U.S. patent application number 11/244097 was filed with the patent office on 2006-02-23 for intermediate products, methods for their preparation and use thereof.
Invention is credited to Ronny Lundin, Jacob Westman.
Application Number | 20060041095 11/244097 |
Document ID | / |
Family ID | 30003090 |
Filed Date | 2006-02-23 |
United States Patent
Application |
20060041095 |
Kind Code |
A1 |
Westman; Jacob ; et
al. |
February 23, 2006 |
Intermediate products, methods for their preparation and use
thereof
Abstract
Novel solid supported intermediate products of the general
formula ##STR1## coupled to a solid polymeric support through one
or both of the R.sup.1 groups or through the R.sup.4 group which
are suitable for synthesis of heterocyclic compounds are disclosed.
Methods for preparing such intermediate products are also disclosed
and also the use of the intermediate products in simple and fast
methods on solid phase for synthesis of heterocycles.
Inventors: |
Westman; Jacob; (Vange,
SE) ; Lundin; Ronny; (Ekero, SE) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
30003090 |
Appl. No.: |
11/244097 |
Filed: |
October 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10448060 |
May 30, 2003 |
|
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11244097 |
Oct 6, 2005 |
|
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60384133 |
May 31, 2002 |
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Current U.S.
Class: |
526/316 ;
526/227; 526/258; 526/317.1; 526/346; 526/347.2 |
Current CPC
Class: |
C07D 231/12 20130101;
C07D 231/14 20130101; C08F 8/32 20130101; C07D 261/08 20130101;
C07B 2200/11 20130101; C07C 233/85 20130101; C07D 311/74 20130101;
C07D 471/04 20130101; C07D 455/02 20130101; C07D 401/04 20130101;
C07C 225/16 20130101; C07C 229/34 20130101 |
Class at
Publication: |
526/316 ;
526/317.1; 526/227; 526/258; 526/347.2; 526/346 |
International
Class: |
C08F 16/36 20060101
C08F016/36 |
Claims
1. A method of preparing an intermediate product suitable for
synthesis of heterocyclic compounds, which is a compound of general
formula I ##STR11## coupled to a solid polymeric support through
one or both of the R.sup.1 groups, wherein the R.sup.1 groups
represent the same or different groups chosen from lower alkyl with
1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms in the
ring, heterocyclic compounds including one or more heteroatoms,
benzyl groups; two R.sup.1 groups together can be included in
heterocyclic ring containing one or more nitrogen atoms; R.sup.2
represents H or a lower alkyl with 1 to 6 carbon atoms; R.sup.4
represents unsubstituted or substituted aromatic ring(s),
unsubstituted or substituted heteroaromatic ring(s) with one or
more heteroatoms, or OR.sup.5; when R.sup.4 is unsubstituted or
substituted aromatic ring(s), unsubstituted or substituted
heteroaromatic ring(s), R.sup.3 represents H, alkyl, unsubstituted
or substituted aromatic ring, unsubstituted or substituted
heteroaromatic ring with one or more heteroatoms, or COOR.sup.5;
when R.sup.4 is OR.sup.5, R.sup.3 is CN, COOR.sup.5, NCOR.sup.5,
NCOOR.sup.5 or COR.sup.5; the R.sup.5 groups, which can be the same
or different, represent H, alkyl, benzyl, unsubstituted or
substituted aromatic ring(s), unsubstituted or substituted
heteroaromatic ring(s) with one or more heteroatoms; which
comprises preparing a polymeric support with a reactive secondary
amine according to the following reaction whereby a product of
formula IV is obtained ##STR12## wherein Y is a spacer group which
can be alkyl, benzyl, trityl or [OCH.sub.2CH.sub.2].sub.n, R.sup.1
is as defined above, X is NH.sub.2, halogen or triflate; when X is
NH.sub.2, A is halogen or triflate, and when X is halogen or
triflate, A is NH.sub.2, and reacting the product of formula IV
with a N-disubstituted carboxamide acetal of the general formula II
##STR13## wherein the R.sup.7 groups are different or the same
chosen from C1 -C6 alkyl, cycloalkyl with 3 to 6 carbon atoms ,
benzyl groups, cyclic compounds including heteroatoms, the two
R.sup.7 groups could together be part of a carbocyclic or
heterocyclic ring, the R.sup.8 groups could be the same or
different chosen from straight, branched or cyclic alkyl chains,
benzyl groups, and alkyl chains with substituents; the two R.sup.8
groups could together be part of a carbocyclic ring and a substance
with a methylene or methyl group adjacent to a keto function
according to the general formula III ##STR14## where R.sup.3,
R.sup.4 are as defined above, whereby a compound of formula I
coupled to the polymeric support through one or both of the R.sup.1
groups is obtained.
2. A method of preparing an intermediate product suitable for
synthesis of heterocyclic compounds, which is a compound of general
formula I ##STR15## coupled to a solid polymeric support through
one or both of the R.sup.1 groups, wherein the R.sup.1 groups
represent the same or different groups chosen from lower alkyl with
1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms in the
ring, heterocyclic compounds including one or more heteroatoms,
benzyl groups; two R.sup.1 groups together can be included in
heterocyclic ring containing one or more nitrogen atoms; R.sup.2
represents H or a lower alkyl with 1 to 6 carbon atoms, such as
methyl; R.sup.4 represents unsubstituted or substituted aromatic
ring(s), unsubstituted or substituted heteroaromatic ring(s) with
one or more heteroatoms, or OR.sup.5; when R.sup.4 is unsubstituted
or substituted aromatic ring(s), unsubstituted or substituted
heteroaromatic ring(s), R.sup.3 represents H, alkyl, unsubstituted
or substituted aromatic ring, unsubstituted or substituted
heteroaromatic ring with one or more heteroatoms, or COOR.sup.5;
when R.sup.4 is OR.sup.5, R.sup.3 is CN, COOR.sup.5, NCOR.sup.5,
NCOOR.sup.5 or COR.sup.5; the R.sup.5 groups, which can be the same
or different, represent H, alkyl, benzyl, unsubstituted or
substituted aromatic ring(s), unsubstituted or substituted
heteroaromatic ring(s) with one or more heteroatoms; which
comprises preparing a polymeric support with a reactive secondary
amine according to the following reaction, whereby a product of
formula V is obtained ##STR16## wherein Y is as defined in claim 1,
R.sup.10 is a secondary amine, B and D are functional groups which
form a covalent bond when reacted with each other, and when n=0 B
is a leaving group, and reacting the product of formula V with a
N-disubstituted carboxamide acetal of the general formula II
##STR17## wherein R.sup.7 and R.sup.8 are defined as in claim 1,
and a substance with a methylene or methyl group adjacent to a keto
function according to the general formula III ##STR18## where
R.sup.3, R.sup.4 are as defined in claim 1, whereby a compound of
formula I coupled to the polymeric support through one or both of
the R.sup.1 groups is obtained.
3. A method according to claim 1 or 2, wherein the reactions are
performed under heating.
4. A method according to claim 3, wherein the heating is induced by
the use of microwaves.
5. A method according to claim 1 or 2, wherein the solid polymeric
support is polystyrene beads that are lightly cross-linked with
1-2% divinylbenzene and optionally grafted with polyethylene
glycol.
6. A method according to claim 1, wherein the solid polymeric
support is polystyrene beads which are functionalized with halogen
and triflate or NH.sub.2.
7. A method according to claim 2, wherein the solid polymeric
support is polystyrene beads which are functionalized with B as
defined in formula V.
8. A method according to claim 1, wherein the solid polymeric
support is polystyrene beads which are functionalized with halogen
or hydroxyl.
9. A method according to claim 1 or 2 where the substance with a
methylene or methyl group adjacent to a keto function according to
the general formula III is a substituted acetophenone or beta
ketoester.
10. A method according to claim 1 or 2 where the substance
according to the general formula III is a N-substituted glycine
ester or a substituted acetic acid ester.
11. A method according to claim 1 or 2 wherein the disubstituted
carboxamide acetal of formula II is dimethylformamide diacetal.
12. A method according to claim 1 or 2, wherein with R.sup.1 the
lower alkyl is methyl or ethyl.
13. A method according to claim 1 or 2, wherein with R.sup.1 the
cycloalkyl is cyclopentyl or cyclohexyl.
Description
[0001] This application is a Divisional of co-pending Application
No. 10/448,060 filed on May 30, 2003, which is a non-provisional
application of 60/384,133 filed on May 31, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates to novel solid supported
intermediate products suitable for synthesis of heterocyclic
compounds and methods for preparing such intermediate products. The
invention also relates to use of the intermediate products in
simple and fast methods on solid phase for synthesis of
heterocycles with large structural diversity in high yields and
high purity.
BACKGROUND OF THE INVENTION
[0003] Highly functionalized heterocycles of various ring sizes,
with different heteroatoms and substitution patterns are of major
interest in the pharmaceutical and agricultural industry due to the
many intrinsic biological properties of these substances.
[0004] In medicinal chemistry in general, and combinatorial
chemistry in particular, the use of versatile synthons or versatile
scaffolds, which are available after only a few reaction steps, are
of great interest. An example of a reagent producing such synthons
is N,N-dimethylformamide diethyl acetal (DMFDEA), cf. Abdulla, R.
F.; Brinkmeyer, R. V., Tetrahedron, 1979, 35, 1675-1735.
Condensation reactions between an activated methyl or methylene
group adjacent to an ester or keto functionality and DMFDEA form
dimethylaminopropenoates(A) or dimethylaminopropenones (B), see
FIG. 1.
[0005] These intermediates, in which the dimethylamino moiety acts
as a good leaving group, have been used in reactions in solution
under conventional heating methods which has been described for
example in Stanovnik, B.; Svete, J., Synlett, 2000, 8, 1077-1091.
The intermediates could then be reacted with dinucleophiles to form
different heterocycles. The availability of starting materials,
which could form activated alkylaminopropenones or
alkylaminopropenoates with DMFDEA is large and the number of
possible heterocycles with large diversity, which are possible to
form in a subsequential step from these types of intermediates is
substantial. The formation of heterocycles from these intermediates
takes place via a cascade or domino-type reaction, cf. Tietze, L.
F., Chem.Rev.,1996,115-136, which means that it involves two or
more new bond formations taking place under the same reaction
conditions. The advantages of this kind of reaction as compared to
traditional multi-step reactions are simplified engineering, no
intermediate work-up, minimized waste handling and lower cost of
purification. All of these are important factors to consider when
working the synthesis of combinatorial libraries.
[0006] Microwave heating has been used in organic synthesis since
1986, cf. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera,
L.; Laberge, L.; Rousell, J., Tetrahedron Lett. 1986, 27, 279-282.
Microwave heating reduces the reaction times in comparison with
traditional heating. In addition, the yields of the reactions are
often increased and the time for optimizing the reaction conditions
is minimized in comparison to conventional heating methods.
SUMMARY OF THE INVENTION
[0007] The present invention relates in one aspect to new
intermediate products of the general formula I suitable for
synthesis of heterocyclic compounds.
[0008] In another aspect the present invention relates to methods
for preparing intermediates of formula I.
[0009] According to another aspect the invention relates to the use
of an intermediate product of the general formula I for synthesis
of heterocyclic compounds.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows condensation reactions between an activated
methyl or methylene group adjacent to an ester or keto
functionality and DMFDEA form dimethylamino-propenoates(A) or
dimethylaminopropenones (B)
[0011] FIG. 2 shows examples of heterocyclic compounds prepared by
reaction of intermediate products according to the present
invention, 3-dimethylamino propenoates, with different
dinucleophiles are illustrated.
[0012] FIG. 3 shows examples of heterocyclic compounds prepared by
reaction of intermediate products according to the present
invention, 3-dimethylamino propenones, with different
dinucleophiles are illustrated.
[0013] FIG. 4 shows an example of the formation of an intermediate
product wherein the substrate is bound to the solid resin could be
carried out in a two-step reaction.
[0014] FIG. 5 shows an example of a synthesis method for preparing
solid phase bound dialkylamino propenones.
[0015] FIG. 6 shows examples of synthesis of heterocycles via solid
phase bound dialkylamino propenoates.
[0016] FIG. 7 shows examples of synthesis of heterocycles via solid
phase bound dialkylamino propenones.
DETAILED DESCRIPTION OF THE INVENTION
[0017] More closely the invention relates to an intermediate
product suitable for synthesis of heterocyclic compounds which
intermediate compound has the general formula I ##STR2## coupled to
a solid polymeric support through one or both of the R.sup.1
group(s) or through the R.sup.4 group wherein when coupled to the
polymeric support through R.sup.1 The R.sup.1 groups represent the
same or different groups chosen from lower alkyl with 1 to 6 carbon
atoms, such as methyl, ethyl, cycloalkyl with 3 to 6 carbon atoms
in the ring, such as cyclopentyl, cyclohexyl, heterocyclic
compounds including one or more heteroatoms, benzyl groups. Two
R.sup.1 groups together can be included in a heterocyclic ring
containing one or more nitrogen atoms; R.sup.2 represents H or a
lower alkyl with 1 to 6 carbon atoms, such as methyl; R.sup.4
represents unsubstituted or substituted aromatic ring(s),
unsubstituted or substituted heteroaromatic ring(s) with one or
more heteroatoms, or OR.sup.5; when R.sup.4 is unsubstituted or
substituted aromatic ring(s), unsubstituted or substituted
heteroaromatic ring(s), R.sup.3 represents H, alkyl, unsubstituted
or substituted aromatic ring, unsubstituted or substituted
heteroaromatic ring with one or more heteroatoms, or COOR.sup.5;
when R.sup.4 is OR.sup.5, R.sup.3 is CN, COOR.sup.5, NCOR.sup.5,
NCOOR.sup.5, or COR.sup.5; the R.sup.5 groups, which can be the
same or different, represent H, alkyl, benzyl, unsubstituted or
substituted aromatic ring(s), unsubstituted or substituted
heteroaromatic ring(s) with one or more heteroatoms; and wherein
when coupled to the polymeric support through R.sup.4 R.sup.1 and
R.sup.2 are as defined above, R.sup.3 is as defined above except
COOR.sup.5 and COR.sup.5, R.sup.4=OR.sup.5 where R.sup.5 is as
defined above except H.
[0018] When producing a large number of substances in solution the
subsequent purifications will be time-consuming. However, it has
according to the present invention been found that solid phase
technique, which allows for easy automation together with microwave
assisted heating, gives rise to unexpected advantages such as high
yields of the heterocyclic compounds with high purity and
possibility to eliminate time-consuming purification steps, which
are necessary when producing heterocyclic compounds in solution
according to the above mentioned prior art. Furthermore, in the
method according to the present invention a large excess of reagent
could be used in a reaction with a resin bound substrate whereby
the reaction is driven to completion. The redundant amount of
reagent could then be removed by a simple filtration. Furthermore,
by the use of microwave heating in solid phase synthesis in
accordance with the present invention the reaction times in the
heterogeneous systems can be substantially shortened as compared to
other methods of heating.
[0019] The intermediate products according to the present invention
are suitable to use for preparing heterocyclic compounds by
reaction with dinucleophiles and in FIG. 2 examples of heterocyclic
compounds prepared by reaction of intermediate products according
to the present invention, 3-dimethylamino propenoates, with
different dinucleophiles are illustrated.
[0020] In FIG. 3 examples of heterocyclic compounds prepared by
reaction of intermediate products according to the present
invention, 3-dimethylamino propenones, with different
dinucleophiles are illustrated.
[0021] The solid polymeric support to which the compounds are
coupled could be the following: a.) beads, pellets, disks, fibers,
gels, or particles such as cellulose beads, pre-glass beads, silica
gels, polypropylene beads, polyacrylamide beads, polystyrene beads
that are lightly cross-linked with 1-2% divinylbenzene and
optionally grafted with polyethylene glycol and optionally
functionalized with amino, hydroxy, carboxy or halo groups; and b.)
soluble supports such as low molecular weight non-cross-linked
polystyrene and polyethylene glycol. The term solid support is used
interchangeably with the term resin or bead in this invention and
is intended to mean the same thing. For propenoates any resin which
can form an alkyl or benzylic ester from a carboxylic acid such as
polystyrene-divinylbenzene resins eg. Merrifield resin (benzyl
chloride handle), Wang resin (benzyl alcohol handle), Tentagel PHB
(benzyl alcohol handle), Resin with PAM anchor, Rink resin, PEGA
resin are examples of suitable resins. For propenones any resin
with a dialkyl amine handle, any resin which can form a dialkyl
amine or benzyl alkyl amine handle such as Merrifield resin
(displacement of a chloride with an alkylamine), Rink resin
(methylation of a primary amine with methyliodide), amino methyl
resin, trisamine resin, SASRIN resin, Behring resin, PAM resin,
N-methylaminomethyl resin HCl are examples of suitable resins for
use as solid support.
[0022] In the methods for preparing the intermediates according to
the present invention N-disubstituted carboxamide acetals of the
general formula II are suitable to use as a reactant ##STR3##
wherein the two R.sup.7 groups are the same or different groups
selected from alkyl groups with 1 to 6 carbon atoms, cycloalkyl
groups with 3 to 6 carbon atoms, benzyl groups, cyclic compounds
including heterocyclic compounds with one or more heteroatoms,
R.sup.7 is suitably methyl, ethyl. The two R.sup.7 groups could
together be part of a carbocyclic or heterocyclic ring, for example
imidazole. The two R.sup.8 groups are the same or different groups
selected from straight, branched or cyclic alkyl chains,
substituted such alkyl chains, benzyl groups . R.sup.8 is suitably
Me, Et. The two R.sup.8 groups could together be part of a
carbocyclic ring for example 1,3 dioxane.
[0023] In a method of preparing an intermediate of formula I, which
is coupled to the solid polymeric support through one or both
R.sup.1 groups (propenones) a polymeric support with a reactive
secondary amine is prepared according to the following reaction
whereby a product of formula IV is obtained ##STR4## wherein Y is a
spacer group which can be alkyl, benzyl, trityl or
[OCH.sub.2CH.sub.2].sub.n, R.sup.1 is as defined in claim 1, X is
NH.sub.2, halogen or triflate. When X is NH.sub.2, A is halogen or
triflate, and when X is halogen or triflate, A is NH.sub.2, which
product of formula IV then is reacted with a N-substituted
carboxamide acetal of the general formula II as defined above and a
substance with a methylene or methyl group adjacent to a keto
function according to the general formula III ##STR5## where
R.sup.3, R.sup.4 are as defined in claim 1, whereby a compound of
formula I coupled to the polymeric support through one or both of
the R.sup.1 groups is obtained.
[0024] In another method of preparing an intermediate of formula I,
which is coupled to the solid polymeric support through one or both
of the R.sup.1 groups (propenones), a polymeric support with a
reactive secondary amine is prepared according to the following
reaction, whereby a product of formula V is obtained ##STR6##
wherein Y is as defined above, R.sup.10 is a secondary amine, B and
D are functional groups which form a covalent bond when reacted
with each other, and when n=0, B is a leaving group, which product
of formula V then is reacted with a N-disubstituted carboxamide
acetal of the general formula II as defmed above and a substance
with a methylene or methyl group adjacent to a keto function
according to the general formula III as defined above, whereby a
compound of formula I coupled to the polymeric support through one
or both of the R.sup.1 groups is obtained.
[0025] In a method of preparing an intermediate of formula I, which
is coupled to the solid polymeric support through the R.sup.4 group
(propenoates) a polymeric support of the general formula VI
##STR7## with a reactive X end group, wherein X and Y are as
defined in claim 2, is reacted with a compound of the general
formula VII ##STR8## wherein R.sup.3 is defined as in claim 1 and
R.sup.9 is H, alky, benzyl or phenyl, whereby a product of the
formula VIII ##STR9## is obtained, which product of formula VIII
then is reacted with a N-disubstituted carboxamide acetal of the
general formula II as defined above, whereby a compound of formula
I is obtained which is coupled to the solid polymeric support
through the R.sup.4 group.
[0026] In the above methods for preparing the intermediates
according to the present invention it is suitable to carry out the
reactions by means of heating. The heating is suitably induced by
the use of microwaves. The temperature is generally between 100 and
250.degree. C. It is often suitable to carry out the reactions in a
closed vessel.
[0027] The intermediate products according to the present invention
are useful for the synthesis of heterocyclic compounds wherein a
solid supported intermediate compound of the general formula I is
reacted with a dinucleophile, i.e. a substance with two
nucleophilic atoms selected from N, C, O and S adjacent to each
other or separated by one or more carbon atoms, by heating the
intermediate compound and the dinucleophilic substance in a
solution for a short period of time which, after evaporation of the
solvent, produces the desired heterocyclic compound in high yield
and high purity.
[0028] The heating is suitably induced by the use of microwaves and
a useful temperature is between 100 and 250.degree. C. The reaction
time needed is short and suitably less than 30 minutes.
[0029] Dialkylamino propenoates coupled to a solid support react
with dinucleophiles in a two-step reaction wherein substitution of
the dialkylamino group is followed by a nucleophilic attack on the
ester functionality, which cleaves the ester.
[0030] Dialkylamino propenones coupled to a solid support react in
a somewhat different manner with dinucleophiles. A condensation
reaction with the keto function is followed by the substitution of
the dialkylamino group.
[0031] Heterocycle formation from dialkylamino propenones and
dialkylamino propenoates. The intermediates could be reacted with
many dinucleophiles such as hydrazines, amidines, diketo substrates
and 2-amino-pyridines to form heterocyclic compounds such as
isoxazoles, pyrazoles, chromones, pyrimidines, pyranones,
pyrimidones, pyranones, pyrimidones and substituted
4H-quinolizin-4-ones all of which have great interest as potential
druglike compounds. Many of the mentioned products have in the
literature been described to induce biological activity.
[0032] Dinucleophiles are defined as any substances with two
nucleophilic atoms adjacent to each other or separated by one or
more carbon atoms. The nucleophilic atoms are chosen from N, C, O,
S. Examples of suitable dinucleophiles are hydroxylamine,
hydrazine, substituted hydrazines, substituted amidines,
2-aminopyridines, 2-pyridino acetonitrile, 2-aminopyrazoline,
2-aminopyridazine, substituted 1,3-diketohexane and cyclohexane,
2-aminothiazole and 3-amino-2-pyraxolin-5-ones. Examples of some
dinucleophiles are illustrated below. ##STR10## Synthesis of solid
phase bound dialkylamino propenoates
[0033] Formation of an intermediate product wherein the substrate
is bound to the solid resin could be carried out in a two-step
reaction, an example of which is shown in FIG. 4.
[0034] FIG. 4 shows the reaction between a solid support,
Merrifield resin, and hippuric acid (1) in the first step and
reaction of the product formed (2) with DMFDEA (3) which gives the
intermediate product (4). Magic angle spinning NMR (MAS-NMR)
analysis (Wehler, T.; Westman, J. Tetrahedron Le used for the
protocol development. An ester linkage wa xylic acid substrate and
the solid phase resin in step o area from the methylene group in
the resin handle (Ph from the solid phase benzylester methylene
group (PhCH.sub.2determined. In this example the Merrifield resin
was treated with the N-acylated glycine derivative (hippuric acid)
together with cesium carbonate in DMF under microwave heating at
200.degree. C. for 10 minutes. MAS-NMR analysis and elemental
analysis showed a loading of approximately 1 mmol/g (80% yield),
which is in the same range as described in the literature but in
approximately a 100-fold shorter reaction time. Merrifield resin
was suitable to use due to the high loading capacity and high
thermal stability. After washing the resin was mixed with 5 eq.
DMFDEA in 2.5 ml DMF and exposed to microwaves at 180.degree. C.
for 10 minutes to form the dimethylamino propenoate intermediate
product 4 according to the invention.
Synthesis of solid phase bound dialkylamino propenones
[0035] An example of a synthesis method for preparing solid phase
bound dialkylamino propenones is illustrated in FIG. 5.
[0036] In the first step in this synthesis Merrifield resin was
treated with methyl amine in water under microwave heating at
150.degree. C. for 10 minutes to form a benzyl methyl amine on the
solid resin (13). After washing the resin was treated with 5 eq.
DMFDEA together with 5 eq. 4-phenoxyacetophenone under microwave
heating at 180.degree. C. for 10 minutes in DMF to form the
intermediate product [14), the solid supported benzyl methyl
aminopropenone according to the present invention in a
three-component reaction.
[0037] The intermediate products according to the present invention
were then used for the synthesis of heterocycles by reacting the
solid supported intermediates with dinucleophiles in a suitable
solvent e.g. at 180.degree. C. for 10 min.
[0038] In FIG. 6 examples of synthesis of heterocycles via solid
phase bound dialkylamino propenoates are illustrated.
[0039] In FIG. 7 examples of synthesis of heterocycles via solid
phase bound dialkylamino propenones are illustrated.
[0040] The invention is illustrated by means of the following
examples, which are presented only for illustrative purpose and are
not meant to limit the scope of the invention in any way.
EXAMPLES
[0041] The microwave-assisted reactions were performed in a single
mode microwave cavity, an instrument from Personal Chemistry. NMR
spectra were recorded in CDCl.sub.3 or DMSO-d.sub.6 at 25.degree.
C., using a Bruker at 300 MHz (.sup.1H)/75 MHz (.sup.13C) or a
Varian 600 MHz instrument with a Nano probe for the MAS-NMR
analysis. All NMR spectra recorded were in agreement with the
postulated structures and only selected data are reported.
Elemental analyses were performed by Mikrokemi AB, Uppsala, Sweden.
All starting reagents were of the best grade available (Aldrich or
Lancaster) and were used without purification. The reactions were
run in a closed vessel and that in several cases the pressure
during the reaction was between 5-20 bar.
[0042] Coupling of N-benzoyl glycine to Merrifield resin (2). 200
mg Merrifield resin (1.25 mmol/g loading capacity) was swelled in
2.5 mL DMF, 1.25 mmol (5 equiv.) N-benzoyl glycine (Hippuric acid)
(1) and 1.25 mmol Cs.sub.2CO.sub.3 were added and the reaction
mixture was heated at 200.degree. C. for 10 min. The reaction
mixture was then cooled down to room temperature by pressurized
air. The residue was then washed several times with DMF, water and
DCM. The resin was dried under reduced pressure in a desiccator.
MAS-NMR analysis indicated compound 2 in a yield of 80% (approx.
1.0 mmol/g loading). 1H NMR (CDC13): .delta. 4.24 (COCH.sub.2NCO),
5.11 (PhCH.sub.2CO), 7.3-7.4 (4H, aromatic), 7.8 (1H, aromatic).
Elemental analysis: 1.35 weight percent giving 0.96 mmol/g
loading.
[0043] Methylamination of Merrifield resin (13). 200 mg Merrifield
resin (1.25 mmol/g loading capacity) was treated with 2.0 mL
methylamine in water (40% w/w) (excess) at 150.degree. C for 5 min.
The reaction mixture was then cooled to room temperature by
pressurized air. The residue was washed several times with Water,
DCM and MeOH to give compound 13. Elemental analysis gave 1.52
weight percent giving approx. 1.08 mmol/g loading.
[0044] Dimethyl amino propenoates from N-benzoyl glycine on solid
support (4). 250 mg of solid supported N-benzoyl glycine benzyl
ester 2 (approximately 0.25 mmol) was swelled in 2.5 mL DMF, 1.57
mmol DMFDEA was added and the reaction mixture was heated at
180.degree. C. for 10 min. The reaction mixture was then cooled to
room temperature by pressurized air. The residue was washed several
times with DMF, water and DCM. The resin was dried under reduced
pressure in a desiccator. MAS-NMR analysis indicate compound 4 but
no yield was determined due to low resolution.
[0045] Benzyl methyl amino propenones from 4-phenoxy acetophenone
on solid support (14). 200 mg of benzyl methylamine on solid
support 13 (approximately 0.2 mmol) was swelled in 2.0 mL DMF, 214
.mu.L DMFDEA and 155 .mu.L 4-phenoxy acetophenone were added and
the reaction mixture was heated at 180.degree. C. for 10 min. The
reaction mixture was then cooled down to room temperature by
pressurized air. The residue was washed several times with DMF,
water and DCM. The resin was dried under reduced pressure in a
desiccator. MAS-NMR analysis indicated compound 14 but no yield was
determined due to low resolution.
[0046] Benzyl methyl amino propenones from ethyl
4-nitrobenzoylacetate on solid support (19). 200 mg of Benzyl
methylamine on solid support 13 was treated with ethyl
4-nitrobenzoylacetate as described above for the synthesis of
compound 19. MAS-NMR analysis indicated compound 19 but no yield
was determined due to low resolution.
[0047] 3-(benzoyl)amino-4H-pyrido[1,2-a]pyrimidin-4-one (6.) 100 mg
of the solid supported compound 4 were added to 6.6 mg
2-aminopyridine (5) (0.07 mmol) in 0.5 mL of acetic acid. The
solution was exposed to microwaves at 180.degree. C. for 10 minutes
and then cooled to room temperature. The acetic acid was evaporated
giving 14.2 mg of product 6, a total yield of 77% and 96% purity
based on LC/MS analysis. The structure was confirmed by .sup.1 H
NMR (300 MHz, CDCl.sub.3): .delta.7.16 (dt, 1H, ArH), 7.45-7.65 (m,
4H, ArH), 7,75 (dd, 1H, ArH), 7.95 (dd, 2H, ArH), 8.84 (s, 1H, NH),
8.95 (dd, 1H, ArH), 9.75 (s, 1H, pyrimidin-H).
[0048] 3-(benzoyl)amino-1-cyano-4H-quinolizin-4-one (17.) 100 mg of
the solid supported compound 4 were added to 5.6 .mu.L
2-pyridyl-acetonitrile (15) (0.05 mmol) in 0.5 mL of acetic acid.
The solution was exposed to microwaves at 180.degree. C. for 10
minutes and then cooled to room temperature. The acetic acid was
evaporated. The residue was dissolved in DCM and filtered through a
plug of silica. Crude analysis showed a LC/MS purity of 94%.
Evaporation of the solvent gave the product 17 in 13.3 mg, a total
yield of 92%. The structure was confirmed by .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.NMR 7.02 (ddd, 1H, ArH), 7.32-7.42 (m, 4H,
PhH), 7.77 (m, 2H, ArH), 7.81 (dt, 1H, ArH), 8.88 (s, 1H, 1VH),
8.92 (dt, 1H, ArH), 9.11 (s, 1H, quinolizin-4-one).
[0049] 3-(benzoyl)amino-5-oxo-5,6,7,8-tetrahydro-2H-1
-benzopyran-2-one (18). 100 mg of the solid supported compound 4
were added to 7.0 mg 5,5 dimethyl-1,3-cyclohexanedione (16) in 0.5
mL of acetic acid. The solution was exposed to microwaves at
180.degree. C. for 10 min. and then cooled to room temperature. The
acetic acid was evaporated giving 14.8 mg of product 18, a total
yield of 95% and 98% purity based on LC/MS analysis. The structure
was confirmed by .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.1.2 (s,
6H, CH.sub.3) 2.48 (s, 2H, CH.sub.2), 2.78 (s, 2H, CH.sub.2),
7.5-7.7 (m, 3H, ArH), 7.92 (m, 2H, ArH), 8.59 (s, 1H, NH), 8.83 (s,
1H, CH).
[0050] (4-phenoxy)phenylisoxazole (23). 200 mg of the solid
supported compound 14 was mixed with 0.1 (0.5 equiv.) mmol of
hydroxylamine hydrochloride (20) and 2 mL of EtOH. The mixture was
exposed to microwaves at 180.degree. C. for 10 minutes and then
cooled to room temperature. The solvent was evaporated. The product
23 was isolated in 81% yield and 87% purity based on LC/MS analysis
and characterized by .sup.1H NMR (300 MHz, CDC1.sub.3): 6 6.44 (d,
1H, J=1.9 Hz, isoxazole), 7.04 (m, 4H, ArH), 7.17 (dt, 1H, ArH),
7.38 (m, 2H, ArH), 7.76 (m, 2H, ArH), 8.25 (d, 1H, J=1.9 Hz,
isoxazole).
[0051] 1-phenyl-5-(4-phenoxyphenyl)-pyrazole (24). 200 mg of the
solid supported compound 14 was mixed with 0.1 (0.5 equiv.) mmol of
phenylhydrazine (21) and 2 mL of acetic acid. The mixture was
exposed to microwaves at 180.degree. C. for 10 minutes and then
cooled to room temperature. The solvent was evaporated. The product
24 was isolated in 81% yield and 93% purity and characterized by
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.6.48 (d, 1H, J=1.9 Hz,
pyrazole), 6.91 (dd, 2H, ArH), 7.03 (m, 2H, ArH), 7.18 (dd, 2H,
ArH), 7.3-7.4 (m, 8H, ArH), 7.71 (d, 1H, J=1.9 Hz, pyrazole).
[0052] Ethyl (1-phenyl-3-(4-nitro)-phenyl pyrazo le-4-carboxylate
(25). 200 mg of the solid supported compound 19 were treated as
described for compound 24 using EtOH as solvent. The EtOH was
evaporated giving 31.0 mg of product 25 in 92% yield and 91%
purity. The structure was confirmed by .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.1.28 (t, 3H, CH.sub.3CH.sub.2), 4.25 (q, 2H,
CH.sub.2CH.sub.3), 7.20 (m, 2H, ArH), 7.35 (m, 3H, ArH), 7.51 (d,
2H, ArH), 8.21 (d, 2H, ArH), 8.23 (s, 1H, pyrazole).
[0053] Ethyl
2-(4-pyridyl)-4-(4-nitrophenyl)-pyrimidine-5-carboxylate (26). 200
mg of the solid supported compound 19 in 2 mL DMF was treated with
0.1 mmol (approx. 0.5 equiv.) 4-amidinopyridine hydrochloride (22)
and 0.15 mmol KOH, exposed to microwaves at 180.degree. C. for 10
minutes and then cooled to room temperature. The solvent was
evaporated. The product (26) was isolated in 94% (32.7 mg) in 91%
purity. The structure was characterized by .sup.1H NMR (300 MHz,
CDC1.sub.3): 6 1.22 (t, 3H, CH.sub.3CH.sub.2), 4.28 (q, 2H,
CH.sub.2CH.sub.3), 7.54 (m, 3H, PhH), 7.85 (m, 2H, PhH), 8.35 (dd,
2H, pyridyl), 8.56 (dd, 2H, pyridyl), 9.31 (s, 1H, pyrimidine).
[0054] According to the present invention activated
aminopropenoates and aminopropenones on solid phase are provided
which intermediate products can be used in combinatorial syntheses
of a large number of different heterocycles with an overall
reaction time of approximately 30 minutes to give the products in
high purity in high to excellent yields. One major benefit obtained
by this approach is that purification is not needed.
* * * * *