Improved syntheses of 5-hydroxy-2-pyridones (2,5-dihydroxypyridines)

Article abstract of DOI:10.1080/00397910701865819

Improved syntheses of 5-hydroxy-2-pyridone, 6-chloro-5-hydroxy-2-pyridone, 2,4-dihydroxynicotinic acid, and three methyl-substituted 5-hydroxy-2-pyridones are reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701865819

This article was downloaded by: [University of Illinois Chicago]
On: 22 October 2014, At: 17:12
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Improved Syntheses of
5‐Hydroxy‐2‐Pyridones
(2,5‐Dihydroxypyridines)
E. J. Behrman a
a Department of Biochemistry , Ohio State University , Columbus, Ohio, USA
Published online: 17 Apr 2008.
To cite this article: E. J. Behrman (2008) Improved Syntheses of 5‐Hydroxy‐2‐Pyridones
(2,5‐Dihydroxypyridines), Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:8, 1168-1175, DOI: 10.1080/00397910701865819
To link to this article: http://dx.doi.org/10.1080/00397910701865819
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 38: 1168–1175, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701865819
Improved Syntheses of 5-Hydroxy-2-
Pyridones (2,5-Dihydroxypyridines)
E. J. Behrman
Department of Biochemistry, Ohio State University, Columbus,
Ohio, USA
Abstract: Improved syntheses of 5-hydroxy-2-pyridone, 6-chloro-5-hydroxy-2-
pyridone, 2,5-dihydroxynicotinic acid, and three methyl-substituted 5-hydroxy-2-
pyridones are reported.
Keywords: Elbs oxidation, peroxydisulfate, 2,5-dihydroxypyridines, 5-hydroxy-2-
pyridones
The procedure described here for the synthesis of 5-hydroxy-2-pyridone by an
Elbs oxidation of 2-pyridone (Fig. 1) has improvements over previous
syntheses by this route, which include a higher yield, omission of unnecessary
iron salts, a reproducible melting point, and, particularly, a detailed descrip-
tion in the style of Organic Syntheses.
Two reports[1,2] of the synthesis of 5-hydroxy-2-pyridone actually give
the 2,3-isomer.[3] Adams and Govindachari[4] were the first to synthesize
the 2,5-isomer in 1947. Two other routes were reported in 1950 and
1959.[5,6] All three are multistep, low-yielding procedures. A much simpler
approach was reported by Behrman and Pitt in 1958[7] by application of the
Elbs peroxydisulfate oxidation to 2-pyridone. Improvements to this
[8]
¨
procedure were made by Mohrle and Weber in 1970. The intermediate
sulfate ester has also been isolated.[9] The Elbs oxidation has been
reviewed.[10,11] 5-Hydroxy-2-pyridone is an intermediate in the bacterial
metabolism of a number of pyridine derivatives including nicotinic acid.[12]
Received in the USA November 6, 2007
Address correspondence to E. J. Behrman, Department of Biochemistry, The Ohio
State University, Columbus, Ohio 43210, USA. E-mail: behrman.1@osu.edu
1168

5-Hydroxy-2-Pyridones
1169
Figure 1. Synthesis of 2,5-dihydroxypyridines.
It has been linked with damage to DNA[13]and shows activity as an antitumor
agent.[14]
The syntheses of five other 5-hydroxy-2-pyridones are also described.
The methodology for each varies according to the solubility properties
of the 2-pyridones used as starting materials and the products.
2,5-Dihydroxy-6-chloropyridine is a new compound, whereas 2,5-dihydroxy-
nicotinic acid[15,16] and three methyl-substituted 2,5-dihydroxypyridines
(3-methyl-,[17] 4-methyl-,[17] 6-methyl-[17,18]) have been reported but with
few details of the syntheses or properties.
Crystals of the 6-substituted 2,5-dihydroxypyridines exhibit an unex-
pected property that we have explored so far in greatest detail with the
6-chloro compound. Combustion analysis showed the presence of one
molecule of chloroform (used for crystallization) per eight molecules of the
pyridine. The chloroform was also seen in the NMR and IR spectra. It
could not be removed by heating in vacuo at 60 8C. Vacuum sublimation
gave chloroform-free material. Preliminary X-ray crystallographic data
show the presence of channels within the crystal that contain disordered
molecules of chloroform.[19] NMR data for the 6-methyl compound suggest
similar stoichiometry for crystals containing acetone or 2-propanol. This is
an unusual finding that will be published separately.
EXPERIMENTAL
General Procedures
The 2-pyridones were bought from Alfa-Aesar and used as supplied.
UV-visible spectra were taken on a Shimadzu Bio-mini with a resolution of
about 2 nm in 5 Â 1024 M HCl. IR spectra were recorded in Nujol mulls on
a Nicolet Impact 410 single-beam instrument. Melting points were determined
in evacuated capillaries or under nitrogen.
5-Hydroxy-2-pyridone
2-Pyridone (14.6 g, 0.15 mol) and NaOH (16.9 g, 0.42 mol) are dissolved in
300 mL of water in a 1-L Erlenmyer flask equipped with a magnetic stirring
bar and stoppered to keep out CO2. Ice (200 g) is added to cool the solution

1170
E. J. Behrman
to about 5 8C, and then potassium peroxydisulfate (40.5 g, 0.15 mol) is added.
The flask is placed in an empty ice bucket, and the mixture is stirred. Room
temperature (23–25 8C) is reached in about 3 h. At this point, room-tempera-
ture water (500 mL) is added to the ice bucket to serve as a heat sink. The per-
oxydisulfate dissolves completely in about 2.5 h more. The homogeneous
reaction mixture is allowed to stand at rt for 20 h. The clear orange solution
is treated with conc. sulfuric acid (15 mL, 0.285 mol, 0.57 equiv), which is
added all at once with stirring. A few boiling chips are added, and then the
solution is boiled gently on a hot plate under a nitrogen atmosphere for 1 h.
There is no need to reflux. The solution turns from orange to brown, and
the volume is reduced by about 100 mL. The solution is cooled to about
15 8C in an ice-water bath. A solution made by dissolving 40 g of NaOH in
100 mL of water is added in 5- to 10-mL portions with stirring under
nitrogen such that the internal temperature stays colder than 20 8C to bring
the solution to pH 6. The pKa of the product is 8[20] (formation of the
anion). The estimated pKa for formation of the cation is 0.4.
The last few mL of the NaOH solution are added 1 mL at a time so as to
avoid exceeding pH 6. The total volume of NaOH added is about 50 mL
(0.45 mol). Most of the water is removed from the neutral solution in two
portions to form a damp solid using a rotary evaporator (ca. 23 mmHg) at
45 8C in a 1-L round-bottomed flask. Absolute ethanol (50 mL) is added
and then removed on the rotary evaporator. This procedure is repeated with
another 50 mL of ethanol. Note: if the salt cake is dried too thoroughly, it is
difficult to remove from the flask. The damp salt cake is removed from the
flask using appropriately bent spatulas, spread out in a thin layer in a pie
plate, and allowed to air dry overnight at rt. The dry chocolate-brown salt
cake weighing about 100 g is powdered in a mortar, placed in a 32-
cm-diameter Whatman No. 1 circular filter paper, and then extracted in a
Soxhlet apparatus with chloroform (250 mL in a 500-mL round-bottomed
flask; the chloroform contained 0.75% ethanol) for 8 h. The Soxhlet
apparatus used for this step and subsequent extractions had a 55/50 upper
female joint and a 24/40 lower male joint. The joints should be greased
lightly. The working volume of the chamber was about 180 mL. Note that it
is impractical to try to remove all of the 2-pyridone in this way as even
45 h was insufficient.
Heating is carried out at such a rate that one cycle of the extraction takes
about 12–13 min. This process removes about 90% of excess 2-pyridone
(4.5 g) and all of the by-product, 3-hydroxy-2-pyridone (0.5 g) (1H NMR).
The extracted salt cake is removed from the Soxhlet apparatus and allowed
to air dry overnight. The salt cake is re-extracted for 24 h with 2-propanol
(250 mL in a 500-mL round-bottomed flask) in the Soxhlet apparatus under
nitrogen saturated with 2-propanol using a gas-washing bottle equipped
with a coarse frit. Nitrogen is introduced via a 5-in. piece of glass tubing
inserted into the top of the condenser. The contents of the flask are cooled
and allowed to stand at 5 8C overnight in a refrigerator.

5-Hydroxy-2-Pyridones
1171
The solids are filtered on a Bu¨chner funnel and the mother liquors saved.
The solids are washed (3 Â 10 mL) with cold methanol (220 8C), which
removes dark-colored material without dissolving appreciable amounts of
product. This process yields 4.2–4.9 g of crude product as a brown powder
of about 95% purity. The impurity is largely 2-pyridone (1H NMR). The
salt cake is re-extracted in the Soxhlet apparatus with fresh 2-propanol
(250 mL) for another 24 h. This extract is combined with the mother liquors
from the first Soxhlet extraction and taken to dryness on a rotary evaporator
at 45 8C. The flask and its contents are cooled to 220 8C. The solids are
swirled with 12–15 mL of cold methanol. The suspended solids are filtered
on a Bu¨chner funnel and washed with cold methanol.
This yields an additional 2.2–2.7 g of crude product as a pinkish-brown
powder of about 90% purity. The overall yield allowing for impurities is
6.4 g (38%). The corrected yield allowing for the recovered starting
material is 56%.
Crystallization is performed from 95% ethanol. Six g of 95% purity
material are combined with 2 g of 90% purity product. This mixture is
dissolved in 700 mL of boiling 95% ethanol, Norite (1 g) is added, and the
solution is filtered by gravity. The solution is slowly cooled to rt under
nitrogen and then stored in a refrigerator overnight. The crystals are filtered
on a Bu¨chner funnel, washed with 5–10 mL of cold ethanol, and allowed to
air dry. The yield is 3.2 g of a reddish-tan material.
The volume of the mother liquors is reduced to about 300 mL by boiling
in a l-L Erlenmyer on a hot plate while a slow stream of nitrogen is bubbled
through the solution. Approximately 0.5 g of Norite is added to the boiling
ethanol, which is filtered by gravity. The solution is slowly cooled to rt
under nitrogen and then stored in a refrigerator overnight, which provides
an additional crop of solid (0.6 g). Reduction of the mother liquors from the
second crystallization to 100 mL, addition of 0.2 g of Norite, filtration, and
cooling in a refrigerator gives a third crop of solid (approximately 1 g). The
three crystallizations (all of the same purity) provide a total of 4.8 g (60%)
1
of better than 98% purity as judged by H NMR and UV spectroscopy. A
second crystallization gives almost colorless material. These crystals are
stable in air at rt for at least 50 years.
An alternative method of purification is fractional sublimation. Sublima-
tion at 0.05 mm Hg is first carried out at 100 8C to remove 2-pyridone and then
at a higher temperature to sublime the product. A 0.5-g sample of 95% purity
is finely ground and placed in a 40-mL Dailey sublimation apparatus available
from Safety Emporium, Lexington, KY; the manufacturer is ChemGlass. Sub-
limation for 3 h at 100 8C gives a small white sublimate of 2-pyridone. This is
removed, and then the residue is sublimed for 2.5 h while the temperature is
gradually raised to 190 8C. The sublimate is a reddish powder that weighs
0.45 g and is about 98% pure. About 20 mg of dark material remains in the
apparatus. Several previous reports have used sublimation for purifi-
cation.[4,5,8] Tipson[21] provides a good discussion of the subject.

1172
E. J. Behrman
Physical Properties of 5-Hydroxy-2-pyridone
The literature reports of the melting behavior are not in good agreement with
each other except that discoloration is reported and the decomposition point is
reported over a wide range. If the melting point is taken in an evacuated
capillary, little darkening occurs and a sharp melting point is observed:
261–263 8C.
IR (Nujol): 1671, 1625, 1556, 1310, 1293, 1245, 1002, 945, 842, 826,
798 cm21. Additional bands appear in a halocarbon mull: 3276, 3250, 3083,
2913, 2825, 2768, 2701, and 1448 cm21. These data are in accord with the
spectrum shown in ref. [4] and in the Sadtler catalogue, no. 15057 (KBr).
1H NMR (600 MHz, DMSO-d6) d: 6.30 (d, J ¼ 9.4, H-3); 6.96 (d, J ¼ 3,
H-6); 7.16 (dd, J ¼ 9.4, 3, H-4); 8.78 (s, OH); 10.76 (br, NH). 13C NMR (151
MHz, DMSO-d6) d: 159.3 (C-2), 141.2 (C-5), 133.5 (C-4), 121.0 (C-6), 117.7
(C-3). These data are in accord with those given by Hunt et al.[18] UV:
(5 Â 1024
M HCl), lmax 230, 320 nm. 1: 6800 + 200, 5350 +
150 M21 cm21. These data are in accord with those of Refs. [5] and [7].
The UV spectrum is a convenient way to assay the purity of a sample quanti-
tatively; 2-pyridone has no appreciable absorption at 320 nm but absorbs
strongly at 230 nm (lmax 224, 294 nm). FeCl3 complex: lmax 510 nm. Anal.
calcd. for C5H5NO2: C, 54.05; H, 4.54; N, 12.61. Found (first crystallization
from ethanol): C, 53.68; H, 4.36; N, 12.37; (second crystallization): C,
54.11; H, 4.70; N, 12.40.
General Procedures for the Substituted Pyridones
Reactions of the pyridones with peroxydisulfate and hydrolysis of the sulfate
esters are all carried out in the same way as described for the parent compound
but on a scale of 0.01 to 0.05 mol.
5-Hydroxy-6-chloro-2-pyridone
Unreacted starting material (6-chloro-2-pyridone, ca. 30%) is removed by
extraction of the neutralized hydrolysate with chloroform. The extracted
solution is dried by rotary evaporation. The dried salt cake is extracted in a
Soxhlet apparatus with chloroform for 7 h with a cycle time of 9 min. Evap-
oration of the solvent yields the crude product in 30–40% yield (60–70%
allowing for recovered starting material). The material crystallizes from
chloroform or 1,2-dichloroethane. The data are for the crystals from
chloroform.
Mp (under nitrogen): 151–152 8C dec. IR: 3312, 1668, 1605, 1494, 1326,
1284, 1241, 1210, 1183, 1086, 913, 812, 756 (CHCl3), 692 cm21. UV: 1, l
max: 5700, 301 nm; 5500, 222 nm; sh. 340. FeCl3 complex: l max,
511 nm, sh. 545. The ortho isomer has lmax at 614 nm. NMR (DMSO-d6,

5-Hydroxy-2-Pyridones
1173
600 MHz): d 10.53 (s, NH); 9.65 (s, OH), 7.24 (d, H4, J ¼ 8.5 Hz), 6.48
.
(d, H3, J ¼ 8.5 Hz). CHCl3 at 8.30. Anal. calcd. for C5H4ClNO2 0.125
CHCl3: C, 38.36; H, 2.59; N, 8.73. Found: C, 38.47; H, 2.63; N, 8.63.
5-Hydroxy-6-methyl-2-pyridone
Unreacted starting material (6-methyl-2-pyridone) is removed by extraction of
the neutralized hydrolysate with chloroform. The extracted solution is dried
and then extracted in an Soxhlet apparatus with chloroform for 5 h to yield
a small quantity of 3-hydroxy-6-methyl-2-pyridone (blue color with ferric
chloride, lmax ¼ 590 nm). The remaining dry salt cake is extracted with
2-propanol for 3 h to yield about 60% of crude product. The material crystal-
lizes from ethanol–acetone mixtures or from 2-propanol. The data are for the
material crystallized from ethanol–acetone.
Mp (under nitrogen): 260–262 8C dec. IR: 3260, 1709 (acetone), 1657,
1626, 1541, 1453, 1380, 1316, 1264, 1232, 1173, 940, 827, 788 cm21
.
UV: 1, lmax: 7050, 322 nm; 6650, 229 nm. FeCl3 complex: lmax, 500 nm.
NMR (DMSO-d6, 600 MHz): d 10.95 (NH); 8.40 (OH); 7.10 (d, H-4,
J ¼ 9.3 Hz); 6.07 (d, H-3, J ¼ 9.3 Hz), 2.08 (Me). Acetone at 2.09.
5-Hydroxy-4-methyl-2-pyridone
The crude product crystallizes directly from the neutralized hydrolysate in
about 60% yield. Recrystallization from water with Norite gives almost
colorless crystals. Mp (under nitrogen): 255–260 8C (dec. without melting).
IR: 3486, 1670, 1623, 1312, 1243, 1007, 948, 937, 867, 833, 796 cm21
.
UV: 1, lmax: 5190, 309 nm; sh. 227. FeCl3 complex lmax: 507 nm. NMR
(DMSO-d6, 800 MHz): d 10.7 (NH); 8.68 (OH); 6.82 (H-6); 6.16 (H-3);
2.03 (Me).
5-Hydroxy-3-methyl-2-pyridone
The neutralized hydrolysate is dried and then extracted in the Soxhlet with
chloroform to remove starting material (3-methyl-2-pyridone). The salt cake
is redried and reextracted in the Soxhlet with 2-propanol. Removal of the
solvent gives the crude product in about 50% yield as a pink powder. It can
be crystallized, but in poor yield, from 2-propanol. A better procedure is to
precipitate it as a powder from a 2-propanol solution by the addition of
benzene. This yields material of better than 95% purity.
Mp (under nitrogen): 223–225 8C (dec.). IR: 3070, 1666, 1623, 1570,
1431, 1384, 1367, 1278, 1202, 1010, 821, 710 cm21. UV: 1, lmax: 5725,
315 nm; 5200, 230 nm. FeCl3 complex: lmax, 532, 503 nm.
NMR (DMSO-d6, 800 MHz): d 10.96 (NH); 8.60 (OH); 7.05 (d, H-4,
J ¼ 1.7 Hz); 6.68 (d, H-6, J ¼ 2.2 Hz); 1.94 (Me).

1174
E. J. Behrman
Potassium 2-Hydroxynicotinic Acid 5-Sulfate and 2,5-
Dihydroxynicotinic Acid
The reaction is carried out as described in Ref. [15] except that ferrous sulfate
is omitted. The precipitate that forms upon acidification contains product,
inorganic salts, and the starting material, 2-hydroxynicotinic acid. Soxhlet
extraction of the dried precipitate with acetone removes 2-hydroxynicotinic
acid. The residue is then dissolved in hot water, filtered, and cooled to yield
the potassium salt of the sulfate ester in about 30% yield (60% allowing for
recovered starting material).
Mp 293–296 8C (dec.), lit.[15] 292 8C. IR: 1732, 1646, 1604, 1557, 1448,
1402, 1291, 1254, 1062, 956, 905, 856, 805, 763, 736, 717, 644 cm21. UV: 1,
lmax: 4400, 333 nm; 4700, 236 nm. FeCl3 complex lmax 400 nm (sh). NMR
(DMSO-d6, 600 MHz): d 15.06 (COOH), 13.33 (NH), 8.27 (H-4, J ¼ 3 Hz),
7.78 (H-6, J ¼ 3 Hz).
Hydrolysis of the sulfate ester in boiling 5% sulfuric acid for 30 min,
decolorization with Norite, and cooling gives 2,5-dihydroxynicotinic acid
hemihydrate in moderate yield.
Mp 294–295 8C (dec.), lit. 306–308 8C[15]; 198–200 8C.[16] IR: 3386,
1713, 1605, 1551, 1416, 1208, 1078, 913, 840, 803, 607 cm21. UV: 1,
lmax: 6930, 355nm; 6680, 238nm. FeCl3 complex lmax: 441 nm. NMR
(DMSO-d6, 600 MHz): d 15.57 (COOH), 13.10 (NH), 9.68 (OH), 8.03
(H-4, J ¼ 3.1 Hz), 7.42 (H-6, J ¼ 3.1 Hz).
ACKNOWLEDGEMENT
I thank A. Gunadi for carrying out a number of the reactions.
REFERENCES
¨
1. Kudernatsch, R. Uber die directe Einfu¨hrung von Hydroxyl in das b-Oxypyridin.
Monatsh. Chem. 1897, 18, 613–628.
2. Aso, K. Formation of 2,5-dihydroxypyridine by the action of hydroxylamine on 2-
furaldehyde. Rikagaku Kenkyusho Iho [Bull. Inst. Phys. Chem. Res. (Tokyo)] 1939,
18, 177–179.
3. Schickh, O. V.; Binz, A.; Schulz, A. Derivate des 3-amino-pyridins. Ber. Dtsch.
Chem. Ges. 1936, 69, 2593–2605.
4. Adams, R.; Govindachari, T. R. The structure of leucenol. III. J. Am. Chem. Soc.
1947, 69, 1806–1808.
5. Den Hertog, H. J.; Wibaut, J. P.; Schepman, F. R.; Van Der Wal, A. The
dihydroxy- and diethoxypyridines. Rec. Trav. Chim. Pays-Bas 1950, 69, 700–710.
6. Moore, J. A.; Marascia, F. J. Heterocyclic studies. VII. J. Am. Chem. Soc. 1959, 81,
6049–6056.

5-Hydroxy-2-Pyridones
1175
7. Behrman, E. J.; Pitt, B. M. The elbs peroxydisulfate oxidation in the pyridine
series. J. Am. Chem. Soc. 1958, 80, 3717–3718.
¨
8. Mohrle, H.; Weber, H. Zur Kentnis der 1-methyl-3-hydroxypyridone-(2) und -(6).
Tetrahedron 1970, 26, 3779–3785.
9. Nantka-Namirski, P.; Rykowski, A. Dwupirydyle. Acta Polon. Pharm. 1974, 31,
433–438.
10. Behrman, E. J. The persulfate oxidation of phenols and arylamines. Org. React.
1988, 35, 421–511.
11. Behrman, E. J. The elbs and boyland-sims peroxydisulfate oxidations. Beilstein
J. Org. Chem. 2006, 2, 22.
12. (a) Fetzner, S.; Tshisuaka, B.; Lingens, F.; Kappl, R.; Hu¨ttermann, J. Bacterial
degradation of quinoline and drivatives. Angew. Chem. Int. Ed. 1998, 37,
576–597; (b) Kaiser, J.-P.; Feng, Y.; Bollag, J.-M. Microbial metabolism of
pyridine, quinoline, acridine, and their derivatives. Microbiol. Rev. 1996, 60,
483–498.
13. Kim, S. G.; Novak, R. F. Role of P450IIE1 in the metabolism of 3-hydroxypyri-
dine. Cancer Res. 1990, 50, 5333–5339.
14. Hwang, D. R.; Driscoll, J. S. Pyridones as potential antitumor agents. J. Pharm.
Sci. 1979, 68, 816–819.
15. Nantka-Namirski, P.; Rykowski, A. Synthesis of 2,5-dihydroxynicotinic acid. Acta
Polon. Pharm. (Eng. Trans.) 1972, 29, 129–134.
16. Guarneri, M.; Fiorini, F. Su alcuni derivati aminici e ossidrilici dell’acido nicoti-
nico. Ann. Chim. (Rome) 1961, 51, 1187–1193.
17. Ashworth, P. Electron spin resonance studies of azasemiquinones. Tetrahedron
1976, 32, 261–267.
18. Hunt, A. H.; Mynderse, J. S.; Samlaska, S. K.; Fukuda, D. S.; Maciak, G. M.;
Kirst, H. A.; Occolowitz, J. L.; Swartzendruber, J. K.; Jones, N. D. Stucture eluci-
dation of A58365A and A58365B. J. Antibiotics 1988, 41, 771–779.
19. Parkin, S. Personal communication, 2007.
20. Albert, A. Ionization constants of heterocyclic substances. Part IV. J. Chem. Soc.
1960, 1020–1023.
21. Tipson, R. S. Sublimation. In Technique of Organic Chemistry; Weissberger, A.,
Ed.; Interscience: New York, 1951; Vol. 4, Chapter 7.