Organic compounds

Details Organic compounds Organic compounds

1997-12-03

2001-01-23

Lipman, Bernard (Department: 1713)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S333400, C525S333600, C525S383000, C525S386000

Reexamination Certificate

active

06177520

ABSTRACT:

This invention relates to benzaldehyde derivatives and in particular to use of such derivatives as linkers for solid phase synthesis of secondary amines and disubstituted carbamates.
Accordingly the present invention provides the use of a compound of formula I
wherein
R
1
is a C
1-4
alkoxy or thioalkoxy group, and
R
2
is a group of formula SR
10
or OR
10
wherein R
10
is a C
1-4
carboxylic or thiocarboxylic acid residue in salt, ester, free acid or activated form,
or an activated form thereof,
as a linker in solid phase synthesis of organic compounds.
In the use of the invention the symbols of formula I have the following preferred meanings.
Preferably R
1
is a C
1-4
alkoxy group, most preferably a methoxy group.
Preferably R
2
is a group of formula OR
10
.
Preferably R
10
is a C
2
carboxylic acid residue. Preferably R
10
is in free acid or activated form, e.g. as an acid halide or anhydride. Most preferably R
10
is a group of formula —CH
2
—COOH or an activated form thereof.
Preferred compounds for use in the invention are compounds of formula II
especially compounds having the preferred significances for R
1
and R
2
given above.
A particularly preferred compound for use in the invention is the compound of formula IX
or an activated form thereof. The particularly preferred compound of formula IX is commercially available.
The compounds of formula I are useful as linkers for solid phase synthesis. Compounds of formula I when attached to a solid phase provide novel solid phase systems.
Thus in a further aspect the invention provides a solid phase system of formula III
wherein
R
1
is as defined above;
R
2
′ is the diradical of R
2
as defined above;
A is a spacer selected from the group consisting of C
1-4
alkyl, —NH—, —NR— (urethane), —O— (ether) and
P is a solid phase carrier material,
or an activated form thereof.
In particular the invention provides a solid phase system of formula IV
or especially a solid phase system of formula IVa
wherein the symbols are as defined above, or activated forms thereof.
Any suitable solid phase carrier material may be used in the present invention, including those known and used in the solid phase synthesis art. For example, the solid phase may be a naturally occurring or synthetic organic or inorganic polymer in particulate form, e.g. as beads, or preferably as a surface coating or layer on a suitable inert substrate material. Examples of suitable polymer materials include crosslinked polystyrene or a graft copolymer of polyethylene glycol on polystyrene, e.g. polystyrene pins, Gly-HMD-MA/DMA pins and HEMA pins. Conveniently the polymer comprises surface amino groups, e.g. amino methyl groups, to facilitate attachment of the compound of formula I.
The solid phase systems of formulae III, IV and IVa are prepared by coupling a corresponding compound of formulae I, II or IX, or an activated form thereof, with a solid phase. Such processes are included within the scope of the invention.
The compounds of formula I and the solid phase systems of formula III are particularly useful for the solid phase preparation of secondary amines and disubstituted carbamates. Conveniently the present invention involves the synthesis of a secondary amine intermediate of formula V
especially an intermediate of formula Va
wherein R
1
, R
2
′, A and P are as defined above,
R
3
and R
4
which may be the same or different are organic chemical residues, e.g. residues selected to provide desired biological activities in the resultant secondary amine and carbamate products.
For example, R
3
and R
4
which may be the same or different are is —R
5
, —R
5
C(O)R
6
, —R
5
C(O)OR
6
, —R
5
OC(O)R
6
, —R
5
OC(O)OR
6
, —R
5
NR
6
C(O)R
7
, —R
5
C(O)NR
6
R
7
, —R
5
OC(O)NR
6
R
7
, —R
5
NR
6
C(O)NR
7
R
8
, —R
5
NR
6
C(O)OR
7
, —R
5
—O—R
6
, —R
5
—NR
6
R
7
, —R
5
—S—R
6
, —R
5
—SO
m
—R
6
, —R
5
OR
6
—O—R
7
, —R
5
NR
6
R
7
—O—R
8
, —R
5
SO
m
R
6
—O—R
7
, —R
5
C(O)R
6
—O—R
7
, —R
5
C(O)OR
6
—O—R
7
, —R
5
OC(O)R
6
—O—R
7
, —R
5
OC(O)OR
6
—O—R
7
, —R
5
NR
6
C(O)R
7
—O—R
8
, —R
5
C(O)NR
6
R
7
—O—R
8
, —R
5
OC(O)NR
6
R
7
—O—R
8
, —R
5
NR
6
C(O)NR
7
R
8
—O—R
9
, —R
5
NR
6
C(O)OR
7
—O—R
8
, —R
5
OR
6
—S—R
7
, —R
5
NR
6
R
7
—S—R
8
, —R
5
SO
m
R
6
—S—R
7
, —R
5
C(O)R
6
—S—R
7
, —R
5
C(O)OR
6
—S—R
7
, —R
5
OC(O)R
6
—S—R
7
, —R
5
OC(O)OR
6
—S—R
7
, —R
5
NR
6
C(O)R
7
—S—R
8
, —R
5
C(O)NR
6
R
7
—S—R
8
, —R
5
OC(O)NR
6
R
7
—S—R
8
, —R
5
NR
6
C(O)NR
7
R
8
—S—R
9
, —R
5
NR
6
C(O)OR
7
—S—R
8
, —R
5
OR
6
—NR
7
R
8
, —R
5
NR
6
R
7
—NR
8
R
9
, —R
5
SO
m
R
6
—NR
7
R
8
, —R
5
C(O)R
6
—NR
7
R
8
, —R
5
C(O)OR
6
—NR
7
R
8
, —R
5
OC(O)R
6
—NR
7
R
8
, —R
5
OC(O)OR
6
—NR
7
R
8
, —R
5
NR
6
C(O)R
7
—NR
8
R
9
, —R
5
C(O)NR
6
R
7
—NR
8
R
9
, —R
5
OC(O)NR
6
R
7
—NR
8
R
9
, —R
5
NR
6
C(O)NR
7
R
8
—NHR
9
or —R
5
NR
6
C(O)OR
7
—NR
8
R
9
,
where R
5
, R
6
, R
7
, R
8
and R
9
are each independently C
1-10
alkyl, C
1-10
alkenyl, C
1-10
alkynyl, C
6-10
aryl, C
6-14
aralkyl, C
6-14
aralkenyl or C
6-14
aralkynyl and m is 1,2,3 or 4; and where R
5
, R
6
, R
7
, R
8
and R
9
are each unsubstituted or substituted with up to 6 substituents selected from halo, NO
2
, —OH, C
1-4
alkyl, —SH, —SO
3
, —NH
2
, C
1-4
acyl, C
1-4
acyloxy, C
1-4
alkylamino, C
1-4
dialkylamino, trihalomethyl, —CN, C
1-4
alkylthio, C
1-4
alkylsulfinyl, or C
1-4
alkylsufonyl, provided that all the R substituents are not identical,
or each R
3
or R
4
alone or together forms a cyclic structure, e.g. a carbocyclic or heterocyclic ring. Preferred examples for such a carbocyclic ring are C
5
-C
8
carbocyclic rings. Preferred examples for such a heterocyclic ring are pyrrole, imidazole, benzimidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phtalazine, quinoxaline, benzodiazine, quinazoline, pteridine, carbazole, beta-carboline, thiophene, benzothiophene, furan, benzofuran, triazole, isoxazole, oxazole, thiazole, isothiazole, pyrone, indoxazine or benzopyrone. Such cyclic structures can be unsubstituted or substituted by at least one residue selected from the group consisting of halo, NO
2
, —OH, C
1-4
alkyl, —SH, —SO
3
, —NH
2
, C
1-4
acyl, C
1-4
acyloxy, C
1-4
alkylamino, C
1-4
dialkylamino, trihalomethyl, —CN, C
1-4
alkylthio, C
1-4
alkylsulfinyl and C
1-4
alkylsulfonyl.
The intermediates of formula V may be prepared from the solid phase systems of formulae III by processes involving reductive amination with a primary amine followed by a second reductive amination with an aldehyde or ketone.
Thus in a further aspect the invention provides a process for the preparation of an intermediate of formula V comprising reacting a solid phase system of formula III with a primary amine, e.g. in the presence of sodium cyanoborohydride, dissolved e.g. in DMF/AcOH 97:3, or in the presence of titanium tetraisopropoxide and sodium cyanoborohydride, dissolved e.g. in dichloromethane, followed by a reaction with an aldehyde or ketone, e.g. in the presence of sodium cyanoborohydride, dissolved e.g. in DMF/AcOH 97:3, or in the presence of titanium tetraisopropoxide and sodium cyanoborohydride, dissolved e.g. in dichloromethane.
The intermediates of formula V may be used to prepare corresponding carbamates and secondary amines by appropriate cleavage of the —NR
3
R
4
group from the intermediate with a suitable cleavage reagent followed by further processing as required.
Thus for example, carbamates may be prepared from the intermediates of formula V by treatment with a corresponding activated carbonate, such as a halocarbonate, e.g. a chlorocarbonate, e.g. a compound of formula VI
wherein R
11
is a functional group which does not react with a chlorocarbonate, wherein R
11
preferably is as defined as residues R
3
or R
4
of compunds of formulae V or Va, above, inclusive the respective preferences, to yield a carbamate, e.g. of formula VII
wherein the symbols R
3
, R
4
and R
11
are as defined above.
Thus also for example, secondary amines may be prepared from the intermediates of formula V by a two step process involving
i) a first st

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