[Contribution
from
Pharmaceutical
the
Institute, University
of
Tokyo]
RECENT JAPANESE WORK ON THE CHEMISTRY OF PYRIDINE 1-OXIDE AND RELATED COMPOUNDS1 EIJI OCHIAI Received October 22, 1952
The introduction of substituents into pyridine rings has long been a difficult problem. The principal reason is that pyridine, because of the polar effect of the hetero nitrogen atom, is very resistant to substitution by means of electrophilic reagents. The nitration of pyridine was long thought to be impossible; not until 1912 did Friedl (1) show that it could be performed, and then only at high temperatures (over 300°). 3-Nitropyridine is produced in poor yield, not more than 15 or 20 % in spite of many efforts to find better conditions for the reaction (2-5). In pyridine homologs, it was observed that methyl groups in the a and y positions activated the introduction of nitro groups, just as in benzene homologs. Thus Plazek (6) found that, in nitration with potassium nitrate in fuming sulfuric acid, 2,6-lutidine and 2,4,6-collidine give 3-nitro derivatives in good yield, while -picoline remains difficult to nitrate. The preparation of 2-aminopyridine by Tschitschibabin (7) helped to remove this barrier to progress in pyridine chemistry. This discovery opened a new route to the preparation of a- and /3-substituted pyridines (8), but the preparation of -substituted pyridines remained, in spite of some improvements, rather difficult. For example, Koenigs (9) prepared 4-hydroxy- and 4-amino-pyridine by hydrolysis or ammonolysis of 4-pyridylpyridinium chloride, which can be prepared by the action of thionyl chloride on pyridine. In this process, at least half of the pyridine is consumed in formation of glutacondialdehyde. Bobranski (10) obtained 4-chloropyridine by the action of sulfuryl chloride on pyridine 1-oxide. The yield of 4-chloropyridine was only 43%, and it was diffcult to separate from 2-chloropyridine, the principal product of the reaction. In 1940 Linton (11) reported that the dipole moment of pyridine 1-oxide is 4.24 D, a value much lower than calculated from the group moment of the N-oxide function (4.38 D) and the moment of pyridine. He concluded that the participation of structures II-IV in the resonance system of pyridine 1-oxide was
responsible.
A
A
Z\
A
\nX
\N
00
^ h
t-H CO
cq
¿ CO ¿ ^
©
xw
10 ·
S
43
ft
O ©
""©
5
fl
>-
a
GO
o
GO
OQ
02
GO
GO
©
©
©
©
©
©
©
©
©
©
©
©
©
©
©
ft ¡5
¡25
£ £
a a 6=
o
S X X X X X GO •e
a,
£ o i*
¡z;
o
z "3 "y >1
A
H ’S
I 1
H •s l-i
02
Ü
ID ¿ 9 00 2
cq Ja
b,
¿ co
¿ ^
©
g*-8
544
E. OCHIAI
obtained in nearly theoretical yield. In a control experiment, -pyridone was analogously heated with acetic anhydride and submitted to catalytic hydrogenation, but there was no uptake of hydrogen and the starting materials were TABLE VIII 4-Amino Derivatives
of
Pyridine, Quinoline,
and
Pyridine 1-Oxides
4-position M.P., °C.
PYRIDINE
N(C2Hs)2
Base:
QUINOLINE
M.P., °C,
b.p. 100° (bath temp.) a.t 0.04
PYRIDINE 1-OXIDE
M.P., °C.
Hydrochloride:
184-186
needles
mm.
Morpholino
Picrate:
169-170
needles Base:
101-104
Base:
b.p. 190° (bath temp.)
platelets
Base: prisms
75-78
at 0.002 mm.
Picrate: flakes
186-187
Picrate:
220
needles
Piperidino
Picrate:
Base:
84
platelets Picrate:
210
168-169
prisms
(dec.)
needles
Reduction
TABLE IX Amine Oxides with Phosphorus Trichloride
of
STARTING MATERIAL
Quinoline 1-oxide 4-Nitroquinoline 1-oxide 4-Hydroxyquinoline 1-oxide
Pyridine 1-oxide 4-Nitropyridine 1-oxide 4-Hydroxypyridine 1-oxide
PRODUCT
YIELD, %
Quinoline 4-Chloroquinoline 4-Hydroxyquinoline plus 4-Chloroquinoline Pyridine
Nearly theoretical
4-Nitropyridine 4-Hydroxypyridine
82 40 30 48 79
54
recovered without change from the mixture (41, 42). This indicates the formation of an intermediate adduct, with the course of reaction as follows: AczO
xV I o
zx
H
XsZOAc
^N OAc
OAc
ZX
H.0
ZX / 1=0 H
CHEMISTRY OF PYRIDINE
1-OXIDE
545
It is known that -pyridone can be acetylated only with complete exclusion of water, and thus that -acetoxypyridine is saponified on contact with water. As a practical application of these two characteristics of the N-oxide function, we have converted quinine and dihydroquinine into the corresponding 2-hydroxy derivatives (43). The appropriate cinchona alkaloid was transformed, by heating with hydrogen peroxide in acetic acid, into the corresponding diamine dioxide in which both the quinoline and quinuclidine nitrogens were oxidized to the N-oxide condition. This was then treated with cold sulfurous acid whereupon the N-oxide group in the quinuclidine moiety was reduced while that in the quinoline moiety remained unchanged. In both cases yields were good. The Ar-mono N-oxide so prepared was heated at 110° with acetic anhydride in acetic acid solution; this isomerized it to the desired 2-hydroxy derivative of quinine or dihydroquinine. In this way the identity of 2-hydroxyquinine with the product of the metabolism of quinine was established (44). The latter was prepared by Geiling, et al. (45) by the action of rabbit liver brei on quinine, and its structure was proposed by Mead and Koepfli (46). OH
¿H:
-R
I
CH-
CH3oX
/X
CH,
XX
H,0, AcOH
OH
Zl\ CH,
-R
OH
I
CHsO
CH-
\/
CH,
¡X
CH-
X/
AciO
ch3o
XxA·,
R
CH,j
/
XAn^'OH
\An^ I
o R
=
—
CH=CH,
or
—C2H5
General considerations. One finds, in comparing the N-oxides of pyridine and related heterocycles with the N-oxides of the usual tertiary amines, certain similarities and certain differences, as outlined below: Dipole moments: The usual amine oxides have very high dipole moments. The dipole moments of the heterocyclic amine oxides are significantly lower. Melting and boiling points: Amine oxides of the usual tertiary amines have very high melting points. The melting points of amine oxides related to pyridine are lower. Amine oxides in the pyridine and quinoline series can be distilled at reduced pressure. Solubility: The usual amine oxides dissolve readily in water and do not dissolve in fat solvents; the heterocyclic amine oxides tend to have this same solubility
546
E. OCHIAI
behavior, but in the absence of water can be made to dissolve in some non-polar solvents. Susceptibility to reduction: The usual amine oxides are readily reduced by common reducing agents such as sulfurous acid; they release iodine from acidic potassium iodide solutions. Amine oxides related to pyridine and quinoline are, as discussed above, remarkably resistant to reduction. Alkaline cleavage of their alkylation products: Tertiary amine oxides undergo O-alkylation. Treatment of the alkylated material with alkali causes cleavage, furnishing the original tertiary amine and an aldehyde. Both types of amine oxides undergo this reaction (47). R3N
O-->
->
R'CHzX
OH-
+
R3N—OCH2R
R3N + R'CHO
->
x-
The differences are as marked as the similarities, and one must in general consider the N-oxides of heterocyclic bases as a separate class of compounds. Colonna (48) has chosen to consider the N-oxides of pyridine and related compounds as aldonitrones, observing that in these amine oxides, as in the aldonitrones, there is a double bond between the nitrogen atom and an «-situated methine group. He views the transformation of pyridine 1-oxide into 2- and 4chloropyridines by the action of sulfuryl chloride as a sort of Beckmann rearrangement. However, the nitrones are in general easily reduced, just as the usual amine oxides, and therefore the amine oxides of the pyridine and quinoline series are to be more or less differentiated from the true aldonitrones. Something of the reason for these differences in chemical behavior can be discerned by examination of the possibilities for resonance in these three classes of compounds. In the usual amine oxides, there are no possibilities for delocalization of electrons, and the chemical and physical properties, the high polarity and the ease of reduction, are representative of a pure coordinate-covalent nitrogenoxygen linkage. In aldonitrones, there are some opportunities for resonance. But in amine oxides related to pyridine, there is resonance between several important types of structures. R=
Ri—CH=N—R2
Ri—N—>0
I
I
O
Rs
Usual amine oxide
Aldonitrone
/X
/
^>
+
/\
|
1
\N/
\N/
\N/ I 1
0
0
0
O
0
Via
VIb
VII
Villa
VIHb
CHEMISTRY OF PYRIDINE
1-OXIDE
547
This important resonance in amine oxides of heterocyclic bases related to pyridine has several consequences. First, it stabilizes the amine oxide structure, making it resistant to reduction. Second, because of the contribution of structures VI, the polarity of these amine oxides is less than expected. Thirdly, because of the participation of structures VI, these amine oxides are vulnerable to electrophilic substitution in the a- and -positions. (As mentioned above, the predominance of -reactivity over «-reactivity is a consequence of the strong inductive effect of the N-oxide group.) And finally, because of the participation of structures VIII, amine oxides of the pyridine and quinoline series are susceptible to nucleophilic substitution in the a- and -positions. The paradox of activation of both electrophilic and nucleophilic substitution by the same structure is resolved by recalling that it is not only the electron distribution in the isolated molecule which determines the rates of substitution reactions, but also the extent to which the molecule is polarized by the approaching reagent. The heterocyclic N-oxide function has the remarkable property of being strongly polarizable in both directions. Amine Oxides Derived AMINE OXIDE
4-Methylpyrimidine N-oxide.............
TABLE X from Other Heterocyclic Bases BASE
Prisms b.p. 90-110° (bath temp.) at 0.014 mm.
4-Methylthiazole 3-oxide................. 2,4-DimethylthiazoIe 3-oxide............. Tetramethylpyrazine 1,4-dioxide......... Needles
M.P., °C.
78
PICSATE
M.P.,
Needles
133-135
Needles Needles
130-132
°C.
152
224
From all these considerations, it appears that the amine oxides of the pyridine and quinoline series should be regarded as a distinct class of compounds, unlike either the ordinary amine oxides or the aldonitrones (29). The number of heterocyclic amine oxides is still small and as yet restricted to a few heterocyclic types. When one considers the number and variety of the heterocyclic tertiary amines, it becomes clear that the amine oxides mentioned in this paper are only the first representatives of a new class of compounds. The compounds listed in Table X were prepared in brief explorations (49, 50) of other heterocyclic amine oxide types; the chemistry of these compounds is still to be
investigated. Finally, I wish to express to my esteemed colleagues Misses M. Katada and Z. Sai and Messrs. K. Arima, M. Ishikawa, T. Itai, E. Hayashi, M. Hamana, T. Naito, I. Nakayama, T. Okamoto, T. Teshigawara, and Y. Yoshino my heartfelt gratitude for sharing in the joys and in the trials of this research in spite of the many difficulties of the war and postwar periods. Translator’s postscript: Very recent publications from Professor Ochiai’s laboratory have described further significant developments in the chemistry of
548
E. OCHIAI
heterocyclic N-oxides. Hayashi (51) has described the bromination, iodination, and mercuration of 4-hydroxypyridine 1-oxide; in all cases substitution occurred in the ¡3-positions, ortho to the hydroxy group. Nakayama (52) has reduced 4-nitroquinoline 1-oxide to 4-nitroquinoline by the use of phosphorus tribromide; he found 4-nitroquinoline to be somewhat less susceptible to nucleophilic substitution than its 1-oxide. Okamoto (53) found that a nitro group in the 5- or 6-position of quinoline 1-oxide is replaced by methoxy on treatment with sodium methoxide; this demonstrates activation of nucleophilic substitution in the Bz-ring by the N-oxide function. Ochiai and Futaki (54) and Ochiai and Ogura (55) have described the nitration and bromination of 4-hydroxypyridine 1-oxide and 4-hydroxy quinoline 1-oxide and several chemical transformations of the products of substitution. Virtually the only research in this field outside of Japan has been conducted by Professor H. J. den Herfcog in Holland. Although many of Ochiai’s most significant publications antedate den Hertog’s work, Ochiai’s work was not known outside Japan, and the Dutch research was performed independently, den Hertog’s group has described the oxidation of pyridine to pyridine 1-oxide by hydrogen peroxide in acetic acid (56), the nitration of pyridine 1-oxide (57), reduction and displacement of the nitro group in 4-nitropyridine 1-oxide by alkaline reagents (56), and the nitration of 2-ethoxypyridine 1-oxide to give 2-ethoxy-4nitropyridine 1-oxide (58). The last-mentioned discovery shows that the N-oxide function surpasses the ethoxy group in activation of electrophilic substitution. REPRESENTATIVE
PREPARATIVE
PROCEDURES
Pyridine 1-oxide. To a solution of 40 g. of pyridine in 300 cc. of glacial acetic acid, 50 cc. of 35% aqueous hydrogen peroxide was added and the mixture was heated in a water-bath at 70-80°. After three hours a further 35 cc. of hydrogen peroxide solution (altogether ca. 1.7 moles of peroxide) was added and the mixture was maintained an additional nine hours at the same temperature. The mixture was concentrated to about 100 cc. in a vacuum, diluted with 100 cc. of water, and then again concentrated in a vacuum as far as possible. The residue was made strongly alkaline with anhydrous sodium carbonate, shaken with 250 cc. of chloroform, and allowed to stand. The resulting deposit of sodium carbonate and sodium acetate crystals was collected. The filtrate was dried with sodium sulfate, the solvent removed by distillation, and the residue distilled in a vacuum. The yield of pyridine 1-oxide, b.p. 138-140°/15 mm., was 46 g. (96%). Quinoline 1-oxide. To 129 g. of quinoline in 300 cc. of glacial acetic acid, 90 cc. of 29% aqueous hydrogen peroxide was added, and the mixture was heated three hours at 67-70°. An additional 80 cc. of hydrogen peroxide solution (altogether about 1.5 moles of peroxide) was added and the reaction mixture was concentrated as much as possible in a vacuum and treated with portions of hot saturated aqueous sodium carbonate solution until an alkaline test was obtained. The mixture was extracted with chloroform and the extracts were concentrated at 80°. The precipitated inorganic salts were removed by hot filtration and the filtrate again concentrated to the smallest possible volume. On standing, the residue crystallized, and the following day it was broken up under ether, filtered, and washed with ether. The crystalline quinoline 1-oxide dihydrate so obtained weighed 167 g. (92%), and had m.p. 60-62°, b.p. 171-17274 mm. 4-Nitropyridine 1-oxide. Pyridine 1-oxide (10 g.) was dissolved in a mixture of 30 cc. of sulfuric acid (sp. gr. 1.84) and 12 g. of nitric acid (sp. gr. 1.48), and the solution was heated 3.5 hours at 128-130°. The reaction mixture was poured onto ice and, with stirring, neutra-
CHEMISTRY OF PYRIDINE
1-OXIDE
549
lized with portions of sodium carbonate. Just when crystals of sodium sulfate began to precipitate, the neutralization was interrupted and the precipitated crystals were collected, washed with ice-water, and dried. The filtrate was extracted with chloroform and the extracts concentrated, whereupon the residue crystallized. The two crops of crystals were combined and recrystallized from acetone. There resulted 10.6 g. of 4-nitropyridine 1-oxide (72%) as yellow rhombs, m.p. 159°. 4-Nitroquinoline 1-oxide. Quinoline 1-oxide dihydrate (60 g.) was dissolved in 130 cc. of sulfuric acid (sp. gr. 1.84). To this solution at 65-70°, 45 g. of nitric acid (sp. gr. 1.36) was added portionwise over a period of 35 to 40 minutes. The mixture was maintained an additional two hours at 70° with frequent swirling, cooled, and poured onto ice. The nitro compound precipitated as an orange powder which was collected and washed with water, dilute sodium carbonate solution, water, and a small amount of alcohol, in that order. The powder was then dried and recrystallized from acetone. 4-Nitroquinoline 1-oxide was obtained as yellow needles or leaflets, m.p. 153-154°, in the amount of 47 g. (67%). 4-Chloropyridine 1-oxide. 4-Nitropyridine 1-oxide (1 g.) was combined with 5 cc. of acetyl chloride and heated to 50° on the water-bath. The reaction mixture, which thereupon set to a crystalline mass, was treated with ice-water, made alkaline with sodium carbonate solution, and extracted with chloroform. The chloroform solution was dried over potassium carbonate and concentrated. The scaly residue was recrystallized from acetone, furnishing 0.85 g. (92%) of 4-chloropyridine 1-oxide, m.p. 169.5° with decomposition. 4-Chloroquinoline 1-oxide. To 50 cc. of acetyl chloride at 0°, 10 g. of 4-nitroquinoline 1-oxide was added in portions with ice cooling. The reaction mixture was carefully held below 40° for 40 minutes, and then treated with ice-water. Neutralization with sodium carbonate freed 2,4-dichloroquinoline which was swept out by steam-distillation; 0.11 g. were obtained. The residue was made basic by addition of more sodium carbonate and was extracted with chloroform. The yellow needle-like residue from evaporation of the chloroform solution was recrystallized from acetone, giving 9.3 g. (98%) of 4-chloroquinoline 1-oxide, m.p. 133-133.5°. 4-Benzyloxypyridine 1-oxide. To 12 g. of 4-nitropyridine 1-oxide in 80 cc. of benzyl alcohol, a solution of 2 g. of sodium in 100 cc. of benzyl alcohol was added in portions and the mixture was allowed to stand overnight. The precipitated sodium nitrite was collected and was washed with a little benzyl alcohol. The filtrate and the wash solution were together concentrated in a vacuum, whereupon the originally light yellow solution became orangered. After cooling, the concentrated solution was diluted with ether and allowed to stand. Needles precipitated; these were washed with ether and then with acetone, and dried. Weight: 13.3 g. The filtrate was again concentrated in a vacuum and treated with ether; on standing, an additional 1.5 g. of crystals separated. Both crops were together recrystallized from a mixture of acetone and methanol. 4-Benzyloxypyridine 1-oxide (14 g., 80%) was obtained as prisms of m.p. 175-177°. 4-Hydroxy pyridine 1-oxide. A. From 4-benzyloxypyridine 1-oxide. To 23 g. of 4-benzyloxypyridine 1-oxide in 60 cc. of methanol, a solution of 3 g. of sodium in 40 cc. of methanol was added. After the addition of 0.5 g. of palladium-on-charcoal (40% Pd), the mixture was shaken in a hydrogen atmosphere. The rapid reduction stopped after consumption of a mole of hydrogen. The filtrate from removal of the catalyst was evaporated, whereupon 4-hydroxypyridine 1-oxide precipitated as its sodium salt. After addition of a small amount of acetone, the sodium salt was collected and dried; it weighed 15.9 g., nearly the theoretical yield. This salt was dissolved in the least possible amount of hot water. When the solution was made weakly acidic by addition of acetic acid, crystals of 4-hydroxypyridine 1-oxide precipitated. After recrystallization from ethanol, they showed m.p. 239-241° with decomposition. B. From 4-nitropyridine 1-oxide. A solution of 12 g. of dimethylaniline in 70 cc. of acetic anhydride was heated on the water-bath. To this solution 14 g. of 4-nitropyridine 1-oxide was added in portions over a period of 40 minutes. The reaction mixture, which first acquired a red tint and then a green one, was after a further 20 minutes of heating concen-
550
E. OCHIAI
trated in which
were
The addition of 20 cc. of methanol caused precipitation of crystals collected, washed with acetone, and recrystallized from ethanol. The yield was
a vacuum.
7.3 g.
4-Morpholinopyridine 1-oxide. One gram of 4-chloropyridine 1-oxide, 1 g. of morpholine, and 1.5 cc. of water were heated five hours in a sealed tube at 130-140°. The mixture was made alkaline with sodium carbonate and was extracted with chloroform. Recrystallization of the chloroform-extracted material from acetone furnished 0.74 g. (53.2%) of 4-morpholinopyridine 1-oxide as prisms of m.p. 75-78°. 4-Piperidinoquinoline. A. From 4-chloroquinoline 1-oxide. One gram of 4-chloroquinoline 1-oxide and 2 cc. of piperidine were heated 5 hours in a sealed tube at 135-145°. Excess piperidine was removed by evaporation in a vacuum, and the residue was treated with concentrated potassium carbonate solution and extracted with chloroform. The chloroform extract was distilled at reduced pressure, whereupon the greatest part distilled at 190-200° (bath temperature) at 0.05 mm. and crystallized spontaneously in the receiver. Recrystallization from ethanol furnished 0.8 g. (67%) of 4-piperidinoquinoline as leaflets, m.p. 84°. B. From 4-thiophenoxyquinoline 1-oxide. A mixture of 1 g. of 4-thiophenoxyquinoline 1-oxide and 2 cc. of piperidine was heated five hours in a sealed tube at 195-205°. The resulting 4-piperidinoquinoline (0.6 g., 71%) was purified as described above. Quinoline 1-oxide-4-thiouronium chloride. One gram of 4-chloroquinoline 1-oxide and 0.45 g. of thiourea were mixed with 10 cc. of absolute ethanol, heated one hour under reflux, and filtered after cooling. Quinoline l-oxide-4-thiouronium chloride (1.28 g., 89%) was obtained as light yellow needles, m.p. 165.5° with decomposition. 4-Mercaptoquinoline 1-oxide. The above thiouronium chloride was suspended in 6 cc. of -water and 3 cc. of 10% sodium hydroxide solution -was added, whereupon the crystals dissolved to form an orange-red solution. The solution was filtered, acidified with acetic acid, and the resulting orange-red crystals were collected and washed with water. The yield of 4-mercaptoquinoline 1-oxide, m.p. 140-140.5° with decomposition, was 0.55 g. (80%). 4-Nitropyridine. To 1 g. of 4-nitropyridine 1-oxide suspended in 15 cc. of ice-cold chloroform, 1.9 cc. of phosphorus trichloride was added and the mixture was heated one hour at 70-80°. After cooling and the addition of water, the reaction mixture was made alkaline by addition of sodium hydroxide a,nd was extracted with chloroform. The chloroform solution was dried over sodium sulfate, evaporated to dryness, and the residue was recrystallized from petroleum ether. The yield of 4-nitropyridine, m.p. 50°, was 0.7 g. (79%).
Tokyo,Japan REFERENCES (1) Friedl, Ber., 45, 428 (1912). (2) Friedl, Monatsh., 34, 759 (1913). (3) Kirpal and Reiter, Ber., 68, 699 (1925). (4) Schaarschmidt, Balzerkiewicz, and Gante, Ber., 68, 499 (1925). (5) Schorygin and Toptschijew, J. Gen. Chem. (U.S.S.R.), 7, 193 (1937); C. 1937, II, 4039. (6) Plazek, Ber., 72, 577 (1939). (7) Tschitschibabin and Sei:de, J. Russ. Phys.-Chem. Soc., 46, 1216 (1914); C. 1915, I, 1064.
(8) von Schickh, Angew. Chem., 61, 779 (1938). (9) Koenigs and Greiner, Ber., 64, 1049 (1931). (10) Bobranski, Kochanska, and Kowalewska, Ber., 71, 2385 (1938). (11) Linton, J. Am. Chem. Soc., 62, 1945 (1940). (12) Meisenheimer, Ber., 69, 1848 (1926). (12a) Boehme, Ber., 70, 379 (1937). (13) Ochiai, Hayashi, and Katada, J. Pharm. Soc. Japan, 67, 33 (1947).
CHEMISTRY OF PYRIDINE
1-OXIDE
551
(14) Ochiai and Sai, J. Pharm. Soc. Japan, 65, (B), 18 (1945). (15) Ochiai, Ishikawa, and Arima, J. Pharm. Soc. Japan, 63, 79 (1943). (16) Ochiai and Hayashi, J. Pharm. Soc. Japan, 67, 157 (1947). (17) Kirpal and Boehm, Ber., 64, 767 (1931). (18) Ochiai, Hayashi, and Katada, J. Pharm. Soc. Japan, 67, 79 (1947). (19) Katada, J. Pharm. Soc. Japan, 67, 56 (1947). (20) Ishikawa, J. Pharm. Soc. Japan, 65, (B), 105 (1945). (21) Ochiai, Ishikawa, and Sai, J. Pharm. Soc. Japan, 63, 280 (1943). (22) Ochiai and Okamoto, J. Pharm. Soc. Japan, 70, 384 (1950). (23) Ishikawa, Proc. Imp. Acad. {Tokyo), 20, 599 (1944). (24) Ishikawa, J. Pharm. Soc. Japan, 65, (B), 98 (1945). (25) Bird and Ingold, J. Chem. Soc., 918 (1938). (26) Ochiai and Katada, J. Pharm. Soc. Japan, 63, 186 (1943). (27) Ochiai and Suzuki, J. Pharm. Soc. Japan, 67, 30 (1947). (28) Ochiai and Naito, J. Pharm. Soc. Japan, 64, 206 (1944). (29) Ochiai, Proc. Imp. Acad. {Tokyo), 19, 307 (1943). (30) Ochiai, Naito, and Katada, Proc. Imp. Acad. {Tokyo), 19, 574 (1943). (31) Ochiai and Teshigawara, J. Pharm. Soc. Japan, 65, (B), 435 (1945). (32) Ochiai and Naito, J. Pharm. Soc. Japan, 65, (B), 441 (1945). (33) Ochiai, Itai, and Yoshino, Proc. Imp. Acad. {Tokyo), 20, 141 (1944). (34) Itai, J. Pharm. Soc. Japan, 65, (B), 4 (1945). (35) Hayashi, J. Pharm. Soc. Japan, 70, 145 (1950). (36) Itai, J. Pharm. Soc. Japan, 65, (A), No. 9-10, 8 (1945). (37) Itai, J. Pharm. Soc. Japan, 69, 545 (1949). (38) Katada, J. Pharm. Soc. Japan, 67, 53 (1947). (39) Katada, J. Pharm. Soc. Japan, 67, 56 (1947). (40) H aman a, J. Pharm. Soc. Japan, 71, 263 (1951). (41) Katada, J. Pharm. Soc. Japan, 67, 51 (1947). (42) Ochiai and Okamoto, J. Pharm. Soc. Japan, 68, 88 (1948). (43) Ochiai, Okamoto, and Kobayashi, J. Pharm. Soc. Japan, 68, 109 (1948). (44) Hamana, J. Pharm. Soc. Japan, 68, 113 (1948). (45) Kelsey, Ceiling, Oldham, and Dearborn, J. Pharmacol. Exptl. Therap., 80, 391 (1944); Chem. Abstr., 38, 4031 (1944). (46) Mead and Koepfli, J. Biol. Chem., 154, 507 (1944). (47) Ochiai, Katada, and Naito, J. Pharm. Soc. Japan, 64, (A), 210 (1944). (48) Colonna, Boll. sci. fac. chim. ind., Bologna, 1940, No. 4, 134; Chem. Abstr., 34, 7290 (1940). (49) Ochiai, Sai, and Ishikatva, J. Pharm. Soc. Japan, 65, (B), 14 (1945). (50) Ochiai and Hayashi, J. Pharm. Soc. Japan, 67, 34 (1947). (51) Hayashi, J Pharm. Soc. Japan, 71, 213 (1951). (52) Nakayama, J. Pharm. Soc. Japan, 71, 1088 (1951). (53) Okamoto, J. Pharm. Soc. Japan, 71, 297 (1951). (54) Ochiai and Futaki, J. Pharm. Soc. Japan, 72, 274 (1952). (55) Ochiai and Ogura, J. Pharm. Soc. Japan, 72, 767 (1952). (56) den Hertog and Combe, Rec. trav. chim., 70, 581 (1951). (57) den Hertog and Overhoff, Rec. trav. chim., 69, 468 (1950). (58) den Hertog, Kolder, and Combe, Rec. trav. chim., 70, 591 (1951).
