Use of oligosalicylates in the preparation of phenolic amido acids

Article abstract of DOI:10.1081/SCC-200061542

A simplified methodology has been developed for preparing salicylamides from the corresponding acids via oligosalicylates which both protect the phenolic group and, at the same time, activate the carboxyl for coupling. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200061542

w
Synthetic Communications , 35: 1567–1575, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200061542
Use of Oligosalicylates in the Preparation of
Phenolic Amido Acids
David Gschneidner, JoAnne Corvino, John Freeman,
Doris O’Toole, Lynn Shields, and Eric Wang
Emisphere Technologies Inc., Tarrytown, New York, USA
Abstract: A simplified methodology has been developed for preparing salicylamides
from the corresponding acids via oligosalicylates which both protect the phenolic
group and, at the same time, activate the carboxyl for coupling.
Keywords: Amide coupling, activated ester, salicylamide, oligomer
INTRODUCTION
The reaction of an amine with a carboxylic acid derivative to form an amide is
[
well-known chemistry, and numerous methods of amide preparation have
1]
[2]
been reported.
The most straightforward synthesis of amides is the
[1]
acylative coupling of an amine with an acid chloride. The reaction is often
complicated by unwanted side reactions, particularly when other functional
groups are present. Additionally, acid chlorides are corrosive and moisture
sensitive, and can be difficult to use on a large scale. In many cases, the acid
chlorides are not commercially available and must be prepared from their
more readily available acid precursors. Taken together, these issues have
created the need for alternative, uncomplicated amide syntheses.
The synthesis of phenolic amido acids (see Fig. 1) from acid chlorides
represents a difficult challenge. When the phenolic group is left unprotected,
the yields are typically low and by-products are produced that make purifi-
cation complicated. For this reason, it is preferable to protect the phenol
before making the acid chloride. The protected acid chloride can be used
Received in the USA February 11, 2005
Address correspondence to David Gschneidner, Emisphere Technologies Inc.,
785 Old Saw Mill River Road, Tarrytown, NY 10591, USA. E-mail: dgschnei@
emisphere.com
1
567

1568
D. Gschneidner et al.
Figure 1. Genetic structure of a phenolic amido acid.
for coupling with an amine. This process then requires a subsequent deprotec-
tion step (see Scheme 1). In many cases, the protecting group is often a
reactive moiety, such as an acetate, and can be the source of by-product
formation. Finally, the coupling reaction is often most conveniently
conducted in an aqueous medium (Schotten–Baumann conditions). These
conditions result in lower yields of the desired amide because of competitive
and unselective hydrolysis of the acid chloride by the solvent. In our hands,
typical overall yields for the four-step process are around 40%.
RESULTS AND DISCUSSION
As part of our program to prepare oral drug-delivery agents that have phenolic
amide functionality, a simpler, more efficient synthetic route to these
compounds was needed. Thus, we sought a general procedure for coupling
Scheme 1.

Phenolic Amido Acid Preparation
1569
phenolic esters, especially those bearing electron-withdrawing groups (EWG)
on the aryl ring, with amines. For the reasons discussed previously and
[
3]
because phenolic esters are active electrophiles, we decided to examine oli-
gomeric salicylates as coupling agents for the preparation of phenolic amido
acids. This methodology combines the two-step protection and activation
sequence into a single synthetic step. Similarly, the coupling and deprotection
steps are also combined. Thus, the use of oligosalicylate coupling agents
efficiently transforms a four-step procedure into a two-step procedure.
The overall process is shown in Scheme 2. Polymerization of salicylic
[
4]
acid is a well-known reaction. In the present study, we found that low-
molecular-weight oligomers are preferred because they are more soluble
than higher polymers in organic aprotic polar solvents such as dioxane.
The oligosalicylates were prepared by heating the salicylic acid in xylenes
in the presence of acetic anhydride. The volatiles were distilled to a final
temperature of 190–2008C. Acetic acid production continues throughout
the oligomerization process. The desired oligomer was isolated by either
pouring into a tray to form a glass or by charging the molten oligomer
directly to the coupling reaction solvent (dioxane or 1,2-dimethoxyethane).
Amide bond formation can be accomplished by adding an aqueous
solution of the amino acid containing a slight excess of base to the
oligomer solution. The base, sodium hydroxide or potassium carbonate, is
required when the amine contains acid groups. For simple amines, no added
base is needed. In general, the reactions are complete after heating for
3–6 h at 708C. The reaction is readily followed by high-pressure liquid chrom-
atography (HPLC). The reactions are clean and, in most cases, the only
by-product is salicylic acid. Pure products are easily obtained by exploiting
Scheme 2.

1570
D. Gschneidner et al.
the pK differences between aliphatic acids and salicylic acids (about 1.8 pH
a
units) and/or recrystallization.
A representative oligosalicylate chromatogram is shown in Fig. 2a for
oligosalicylate. The numerous peaks represent the various molecular-weight
oligomer components. As the reaction proceeds, two distinct peaks replace
the complicated oligosalicylate HPLC profile. At the completion of the
reaction only these two new components remain, the desired amide 1 and
the salicylic acid by-product (Fig. 2b).
Table 1 shows results using various substrates (the yields quoted are
unoptimized). In general, the procedure works best with aliphatic amines.
Aromatic amines, however, do not appear to be sufficiently reactive to give
good product yields (Entry 13), unless the oligosalicylate is further
activated by additional EWGs on the aromatic ring (Entry 14).
Figure 2. (top) HPLC trace of oligosalicylate, (bottom) HPLC trace following
reaction with amine. The peak on the left is salicylic acid and the peak on the right
is product.

Phenolic Amido Acid Preparation
1571
Table 1. Amination of oligosalicylates with aminoacids
a
Yield
(%)
Entry
Phenolic Acid
Amine
1
X ¼ H
8-aminocaprylic acid
74
2
3
4
5
6
7
8
9
X ¼ 3-Me
8-aminocaprylic acid
8-aminocaprylic acid
8-aminocaprylic acid
8-aminocaprylic acid
8-aminocaprylic acid
8-aminocaprylic acid
8-aminocaprylic acid
4-aminobutyric acid
10-aminodecanoic acid
11-aminoundecanoic acid
10-aminodecanoic acid
41
71
44
59
56
51
53
47
32
47
20
0
X ¼ 4-Me
X ¼ 5-Cl
X ¼ 5-Br
X ¼ 3,5-diF
X ¼ 3-F, 5-Cl
X ¼ 3-Cl, 5-F
X ¼ 4-OMe
X ¼ 4-OMe
X ¼ 3,5-diCl
X ¼ 3,5-diCl
X ¼ H
1
1
1
1
0
1
2
3
1
4
X ¼ 3,5-diCl
46
1
1
5
6
4 ¼ OH
3 ¼ OH
8-aminocaprylic acid
8-aminocaprylic acid
12
10
a
Yields are for recrystallized products.
Overall, the reaction works well with a variety of substituted salicylic acid
oligomers. Both electron-withdrawing and electron-donating groups are well
tolerated. In addition, nonconjugated carboxylic acid oligomers give signifi-
cantly lower yields, probably because of their inability to act as good
leaving groups (Entries 15 and 16).
CONCLUSION
In summary, the use of oligosalicylate coupling reagents to prepare phenolic
amido acids represents a novel and useful synthetic methodology. This
chemistry facilitates amide bond formation in which the protection of the
hydroxyl group is incorporated into the activation procedure, and, similarly,

1572
D. Gschneidner et al.
deprotection is an inherent part of the coupling reaction. Additionally, this
reaction sequence avoids the use of corrosive and difficult-to-handle acid
chloride reagents. This procedure using oligosalicylates as coupling agents
is a simple, straightforward method for the preparation of amides.
EXPERIMENTAL
General
Melting points are uncorrected. NMR spectra were measured using a Bruker
1
AM300 (300 MHz) spectrometer. H chemical shifts are reported in d ppm
relative to dimethylsulfoxide (DMSO) as an internal standard. Reverse-phase
HPLC was performed with
50 Â 4.6mm, 5 mm particle size, 300 A pore size) column and a UV
detector (220 nm). The sample was eluted with 0.1% trifluoroacetic acid
a Vydac Protein and Peptide (C ,
18
2
(
(
TFA) in water (mobile phase A) and a 0.1% TFA in 50% acetonitrile/water
mobile phase B) (flow rate, 1 mL/min; gradient, 0% to 100% B over
2
0 min and 100% B throughout). Microanalytical data was obtained from
Robertson Microlit Laboratory, Inc. (Madison, NJ). All starting materials
were purchased from commercial sources and used without further purification.
Preparation of Oligosalicylate. Acetic anhydride (14.50 mL, 15.69 g,
0
.154 mol, 1.02 eq), salicylic acid (20.79 g, 0.151 mol, 1.00 eq), and xylenes
60 mL) were added to a 250-mL, three-neck flask fitted with a magnetic
(
stir bar, a thermometer, and a Dean–Stark trap with condenser. The flask
was placed in a sand bath and heating of the cloudy white mixture began.
The reaction mixture became a clear solution around 1008C. Most of
the volatile organics (xylenes and acetic acid) were distilled into the
Dean–Stark trap over three hours (135–1468C). Distillation was continued
for another hour (a total of 75 mL distilled), during which the pot temperature
slowly rose to 1958C and the distillate slowed to a trickle. The residue was
poured off while still hot into an aluminum tray. Upon cooling, a brittle
yellow glass formed. The solid was ground to a fine powder. The 18.95 g of
oligosalicylate produced was used without further purification.
Preparation of N-(salicyloyl)-8-aminocaprylic Acid (1). A solution of
4
.96 g (17.9 mmol, 1.19 eq) of a 50% (by weight) aqueous potassium
carbonate, 2.39 g of 8-aminocaprylic acid (15.0 mmol, 1.00 eq), and water
3 mL) were charged to a 250-mL, round-bottom flask equipped with a
(
magnetic stir bar and an addition funnel. The white cloudy mixture was
treated with a solution of oligosalicylate (2.44 g, 20.2 mmol 1.35 eq) and
dioxane (40 mL), added over 3 min. The addition funnel was replaced with
a condenser, and the reaction mixture was heated to 908C for 4 h (at which
time the reaction was determined to have finished, by HPLC). The clear
orange reaction mixture was cooled to 408C, filtered, and acidified to

Phenolic Amido Acid Preparation
1573
pH ¼ 1 with 3% (by weight) aqueous hydrochloric acid. The mixture was
concentrated in vacuo (608C, 50 mm) to remove all the dioxane and some
of the water. The solid (which precipitated from solution during stripping)
was isolated by filtration while still warm. The light pink solid was recrystal-
lized from 70 mL of 65% ethanol/water. The solid was recovered by filtration
and was dried over 18 h in a 508C vacuum oven. The N-(salicyloyl)-8-
aminocaprylic acid was isolated as a white solid (3.11 g, 74%), mp 117–
1
8
8C; H NMR (DMSO-d ) d 12.75 (s, 1H), 12.00 (s 1H), 8.80 (t, 1H), 7.83
6
(
dd, 1H), 7.38 (td, 1H), 6.87 (m, 2H), 3.27 (q, 2H), 2.19 (t, 2H), 1.51
m, 4H), 1.29 (m, 6H). Anal. calcd. for C H NO : C, 64.50; H, 7.58; N,
(
1
5
21
4
5
.01. Found: C, 64.44; H, 7.54; N, 5.00.
The following compounds were similarly prepared from the correspond-
ing carboxylic acids and amines:
Preparation of N-(3-methylsalicyloyl)-8-aminocaprylic Acid (2). Mp 88–
1
9
08C, H NMR (DMSO-d ) d 13.3 (s, 1H), 12.0 (s, 1H), 8.8 (t, 1H), 7.66
6
(
d, 1H), 7.28 (d, 1H), 6.76 (t, 1H), 3.26 (m, 2H), 2.2 (m, 6H), 1.5 (m, 4H),
1.28 (s, 2H). Anal. calcd. for C H NO : C, 65.51; H, 7.90; N, 4.77.
16 23 4
Found: C, 65.44; H, 8.02; N, 4.56.
Preparation of N-(4-methylsalicyloyl)-8-aminocaprylic Acid (3). Mp 112–
1
1
148C; H NMR (DMSO-d ) d 12.8 (s, 1H), 12.0 (s, 1H), 8.7 (t, 1H), 7.7
6
(
d, 1H), 6.6 (d, 2H), 3.2 (q, 2H), 2.28 (s, 3H), 2.18 (t, 2H), 1.46 (m, 4H),
1.28 (s, 6H). Anal. calcd. for C H NO : C, 65.51; H, 7.90; N, 4.77.
16 23 4
Found: C, 65.66; H, 7.85; N, 4.69.
Preparation of N-(5-chlorosalicyloyl)-8-aminocaprylic Acid (4). Mp 125–
1
1
588C; H NMR (DMSO-d ) d 12.0 (s, 1H), 8.8 (m, 1H), 7.95 (m, 1H), 7.42
6
(9, 1H), 6.93 (d, 1H), 3.29 (q, 2H), 2.2 (t, 2H), 1.5 (m, 4H), 1.29 (s, 6H). Anal.
calcd. for C H ClNO : C, 57.41; H, 6.42; N, 4.46. Found C, 57.46; H, 6.28;
N, 4.42.
1
5
20
4
Preparation of N-(5-bromosalicyloyl)-8-aminocaprylic Acid (5). Mp 125–
1
1
288C; H NMR (DMSO-d ) d 12.8 (s, 1H), 12.0 (s, 1H), 8.8 (t, 1H), 8.05
6
(
d, 1H), 7.55 (9, 1H), 6.88 (d, 1H), 3.28 (q, 2H), 2.2 (t, 2H), 1.49 (m, 4H),
1
Found: C, 50.48; H, 5.71; N, 3.61.
.28 (s, 6H). Anal. calcd. for C H BrNO : C, 50.29; H, 5.63; N, 3.91.
20
1
5
4
Preparation of N-(3,5-difluorosalicyloyl)-8-aminocaprylic Acid (6). Mp
1
1
09–1108C; H NMR (DMSO-d ) d 13.3 (s, 1H), 12.0 (s, 1H), 9.0 (t, 1H),
6
7
.65 (m, 1H), 7.55 (m, 1H), 3.3 (q, 2H), 2.2 (t, 2H), 1.5 (m, 4H), 1.25
(s, 6H). Anal. calcd. for C H F NO : C, 57.14; H, 6.07; N, 4.44. Found:
15 19 2 4
C, 57.3; H, 6.40; N, 4.43.
Preparation of N-(3-fluoro-5-chlorosalicyloyl)-8-aminocaprylic Acid (7). Mp
1
1
08–1098C; H NMR (DMSO-d ) (s, 1H), 12.0 (s, 1H), 9.05 (s, 1H), 7.8 (q, 1H),
6
7.65 (q, 1H), 3.3 (q, 2H), 2.2 (t, 2H), 1.5 (m, 4H), 1.3 (s, 6H). Anal. calcd. for
C H ClFNO : C, 54.3; H, 5.77; N, 4.22. Found: C, 54.27; H, 5.91; N, 4.14.
15
19
4

1574
D. Gschneidner et al.
Preparation of N-(3-chloro-5-fluorosalicyloyl)-8-aminocaprylic Acid (8).
1
Mp 94.5–968C; H NMR (DMSO-d ) d 13.6 (s, 1H), 12.0 (s, 1H), 12.0
6
(s, 1H), 9.1 (t, 1H), 7.8 (q, 1H), 7.65 (q, 1H), 3.3 (q, 2H), 2.2 (t, 2H), 1.55
(
m, 4H), 1.3 (S, 6H). Anal. calcd. for C H ClFNO : C, 54.3; H, 5.77; N,
1
5
19
4
4
.22. Found: C, 54.36; H, 5.79; N, 4.17.
Preparation of N-(4-methoxysalicyloyl)-10-aminobutyric Acid (9). Mp
1
1
7
30–1348C; H NMR (DMSO-d ) d 13.5 (s, 1H), 12.1 (s, 1H), 8.6 (t, 1H),
6
.78 (d, 1H), 6.4 (m, 2H), 3.7 (s, 3H), 3.3 (q, 2H), 2.28 (t, 2H), 1.76
(m, 2H). Anal. calcd. for C H NO : C, 56.92; H, 5.93; N, 5.53. Found: C,
12 21 5
5
6.76; H, 5.89; N, 5.03.
Preparation of N-(4-methoxysalicyloyl)-10-aminodecanoic Acid (10). Mp
1
1
05–1088C; H NMR (DMSO-d ) d 13.2 (s, 1H), 12.05 (s, 1H), 8.65
6
(s, 1H), 7.7 (d, 1H), 6.44 (m, 2H), 3.78 (m, 2H), 3.2 (q, 2H), 2.2 (t, 2H), 1.5
(
m, 5H), 1.25 (s, 9H). Anal. calcd. for C H NO : C, 64.09; H, 8.01; N,
1
8
27
5
4
.22. Found: C, 64.00; H, 8.17; N, 4.12.
Preparation of Sodium N-(3,5-dichlorosalicyloyl)-11-aminoundecanoate
11). A 500-mL Erlenmeyer flask equipped with a magnetic stir
(
bar was charged with 12.0 g (31.0 mmol) of N-(3,5-dichlorosalicyloyl)-11-
aminoundecanoic acid (prepared using the procedure detailed previously)
and 200 mL of ethanol. The mixture was heated until most of the solids
dissolved, hot filtered, and treated with a solution of 1.26 g (32.0 mmol) of
sodium hydroxide and 3.76 mL of water. The mixture was stirred for 1 h,
during which a white solid formed. The reaction mixture was concentrated
to half the volume and diluted with 300 mL of heptane. The white solid was
isolated by filtration and dried in vacuo, giving a total of 11.98 g of sodium
1
N-(3,5-dichlorosalicyloyl)-11-aminoundecanoate, mp 195–2108C; H NMR
(
DMSO-d ) d 11.86 (t, 1H), 7.5 (d, 1H), 7.08 (d, 1H), 3.2 (q, 2H), 2.17
6
(
t, 2H), 1.47 (m, 4H), 1.35 (s, 12H). Anal. calcd. for C H Cl NNaO : C,
2
1
8
24
4
5
2.39; H, 5.86; N, 3.40; Na, 5.58. Found: C, 52.46; H, 5.92; N, 3.16; Nay 5.37.
Preparation of N-(3,5-dichlorosalicyloyl)-10-amonodecanoic Acid (12).
1
Mp 95–998C; H NMR (DMSO-d ) d 13.75 (s, 1H), 9.14 (t, 1H), 7.99
6
(d, 1H), 7.75 (d, 1H), 3.27 (m, 2H), 2.2 (t, 2H), 1.49 (m, 4H), 1.24 (s, 10H).
Anal. calcd. for C H Cl NO : C, 54.25; H, 6.16; N, 3.72. Found: C,
1
7
23
2
4
5
3.97; H, 6.14; N, 3.47.
Preparation of N-(4-hydroxyphenylacetyl)-8-aminocaprylic Acid (15). Mp
1
1
7
13–1158C; H NMR (DMSO-d ) d 12.0 (s, 1H), 9.25 (s, 1H), 7.9 (t, 1H),
6
.05 (d, 2H), 6.65 (d, 2H), 3.35 (s, 1H), 3.2 (s, 2H), 3.0 (q, 2H), 2.18
(t, 2H), 1.47 (t, 2H), 1.36 (t, 2H), 1.23 (s, 4H). Anal. calcd. for C H NO :
C, 65.53; H, 7.85; N, 4.79. Found: C, 65.03; H, 8.09; N, 4.81.
16 23 4
Preparation of N-(3-hydroxyphenylacetyl)-8-aminocaprylic Acid (16). Mp
1
8
5–888C; H NMR (DMSO-d ) d 12.0 (s, 1H), 9.35 (s, 1H), 7.95 (s, 1H), 7.05
6
(t, 1H), 6.6 (m, 2H), 3.27 (s, 2H), 3.0 (q, 2H), 2.5 (m, 2H), 2.18 (t, 2H), 1.47

Phenolic Amido Acid Preparation
1575
(
m, 2H), 1.37 (m, 2H), 1.23 (s, 6H). Anal. calcd. for C H NO : C, 65.53; H,
1
6
23
4
7
.85; N, 4.79. Found: C, 65.13; H, 7.86; N, 4.67.
Preparation of Oligo(3,5-dichlorosalicylate). Acetic anhydride (7.10 mL,
7
1
.69 g, 0.075 mol, 1.04 eq.), 3,5-dichlorosalicylic acid (15.00 g, 0.0725 mol,
.00 eq.), and xylenes (250 mL) were added to a 250-mL, three-neck flask
fitted with a magnetic stir bar, a thermometer, and a Dean–Stark trap with
condenser. The flask was placed in a sand bath and heating of the cloudy
white mixture began. The reaction mixture became a clear solution around
1
158C. Most of the volatile organics (xylenes and acetic acid) were distilled
into the Dean–Stark trap over 3 h (133–1428C); a total of 40 mL was
distilled. The residue, a tan solid, was placed in a crystallizing dish and
allowed to dry under vacuum. The 15.28 g of oligosalicylate produced was
used without further purification.
Preparation of 3-[4-(3,5-dichlorosalicyloyl)aminophenyl] propionic acid
(
14). A mixture of 0386-24A (12.0 g, 0.0698 mol, 1.10 eq.), 3-(4-aminophe-
nyl)propionic acid (9.42 g, 0.0571 mol, 1.0 eq.), and dioxane (150 mL) were
added to a 500-mL round-bottom flask equipped with a magnetic stir bar
and a condenser. A tan slurry formed. The reaction mixture was heated to
reflux for approximately 5 h. The reaction was determined to be complete
by HPLC. The clear brown reaction mixture was cooled to room temperature.
The dioxane was removed in vacuo. The sticky solid residue was taken up in
2
N NaOH (200 mL). The cloudy yellow-brown mixture was filtered and
extracted with ethyl acetate (350 mL). The clear yellow-brown aqueous layer
was acidified with 2N HCl. A tan solid precipitated and was recovered by fil-
tration. The solid was taken up in ethanol/water (50:50), decolorized with
activated carbon, and crystallized. A tan solid formed and was recovered by
filtration drying under vacuum (508C) overnight to yield 9.3 g (46%) of 3-[4-
1
(
(
(
3,5-dichlorosalicyloyl)aminophenyl)] propionic acid, mp 2258C; H NMR
DMSO-d ) d 12.9 (s, 1H), 12.15 (sm 1H), 10.6 (s, 1H), 8.1 (d, 1H), 7.8
d, 1H), 7.5 (d, 2H), 7.25 (d, 2H), 2.8 (t, 2H), 2.5 (m, 2H). Anal. calcd. for
6
C H Cl NO : C, 54.24; H, 3.67; N, 3.95. Found: C, 54.21; H, 3.68; N, 3.89.
6
1
13
2
4
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1
2
3
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4