Synthesis of oxazolyl-substituted morpholinium salts

Article abstract of DOI:10.1002/jhet.5570430227

Morpholinium salts coupled to oxazolyl moieties have been synthesized via nucleophilic substitution of a series of oxazolyl chlorides with morpholine. The oxazole moieties were first synthesized and then coupled with morpholine. The corresponding hydrochloride and methyl iodide salts were obtained, purified, characterized and then tested for muscarinic receptor binding affinity. Biological test results from MDS Pharma Services revealed no significant muscarinic receptor affinity.

Full text of DOI:10.1002/jhet.5570430227

Mar-Apr 2006
Synthesis of Oxazolyl-Substituted Morpholinium Salts
443
John Boulos* and Christina Stujenske
Department of Chemistry, Barry University, Miami Shores, Fl 33161 USA
Morpholinium salts coupled to oxazolyl moieties have been synthesized via nucleophilic substitution of
a series of oxazolyl chlorides with morpholine. The oxazole moieties were first synthesized and then
coupled with morpholine. The corresponding hydrochloride and methyl iodide salts were obtained,
purified, characterized and then tested for muscarinic receptor binding affinity. Biological test results from
MDS Pharma Services revealed no significant muscarinic receptor affinity.
J. Heterocyclic Chem., 43, 443 (2006).
Introduction.
the appropriate amides to form the corresponding esters in
about 25-26% yield. These esters were then reduced with
lithium aluminum hydride (LAH) in anhydrous ether at
In the search for new selective M muscarinic receptor
1
agonists, hydrochloride and methyl iodide salts of N-
substituted oxazolyl morpholine bases were synthesized
in our laboratory and then tested for biological activity.
-
10 °C to the corresponding hydroxymethyl oxazoles 4a,
b in 60-80% yield. It was found that at lower
temperatures, these esters precipitated out of solution
leading to much lower yields of alcohols. The alcohols
were then chlorinated with triphenyl phosphine [4] in
carbon tetrachloride to provide the corresponding
chloromethyl oxazoles 5a, b in about 55-73% yield. The
chlorides were coupled with morpholine to furnish the
corresponding N-substituted oxazolyl morpholine bases
Muscarinic M receptors are currently therapeutic targets
1
for the symptomatic treatment of Alzheimer's disease.
These compounds were designed to test the cholinergic
hypothesis advanced by Schulman et al [1]. This
hypothesis is based on the fact that while basal forebrain
neurons which express the M muscarinic receptor are at
risk of degenerating, the cortical neurons expressing the
2
6
a, b. The bases were then converted to hydrochloride
M subtype which synapse with them are not altered. In
1
and methyl iodide salts with HCl gas and iodomethane 7a,
b and 8a, b, respectively.
theory, one could design and synthesize muscarinic
selective M -agonists that would activate the cortical
1
neurons. These compounds conform to the structural
constraints imposed by Schulman’s model of the
muscarinic pharmacophore and conform to the five-atom
rule with the NCCOC backbone, one of the criteria for
muscarinic receptor activity. Biological tests conducted
by MDS Pharma Services revealed no significant binding
affinity of these compounds for muscarinic receptors.
Nevertheless, these compounds presented interesting
synthetic challenges and their chemistry is the focus of
this paper.
The strategy employed in the synthesis of these salts is
illustrated in Scheme 1. The first step in the synthesis of
the N-substituted oxazolyl morpholine bases was to
construct the oxazole moiety. Of the many synthetic
routes to 4,5-disubstituted oxazoles, one convenient
method [2] is the treatment of ꢀ-metalated alkyl
isocyanides (prepared from isocyanides) with acylating
agents such as acyl chlorides, carboxylic esters, and N,N-
disubstituted amides. An alternate route [3] is the
treatment of alkylamides with ꢀ-chlorocarbonyl
compounds in acidic media. The latter route was chosen
to synthesize the oxazole carboxylic acid esters 3a, b. In
this reaction, ethyl chloroacetoacetate 2 (obtained from
the chlorination of ethyl acetoacetate 1) was treated with

4
44
J. Boulos and C. Stujenske
Vol 43
EXPERIMENTAL
General: Reagents were purchased from Aldrich Chemical
4-Methyl-5-(4-morpholinomethyl)oxazole hydrochloride
7a).
(
HCl gas was bubbled through a solution of 0.50 g (0.00274
Company unless otherwise noted and all starting liquid materials
were distilled before use. All NMR spectra were obtained using
a Varian 300 MHz spectrometer. IR spectra were recorded using
a Nicolet Impact 400D FT-IR and mass spectra on a Hewlett
Packard 5972 Series MS interfaced with a Hewlett Packard 5890
Series II Plus GC. Elemental analyses were done at Galbraith
Laboratories (Knoxville, Tennessee) and all biological assays
conducted at MDS Pharma Services. Melting points were
determined on a MEL-TEMP II purchased from Laboratory
Devices and are uncorrected.
mol) of the base (6a) dissolved in 10 mL of dichloromethane for
about 15-20 minutes. About 2 mL of anhydrous methanol was
added to dissolve the solid. The resulting solution was concen-
trated and the solid residue recrystallized from 1-butanol to
1
afford 0.45 g of (7a) (60 %). H nmr (D O): ꢀ 2.1 (s, 3H), 3.2
2
(
bm, 4H), 3.6-3.8 (bm, 4H), 4.4 (s, 2H), 8.1 (s, 1H); ms: m/z 182
+
(M ) consistent with anticipated structure upon loss of HCl, 123,
9
6, 86, 56, 42.
Anal. Calcd. for C H N O Cl: C, 49.43; H, 6.91; N, 12.81;
9
15
2
2
Cl, 16.21. Found: C, 49. 54; H, 6.90; N, 12.79; Cl, 15.98.
5
-Hydroxymethyl-4-methyloxazole (4a).
4
-Methyl-5-(4-morpholinomethyl)oxazole Methyl Iodide Salt
To 50 mL of anhydrous ether at -10 °C under nitrogen were
(8a).
added simultaneously, with mechanical stirring, a solution of the
ester (3a) (11.5 g, 74 mmol) in 15 mL of anhydrous ether and a
solution of LAH (2.66 g, 70 mmol) in 56 mL of anhydrous
ether. After 2.5 hours (including one hour for initial dropwise
addition), ethyl acetate (11 mL) was added slowly. The solution
was allowed to warm to room temperature, and excess LAH was
destroyed with 95% ethanol. The reaction mixture was
hydrolyzed with tartaric acid (19 g in water) and then made
alkaline with 6 N NaOH. The solution was saturated with
K CO , and the two layers were separated. The aqueous layer
About 5 mL of iodomethane was added to a mixture
containing 0.30 g of the base (0.00165 mol) (6a) dissolved in 10
mL of acetonitrile. The reaction mixture was stirred at room
temperature overnight, concentrated and the residue was
recrystallized from n-butanol to afford 0.35 g of the salt
1
(
4
66.0%). H nmr (D O): ꢀ 2.15 (s, 3H), 3.1 (s, 3H), 3.25-3.6 (m,
2
H), 4.0 (m, 4H), 4.65 (s, 2 H), 8.2 (s, 1H).
Anal. Calcd. for C H N O I: C, 37.06; H, 5.29; N, 8.64; I,
1
0
17
2
2
3
9.16. Found: C, 36.97; H, 5.19; N, 8.71; I 39.24.
2
3
was extracted with benzene, and the benzene solution was dried
over MgSO ; the ether layer was also dried over MgSO . Both
layers were concentrated, and the residues combined and
distilled; the fraction boiling between 119-120 °C/13-14 mm Hg
5-Hydroxymethyl-2,4-dimethyloxazole (4b).
4
4
The ester (3b) (13 g, 70 mmole) and LAH (3.47 g, 90 mmol)
were used. The procedure was the same as described in (4a). About
7
.67 g of the alcohol were recovered (80%) at 95 °C/3-4 mm Hg.
afforded 4.3 g of alcohol (60%). Literature values: [3] bp 120
1
1
H nmr (CDCl ): ꢀ 2.1 (s, 3H), 2.5 (s, 3H), 3.0-3.5 (bs, 2H), 4.6 (s,
3
°
C/13 mm Hg, (63%). H nmr (CDCl ): ꢀ 2.2 (s, 3H), 3.1 (bs,
3
-1
2
H); ir (CCl ): 3600-3200 (OH), 1640, 1570, 1440 cm .
4
1
1
H), 4.6 (s, 2H), 7.8 (s, 1H); ir (CCl ): 3600-3200 (OH), 1600,
4
-1
490, 1440 cm .
Anal. Calcd. for C H NO : C, 56.68; H, 7.13; N, 11.02.
6 9 2
Found: C, 56.75; H, 6.98; N, 11.15.
5
-Chloromethyl-4-methyloxazole (5a).
A mixture of the alcohol (4a) (1.21 g, 0.010 mol) in
5
-chloromethyl-2,4-dimethyloxazole (5b).
A mixture of the alcohol (4b) (6.0 g, 0.047 mol), anhydrous
anhydrous carbon tetrachloride (15.33 g, 0.10 mol) was added to
a dry, 300-mL single-necked flask furnished with a magnetic
stirring bar and a reflux condenser (to which was attached a
Drierite-filled drying tube). To this solution, triphenyl phosphine
carbon tetrachloride (45 mL) and of triphenyl phosphine (17.04
g, 0.065 mol) was refluxed for 2 hours. The reaction mixture
was allowed to cool to room temperature and then diluted with
1
00 mL of dry pentane. The mixture was filtered, and the filtrate
(3.65 g, 0.010 mol) was added, and the reaction mixture was
was concentrated to one-fourth of its original volume. The
concentrated product was distilled to yield 3.73 g of the chloride
refluxed for 1 hour. The mixture was allowed to cool to room
temperature; dry pentane was added (100 mL), and stirring was
continued for an additional 5 minutes. The triphenyl phosphine
oxide precipitate was filtered, and the residue was washed with
1
(54.6%) which was collected at 53-54 °C/2-3 mm Hg. H nmr
(CDCl ): ꢀ 2.1 (s, 3H), 2.4 (s, 3H), 4.5 (s, 2H).
3
5
0 ml of dry pentane. The solution was concentrated and then
2
,4-Dimethyl-5-(4-morpholinomethyl)oxazole (6b).
distilled to afford 1.02 g of the chloride (72.8%), bp 47-49 °C/3-
4
1
The chloride (5b) (1.73 g, 0.012 mole) was treated with
mm Hg. Literature values: [6] bp 65-67/12 mm Hg). H nmr
(
CDCl ): ꢀ 2.5 (s, 3H), 4.4 (s, 2H), 7.9 (s, 1H).
morpholine as described in (6a). About 1.02 g of fairly pure base
3
1
was recovered (36.6 %). H nmr (CDCl ): ꢀ 2.1 (s, 3H), 2.4 (s,
3
4
-Methyl-5-(4-morpholinomethyl)oxazole (6a).
3
H), 2.5 (m, 4H), 3.5 (s, 2H), 3.8 (m, 4H).
The chloride (5a) (1.02 g, 0.008 mol) was added to a mixture
2
,4-Dimethyl-5-(4-morpholinomethyl)oxazole hydrochloride (7b).
About 0.80 g of the base (6b) (0.00408 mol) was converted
of sodium carbonate in 5 mL of benzene and morpholine (0.68
g, 0.008 mol), dissolved in 5 mL of benzene, was added
dropwise with stirring. After 12 hours of additional stirring, the
reaction mixture was refluxed for about 5 hours. The mixture
was cooled to room temperature, diluted with benzene and
to the hydrochloride salt as described in (7a); 0.60 g of the
salt (63.8%) was recovered after recrystallization from 1-
butanol, mp 222-224 °C. H nmr (D O): ꢀ 2.1 (s, 3H), 2.45 (s,
1
2
filtered. The filtrate was concentrated under vacuum to dryness
3H), 3.2-3.4 (bm, 4H), 3.6-4.0 (bm, 4H), 4.4 (s, 2H); ms: m/z
196 (M ) consistent with the anticipated structure upon loss of
1
+
to yield 0.85 g of fairly pure base (58.7%). H nmr (CDCl ): ꢀ
3
2
.2 (s, 3H), 2.4 (t, 4H), 3.5 (s, 2H), 3.7 (t, 4H), 7.8 (s, 1H).
HCl, 110, 86, 56, 42.

Mar-Apr 2006
Synthesis of Oxazolyl-Substituted Morpholinium Salts
445
REFERENCES AND NOTES
Anal. Calcd. for C H N O Cl: C, 51.61; H, 7.36; N, 12.04;
1
0
17
2
2
Cl, 15.24. Found: C, 51.85; H, 7.37; N, 11.98; Cl, 14.96.
[
1] J. M. Schulman, M. L. Sabio and R. L. Disch, J. Med. Chem.,
6, 817(1983).
2] U. Schollkopf and R. Schroder, Angew. Chem. Int. Ed. Engl.,
10, 330 (1971).
[3] A. Dornow and H. Hell, Chem. Ber., 94, 1248 (1961).
2
2
,4-Dimethyl-5-(4-morpholinomethyl)oxazole methyliodide (8b).
About 0.40 g of the base (6b) (0.00204 mol) was
[
converted to the methyl iodide salt as described in (8a) to
1
[4] Org. Syntheses Coll. Vol. 6, John Wiley & Sons, New York,
NY, 1988, pp 634-637.
afford 0.35 g of material (50.7%). H nmr (D O): ꢀ 2.04
2
(
(
s, 3H), 2.35 (s, 3H), 3.05 (s, 3H), 3.35-3.5 (m, 4H), 4.0
bm, 4H), 4.6 (s, 2H).
[
5] Org. Syntheses Coll. Vol. 4, John Wiley & Sons, New York,
NY, 1967, pp 590-593.
[6] U. H. Lindberg and J. Pedersen, B. Ulff, Acta Pharmaceutica
Suecica, 4, 5 (1967).
Anal. Calcd. for C H N O I: C, 39.07; H, 5.66; N, 8.28; I,
11
19
2
2
3
7.53. Found: C, 38.97; H, 5.69; N, 8.21; I, 37.24.