1
-C
15
hydrocarbyl)silyl is preferably C
1
-C
6
alkyldi (C
6
-C
8
aryl)silyl, especially tert-butyldiphenylsilyl, or branched C
2
-C
4
alkyl di (C
1
-C
4
alkyl)silyl, especially thexyldimethylsilyl.
R
1
may be any hydroxy-protecting group capable of protecting a 5′-hydroxyl group against undesired reaction. Such groups are well known and include C
1
to C
10
aliphatic, e.g. alkyl groups; C
3
to C
8
cycloaliphatic, e.g. cycloalkyl, groups; C
6
to C
10
aromatic, e.g. aryl, groups; C
7
to C
40
araliphatic, e.g. aralkyl or C
1
to C
4
-alkoxy-substituted aralkyl groups; groups of formula —COR or —SO
2
R where R is a C
1
to C
10
aliphatic group, a C
3
to C
8
cycloaliphatic group, a C
6
to C
10
aromatic group or a C
7
to C
40
araliphatic group; and tri(C
1
-C
15
hydrocarbyl)silyl groups. Preferably R
1
is hydrogen or a 5′-protecting group conventionally used in oligonucleotide synthesis, more preferably hydrogen, a C
7
to C
40
araliphatic group or a tri(C
1
-C
15
hydrocarbyl)silyl group, especially an unsubstituted or substituted triphenylmethyl group such as methoxytrityl, dimethoxytrityl or tris tert-butyltrityl or a C
1
-C
6
alkyldi(C
6
-C
8
aryl)silyl group such as tert-butyldiphenylsilyl, particularly dimethoxytrityl or tert-butyldiphenylsilyl.
R
2
, the 2′ nucleoside-modifying atom or group, i.e. an atom or group which may be attached to the 2′ position of a nucleoside in place of a hydrogen atom or hydroxy group to effect a modification, may be a halogen atom such as a fluorine, chlorine or bromine atom; C
1
to C
10
unsubstituted alkyl, such as methyl, trifluoromethyl, ethyl, propyl, butyl, pentyl, hexyl, octyl or decyl; C
6
to C
10
aryl such as phenyl, tolyl or xylyl; C
7
to C
13
aralkyl such as benzyl; amino, C
1
to C
10
alkyl amino such as methylamino, ethylamino or octylamino; C
1
to C
10
alkylthio such as methylthio, ethylthio or octylthio; azide; nitrate; nitrite; cyanide; cyanate; methanesulphonate; C
1
to C
10
aminoalkylamino; a group of formula —OR
6
or —OCOR
6
where R
6
is a C
1
to C
30
organic group; substituted silyl; an RNA cleaving group; a cholesteryl group; a conjugate; a reporter group; an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide.
Preferably R
2
is hydrogen, halogen, hydroxy or a group of formula —OR
6
or —OCOR
6
where R
6
is a C
1
to C
10
alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, r-octyl, 2-ethylhexyl, n-nonyl or n-decyl, C
2
to C
10
alkenyl group such as vinyl, allyl, methallyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl, a C
3
to C
8
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl or cyclooctyl, a C
4
to C
10
cycloalkylalkyl group such as cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, methylcyclohexylmethyl, cyclohexyl ethyl or dimethyl cyclohexylethyl, a C
6
to C
10
aryl group such as phenyl, ortho-, meta- or para-tolyl, ortho-, meta- or para-xylyl or naphthyl or a C
7
to C
25
aralkyl group such as benzyl, phenylethyl, diphenylmethyl or triphenylmethyl, any of which groups may be unsubstituted or substituted, for example by halogen, hydroxy, C
1
to C
4
alkoxy or cyano, or, where R
2
is of formula —OR
6
, R
6
is a tri(C
1
-C
15
hydrocarbyl)silyl group.
In more preferred embodiments, R
2
is hydrogen, hydroxy, fluorine, a group of formula —OR
6
where R
6
is a C
1
to C
4
alkyl group, a C
2
to C
4
alkenyl group, a C
7
to C
13
aralkyl group or a group of formula —(R
7
—O)
n
—R
8
where R
7
is C
1
to C
4
alkylene, R
8
is C
1
to C
4
alkyl and n is 1 to 8, or R
2
is a group of formula —OCOR
6
where R
6
is C
1
to C
4
alkyl or C
6
to C
8
aryl. In especially preferred embodiments, R
2
is hydrogen, hydroxy, fluorine, methoxy, ethoxy, allyloxy, benzyloxy, methoxyethoxy, —O(CH
2
—CH
2
—O—)
3
—CH
3
, acetoxy or benzoyloxy.
R
3
, R
4
or R
5
as C
1
to C
10
alkyl may be, for example a straight or branched group such as methyl, ethyl, n-propyl, isopropyl, r-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl or n-decyl. R
3
, R
4
or R
5
as C
2
to C
10
alkenyl may be, for example, vinyl, allyl, methallyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. R
3
, R
4
or R
5
as C
4
to C
10
cycloalkylalkyl may be, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, methylcyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, methylcyclohexylmethyl, methylcyclohexylethyl, dimethylcyclohexylmethyl or dimethylcyclohexylethyl. R
3
, R
4
or R
5
as C
6
to C
10
aryl may be, for example, phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl or p-xylyl. R
3
, R
4
or R
5
as C
7
to C
13
aralkyl may be, for example, benzyl, phenylethyl or diphenylmethyl. Any of the above groups as R
3
, R
4
or R
5
may be unsubstituted or substituted as hereinbefore described.
When R
4
and R
5
together with the attached nitrogen atom denote a heterocyclic ring, this ring may be, for example, a five-membered ring such as a pyrrolidine ring, a six-membered ring such as a piperidine, 2,6-dimethylpiperidine, N-methylpiperazine, morpholine or thiomorpholine ring, a seven-membered ring such as a perhydroazepine ring, an eight-membered ring such as a perhydroazocine ring, a nine-membered ring such as perhydroazonine ring, a ten-membered ring such as a perhydroazecine ring, an eleven-membered ring such as an azacycloundecane ring, a twelve-membered ring such as an

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