A convergent synthesis of CGS23305, a thromboxane synthase inhibitor

Article abstract of DOI:10.1055/s-1999-3458

A convergent synthesis of CGS23305 was discovered. The route to the pyridine aldehyde intermediate 5 was reduced from four to two steps. The pyridine aldehyde was converted to the key pyridine aldehyde ester intermediate 7 via Michael Addition of the N,N-diethylenamine 6 to ethyl acrylate. A Wittig alkenation using the multifunctional moiety 19 completed the carbon skeleton assembly. Hydrogenation and hydrolysis afforded CGS23305 in 44% overall yield from 14 (6 steps).

Full text of DOI:10.1055/s-1999-3458

PAPER
769
A Convergent Synthesis of CGS23305, A Thromboxane Synthase Inhibitor
Andrew T. Bach, John A. Carlson,1 Peter P. Giannousis*
Chemical Development, Novartis Pharmaceuticals Corporation,2 564 Morris Avenue, Summit, New Jersey 07901, USA
Fax +1(973)7812188; E-mail: peter.giannousis@pharma.novartis.com
Received 30 November 1998
The alkylation of 5 was carried out in a one-pot sequence.
The N,N-diethylenamine 6 was formed with N,N-diethyl-
trimethylsilylamine in toluene at ambient temperature
over 1 hour with catalytic p-toluenesulfonic acid.7 Micha-
Abstract: A convergent synthesis of CGS23305 was discovered.
The route to the pyridine aldehyde intermediate 5 was reduced from
four to two steps. The pyridine aldehyde was converted to the key
pyridine aldehyde ester intermediate 7 via Michael Addition of the
N,N-diethylenamine 6 to ethyl acrylate. A Wittig alkenation using el reaction with ethyl acrylate in refluxing acetonitrile fol-
the multifunctional moiety 19 completed the carbon skeleton as-
lowed by quenching with water gave the expected C-
alkylated product 7.8 Presumably other acrylate esters
(e.g. methyl, benzyl, or t-butyl) could be used in this reac-
tion to form the corresponding esters. The first half of the
convergent synthesis was now complete.
sembly. Hydrogenation and hydrolysis afforded CGS23305 in 44%
overall yield from 14 (6 steps).
Key words: convergent synthesis, pyridine, aldehydes, thrombox-
ane inhibitor
We next investigated the preparation of an appropriate
propyl sulfonamide phosphonium salt, to be used in the
Wittig alkenation. This piece was made by sulfonylating
3-bromopropylamine hydrobromide (16) with p-chlo-
robenzenesulfonyl chloride (17) using triethylamine and a
catalytic amount of 4-dimethylaminopyridine (4-DMAP).
The reaction was complete in 1 hour. It should be noted
that without the 4-DMAP the reaction was incomplete in
24 hours. The bromine of 18 was then displaced with
As previously reported in the literature, CGS23305 (10) is
a racemic mixture whose enantiomers differ little in their
ability to inhibit thromboxane synthase.3 Our work initial-
ly focused on discovering a convergent synthesis of the
active ingredient (10) that is amenable to scaleup. We then
concentrated on finding a shorter path to the pyridine al-
dehyde intermediate, 5.
Success was achieved with a route (see Scheme 1) that be-
gan with tetrahydrofuran (1) which was opened (via a lit-
erature procedure) with tert-butyldimethylsilyl (TBDMS)
chloride and sodium iodide to yield the TBDMS ether io-
dide 2.4 Distillation provided clean iodide which was used
to alkylate the potassium salt of 3-hydroxypyridine 20 at
100 °C in DMF to produce the pyridinyl silyl ether 3. The
next step in the sequence was to remove the TBDMS
group of 3 to form the pyridinyl alcohol 4. Attempts to
carry out the deprotection with ferric chloride in acetoni-
trile gave no reaction.5 However, reaction with aqueous
1 M HCl in methanol quantitatively yielded the hydro-
chloride salt of the alcohol product 4 as a recrystallizable
solid. After being formed in situ, the free base alcohol was
oxidized, using hypochlorite/4-methoxy TEMPO in a bi-
phasic system, to the corresponding aldehyde 5.6
triphenylphosphine in refluxing toluene to form the phos-
phonium bromide (19). The dianion salt of the Wittig re-
agent (19) was formed and then reacted with the aldehyde
(7) to form the mixed alkene product 8. (The trans/cis ra-
tio was roughly determined to be 3/1, respectively, by re-
versed phase HPLC.)
The entire carbon skeleton was now assembled. In order
to complete the synthesis of the active ingredient, only a
hydrogenation and a hydrolysis remained. Our results dic-
tated that we should perform the hydrogenation first for
two key reasons; 1) performing the hydrogenation first al-
lows for the potential of telescoping the two steps, and 2)
the hydrogenation was complete faster on the unsaturated
ester than on the unsaturated acid. We decided to evaluate
two carbon supported catalysts, platinum and palladium,
for our hydrogenation study. Our chief concern was to
minimize the amount of dechlorination by hydrogenoly-
sis. Hydrogenation with platinum was successful and at
most 0.3% dechlorination occurred. Palladium hydroge-
nation, on the other hand, produced extensive dechlorina-
tion (25% after 30 minutes, 100% after 5 hours). Finally,
the active ingredient 10 was prepared with sodium hy-
droxide in methanol/water. Hence, to telescope these two
reactions, one could, upon completion of the hydrogena-
tion, simply filter off the catalyst and add the base to com-
plete the hydrolysis.
Our goal of discovering a convergent active ingredient
synthesis was achieved. We now concentrated on finding
a shorter path to the pyridine aldehyde 5. Four different
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770
A. T. Bach et al.
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Scheme 1
four-carbon alkylating agents were evaluated (see Scheme olane (14). Alkylation of 3-hydroxypyridine with this
2). An attempt to alkylate 3-hydroxypyridine with the moiety was also successful and yielded the pyridine acetal
first, 4-chlorobutan-1-ol, was unsuccessful under the usu- 15. The acetal was then cleanly opened to the aldehyde 5
al conditions (potassium t-amylate/DMF). Alkylation with 1 M HCl.9 With this latter route, we now had short-
with the next four-carbon halide, 4-bromobutyl acetate ened the path to 5 by two steps (as compared with the syn-
(11) was successful, and the pyridine acetate 12 was then thesis that started with tetrahydrofuran). An especially
hydrolyzed to the alcohol 13 with sodium hydroxide. The attractive feature was that 5 was formed very cleanly un-
alcohol was converted to the aldehyde 5 via the previously der acidic conditions. When 5 was formed under the basic
mentioned 4-methoxy TEMPO oxidation. The third four- conditions of the TEMPO oxidation, some decomposi-
carbon halide evaluated was 2-(3-chloropropyl)-1,3-diox- tion/side products were observed. The last of the four-car-
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PAPER
A Convergent Synthesis of CGS23305, A Thromboxane Synthase Inhibitor
771
Scheme 2
h at this temperature. The solution was allowed to cool to 25 °C and
quenched with sat. aq NH4Cl (250 mL). H2O (1030 mL) was added
and the aqueous layer extracted with EtOAc (2 x 730 mL). The
combined organic layers were washed with sat. NaHCO3 (580 mL),
10% K2CO3 (580 mL), H2O (580 mL) and then concentrated in vac-
uo to 36.85 g (82%) of 3 as a colorless oil (bp 116–120 °C at 0.7
torr).
bon halides evaluated was 2-(3-bromopropyl)-5,5-
dimethyl-1,3-dioxolane. Alkylation of 3-hydroxypyridine
was successful. The six-membered ring acetal, however,
could not be opened, even under stringent conditions
(30% hydrogen bromide/acetic acid).
In conclusion, we have discovered and developed a rather
short and relatively inexpensive synthesis of CGS23305
(10) which could be readily adapted for use in pilot plant
scale operations.
IR (neat): ν = 836, 1049, 1103, 1261, 1280 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.01 (s, 6H), 0.84 (s, 9H), 1.59
(m, 2H), 1.75 (m, 2H), 3.61 (t, J = 6.2 Hz, 2H), 4.02 (t, J = 6.4 Hz,
2H), 7.31 (m, 2H), 8.13 (dd, J = 1.5, 2.8 Hz, 1H), 8.25 (d, J = 2.5
Hz, 1H).
All reactions were carried out under N2. All solvents and reagents
were used as supplied by commercial sources. GC assays were per-
formed by an HP5890 Series II with an HP3396A integrator using
a DB-1 (J&W) Megabore column (TCD). TLC assays were per-
formed using Analtech Silica gel HLF plates. HPLC assays were
performed using a Waters 484 detector and a Waters C18 µbonda-
pak column. Purification by column chromatography was per-
13C NMR (75 MHz, DMSO-d6): δ = 17.9, 25.2, 25.7, 28.7, 62.2,
67.6, 120.7, 124.0, 137.8, 141.5, 154.8.
MS (DCI, NH3): m/z = 282 (M + H)+.
Anal. calcd C (64.01), H (9.67), N (4.98). Found C (63.91), H
(9.76), N (4.95).
1
formed on silica gel (230–400 mesh ASTM). H and 13C NMR
4-(Pyridin-3-yloxy)butan-1-ol hydrochloride (4)
spectra were recorded on a Bruker AM 300. Direct chemical ioniza-
tion (DCI) mass spectra were recorded on a Hewlett-Packard 5985B
mass spectrometer. Electrospray ionization (ESI) mass spectra were
obtained using a Micromass Platform II mass spectrometer. Melting
points were measured on an Mettler DSC 12 E apparatus. Boiling
points were determined using a short path distillation apparatus. El-
emental analyses were performed by Robertson Microlit Labs,
Madison, NJ.
To a flask containing 3 (20.73 g, 0.07 mol) was added MeOH (207
mL). The resulting colorless solution was cooled to 5 °C and 37.5%
HCl (5.0 mol equiv) was added over 10 minutes. The resulting col-
orless solution was stirred for 1 h and then was concentrated in vac-
uo to a solid which was recrystallized with MeCN to yield 14.90 g
(99%) of 4 as a white solid (mp 103.5–108.4 °C).
IR (KBr): ν = 812, 1038, 1053, 1282, 1620 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.52 (m, 2H), 1.75 (m, 2H),
3.42 (t, J = 6.4, 2H), 4.21 (t, J = 6.6 Hz, 2H), 7.97 (m, 1H), 8.20 (m,
1H), 8.50 (d, J = 5.3 Hz, 1H), 8.67 (d, J = 2.7 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 25.0, 28.6, 60.1, 69.7, 127.9,
128.9, 131.6, 133.9, 157.0.
3-[4-(tert-Butyl Dimethylsilyloxy)butoxy]pyridine (3)
To a solution of 3-hydroxypyridine (20) (30.26 g, 0.32 mol) in DMF
(500 mL) was added 25% potassium t-amylate in toluene (160.7 g,
0.32 mol) over 15 minutes. To this pale yellow solution was added
tert-butyl-(4-iodobutoxy)dimethylsilane (2), (50.0 g, 0.16 mol) in
DMF (500 mL). The solution was heated to 100 °C and stirred for 2
MS (ESI): m/z = 168 (M + H)+.
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A. T. Bach et al.
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Anal. calcd C (53.08), H (6.93), N (6.88). Found C (53.18), H
(6.97), N (6.79).
moved via vacuum distillation. After cooling to 25 °C, extracted
with CH2Cl2 (2 x 100 mL) and concentrated in vacuum. Flash chro-
matography (EtOAc) yielded 25.42 g (80%) of 7 as a pale yellow
oil (bp 156–158 °C at 0.7 torr). (Note: 7 should be stored in a refrig-
erator under N2 to prevent decomposition.)
4-(Pyridin-3-yloxy)butanal (5)
From Compound 4
IR (neat): ν = 1029, 1189, 1263, 1728, 2724 cm–1.
To a flask containing 4 (6.16 g, 0.03 mol) was added 1 M aq NaOH
(1.0 mol equiv). The resulting colorless solution was cooled to, and
held at < 5 °C. To this chilled solution was added 4-methoxy TEM-
PO (0.01 mol equiv) in CH2Cl2 (110 mL) followed by an 8 min
dropwise addition of a solution consisting of 5.7% NaOCl (1.25 mol
equiv), H2O (55 mL), NaHCO3 (1.00 mol eq), and KBr (0.1 mol
equiv). The resulting clear, pale yellow, biphasic mixture was
stirred for 0.5 h and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (55 mL). The combined organic layers
were washed with H2O (55 mL), brine (55 mL) and concentrated in
vacuo to 4.55 g (91%) of 5 as a clear, colorless oil (bp 103–105 °C
at 0.7 torr). (Note: 5 should be stored in a refrigerator under N2 to
prevent decomposition.)
1H NMR (300 MHz, DMSO-d6): δ = 1.14 (t, J = 7.1 Hz, 3H), 1.71
(m, 1H), 1.89 (m, 2H), 2.09 (m, 1H), 2.33 (m, 2H), 2.51 (m, 1H),
4.02 (m, 4H), 7.30 (m, 2H), 8.14 (dd, J = 1.9, 2.2 Hz, 1H), 8.22 (m,
1H), 9.60 (d, J = 1.9 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 14.0, 22.9, 27.5, 30.8, 47.5,
59.8, 65.6, 120.9, 124.1, 137.8, 141.8, 154.5, 172.4, 204.4.
MS (ESI): m/z = 266 (M + H)+.
Anal. calcd C (63.38), H (7.22), N (5.28). Found C (63.48), H
(7.15), N (5.27).
N-(3-Bromopropyl)-4-chlorobenzenesulfonamide (18)
To a mixture of 16 (150.00 g, 0.68 mol), 17 (144.68 g, 0.68 mol) and
4-DMAP (0.1 mol equiv) was added CH2Cl2 (1 L). To the resulting
yellow suspension was added Et3N (2 mol eq) in CH2Cl2 (0.5 L)
over 40 min. This mixture was stirred for 1 h, then H2O (0.5 L) was
added followed by sat. NaHCO3 (1.0 L). After stirring for 15 min
the two layers were separated and the aqueous layer was extracted
with CH2Cl2 (1.0 L). The combined organic layers were washed
with 1 M HCl (1 L), H2O (1 L) and then concentrated to 202.63 g
(95%) of 18 as a white solid (mp 57.3–59.2 °C, not reported in
literature10).
From Compound 13
To a flask containing 13 (50.00 g, 0.30 mol) was added 4-methoxy
TEMPO (0.01 mol equiv) in CH2Cl2 (1100 mL). The resulting very
pale red solution was cooled to, and held at < 5 °C. To this chilled
solution followed by a dropwise (8 minute) addition of a solution
consisting of 5.7% NaOCl (1.25 mol equiv), H2O (1600 mL),
NaHCO3 (1.00 mol equiv), NaCl (1.00 mol equiv), and KBr (0.1
mol equiv). The resulting clear, pale yellow biphasic mixture was
stirred for 0.5 h and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (1000 mL). The combined organic lay-
ers were washed with H2O (500 mL), brine (500 mL) and concen-
trated in vacuo to 44.95 g (91%) of 5 as a clear, colorless oil.
IR (KBr): ν = 832, 1158, 1327, 1588 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.89 (quintet, J = 6.6 Hz, 2H),
2.87 (dt, J = 6.1, 6.6 Hz, 2H), 3.48 (t, J = 6.5, 2H), 7.67 (m, 2H),
7.80 (m, 3H).
13C NMR (75 MHz, DMSO-d6): δ = 31.6, 32.2, 40.9, 128.5, 129.4,
137.3, 139.2.
From Compound 15
To a flask containing 15 (7.68 g, 0.037 mol) was added 1 M HCl
(0.074 mol) through an addition funnel over 10 min. While agitat-
ing, the mixture was heated to, and held at 60–65 °C for 2 h. Neu-
tralized to pH=7 with sat. NaHCO3, and extracted with CH2Cl2 (2 x
150 mL). The combined organics were washed with H2O (150 mL)
and brine (150 mL), The organic layer was concentrated in vacuo to
yield 5.67 g (94%) of 5 as a colorless oil.
MS (DCI, NH3): m/z = 314 (M + H)+.
Anal. calcd C (34.58), H (3.55), N (4.48). Found C (34.53), H
(3.65), N (4.54).
IR (neat): ν = 1054, 1265, 1278, 1724, 2727 cm–1.
[3-(4-Chlorobenzenesulfonylamino)propyl]triphenylphospho-
nium Bromide (19)
1H NMR (300 MHz, DMSO-d6): δ = 1.98 (m, J = 6.8 Hz, 2H), 2.60
(d, J = 6.1 Hz, 2H), 4.03 (t, J = 6.4 Hz, 2H), 7.32 (m, 2H), 8.15 (dd,
J = 1.5, 2.9 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 9.71 (s, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 21.5, 39.6, 67.1, 120.8, 124.1,
137.8, 141.7, 154.6, 202.7.
To a mixture of 18 (100.00 g, 0.32 mol) and PPh3 (83.90 g, 0.32
mol) was added toluene. The resulting pale yellow solution was
heated to reflux and stirred for 16 h. The white solids that precipi-
tated were filtered off after the reaction was allowed to cool to r.t.
The solids were washed and then dried in vacuum at 35 °C to yield
162.00 g (88%) of 19 as a white solid (mp 214.9–234.0 °C).
MS (ESI): m/z = 166 (M + H)+.
IR (KBr): ν = 760, 781, 828, 1095, 1158, 1333, 1584 cm–1.
Anal. calcd C (65.44), H (6.71), N (8.48). Found C (65.33), H
(6.65), N (8.50).
1H NMR (300 MHz, DMSO-d6): δ = 1.61 (m, 2H), 2.97 (m, 2H),
3.62 (m, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.77 (m, 14H), 7.89 (m, 3H),
8.02 (t, J = 5.8 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 17.8, 18.5, 22.3, 42.4, 42.7,
117.6, 118.7, 128.5, 129.4, 130.2, 130.4, 133.4, 133.5, 134.9, 135.0,
137.3, 139.2.
N,N-Diethyl-4-(pyridin-3-yloxy)but-1-en-1-amine (6)
To a solution of 5 (20.00 g, 0.12 mol), p-toluenesulfonic acid (0.01
mol equiv), and toluene (100 mL) was added N,N-diethyltrimethyl-
silylamine (3.0 mol equiv) over 12 min. After the resulting exo-
therm (22 –> 40 °C) subsided, the reaction was allowed to stir for 1
h. The toluene was exchanged with acetonitrile via azeotropic dis-
tillation and the final concentration yielded 6 as a orange oil which
was used in the next step without further purification.
MS (ESI): m/z = 494 (M + H)+.
Anal. calcd C (56.41), H (4.56), N (2.44). Found C (56.49), H
(4.57), N (2.39).
4-Formyl-6-(pyridin-3-yloxy)hexanoic Acid Ethyl Ester (7)
To 6 (0.12 mol) prepared as above, was added MeCN (50 mL). To
the resulting orange colored solution was added ethyl acrylate (6.0
mol equiv). It was then heated to reflux and held at reflux for 0.5 h.
Then H2O (77 mL) was added and the solution heated at reflux for
an additional 0.5 h. The MeCN and excess ethyl acrylate was re-
8-(4-Chlorophenylsulfonylamino)-4-[2-(pyridin-3-yloxy)eth-
yl]oct-5-anoic Acid Ethyl Ester (8)
To a stirred solution of 19 (28.17 g, 0.05 mol) in DMSO (141 mL)
was added 2.5 M butyllithium in hexanes (36.2 mL, 0.09 mol) over
5 min. The resulting red [exothermic (22–>40 °C)] mixture was
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A Convergent Synthesis of CGS23305, A Thromboxane Synthase Inhibitor
MS (ESI): m/z = 455 (M + H)+.
773
held at 40 °C for 5 min to complete the dianion formation. The mix-
ture was subsequently charged with 7 (10.00 g, 0.04 mol) over 5
min. After the slight exotherm (40–>45 °C) subsided, the hazy tan
mixture was allowed to stir at r.t. for 1 h and then cooled to 0 °C.
The reaction was quenched with cold (0 °C) sat. NH4Cl (100 mL)
followed by H2O (100 mL). The resulting white mixture was then
extracted with CH2Cl2 (2 x 100 mL). The combined CH2Cl2 layers
were dried (MgSO4) and then concentrated to a yellow residue.
Flash chromatography (4 EtOAc/1 heptane) yielded 13.23 g (73%)
of the mixed alkene (3:1 E:Z ratio, by HPLC) 8 as a yellow oil.
Anal. calcd C (55.44), H (5.98), N (6.16). Found C (55.49), H
(5.90), N (6.19).
Acetic Acid, 4-(Pyridin-3-yloxy)butyl Ester (12)
To a solution of 3-hydroxypyridine, 20, (146.27 g, 1.54 mol) in
DMF (1500 mL) was added 25% potassium t-amylate in toluene
(776.8 g, 1.54 mol) over 15 min. To this pale yellow solution was
added 4-bromobutyl acetate (150.0 g, 0.77 mol) in DMF (1500 mL).
The solution was heated to 100 °C and stirred for 2 h at this temper-
ature. The solution was allowed to cool to 25 °C and quenched with
sat. aq NH4Cl (750 mL). H2O (3100 mL) was added and the aqueous
layer was extracted with EtOAc (2 x 2200 mL). The combined or-
ganic layers were washed with sat. NaHCO3 (1750 mL), 10%
K2CO3 (1750 mL), H2O (1750 mL) and then concentrated in vacuo
to 177.04 g (82%) of 12 as a colorless oil (bp 138–142 °C at 0.7
torr).
IR (neat): ν = 707, 754, 1095, 1161, 1280, 1333, 1730 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.14 (t, J = 7.0 Hz, 3H), 1.5–
1.9 (m, 5H), 2.0–2.2 (m, 4H), 2.7 (m, 2H), 4.0 (m, 4H), 5.1–5.4 (m,
2H), 7.3 (m, 2H), 7.6–7.8 (m, 5H), 8.1 (m, 1H), 8.3 (m, 1H).
13C NMR (75 MHz, DMSO-d6): E-isomer: δ = 14.1, 29.5, 31.5,
32.2, 33.6, 38.7, 42.6, 59.7, 65.9, 120.8, 124.1, 127.8, 128.4, 129.3,
134.7, 137.2, 137.9, 139.5, 141.6, 154.8, 172.9.
IR (neat): ν = 804, 1049, 1230, 1737 cm–1.
Z-isomer: δ = 14.1, 27.4, 30.0, 31.5, 32.9, 33.9, 42.5, 59.7, 65.8,
120.8, 124.1, 127.5, 128.4, 129.3, 134.1, 137.2, 137.8, 139.4, 141.6,
154.7, 172.8.
MS (ESI): m/z = 481 (M + H)+.
1H NMR (300 MHz, DMSO-d6): δ = 1.75 (m, 4H), 1.99 (s, 3H),
4.04 (m, 4H), 7.32 (m, 2H), 8.14 (dd, J = 1.5, 3.0 Hz, 1H), 8.27 (d,
J = 2.5 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 20.6, 24.8, 25.2, 63.5, 67.3,
120.8, 124.1, 137.8, 141.6, 154.8, 170.4.
Anal. calcd C (57.43), H (6.08), N (5.82). Found C (57.49), H
(6.05), N (5.89).
MS (ESI): m/z = 210 (M + H)+.
Ethyl 8-{[(4-Chlorophenyl)sulfonyl]amino}-4-[2-(pyridin-3-yl-
oxy)ethyl]octanoate (9)
Anal. calcd C (63.14), H (7.23), N (6.69). Found C (63.17), H
(7.19), N (6.61).
Compound 8 (2.00g, 4.2 mmol) was hydrogenated in EtOH (40 mL)
with 5% Pt/C (10.0 wt % of 8) at r.t. for 2 h at 40 psi. The platinum
catalyst was filtered off and the filtrate was concentrated in vacuum
to yield 1.95 g (97%) of 9 as a yellow oil.
4-(Pyridin-3-yloxy)butan-1-ol (13)
To a solution of 1 M aq NaOH (1066.0 mL, 3.0 mol equiv) was add-
ed dropwise 12 (100.00 g, 0.48 mol) in MeOH (1066 mL) over 45
min. The reaction was complete upon the end of the addition. Con-
centrated off the MeOH and extracted the remaining aqueous layer
with CH2Cl2 (3000 mL). The organic layer was washed with H2O
(2000 mL) and brine (2000 mL) and concentrated in vacuo to 59.00
g (99%) of 13 as a colorless oil (bp 128–131 °C at 0.7 torr).
IR (neat): ν = 1095, 1163, 1281, 1332, 1731 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.15 (m, 7H), 1.33 (br s, 2H),
1.52 (m, 3H), 1.62 (m, 2H), 2.25 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8
Hz, 2H), 4.01 (m, 4H), 7.33 (m, 2H), 7.65 (m, 3H), 7.78 (m, 2H),
8.14 (m, 1H), 8.25 (d, J = 2.4 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 14.1, 22.8, 28.0, 29.2, 30.8,
31.9, 32.1, 33.4, 42.5, 59.7, 66.0, 120.8, 124.1, 128.4, 129.3, 137.1,
137.8, 139.5, 141.6, 154.8, 173.0.
IR (neat): ν = 712, 1055, 1237, 1283 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.56 (m, 2H), 1.75 (m, 2H),
3.45 (t, J = 6.4, 2H), 4.02 (t, J = 6.5 Hz, 2H), 4.49 (brs, 1H), 7.30
(m, 2H), 8.14 (dd, J = 1.4, 3.0 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 25.3, 28.9, 60.4, 67.7, 120.8,
124.1, 137.8, 141.5, 154.9.
MS (ESI): m/z = 483 (M + H)+.
Anal. calcd C (55.69), H (5.56), N (6.18). Found C (55.59), H
(5.57), N (6.19).
MS (ESI): m/z = 168 (M + H)+.
8-(4-Chlorophenylsulfonylamino)-4-[2-(pyridin-3-yloxy)ethyl]-
oct-5-anoic Acid (10)
Anal. calcd C (64.65), H (7.84), N (8.38). Found C (64.68), H
(7.97), N (8.39).
To a flask containing compound 9 (1.50 g, 3.1 mmol) was added
EtOH (30 mL). To the resulting pale yellow solution was added
1 M NaOH (1.05 mol. equiv). Let the resulting mixture stir at reflux
for 18 h then concentrated the reaction to a yellow residue. To the
residue was added H2O (20 mL), HOAc (1.05 mol. equiv), and
CH2Cl2 (20 mL) and then separated the resulting biphasic mixture.
The aqueous layer was extracted with CH2Cl2 (20 mL). The com-
bined organic layers were dried (MgSO4) and then concentrated, in
vacuo, to afford a semi-solid which was recrystallized with MeCN
to yield 1.34 g (95%) of 10 as a white solid (mp 81.9–87.6 °C).
3-(3-[1,3]-Dioxolan-2-yl-propoxy)pyridine (15)
To a solution of 3-hydroxypyridine (20) (6.31 g, 0.066 mol) in DMF
(50 mL) was added 25% potassium t-amylate in toluene (33.5 g,
0.066 mol) over 5 minutes. To this pale yellow solution was added
2-(3-chloropropyl)-1,3-dioxolane (5.00 g, 0.033 mol) in DMF (50
mL). The solution was heated to 100 °C and stirred for 2 h at this
temperature. The solution was allowed to cool to 25 °C and
quenched with sat. aq NH4Cl (25 mL). Added water (310 mL) and
extracted the aqueous layer with EtOAc (2 x 220 mL). The com-
bined organic layers were washed with sat. NaHCO3 (175 mL), 10%
K2CO3 (175 mL), H2O (175 mL) and then concentrated in vacuo to
yield 5.96 g (86%) of 15 as a colorless oil (bp 103–105 °C at 0.7
torr).
IR (KBr): ν = 1163, 1274, 1334, 1591, 1710 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.17 (br s, 4H), 1.31 (br s, 2H),
1.48 (m, 3H), 1.61 (m, 2H), 2.16 (t, J = 7.2 Hz, 2H), 2.72 (m, 2H),
4.00 (t, J = 6.5 Hz, 2H), 7.32 (m, 2H), 7.65 (m, 3H), 7.77 (m, 2H),
8.12 (m, 1H), 8.24 (d, J = 2.4 Hz, 1H).
IR (neat): ν = 708, 803, 1054, 1146, 1264, 1279 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.76 (m, 4H), 3.82 (m, 4H),
4.04 (t, J = 6.2 Hz, 2H), 4.84 (t, J = 4.4 Hz, 1H), 7.33 (m, 2 H), 8.14
(dd, J = 1.5, 2.9 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): δ = 22.8, 28.0, 29.2, 30.9, 32.0,
32.1, 33.5, 42.5, 66.0, 120.9, 124.1, 128.4, 129.3, 137.1, 137.8,
139.5, 141.5, 154.8, 174.7.
Synthesis 1999, No. 5, 769–774 ISSN 0039-7881 © Thieme Stuttgart · New York

774
A. T. Bach et al.
PAPER
13C NMR (75 MHz, DMSO-d6): δ = 23.3, 29.7, 64.3, 67.5, 103.3,
120.8, 124.1, 137.8, 141.6, 154.8.
References
(1) Currently at Bachem, 3132 Kashiwa Street, Torrance, CA,
90505.
MS (ESI): m/z = 210 (M + H)+.
(2) Formerly known as CIBA-Geigy Pharmaceuticals Corporati-
on.
Anal. calcd C (63.14), H (7.23), N (6.69). Found C (63.12), H
(7.20), N (6.64).
(3) Bhagwat, S.; Gude, C.; Cohen, D.; Dotson, R.; Mathis, J.; Lee,
W.; Furness, P. J. Med. Chem. 1992, 35, 205.
(4) Nystrom, J. E.; McCanna, T. D.; Helquist, P.; Amouroux, R.
Synthesis 1988, 56.
(5) Dalla Cort, A. Synthetic Communications 1990, 20(5), 757.
(6) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559.
(7) Comi, R.; Franck, R. W.; Reitano, M.; Weinreb, S. M. Tetra-
hedron Lett. 1973, 3107.
(8) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.
(9) Della Ciana, L.; Hamachi, I.; Meyer, T. J. J. Org. Chem. 1989,
54, 1731.
Acknowledgement
We would like to express our thanks to Mr. David Parker and Dr.
Kevin Kunnen for supplying compound 2, and to Dr. Wen-Chung
Shieh for supplying the 3-hydroxypyridine alkylation procedure.
We would also like to express our thanks to Dr. Leonard Hargiss
and to Mr. James Munson for performing the mass spectroscopy as-
says and to Ms. Jennifer Van Savage for performing the infrared
spectroscopy assays.
(10) Jpn. Kokai Tokkyo Koho JP 06,312,973 [94,312,973], 1996;
Chem. Abstr. 1996, 122, 213758c.
Article Identifier:
1437-210X,E;1999,0,05,0769,0774,ftx,en;C07198SS.pdf
Synthesis 1999, No. 5, 769–774 ISSN 0039-7881 © Thieme Stuttgart · New York