Note: Descriptions are shown in the official language in which they were submitted.
6~
P.C. (Ph) 6268B/C
HYPOGLYCEMIC 5-SUBSTITUTED OXAZOLIDINE-2,4-DIONES
The present invention relates to certain 5-
furyl, 5-thienyl, 5-chromanyl, 2, 3-dihydrobenzo[b]furanyl,
5~pyridyl, 5-quinolyl, 5-pyrrolyl, 5-indolyl, 5-
thiazolyl, 5-oxazolyl, 5-isothiazolyl and 5-isoxazolyl
derivatives of oxazolidine-2,4-dione having utility
as hypoglycemic agents.
In spite of the early discovery of insulin and
its subsequent wide-spread use in the treatment of
diabetes, and the later discovery and use of sulfonyl-
ureas (e.g., chlorpropamide, tolbutamide, acetohexamide,
tolazamide~ and biguanides [e.g., phenformin) as oral
hypoglycemic agents, the treatment of diabetes remains
less than satisfactory. The use of insulin, necessary
in a high percentage of diabetics where available
synthetic hypoglycemic agents are not effective,
requires multiple daily, usually self, injection.
Determination of the proper dosage of insulin requires
frequent estimations of the sugar in the urine or in
the blood. The administ~tion of an excess dose of
insulin causes hypoglycemia,~ith effects ranging
from mild abnormalities in blood gluc~se to coma, or
even death. Where e~fective, a synthetic hypoglycemic
agent is preferred over insulin, being more convenient
to administer and less prone to cause severe hypo-
glycemic reactions. However, the clinically available
hypoglycemics are unfortunately fraught with other
toxic manifestations which limit their use. In any
event, where one of these agents may fail in an
individual case, another may succeed. A continuing
need for hypoglycemic agents, which may be less toxic
or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited
above, a variety of other compounds have been reported
to possess this type of activity, as reviewed recently
-2-
by Blank [Burger's Medicinal Chemistry, Fourth Edition,
Part II, John Wiley and Sons, N~Yr (1979), pp. 1057
1080J.
The oxazolidine~2,4-diones of the present in-
vention are novel compounds; this in spite of the
fact that the oxazolidine-2,4-diones are broadly
known as a class of compounds [for an extensive
review, see Clark-Lewis, Chem. Rev. 58, pp. 63-99
(1958)]. Among the compounds known in this class are
5-phenyloxazolidine-2,4-dione, variously reported as
an intermediate to certain beta-lactam antibacterial
agents (Sheehan, UOS. Patent 2,721,197), as an anti-
dPpressant agent (Plotnikoff, ~.S. Patent 3,699,229)
and as an anticonvulsant agent [Brink and Freeman, J.
Neuro. Chem. 19 (7), pp. 1783-1788 (1972)]; a number
of 5-phenyloxazolidine-2,4-diones substituted on the
phenyl ring, e.g., 5-(4-methoxyphenyl)oxazolidine-
2,4-dione [King and Clark-Lewis, J. Chem. Soc., pp.
3077-3079 (1961)], 5-(4-chlorophenyl)oxazolidine-2,4-
dione [Najer et al., Bull. soc. chimO France, pp.
1226-1230 51961)], 5-(4-methylphenyl)oxazolidine-2,4-
dione ~Reibsomer et aI., J. Am. Chem. Soc. 61, pp.
3491-3493 (1939)], and 5-(4-aminophenyl)oxazolidine-
2,4-dione ~German Patent 10 8r026); and 5-(2-pyrryl)-
oxazolidine-2,4-dione ~Ciamacian and Silber, Gazz.
chim. ital. 16, 357 (1886); ser. 19, 1708-1714
(1886)3. The last-named compound, having no prior
known utility, shows only relatively weak hypoglycemic
activity (vide post, Table I).
Oxazolidine-2,4-dione and substituted oxazolidine-
2,4-diones (speci~ically, tha 5-methyl and 5,5-
dimethyl derivatives) have been reported as acid
moieties suitable for forming acid-addition salts
with the hypoglycemic, basic biguanides (Shapiro and
Freedman, ~.S. Patent 2,961,377). We have determined
~6~ 3-
that neither oxazolidine-2,4-dione itself, nor 5,5-
dimethyloxazolidine-2,4-dione possess the hypoglycemic
activity of the compounds of the present invention.
Recently, a group of spiro-oxazolidine-2,4-dione
derivatives have been reported which are aldose re-
ductase inhibitors, thus finding utility in the
treatment of certain complications of diabetes
(Schnur, U.S. Patent 4,200,642).
A process for the synthesis of 3-aryloxazolidine-
2,4-diones (wherein said aryl group is 6 to 12 carbon
atoms, unsubstituted or substituted with one or more
halogen atoms, methyl or methoxy) is the subject of
another recent U.S. Patent tScholz, U.S. 4,220,787).
The utility of these compounds is not specified.
The present invention is concerned with compounds
of the formula
o
R~R
(1)
wherein
R is hydrogen, (Cl-C4)-alkanoyl (e.g., formyl,
acetyl, isobutyryl), benzoyl, (C2-C4)-carbalkcxy
(e.g., carbomethoxy, carbethoxy, carboisopropoxy),
(Cl-C3)-alkylcarbamoyl (e.g., ~-methylcarbamoyl, N-
propylcarbamoyl), (C5-C7)-cycloalkylcarbamoyl (e.g.,
N-cyclohexylcarbamoyl) or di-(Cl-C3~-dialkylcarbamoyl
(e.g., N,N-dimethylcarbamoyl); and
Rl is:
~ 3 -4-
(a) ~ ~n ~ or
R' R'
x~3~
R"
wherein R' is (Cl-C4)alkyl or phenyl, R" is hydrogen,
(Cl-C4)alkyl or phenyl and X is halo (fluoro, chloro,
bromo or iodo); these formulae are intended to
encompass 2- or 3-pyrrolyl and indolyl derivatives,
with substituents as specified;
Y'
(b) y~ ~ -
~ '
y
wherein Y is hydrogen or (Cl-C3)alkoxy, Y~ is hydrogen
or (Cl-C3)alkyl and Y" is hydrog&n or halo;
(c) Z'' ~ N ~ or
z,~ Z~N
wherein Z' is hydrogen, halo or (Cl-C3)alkoxy and Z"
is hydrogen or halo;
(d) {
\~ `
--5--
wherein W is hydrogen or halo, and n is 1 or 2; these
formula are intended to encompass 6- or 7-halo-8-
chromanyl or 5- or 6-halo-7-benzofuranyl derivatives;
~N~ or ~
wherein Q is sulfur or oxygen and V is hydrogen or
(cl-c3)alkyl; or V
(f) ~
wherein Q is.sulfur or oxygen; and V is hydrogen or
(Cl-C3)alkyl; these formula are intended to encompass
3-, 4- and 5-isothiazolyl and isoxa~olyl derivatives;
~ X~
wherein U is sulfur or oxygen; X is hydrogen, fluoro,
chloro, bromo, iodo, methyl, phenyl, benzoyl or (Cl-C3)-
alkoxy; Xl is hydrogen or methyl; and x2 is hydrogen,
fluoro, chloxo, bromo or iodo; when Xl is hydrogen,
the first formula is intended to encompass the full
gamut of 5-(2-furyl)-, 5-(3-furyl)-, 5-~2-thienyl~-
and 5-(3-thienyl~-derivatives of oxazolidine-2,4-
dione wherein the substituent X can be attached to
any vacant carbon position of the furan/thiophene
ring, i.e.,
3~6~
--6--
X X
~Ox ~Ox X' U~OX
Ox X Ox ~ Ox
~X ~ X~ '
where U and X are as defined above and Ox is used as
an abbreviation for the oxazolidin-2,4-dione ring
attached at the 5-position; when both X and Xl are
other than hydrogen, the second substituent can be
inserted at either vacant position in any one of
these six variants; the second formula is intended to
encompass those compounds wherein the oxazolidine is
substituted at the 2-, 3- or 7-position of the
benzo[b]furan/benzo[b]thiophene! ring system, i.e.
~Ox ~
. ~
~ ,
Ox
1~
The invention also encompasses the pharmaceutically
acceptable cationic salts of compounds of the formula (1)
when R is hydrogen, as well as the pharmaceutically
acceptable acid addition salts thereof when
S contains a basic nitrogen function.
It is believed that the inherent, high activity
of these compounds resides primarily in those compounds
wherein R is hydrogen, and that those compounds
wherein R is one of a variety of carbonyl derivatives
defined above represent so-called pro-drugs, i.e.,
the carbonyl side chain is removed by hydrolysis
under physiological conditions, yielding the fully-
active compounds wherein R is hydrogen.
The expression "pharmaceutically acceptable
cationic salts" is intended to define such salts as
the alkali metal salts, (e.g., sodium and potassium),
alkaline earth metal salts (e.g., calcium and magnesium),
aluminum salts, ammonium salts, and salts with organic
amines such as benzathine (~,N'-dibenzylethylenediamine),
choline, diethanolamine, ethylenediamine, meglumine
IN-methylglucamine), benethamine (N-benzylphenethylamine),
diethylamine, piperazine, tromethamine (2-amino-2-
hydroxymethyl-1,3-propanediol), procaine, etc.
The expression "pharmaceutically acceptable acid
addition salts" is intended to include such salts as
the hydrochloride, hydrobromide, hydroiodide, nitrate,
hydrogen sulfate, dihydrogen phosphate, mesylate,
maleate, succinate, etc.
The compounds of the present invention possess
hypoglycemic activity, reflecting their clinical
utility in the lowering of the blood glucose level of
hyperglycemic mammals, including man, to normal
values. They have the special advantage of lowering
-8- ~6~3
blood glucose values to a normal range without danger
of causing hypoglycemia. The compounds of the present
invention are tested for hypoglycemic (anti-hyper-
glycemic) activity in rats, using the so-called
glucose tolerance test, as described in greater
detail hereinafter.
Pre~erred compounds, because of their better
hypoglycemic activity, are those wherein R is hydrogen,
or the pharmaceutically acceptable salts thereof.
Among those compounds of the formula (1) wherein R is
hydrogen, the most preferred compounds, because of
their excellent hypoglycemic activity, are:
5-(1-methyl-2-pyrrolyl)oxazolidine-2,4-dione;
5-(1-ethyl-2-pyrrolyl)oxazolidine-2,4-dione;
5-(1 phenyl-2-pyrrolyl)oxazolidine-2,4-dione;
5-(2-methoxy-3-pyridyl)oxazolidine-2,4-dione;
5-(2~ethoxy-3-pyridyl)oxazolidine-2,4~dione;
5-(5-chloro-2-methoxy-3-pyridyl)oxazolidine-2,4-
dione;
5-t5-chloro-2-ethoxy-3-pyridyl)oxazolidine-2~4
dione;
5-(8-quinolyl)oxazolidine~2,4-dione;
5-(7-methoxy 8-quinolyl)oxazolidine-2 r 4-dione;
5-(6-chloro-8-quinolyl)oxazolidine-2,4-dione;
5-(6-~luoro-8-quinolyl)oxazolidine-2,4-dione;
5-~2-benzthiazolyl)oxazolidine-2,4-dione;
5-(2-~hiazolyl)oxazolidine-2,4-dione;
5-(6-chloro-8-chromanyl)oxazolidine-2,4-dione;
5-(6-fluoro-8-chromanyl)oxazolidine-2,4-dione;
5-(5-chloro-2,3-dihydro-7-benzofuranyl)oxazolidine-
2,4-dione;
5-(3-methyl-5-isoxazolyl)oxazolidine-2,4-dione;
5-(3-thienyl)oxazolidin-2,4-dione;
43
5-~4-bromo-3~thienyl)oxazolidin-2~4-dione;
5-(4-ethoxy-3-thienyl)oxazolidin-2,4-dione;
5-(4-ethoxy-2-methyl~3-thienyl)oxazolidin-2,4-
dione î
$-(4-methoxy-2-methyl~3-thienyl)oxazolidin-2,4-
dione,
5-(3methyl-2-thienyl)oxazolidin-2,4-dione;
5-(3-methoxy-2~thienyl)oxazolidin-2,4-dione;
5-(3-furyl)oxazolidin-2,4~dione;
5-(2-furyl)oxazolidin-2,4-dione;
5-(3-bromo-2-furyl)oxazolidin-2,4-dione;
5-(S-chloro-2-furyl)oxazolidin-2,4~dione;
5-(7-benzo~b]thienyl)oxazolidin-2,4-dione; and
5~5-chloro-7-bsnzo[b]furanyl)oxazolidin-2,4-
dione.
The compounds of khe present invention are pre-
pared by a variety of methods, as summarized in Flow
sheet I, wherein
Rl is as deEined above;
R2 is lower alkyl ~e.g. methyl or ethyl);
R3 i9 hydrogen, lower alkyl or phenyl; and
R4 i~ h~drogen, or acyl such a9 acetyl or
bcnzoyl.
A particularly convenient synthesis or compounds
oE the present invention is via carboximidate (3).
The latter compound is reacted with phosgene in an
in~t solvent such ag tetrahydrofuran in the presence
o~ 2 to 2.3 equivalents of a tertlary amine (e.g.
triethylamine, N-me~hylmorpholine). A further equivalent
3~ of tertiary amine is used lf th~ carboximidate is
introduced as the acid addition salt ~e.g. hydro-
chloride salt). The temperature o the reaction is
not critical, but lower temperatures (e.g. -10 to
10C.) are pre~erred during the initial stages of the
~ ~\
--10--
F I owsh e et
Oxazol idine-2, 4-dione Precursors
o~
OH ~ / ~ OH
Rl ~ OR Rl~ Rl /\C/NH2
NH / OR
(3) ~ t4) / (5)
--/ ~ ~
o~R ~ ~P
~ OH
\r~ `OnR J~c/ OR
~9~ ~6
R~
(10) (8) (7)
~ ` `
reaction, particularly if it is desired to isolate
the intermediate 4-alkoxyoxazol-2-one (4). Isolation
of this intermediate is carried out by simple evapora-
tion of the reaction mixture to dryness. On further
reaction at higher temperatures ~e.g. 20-150C.) or
on aqueous work-up the intermediate (4) is converted
to the desired oxazolidine-2,4-dione. When a primary
or secondary amine function is desired in the final
product, this functionality is introduced via an
oxazolidine-2,4-dione containing a group selectively
reducible le.g. by catalytic hydrogenation or acid/
metal couple~ to the primary or secondary amine. For
example an N-benzylindole can be used as a precursor
for an indole derivative.
-12-
The carboximidate (3~ is conveniently prepared from
the corresponding aldehyde by the sequence:
OSi(CH3)3
Rl/~CN
~ \
/ (12) \ OH
RlCHO
ll) \
(13)
The aldehyde tll) is converted to the cyanohydrin
S (13) by standard procedures (e.g. via the bisulfite
adduct, which is reacted with cyanida in a two phase,
aqueous-organic solvent system). Alternatively, the
aldehyde is converted to the trimethylsilyl cyano-
hydrin (12) by reaction with trimethylsilylcarbonitrile
in the presence o~ a catalytic quantity o~ a Lewis
acid, e.g., zinc iodide~ A reaction inert solvent
(e.g. methylene chloride, ether) is generally used
when the aldehyde is a solid, but is optional when
the aldehyde is a liquid. The temperature of the
reaction is not critical, it being conveniently made
up at reduced temperature (e.g, 0-5C.) and allowed
to proceed at room temperature for a matter of hours
or days, as necessary to achieve complete reaction.
If desired, the trimethylsilyl ether can be hydrolyzed
to cyanohydrin, conveniently at reduced temperature
(e.g. -10~C.) in a two phase strong aqueous acid/organic
solvent system.
-13-
Either the cyanohydrin (13) or the trimethylsilyl
ether (12~ is converted to the carboximidate (3) by
strong acid catalyzed alcoholysis ~using strictly an-
hydrous conditions). A convenient method is to
simply dissolve the nitrile in alcohol which has been
saturated with hydrogen chloride) and allow the
solution to stand until carboximidate formation is
complete. Temperature is not critical, although
lower temperatures (e.g. 0-25C.) generally lead to
more optimal yields.
The aldehydes required for the above syntheses
are broadly available either commercially, or by
literature methods. For example, N-alkylpyrrole-2-
carbaldehydes are obtained by alkylation of pyrrole-
2-carbaldehyde ~Weygand, Organic Preparations, Interscience,
New York, 1945, p. 403) using conditions specif.ically
exemplified hereinafter for the preparation of N-
alkylpyrroles, or by Reimer-Tieman formylation of N-
alkylpyrrole (cf Weygand loc. cit.); 3-formylindoles
are similarly obtained from indoles [cf Boyd and
Robson, Biochem J. 29, p. 555 (1935; Shabica et al.,
. Am. Chem. Soc. 68, p. 1156 ~1946)]; Rosenmund
hydrogenation of the corresponding acid chloride
~e.g. 3-furaldehyde; Hayes, J. Am. Chem. Soc. 71,
2581 (1949)], from halomethyl compounds by the Sommelet
reaction [e.g. 3-thenaldehyde; Campaigne and LaSuer,
J. Am. Chem. Soc. 70, 1557 (1948)], formylation [e.g.
2-thenaldehyde, 3-methyl-2-thenaldehyde, 5-methyl-2-
thenaldehyde; Watson and Michaels, J. Am. Chem. Soc.
72, 1422 (1950), Organic Syntheses 31, 108 (1951); 3-
bromo-2-thenaldehyde; Elliott et al., J~ Chem. Soc.
(C), 2551 (1971~]; reduction of chloromethyl substituted
aldehydes [e.g. 5-methyl-2-furaldehyde, Spence and
Wild, J. Chem. Soc., 338 (1935)], oxidation of the
corresponding alcohol ~e.g. 2-thenaldehyde; Emerson
and Patrick, J. Org. Chem., 14, 790 (1949)], interaction
of Grignard reagents with orthoformic esters ~e.g. 2-
thenaldehdye; Cagniant, Bull. soc. chim. France 16,
849 (1949)], decarboxylation of alpha-keto acids
[e.g. 2-thenaldehyde; Barger and Easson, J. Chem.
Soc., 2100 (1938)], and halogenation [e.g. 2-bromo-3-
thenaldehyde; Elliot et al., loc. cit.]; a variety of
the presently required aldehydes are further available
by the hydrolysis of gem-dihalides, oxidation of
primary alcohols, interaction of Grignard reagents
with orthoformic esters and other methods known in
the art. Additional methods are noted in the Preparations
detailed hereinafter.
Another suitable precursor for those oxazolidine-
2,4-diones of the present invention lacking a primary
or secondary amine function is the alpha-hydroxy
amide (5). The latter compound is converted to the
desired oxazolidine-2,4-dione (1), either by reaction
with alkyl chloroformate in the presence of a basic
catalyst such as potassium carbonate, or by reaction
with a dialkyl carbonate in the presence of a more
strongly basic catalyst such as sodium methoxide or
potassium tert-buto~ide. An alcohol is generally
suitable as solvent for the latter reaction with 1 to
3 equivalents of both dialkyl carbonate and base
employed, preferably 2-3 equivalents of each. When a
primary or secondary amine function is desired in the
final product, this functionality is introduced via
an oxazolidine-2,4-dione containing a suitable precursor
group, as described above.
The required alpha-hydroxy amide is conveniently
prepared from cyanohydrin (13) or from alpha-hydroxy
acid or ester (~):
43
-~5-
OH OH
Rl ~ CN ~ R ~ oR2
(13) \ / (6)
\ OH
o
Convenient conditions for the hydrolysis of the
cyanohydrin (13) are to treat the cyanohydrin in
formic acid with excess concentrated hydrochloric
acid. A temperature range of 0-75Co is generally
satisfactory, depending upon the stability of the
individual amide in this medium. If desired, an
intermediate formate ester of (5) can be isolated
under these conditions. Over hydrolysis to the acid
can be avoided by tlc monitoring of the reaction, as
detailed below. Convenient conditions for the
aminolysis of ester ~6) are to simply heat the ester
in hot concentrated ammonium hydroxide.
The alpha-hydroxy ester (6) itself can also be
employed as the immediate precursor of the desired
oxazolidine-2,4-dione. The ester is reacted with
urea ~or one of certain substituted ureas, such as
phenyl urea or l-acetyl-3-methylurea) in the presence
o~ a basic catalyst such as sodium ethoxide (suitably
; 20 1 equivalent~ in alcohol at a temperature of 50-
110C. The ester to be used for this purpose is by
no means restricted to a simple lower alkyl ester,
but can be any one o a broad variety of esters, e.g.
phenyl, benzyl, etc. Furthermore, the estex can be
replaced by a 1,3-dioxolan-4-one, an alpha-acyloxy
ester or a thioester e.g.,
-16-
CH CH
O ~ , 3 CH3
O C=~ C=O
Rl/~ Rl/~OC2H5 Rl~SCH3
O O
and the urea can be replaced by a urethan.
Two other precursors suitable for the synthesis
of the desired oxazolidine-2,4-diones are the thio
compounds (7) and (8). The 2-thioxo compound (7) is
converted to the desired oxazolidine-2~4-diones under
oxidative conditions, e.g. mercuric ion, aqueous
bromine or chlorine, metaperiodate, or aqueous
hydrogen peroxide, usually in excess and in the
presence o a co-solvent, such as a lower alcohol.
The temperature of reaction is not critical, tempera-
turas in the range 25-100C. being generally satis-
factory. Other methods are usually preferred when
has an amine function, since cornpeting oxidation at
the nitrogen tends to reduce yiel ds and complicates
isolation of the desired product; it has been found,
however, that when the product contains a tert-amine
(e.g., pyridine, quinoline), that periodate or bromine
are reagents well-suited for this purpose. The
oxazolidine-2,4-diones are obtained from the alkyl-
thio compounds (8) by simple acid or base catalyzed
hydrolysis. Preferable conditions are aqueous hydro-
chloric acid in a temperature range of 0-50C.
The precursor 2-thioxo compound (7) is prepared
from the corresponding aldehyde (11), generally
accomplished in an aqueous acidic media by the action
of thiocyanate (1-1.1 equivalents) and cyanide (1 to
1.2 equivalents) at 0-70C., ollowing the method of
Lindberg and Pederson by which method the preparation
of 5-(2-thienyl)-2-thiooxazolidin-4-one has been
reported [Acta Pharm. Suecica 5 (1), pp. 1~-22 (1968);
Chem. Abstr. 69, 52050k]. The precursor 2-alkylthio
compounds (8) can be prepared by alkylation of the 2-
thioxo compounds (7), e.g. with an alkyl halide or
dialkyl sulfate, preferably in the presence of at
least two equivalents of a base such as a lower
alkoxide in a reaction inert solvent such as a lower
alkanol. The 3-alkyl derivative can be a by-product
of this reaction.
Also suitable as a precuror is the 2-imino-oxa-
zolidine-4-one derivative (9), readily hydrolyzed to
the oxazolidine-2,4~dione, preferably under a~ueous
acid conditions. The required 2-iminooxazolidin-4-
one is obtained by condensation of the alpha-hydroxy
ester (6) with guanidine or with thiourea in the
presence of one equivalent of a strong base such as
sodium alkoxide, by ammonolysis of the 2-alkoxy
compound (isomeric with 4) or the 2-thioalkyl compound
(8), by alkali induced cyclization of the appropriate
alpha-halogenureides (RlCHzCoNHcoNHR3 wherein Z is a
halogen such as chloro or bromo), or by the condensation
of the appropxiate al~yl alpha-haloacetates (RlCHzCOOR2)
with urea or a substituted urea (R3NHCoNH2)o
Ammonolysis of the 4-alkoxy derivatives (4)
yields 4-imino derivatives (isomeric with 9). The
latter compounds are also readily hydrolyzed to oxa-
zolidine-2,4-diones. The 4-alkoxy derivatives them-
selves are also prepared from the silver salt of thedesired oxazolidine-2,4-dione.
Also highly useful as precursors of the oxazoli-
dine-2,4-diones of the present invention are the
dialuric acids and acyl dialuric acids (10). These
are readily converted, under mildly basic conditions,
to the desired oxazolidine-2,4-diones. Methods suit-
able for the preparation of precursor dialuric acids
(10) are shown in Flowsheet II, wherein the substit-
uents Rl, R2 and R4 are as defined above, and M is
Li, MgCl, MgBr, MgI, or other suitable metal.
A general method for preparing dialuric acids
appropriate as precursors of the oxazolidine-2 r 4~
diones of the present invention is from the malonic
ester derivatives l14), involving the two stages of
base catalyzed condensation with urea and oxidation
to the hydroxy or acyloxy compound. When the first
stage is oxidation, the intermediate is a so-called
tartronic acid derivative (15), while when the first
stage is condensation, the intermediate is a so-
called barbituric acid (16). When Rl contains an
amine function (e.g. 2-aminophenyl), it is preferred
to carry out oxidation as the first stage, preventing
possible complications of nitrogen oxidation. When
condensation is the second stage, the dialuric acid
is usually not isolated, at least in pure form, and
is further converted, under basic conditions of the
condensation, to the oxazolidine-2,4-dione.
-19-
F 1 owsheet I I
Rl H ~ 4 ~NH COOR2
lX ,~ ~ Rl C-oR4
~ o~N COOR2
R M~ (10) (15)
O~NH
--< ~ COOR2
~NH Rl CH
COOR2
(16) (1~)
-20-
The substituted malonic esters required for the
above syntheses, when not available commercially, are
obtained by literature methods, such as alcoholysis
of alpha-cyano esters [cf. Steele, J. Am. Chem. Soc.
53, 286 (1931)], carbalkoxylation of esters ~cf.
Horning and Finelli, Org. Syntheses 30, 43 (1950)]
and decarbonylation of alpha-keto esters obtained by
the condensation of dialkyl oxalate with carboxylate
esters [Reichstein and Morsman, Helv. Chim. Acta 17,
1123 (1934); Blicke and Zienty, J. Am Chem. Soc. 63,
2946 (1941)].
A less general method for the preparation of the
appropriate dialuric acid intermediate is to react an
electron rich heteroaryl/aryl compound, e.g.,
~
CH3 CH3 H
~ NH
B~3 BI~3~N~
H H
-- ~ ~$ ~
Now available is yet another method for the
preparation of certain dialuric acid intermediates.
This method, preferred when the appropriate starting
materials are readily available, involves the reaction
~ 3
-21-
of alloxan (preferably in anhydrous form) with the
appropriate organometal derivative (e.g., organo-
lithium, Gri~nard reagent). For example:
Li ~N
~Oo/ ~ H
Protection strategies are required when using this
method for preparation of certain oxazolidine-2,4-
diones wherein Rl carries a substituent which is not
compatible with organometallic reactions, e.g., an
acyl group is protected as its ethylenic ketal. In
other cases, such as when Rl carries a group such as
nitro or amino, this method generally lacks utility.
It will be evident to those skilled in the art
that the preferred process for the oxazolidine-2,4-
diones of the present invention will vary from one
given value of Rl to another, depending upon such
Eactors as availability o~ starting materials,
yialds, ability to remove undesirable impurities from
the end-products, the chemical nature of the substituent
groups contained in the final products, etc.
The pharmaceutically-acceptable cationic salts
of the compounds of the present invention which form
such salts are readily prepared by reacting the acid
forms with an appropriate base, usually one equivalent,
in a co-solvent. Typical bases are sodium hydroxide, 25 sodium methoxide, sodium ethoxide, sodium hydride,
potassium methoxide, ma'~nesium hydroxide, calcium
hydroxide, benzathine, choline, diethanolamine,
ethylenediamine, meglumine, benethamine, diethyl-
amine, piperazine and tromethamine. Those salts
which do not precipita~e directly are isolated by
concentration to dryness or by addition o~ a
-22-
non-solvent. In some cases, salts can be prepared by
mixing a solution of the acid with a solution of a
dif~erent salt of the cation (sodium ethylhexanoate,
magnesium oleate), employing a solvent in which the
desired cationic salt precipitates, or can be other-
wise isolated by concentration and addition of a non-
solvent.
The pharmaceutically acceptable acid addition
salts of the compounds of the present invention which
form such salts are readily prepared by reacting the
base forms with an appropriate acid, usually one
equivalent, in a cosolvent. Typical acids are
hydrochloric, hydrobromic, nitric, sulfuric, phosphoric,
methanesulfonic, maleic, succinic, etc. Those salts
which do not precipitate directly are isolated by
concentration to dryness or by addition of a non-
solvent.
3-Acylated derivatives of the present invention
are readily prepared by using standard conditions of
acylation, e.g. the reaction of the oxazolidine-2,4-
dione salt (per se, or conveniently ~ormed in situ
by the addition of one equivalent of a tertiary amine
such as triethylamine or N-metnylmorpholine with an
equivalent o~ the appropriate acid chloride or acid
2S anhydride) or reaction of the oxazolidine-2,4-dione
with the appropriate organic isocyanate, optionally
in the presence of a catalytic amount of tertiary
amine base. In either case, the reaction is carried
out in a reaction inert solvent, such as toluene,
tetrahydrofuran or methylene chloride. The temperature
is not critical, and can be over a broad range (e.g.
0-150C.). It will be evident to those skilled in
the art that such acylation will be complicated by
~23~
competing or e~en selective sidechain (Rl) acylation
when the sidechain contains a primary or secondary
amine function.
It will be evident to those skilled in the art
that the compounds of the present invention are asym-
metric and therefore capable of existing in two opti-
cally active enantiomeric forms. The racemic compounds
of the present invention, being acids when R is ~,
form salts with organic amines. These racemic forms
are there~ore generally capable of resolution into
the optically active forms by the classic method of
forming diastereomeric salts with optically active
amines, now separable by selective crystallization;
alternatively those compounds containing a basic
amine function can be resolved by forming a salt with
an optically active acid, preferrably a strong
organic acid such as a sulfonic acid. In general,
one of the enantiomeric forms is found to have
greater acti~ity than the other.
The reactions employed to prepare the compounds
o~ this invention can generally be monitored by
standard tlc methods, employing commercially available
plates. Suitable eluants arë common solvents such as
chloroform, ethyl acetate or hexane or suitable
combinations thereof which will differentiate starting
materials, products, by-products, and in some cases
intermediates. ~pplying these methods, which are
well Xnown in the art, will permit further improvement
in the methodology of the specific examples detailed
hereinafter, e.g. the selection of more optimal
reaction times and temperatures, as well as aid in
the selection of optimal processes.
. ~
-24~ 3
The oxazolidine-2,4-diones of the present in-
vention are readily adapted to clinical use as anti-
diabetic agents. The hypoglycemic activity required
~or this clinical use is defined by the glucose
tolerance test procedure which follows. Intact male
albino rats are the experimental test animals employed
for such purposes. The test animals are fasted
approximately 18-24 hours. The rats are weighed,
numbered and recorded in groups of five or six as
needed. Each group of animals is then dosed intra-
peritoneally with glucose (one gram per kilogram~ and
orally with either water (controls) or compound (at a
level usually selected from the range 0.1 to lO0
mg/kg). Blood glucose levels (mg/lO0 ml.) are measured
in tail blood samples over a period of 3 hours in
both control and treated groups. With equivalent
zero hour blood glucose levels in control and treated
groups, the % lowering of blood glucose at O.S hour,
l hour, 2 hours and 3 hours is calculated as:
~Control Blood Glucose] - lTreated Blood Glucose] ~ lO~
~Control Blood G uoose]
Clinically useful hypoglycemic agents show activity
in this test. The hypoglycemic activities determined
for compounds of the present invention are summarized
in Table I. This table records % blood glucose
lowering at the O.S hour and 1 hour time points. A
blood glucose lowering of 9~ or greater generally re-
flects statistically significant hypoglycemic activity
in this test. Those compounds which show significant
activity only at the 2 hour or 3 hour points have
such activity recorded in footnotes.
~~8~3
-25-
T~ble I
Hypoglycemic Activity of Oxazolidine-2,4-Diones
n the Rat Glucose ToIerancè Tes~
~,0
Ar ~ NH ~ Lowering
Dose of Blood Glucose Level
Ar (mg.Jk~.) 0.5 hr.1 hr.
2-Thienyl 10 11 8
5-Benzoyl- 25 10 7
3-Bromo- 10 8 6(a)
5-Bromo- 100 36 19
5-Chloxo- 100 26 17
3-Methoxy- 5 13 16
5-Methoxy- 25 9 7
lS 3-Methyl- 100 30 17
14 12
5~Methyl 50 18 10
5-Phenyl 50 1 5(b)
3-Thienyl ~ 10 23 20
17
4-Bromo- 100 31 25
14 9
4-Methoxy- 5 11 8
4-Methoxy-2-methyl- 5 16 14
4-Ethoxy- 5 19 19
4-Ethoxy-2-methyl-S 7 12
4-Propoxy- 5 11 6
2-Furyl 100 27 23
11 7
3-Bromo- 25 18 10
11 11
5-Bromo- 50 19 20
2 11
~6~ 3
-26-
Table I. (Continued)
% Lowering
Dose of Blood Glucose Level
Ar (mg./kg.) 0.5 hr. 1 hr.
5-Chloro- 25 21 20
3-Methoxy- 25 10 10
5-Methyl- 100 27 19
5-Phenyl- 25 6 4(c)
3-Furyl 10 17 13
14 8
2,5-Dimethyl- 100 33(e) 16(f)
4-Iodo- 25 l9(e) O(f~
3-Benzo[b]thienyl 100 11 5
7-Benzo[b]thienyl 100 -4 12(d)
15 7-Benzo[b]furanyl - - -
5-Chloro- 10 23(e) lO(f~
8-Chromanyl
6-Chloro- 10 - 11
6-Fluoro- 10 - 9
2,3-Dihydrobenzo-
furanyl
5-Chloro- 25 - 23(9)
2-Pyrrolyl 100 11 8
l-Methyl- 100 18 17
l-Ethyl- 100 14 16
l-(l-Butyl)- 100 ~ 13
l-Phenyl 100 30 32
3-Indolyl - - -
5-Bromo- 100 9 10
l-Methyl- 100 11 8
'--~
-27-
Table I. (Continued~
~ Lowering
Doseof Blood Glucose Level
Ar (mg./k~.) 0.5 hr. 1 hr.
3-Pyridyl - - ~
2-Methoxy lO - 13
2-Ethoxy- 25 - 20
2-Methoxy-5-chloro- 25 22 17
2-Ethoxy-5-chloro- 10 - 24(g~
5-Quinolyl
6 Methoxy- 20 - 7(h~
8-Quinolyl 18 19 16
6-Chloro- 10 - 16
6-Fluoro- lO - 15
7-Methoxy- 10 - -(i)
2-Thiazolyl- 75 ll 10
2-Benzthiazolyl- 50 8 10
5-isoxazolyl
3-Methyl- 100 ~ 7(j)
(a) 11 at 2 hours.
(b) 9 at 2 hours.
(c) 10 at 3 hours.
(d) 16 at 2 hours; 10 at 3 hours.
(e) At 0.75 hours.
(f) At 1.5 hours.
(g) At 0.75 hours.
(h) 9 at 2 hours.
(i~ 12 at 3 hours.
(j) 24 at 2 hours, 14 at 3 hours.
` ``
-28-
The oxazolidine-2,4-diones of the present
invention are clinically administered to mammals,
including man, via either the oral or the parenteral
route. Administration by the oral route is preferred,
being more convenient and avoiding the possible pain
and irritation of injection. However, in circumstances
where the patient cannot swallow the medication, or
absorption following oral administration is impaired,
as by disease or other abnormality, it is essential
that the drug be administered parenterally. By
either route, the dosage is in the range of about
0.10 to about 50 mg./kg. body weight of the subject
per day, preferably about 0.20 to about 20 mg./kg.
body weight per day administered singly or as a
divided dose. However, the optimum dosage for the
individual subject being treated will be determined
by the person responsible for treatment, generall~
smaller doses being administered initially and there-
after increments made to determine the most suitable
dosage. This will vary according to the particular
compound employed and with the subject being treated.
The compounds can be used in pharmaceutical
preparations containing the compound, or pharmaceutical-
l~ acceptable acid salt thereof, in combination with
a pharmaceutically acceptable carrier or diluent.
Suitable pharmaceutically acceptable carriers include
inert solid fillers or diluents and sterile aqueous
or organic solutions. The active compound will be
present in such pharmaceutical compositions in amounts
sufficient to provide the desired dosage amount in
the range described above. Thus, for oral administration
the compounds can be combined with a suitable solid
or liquid carrier or diluent to ~orm capsules, tablets,
-29-
powders, syrups, solutions, suspensions and the like.
The pharmaceutical compositions can if desired,
contain additional components such as flavorants,
sweeteners, excipients and the like. For parenteral
administration the compounds can be combined with
sterile aqueous or organic media to form injectable
solutions or suspensions. For example, solutions in
sesame or peanut oil, aqueous propylene glycol and
the like can be used, as well as aqueous solutions
of water-soluble pharmaceutically acceptable acid
addition salts of the compounds. The injectable
solutions prepared in this manner can then be admin-
istered intravenously, intraperitoneally, subcutaneously
or intramuscularly, with intramuscular administration
being preferred in man.
The present invention is illustrated by the
followinq examples. However, it should be understood
that the invention is not limited to the specific
de~ails of these examples.
~L~6~ 3
-30-
EXAMPLE 1
Methyl 2-Methoxypyridlne-3-carboxylate
Thionyl chloride (50 ml.) was added to 2-methoxy-
pyridine-3-carboxylic acid (5 g.) in 50 ml. of carbon
tetrachloride and the mixture refluxed for 2 hours.
The reaction mixture was cooled, evaporated to solids
and chased with multiple portions of fresh carbon
tetrachloride. The resulting acid chloride hydro-
chloride was dissolved in excess methanol (50 ml.),
stirred for 16 hours at room temperature, then evapo-
rated an oil and taken up in chloroform. The chloro-
form solution was washed with two portions of saturated
sodium bicarbonate and then one portion of brine~
dried over anhydrous magnesium sulfate, filtered and
evaporated to yield title product as an oil [4.63 g.;
pnmr/CDC13/delta (ppm): 3.9 and 4.1 (2s, 6H), 6.9 (m,
lH), 3.2 (m, 2H)].
By the same procedure, 4-methylpyridine-3-carboxylic
acid is converted to methyl 4-,methylpyridine-3-carboxy-
late.
.
~6~3
-31-
EXAMPLE 2
3 Methanesulrinylmethylcarbonyl-2-Methoxyp~ridine
Sodium hydride (2.69 g., 50% dispersion in oil,
0.056 mole) was washed three times with petroleum
ether. Following the third decantation, traces of
petroleum ether were removed by evaporation in vacuo.
Dimethylsulfoxide (30 ml.) was added and the mixture
heated in an oil bath at 75C. for 45 minutes, by
which time hydrogen evolution had ceased. The mixture
was cooled in an ice-water bath and diluted ~ith
30 ml. of dry tetrahydrofuran. Title compound of the
preceding Example t4.63 g., 0.028 mole) in 10 ml. of
dry tetrahydrofuran was added dropwise over 5 minutes.
The reaction mixture was warmed and stirred at room
temperature for 30 minutest poured into 180 ml. of
water, acidified to pH 4 with lN hydrochloric acid and
extracted with three portions of chloroform. The com-
bined organic layers were dried over magnesium sulfate,
filtered and concentrated to yield title product as an
oil [4.97 g.; pnmr/CDC13/delta (ppm); 2~8 ts, 3H), 4.1
~5, 3H), 4.4 and 4.7 (2d, 2H)t 7.0 (m, lH), 8.3 (m,
2~)].
By the same procedure the 4~methyl compound of
the preceding Example is converted to 3-methanesulfinyl-
methylcar~onyl-4-methylpyridine.
-32-
EXAMPLE 3
S-Methyl 2-Acetoxy-2-(2-methoxy 3-pyridyl)-
thioacetate
Title compound of the preceding Example (3.97 g.),
sodium acetate (3.97 g.) and acetic anhydride (40 ml.)
were combined in 80 ml. of toluene and heated at 115
for 16 hours~ The mixture was cooled and evaporated
to dxyness in vacuo to yield crude product. The
latter was chromatographed on 200 g. of silica gel
with 2:1 chloroform:ethyl acetate as eluant, tlc
monitoring and collecting 10 ml. fractionsO Clean
product fractions 58-79 were combined and concentrated
to an oil. To remove possible traces of residual
acetic anhydride, the oil was taken into wet ethanol,
held for 15 minutes, re-evaporated, chased with toluene,
taken up in chloroform, dried over anhydrous magnesium
sulfate, filtered, and re-evaporated to yield the
title product as an oil [3.16 g.; Rf 0.60 (3:1 ethyl
acetate: methanol); m/e 255; ir (CH2C12) 1748t 1686,
1582, 1460, 1205 om~l].
By the same procedure the methyl compound of the.
preceding Example is converted to S-methyl 2-acetoxy-
2-(4 methyl-3-pyridyl)thioacetate.
-33-
EXAMPLE 4
5-(2-Methoxy-3-p~idyI)oxazo-lidine-2~4-dione
Sodium methoxide (632 mg., 11.7 mmoles) was taken
into 50 ml. of absolute ethanol and the solution
cooled in an ice-water bath. Urea (234 mg., 3.9
mmole) was added, followed by the title compound of
the preceding Example (1.0 g., 3.9 mmole) in 5 ml. of
ethanol~ The mixture was heated at reflux for 16
hours, then cooled to room temperature, neutralized
with 11.7 ml. of lN hydrochloric acid and evaporated
to a gum which was chased with toluene. The gum was
chromatographed on 40 g. of silica gel with 1:2 ethyl
acetate:chloroform as eluant, tlc monitoring and
10 ml. fractions collected. Product containing fractions
6-15 were combined and evaporated to a viscous oil,
which was crystallized from water [75 mg; m.p. 183-
18 6 C ., Rf O . 3 2 ( 1: 2 ethyl acetate:chloroform~].
By the same method, the methyl analog of the
preceding Example is converted to 5-~4-methyl-3-
pyridyl)oxazolidine-2,4-dione.
- ` f`~ L¢~ ~L~
-34-
EXAMPLE S
Ethyl 2-Ethoxyeyridine-3-carboxylate
2-Ethoxypyridine-3-carboxylic acid (4 g.) was
converted to its acid chloride hydrochloride by reflux-
ing with 8.6 ml. of thionyl chloride for 60 minutes.
The reaction mixture was evaporated to solids with
toluene chase to removed the excess thionyl chloride.
The residue was taken into 80 ml. of ethanol and held
for 16 hours at 0C., then evaporated to solids, which
were partitioned between toluene and lN sodium hydroxide.
The aqueous layer was extracted with fresh toluene and
the two organic layers combined, washed with water and
then brine, dried over anhydrous magnesium sulfate,
filtered and evaporated to yield title product as an
oil [3.2 g.; pnmr/CDC13/delta (ppm) 1.6 12s, 6H), 4.4-
5.0 (2q, 4H), 7.2 and 8.2 (m, 3H)].
-35-
EXAMPLE 6
2-Ethoxy-3-methanesulfinylmethyl
carbonvlDvridine
. . ~ .. _ _
Vsing methylene chloride in place of chloroform
in the isolation, the procedure of Example 2 was
employed to convert product of the preceding Example
~3.0 g.) to title product [2.63 g.; m.p. 89-91C.;
pnmr/CDC13/delta (ppm), 1.5 tt, 3H), 2-~ (s, 3H), 402-
4.8 (s and q, 4X), 6~8-7.1 and 8.0-8.4 ~3H)].
EXAMPLE 7
S-Methyl 2-Acetoxy-2-(2-ethoxy-3-pyridyl)-
thioacetate
Using a reaction time of 4 hours at 100C. and
then 48 hours at room temperature, the procedure of
Example 3 was employed to convert the product of the
preceding Example (2.5 gO) to crude product, isolated
as an oil by evaporation of the reaction mixture. The
oil was taken up in ethyl acetate, washed in sequence
with three portions of lN sodium hydroxide, one of
water and one of brine, dried over anhydrous magnesium
sulfate and evaporated to yield title product as an
oil [2.96 g.; Rf 0.78 (10:1 ethyl acetate:methanol);
m/e 2693.
`i ) ~.~6~
-36-
EXAMPLE 8
2-t2-Ethoxy-3-pyridyl)-2-hydroxy _ tamide
Product of the preceding Example (2.9 g.) was
combined with 30 ml. of ethanol and 30 ml. of conc.
ammonium hydroxide, stirred at room temperature for 3
hours and then evaporat~d to yield crude product as an
oil (2.7 g.). The oil was chromatographed on 170 g.
of silica gel using ethyl acetate as eluant and tlc
monitoring. Clean product fractions were combined and
evaporated to yield title product as an oil [0.9 g.;
Rf 0.6 (10:1 ethyl acetate:methanol); pnmr/CDC13/delta
(ppm) 1.4 (t, 3H), 4.5 (q, 2H), 5.4 (s, lH~, 6.2-8.2
(m, 5H)].
``(~ ~LG,~3~3
-37-
EXAMPLE 9
5-(2-Ethoxy-3-pyridyl)oxazolidine~2,4-dione
Product of the preceding Example (900 mg., 4.6
mmole) was combined with 25 ml. of tert-butanol.
Dimethyl carbonate tl.08 g., 9~2 mmole) and then po-
tassium tert-butoxide (1.03 g., 9.2 mmole) were added
and the reaction mixture refluxed for 3.5 hours. The
reaction mixture was cooled, poured into 10 ml. of lN
hydrochloric hydrochloric acid, the pH adjusted to
7.0, and extracted with two portions of ethyl acetate~
The aqueous layer was saturated with salt and extracted
with additional ethyl acetate. The three organic
layers were combined, hack~washed with a small portion
of water and then brine, dried over anhydrous magnesium
sulfate and evaporated to yield crude product as a
viscous oil. Purified title product was obtained by
crystallization from toluene (295 mg., m.p. 140-
143C.; m/e 272)~
Anal. Calcd. for: CloH10O4N2:
C, 54.05; H, 4.54; N, 12.61.
Found: C, 54.34~ H, 4.85, N, 12.70.
(--) ~6~ 3
-38-
"
EXAMPhE 10
Methyl 5-Chloro-2-methoxypyridine-3-
` c rbo~ylate
By the procedure of Example 1, 5-chloro-2-
methoxypyridine-3-carboxylic acid [Sarges et al., J.
Med. Chem. 19, 709 (1976); 10 g.] was converted to its
acid chloride, which was added in one portion to
150 ml. of methanol (slight exotherm), then made basic
with triethylamine (approximately 1.1 equivalents).
The reaction mixture was evaporated to solids and the
residue partitioned between ethyl acetate and water.
The ethyl acetate layer was washed with fresh water and
then brine, dried over anhydrous magnesium sulfate,
filtered and evaporated to yield title-product [9.75 g.,
m.p. 79-81C.; pnmr/CDC13/delta (ppm) 3.8 (s, 3H), 4.1
~s, 3H), 8.1 (d, lH), 8.3 (d, lH)3.
EXAMPLE 11
5-Chloro-3-methanesul:Einylmethylcarbonyl-
_ _ 2-methoxy~yridine
By the procedure of Example 2, the product of the
preceding Example (9.7 g., 0.045 mole~ was converted to
title product isolaked as a visous oil (10.3 g., m/e
249/247).
"<'
-39-
EXAMPLE I2
S-Methyl 2-Acetoxy-2-(5-chloro-2-methoxy-3-
E~_dYI)thioacetate
Using a reaction time of l9 hours at 100C., the
procedure of Example 3 and the isolation method of
Example 7 were employed to convert product of the
preceding Example (10~3 g.) to title product in the
form of a viscous oil (8.8 g.; pnmr/CDCl3 includes
singlet at 6.4; m/e 291/289)~
EXAMPLE I3
2-(5-Chloro-2-methoxy-3-pyridyl)-2-hydroxy-
acetamide
Methanol ~125 ml.) was saturated with anhydrous
ammonia at 0-5C. The product of the preceding Example
(8.8 g.) in 25 ml. of methanol was added and the re-
action mixture stirred overnight at room temperature,
then concentrated to a viscous oil (7.3 g.). The oil
was chromatographed on 400 g. of silica gel using 1:1
chloxoform:ethyl acetate as eluant, tlc monitoring and
10 ml. fractions. Clean product fractions 190-270
were combined and evaporated to yield title product
~1.3 g.; m.p. 110-113C.; mJe 218/216; ir(KBr) 3444,
3410, 1684 cm~l].
~''~';,.~
;i
-40- -
EXAMPLE I4
5-(5-Chloro-2-methoxy-3-pyridyl)oxazolidine-
2,4-dione
.
Using a reflux period of 15 hours, the procedure
of Example 9 was employed to convert the product of
the preceding Example ~1.25 g., 5.8 mmoles) to title
product. To isolate, the reaction mixture was cooled
to room temperature and the pH adjusted to 3 with lN
hydrochloric acid. The mixture was then evaporated in
vacu_ to slightly gummy solids, which gave filterable,
crude product on stirring with 25 ml. of water (1.09 g.,
m.p. 199-204C. Recrystallization from 15 ml. of
ethanol gave purified title product [470 mg.; m.p.
212-214C.; m/e 244/242; ir(KBr) 3174, 3074, 2980,
1830, 1752 cm 1].
-41-
EXAMPLE I5
2-(6-Chloro~8-quinolyl)-2-hydroxyacetamide
Ethyl 2-(6-chloro-8-quinolyl)-2-hydroxyacetate
tl.6 g.) in 300 ml. of conc~ ammonium hydroxide was
heated to reflux. Since complete dissolution did not
result, the reaction mixture was cooled, diluted with
50 ml. of ethanol and reheated to reflux for 0.5 hour.
The reaction mixture was concentrted to a volume of
100 ml., cooled slowly and a crop o title product
(320 mg., m~p. 195-198C.) recovered by filtration.
Additional product (14S mg). was recovered by concen-
tration of the mother liguox to 50 ml. and extraction
into three portions of ethyl acetate. The combined
organic layers were washed with saturated sodium bi-
carbonate, dried over anhydrous magnesium sulfate,
filtered and evaporated to dryness.
By the same procedure, ethyl 2-(6-chloro-2,3-
dihydro-7-benzo[b]furanyl)-2-hydroxyacetate is converted
to ethyl 2-t6-chloro-2,3-dihydro-7-benzo~b]furanyl)-2-
hydroxyacetamide
4~
-42-
EXAMPLE 16
-
5-(6-Chloro-8-quinolylloxazolidin -2,4-dione
Potassium tert-butoxide (292 mg., 2.6 mmoles) was
dissolved in 20 ml. of tert-butanol. Dimethyl carbonate
(234 mg. 2.6 mmoles) and then title compound of the
preceding Example (300 mg., 1.3 mmoles) were added.
The reaction mixture refluxed for 18 hours ! then
cooled to room temperature, adjusted to pH 3 with lN
hydrochloric acid and diluted with lN hydrochloric
acid and ethyl acetate. The aqueous layer was washed
with two additional portions of ethyl acetate. The
organic layers were combined, washed with two portions
of fresh lN hydrochloric acid and then brine, dried
over anhydrous magnesium sulfate, filtered and evaporated
to an oil (130 mg.). Crystallization of the oil from
isopropyl ether gave purified title product [58 mg.,
m.p. 207-210DC.; ir(KBr) 1839, 1825, 1740 cm l].
By the same procedure the ben~ofuran analog of
the preceding Example is converted to 5-(6-chloro-2,3-
dihydro-7-benzo[b]furanyl)oxazc)lidine-2,4-dione.
-~3-
EXAMPLE I7
2-(6-Fluoro-8-quinolyl)-2-hydroxyacetamide
Ethyl 2-(6-fluoro-8-quinolyl)-2-hydroxyacetate
(1.1 g.~ was refluxed for lO minutes in 300 ml. of
conc. ammonium hydroxide. The reaction mixture was
cooled slightly, clarified by filtration and evaporated
to solids. Trituration of the residue with 25 ml. of
toluene gave the title product (860 mg., m.p. 169-
171C.).
EXAMPLE 18
5 (6-Fluoro-g-quinolyI)oxazolidine-2l4-dione
Using a reflux period of 3~5 hours, the product
of the preceding Example (840 mg., 3~8 mmoles) was
converted to title product by the procedure of Example
lS 16. In this case, a pH of 2 was used in the isolation
without addition of excess lN hydrochloric acid and
the crude product was recrystallized from toluene
[120 mg., m.p. 202-204C.; m/e 246; ir(KBr) 1819,
1743, 1363 cm l~.
_4~ 3
EXAMPLE I9
5-(8-QuinoIyl)oxazolidin-4-one-2-thlone
Potassium thiocyanate ~484 mg., 4.9 mmoles) and
potassium cyanide t370 mg., 5.7 mmoles) were combined
in 5 ml. of water and cooled to 0C. Quinoline-8-
carbaldehyde [J. Org. Chem. 41, p. 957 (1976); 779 mg.,
4.9 mmoles] was added, followed by the dropwise addition
of hydrochloric acid (30%, 1.9 ml.). After stirring
for 25 minutes at 0~C., the reaction mixture was
heated to 90-100C. for 25 minutes, cooled, quenched
into crushed ice, adjusted to pH 8 with sodium bicarbonate
and ex~racted with cloroform. The organic layer was
dried over anhydrous magnesium sulfate, filtered and
evaporated to dryness (163 mg.). The latter was
partitioned between lN sodium hydroxide and ethyl
acetate. The basic layer was acidified and extracted
with fresh ethyl acetate. The two ethyl acetate
layers were combined, dried, filtered and evaporated
to yield title product ~72 mg.; R~ 0.65 tethyl acetate)].
The original, pH 8 aqueous layer was salted and extracted
with ethyl acetate to yield an addi ional crop (114 mg.).
The last aqueous phase was acidified and extracted
with ethyl acetate to yield a third crop (115 mg.l.
By the same method, 7-chloroquinoline-8-carb-
aldehyde is converted to 5-(7-chloro 8-quinolyl)oxa-
zolidin-4-one-2-thione.
~:o
-45-
EXAMPLE 20
5-(8-Quinolyl)oxazolidine-2,4-dione
Title compound of the preceding Example (230 mg.,
. -
0.94 mmole) was taken into 6 ml. of 2:1 methanol:water
and cooled to 0C. Bromine (0.07 ml., 21.7 mg., 2.7
mmoles) was added and the reaction mixture allowed to
warm slowly to room temperature, then stirred for 1
hour. The reaction mixture was evaporated to dryness
and the residue partitioned between lN sodium hydroxide
and ethyl acetate. The aqueous layer was separated,
acidified and extracted with two portions of fresh ethyl
acetate. The acidic extracts were combined, dried and
evaporated to an oil (144 mg.l. Crystallization from
toluene-chloroform and recrystallization from toluene
gave purified title product (40 mg., m/e 228).
12 8 3 2 2
C, 61.54; H, 3.70; ~, 11.96.
Found: C, 61.50; H, 3.89; N, 11.52.
By the same method the chloro compound of the
preceding Example is converted to 5-(7-chloro-8-quinolyl)-
oxazolidine-2,4-dione.
-`o
-~6-
EXAMPLE 21
5-(6-Methoxy-5-quinolyl)oxazolidin-4-
_ one-2-thione
By the procedure of Example 19, 6-methoxyquinoline-
` 5 5-carbaldehyde (0.77 g.) was converted to title product.
After quenching into ice, a first crop (190 mg.) was
isolated by extraction into ethyl acetate, drying over
anhydrous magnesium sulfa~e and evaporation to dryness.
A second crop (176 mg.) was isolated in like manner by
adjusting the aqueous phase to pH 8 with bicarbonate
and extracting with additional ethyl acetate. Both
crops had m/e 274. The second crop also had m/e 258,
indicating contamination with the product of the next
step.
"` O ~ 3
-~7-
EXAMPLE 22
5-(6-Methox~-5-quinolyl~oxazolidine-2 ! 4-dione
The combined product crops of the preceding
Example (0.36 g., 1.31 mmole) were taken into 15 ml.
of methanol. Sodium metaperiodiate (0.56 g., 2.62
mmoles) in 7.2 ml. of 5~ sodium bicarbonate was added
dropwise. After stirring for 3 hours at room temperature,
the reaction mixture was quenched with water, acidified
and extracted with two portions of ethyl acetate. The
organic extracts were combined, dried over anhydrous
magnesium sulfate, filtered and evaporated to dryness
(llQ mg.). The aqueous phase was adjusted to pH 7 and
further crude product (100 mg.) obtained by extraction
with ethyl acetate. The crude crops were combined,
taken into lN sodium hydroxide, acidified to pH 4 with
acetic acid and extracted with fresh ethyl acetate.
The latter organic extracts were combined and evapo-
rated to dryness. Trituration of the residue with
ether, allowing the mixture to stand until crystal-
lization was complete, gave title product i34 mg.;m.p. 144-146C.).
~ 3
-4~-
EXAMPLE 23
5-(7-Methoxy-8-quinolyl)oxazolidin-4-
one-2-thione
By the procedure of Example 19, but using adjust-
ment to pH 7 with ~icarbonate after quench and ethyl
acetate for extraction, 7-methoxyqu~noline-8-carb-
aldehyde t2.0 g., 10.7 mmoles) was converted to title
product [1.17 g.; Rf 0.7 (2:1 ethyl acetate:chloro-
form)]. This product was not partitioned between
aqueous base and ethyl acetate, nor was a second crop
isolated by salting the aqueous phase and further
extracting.
EXAMPLE 24
5-(7-Methoxy-8-quinolyl)oxazolidine-2,4-dione
Product of the preceding Example (0.74 g., 2.7
mmoles) was combined with 30 ml. of methanol and
15 ml. of 5% sodium bicarbonate. Sodium metaperiodate
(1.15 g., 5.4 mmoles) in 15 ml. of water was added
dropwise. After stirring for 3 hours at room temperature,
the reaction mixture was quenched with water, acidified
to pH 2-3 and extracted with two portions of ethyl
acetate. The extracts were combined, dried and
evaporated to dryness (360 mg.). Recrystallization
from water gave purified title product (100 mg.; m.p.
25 207-208C.).
Anal. Calcd. for C13HgN2O3.1. H2 :
C, 59.40; H, 4.34; N, 10.66.
Found: C, 59.33; H, 4.01; N, 10.66.
-49-
EXAMPLE 25
5-Hydroxy-5-(1-methyl-2-pyrrolyl)-2,4,6-
(lH,3H,5H)pyrimidinetrione
Alloxan hydrate ~3.2 g., 0.02 mole) was dissolved
in 50 ml. of ethanol by warming. l-Methylpyrrole
(1.6 g., 0.02 mole) was added and the mixture warmed
for 5 minutes on a steam bath, while perfusing with
hydrogen chloride. After standing at room temperature
for 0.5 hour, the reaction mixture was evaporated to
dryness and the residue triturated with water to yield
title product as a solid [2.9 g.; m/e 223; Rf 0.5 (1:1
ethyl acetate:hexane/5% acetic acid)].
EXAMPLE 26
5-(l-Methyl-2-pyr-oIyl)oxazolidine~2~4-dione
Product of the preceding Example (2.8 g.) was
combined with 25 ml. of lN sodium hydroxide and heated
on a steam bath for 30 minutes, by which time complete
dissolution had occurred. On acidification, a gum
precipitated, which solidified on trituration with
water (1.2 g.). ~ecrystallization from methanol-ether
afEorded purified title product ~0.70 g.; m.p. 108-114
(dec); m/e 180].
Anal. Calcd. for C8H8O3N2: C, 53.33; H, 4.48; N, 15.55~
Found: C, 53.16; H, 4.72; N, 15.28.
`" O ~ 3
-50-
EXAMPLE 27
5-Hydroxy-5~ ethyl-2-pyrrolyl)-2,4,6-
(lH,3H,SH)pyrimidiAc~r~one
Potassium pyrrole [J. Chem~ Soc., p. 52 (1931);
1 g.; 0.01 mole] was slurri~d in 5 ml. of tetrahydro-
furan. Ethyl iodide (1 ml., 0.012 mole) was added, a
slight exotherm being noted. The mixture was stirred
for 0.5 hour, heated to reflux for 0.5 hour, cooled to
room temperature, diluted with 15 ml. of water and
extracted with 10 ml. of ether~ The ether extract was
washed with 5 ml. of water, then added to alloxan
hydrate (1.6 g.) which had been dissolved in 25 ml. of
ethanol by heating. The ether was boiled off and the
ethanolic residue refluxed for 0.5 hour, then evapo-
rated to a water-soluble gum. The gum was taken up in
25 ml. of ethyl acetate, washed with two 10 ml. portions
of water and re-evaporated to yield title product as a
gum ~0.6 g., m/e 237).
o
-51-
EXAMPLE 28
5~ Ethyl-2-pyr-roIyl)oxazolidine-2/4-dione
The procedure of the preceding Example was re-
peated on a three times scale. The initially isolated
product gum ~0.03 mole of the pyrimidinetrione~ was
stirred with 60 ml. of lN sodium hydroxide for 0.5
hour, then acidified with conc. hydrochloric acid and
extracted with ethyl acetate. The extract was filtered
from insoluble impurities, and concentrated to a gum
(2O2 g.). The gum was chromatographed on 100 ml. of
silica gel with (1:1 ethyl acetate:hexane as eluant and
tlc monitoring. Early fractions contained the desired
product; these were combined and evaporated to an oil
which crystalliz~d on standing. Trituration with water
gave purified title product (170 mg.; m.p. 90-93C.;
m/e 194).
AnalO Calcd. fo 9 10 3 2 2
C, 54.40; H, 5.32; N, 14.10.
Found: C, 54.37; H, 5.16; N, 13.76.
6~8~3
EXAMPLE 2g
5-Hydxoxy-5-[1-~1-butyl)-2-pyrrolyl)-
_ 2,4,6-(lH,3H,5H)p~rimidinetrione
Potassium pyrrole (3.0 g., 0.03 mole), l-iodo-
butane ~9.2 g., 0.05 moles) and 10 ml. of tetrahydro-
furan were combined and refluxed for 1.5 hours by which
time the reaction mixture had become a thick mass. The
reaction mixture was diluted with 30 ml. of water and
extracted with 35 ml. of ether. The ether was back-
washed with water, then added to a solution of an-
hydrous alloxan (4.8 g., 0.03 mole) obtained by heating
in 50 ml. of ethanol. The ether was distilled away, 6N
hydrochloric acid (5 ml., 0.03 mole) was added, and
the mixture refluxed for 3 minutes, cooled, evaporated
to a gum, and triturated with water to afford title
product [5.1 g.; m.p. 135 (dec); mte 265].
EXAMPLE 30
5~ Butyl)~2-pyrrol~l]oxazolidine-2,4-dione
Product of the preceding Example ~5.1 g., 0.019 mole)
was combined with lN sodium hydroxide (38 ml., 0.038 mole) and
stirred at room temperature for 10 minutes. The reactLon mixture
was filtered, washed with ether, cooled in an ice-water bath,
acidified with conc. hydrochloric acid and extracted with three
portions of ethyl acetate. The organic extracts were combined,
washed with brine, dried over anhydrous sodium sulfate and
evaporated to gummy solids. The latter was chromatographed on
silica gel with ethyl acetate as eluant and tlc monitoring to
yield partially purified product isolated as an oil (950 mg.). The
latter was rechromatographed using 1:1 ethyl acetate:hexane as
eluant, yielding purified title product as an oil [0.59 g.; m/e
222; Rf 0.72 (ethyl acetate~]. Anal. Calcd. for CllHl~O3N2.O.5H2O:
C, 57.38; H, 6.57; N, 12.17.
Found: C, 57.40; H, 6.35; N, 12.15.
,~ -53-
~!
~6~43
EXAMPLE 31
Sodium 5-[1-(1-butyl)-2-pyrrolyl]oxazolidine-2,4-dione
Product of the preceding Example (370 mg., 1.66 mmoles~
was dissolved in 5 ml. of methanol. Sodium bicarbonate (90 mg.,
1.66 mmoles) was added. The resulting solution was evaporated
to dryness and the solid residue triturated with ether to yield
the title product [300 mg.; m.p. 123-126C. (dec); tlc mobility
with 1:1 ethyl acetate:hexanet5% acetic acid as eluant identical
with the free base form].
-5~-
` ~ 3
EXAMPLE 32
~ . . ~
5-Hydroxy-5-(1-phenyl-2-pyrrolyl)-2,4,6-
( IH, 3~, SH ) pyrimidinetrione
l-Phenylpyrrole (1.4 g., 0.01 mole), alloxan
hydrate (1.6 g., 0.01 mole) and 50 ml. of ethanol were
combined and refluxed for 15 minutes. No reaction was
noted by tlc. lN Hydrochloric acid (10 ml., 0.01
mole) was added and the acidified mixture refluxed for
15 minutes. Incomplete reaction was noted by tlc. A
second portion of alloxan hydrate (1.6 g., 0.01 mole)
was added and the mixture refluxed another 15 minute,;,
cooled and evaporated to dryness. Trituration of the
residue with water gave title product ~2.3 g.; m/e
285; m.p. 232-234C. (dec); Rf 0.3 (1:1 ethyl acetate:
hexane)].
14 11 4 3' 2
C, 58.01; H, 4.00; N, 14.50.
Found: C, 57.84; H, 4.05; N, 14.56.
' ' O
-56-
EXAMPLE 33
__
5-(1-Phenyl-2-pyrrolyl)oxazolidine-2,4-dione
The product of the preceding Example (1 g.) was
heated on a steam bath for 20 minutes with 20 ml. of
lN sodium hydroxide. The mixture was then cooled in
an ice-water bath, acidified with conc. hydrochloric
acid and the supernatant decanted from the resulting
gummy precipitate. The gum was taken up in ethyl
acetate, washed with water~ and evaporated to an oil
~0.47 g.). The aqueous decant was also extracted with
ethyl acetate, the extract back washed with water and
evaporated to a second oil (0.28 g.). The two oils
were combined, chromatographed on 150 ml. of silica
gel with 1:1 ethyl acetate:hexane as eluant and tlc
monitoring. The early, product fractions were combined,
evaporated to an oil (410 mg.) and the oil crystallized
from ether-hexane to yield purified title product
[280 mg.; m.p. 130-132C.; m/e 242; Rf 0.47 (1:1 ethyl
acetate:hexane)].
13 10 3 2
Found: C, 64.40; H, 4.35; N, 11.56.
-57-
EXAMPLE_34
5-Hydroxy-5~ methyl-3-indolyl)-2,4,6,-
_ lH~3H,5EI)pyrimidinetrione
Alloxan hydrate (1.6 g., 0.01 mole) l-methylindole
tl.3 g., 0.01 mole) and ethanol (50 ml.~ were combined
and thP mixture refluxed for 0.5 hour, then concen-
trated to half-volume, diluted with water and the
resulting product recovered by filtration [2~7 g., Rf
0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
EXAMPLE 35
5-(l-Methyl-3-indolyI)oxazolidine-2~4-dione
Product of the preceding Example (2 g.) was
heated on a steam bath for 15 minutes with 35 ml. o
lN sodium hydroxide~ The reaction mixture was cooled
to room temperature, acidified to pH 1 with conc.
hydrochloric acid, and decanted from a small amount of
gum (130 mg.). The decant was clariied by filtration,
cooled in an ice-water bath, and the resulting solids
(330 mg~) recovered by filtration. The filtrate was
extracted with ethyl acetate; the extract was back-
washed with water and evaporated to solids (0.61 g.).
The solid products were combine~d and recxystallized
rom ethyl acetate/hexane to yield title product
(0.33 g.; m.p. 152-153.5C.).
Anal- Calcd- for C12H103N2 l25H2
C, 61.99; H, 4.45; N, 12.05.
Found: C, 61.99; H, 4.45; ~, 12.02.
O
-5~-
EXAMPLE 36
5-Hydroxy-5-(5-bromo-3-indolyl)-2,4,6-
(lH,3H,5H)pyrimidinetrione
Alloxan hydrate (1.6 g., 0.01 mole) was dissolved
in 40 ml. of ethanol by heating. 5-Bromoindole (1.96 g.,
0.01 mole) was added and heating near reflux continued
for 15 minutes. Tlc did not indicate that reaction
had occured. lN Hydrochloric acid (10 ml.) was then
added while maintaining the reaction near reflux.
After 10 minutes, the reaction was concentrated to wet
solids. Trituration oE these wet solids with water
gave the title product [3.17 g.~ m.p. 250C.; Rf 0.45
(1:1 ethyl acetate:hexane/5% acetic acid); Rf 0~3 (1:5
ethyl acetate:hexane/5% acetic acid)].
EXAMPLE 37
5-(5-Bromo-3--ind-lyI)oxazolidi-ne-2~4 dione
Product of the preceding Example (3.1 g.) was
heated on a steam bath with 50 ml. of lN sodium hy-
droxide for 15 minutes, then cooled and crude product
~1.25 g.) precipitated by acidiEication with conc.
hydrochloric acid. Chromatography on silica gel,
using 1:1 ethyl acetate:hexane as eluant and tlc
monitoring gave puriied title product [0.41 g.; m.p.
185-189C.; Rf 0.55 (1:5 ethyl acetate:hexane/5
acetic acid)].
Anal. Calcd. for CllH7O3N2Br: C, 44.76; H, 2.38; N, 9.49.
Found: C, 45.10; H, 2.68; N, 9.58.
C~ .
-59-
EXAMPLE 38
S-Hydroxy-5-(2-thiazolyl)-2,4,6-
(lH,3H,5H)pyrimiainetrione
Thiazole tl.7 g., 0.02 mole) was dissolved in
tetrahydrofuran (35 ml.) and cooled to -60C. Butyl-
lithium (9 ml. of 2.4M in hexane, 0.0216 mole) was
added dropwise over 20 minutes, and the reaction mix-
ture stirred for an additional 30 minutes at -60C.
In this manner 2-thiazolyllithium was formed. Anhydrous
alloxan (3 g., 0.021 mole) was dissolved in 20 ml. of
tetrahydrofuran and added dropwise over 20 minutes,
keeping the temperature at -60C. The stirred reaction
mixture was warmed to room temperature over 30 minutes,
then recooled to 0C. lN Hydrochloric acid (25 ml.)
was addecl portion wise and the quenched reaction
mixture extracted with S0 rnl. of ethyl acetate. The
ethyl acetate extract was bacX-washed with 15 ml. of
water, dried over anhydrous sodium sulfate, filtered
and evaporated to yield title product [1.9 g.; m/e
227; Rf 0.4 (1:1 ethyl acetate:hexane/5% acetic acid)].
By the same procedure, oxazole is converted to 5-
hydroxy-5-(2-oxazolyl)-2,4,6-(lH,3H,5H)pyrimidinetrione.
-60-
EXAMPLE 39
5-(2-Thiazolyl)oxazolidine-2,4-dionè
Title product of the preceding Example (1.37 g.)
was stirred at room temperature with 24 ml. of lN
sodium hydroxide. The reaction mixture was allowed to
stand for 25 minutes, acidified with 3 ml. of glacial
acetic acid and extracted with two 50 ml. portions of
ethyl acetate. The extracts were separately dried
over sodium sulfate, filtered and evaporated to solids,
the first yielding 184 my., the second 85 mg. These
solids were combined and chromatographed on 50 ml. of
silica gel with 1:1 ethyl acetate:hexane/5~ acetic
acid as eluant and tlc monitoring. Clean product
fractions were combined, evaporated to dryness and the
residue triturated with hexane to yield purified title
product (155 mg.; m.p. 150-152C.).
Anal. Calcd. for C6H4O3N2S: C, 39.13; H, 2.19; N, 15.21.
Found: C, 39.53; H, 2.52; N, 14.95.
By the same procedure, the other product of the
preceding Example is converted to 5-(2-oxazolyl)oxa-
zolidine 2,4-dione.
~"`o
-61~ 3
EXAMPLE 40
-
5-Hydroxy-5-(2-benzthiazolyl)-2,4,6-
(lH,3H,5H)pyrimidinetrione
By the procedure of Example 38, benzthiazole
5(2.7 g., 0.02 moles) was converted to its 2-lithio
derivative and then reac~ed with anhydrous alloxan to
yield title product, initially isolated as an oil.
The latter was crystallized from ether-hexane [2.2 g.;
Rf 0.55 (1:1 ethyl acetate:hexane/5% acetic acid)].
10EXAMPLE 4~
5-(2-BenzthiazolyI)oxazolidine-2,4~dione
Product of the preceding Example 2.15 g.) was
stirred with 30 ml. of lN sodium hydroxide for 30
minutes. The reaction mixture was extracted with
15 ether and product (0.46 g.) precipitated by acidifi-
cation of the aqueous layer with 6N hydrochloric acid.
Chromatography on 50 ml. of silica gel with 1:1 ethyl
acetate:hexane/5% acetic acid as eluant and tlc
monitoring, followed by recrystallization from acetone-
isopropyl ether gave purified title product ~110 mg.,
m.p. 214-216C. (dec)J.
Anal. Calcd. for CloH603N2S: C, 51.29; H, 2.5~; N, 11.96.
Found: C, 51.51; H, 2.99; N, 12.21.
-62~ 3
EXAMPLE 42
2-(6-Chloro-8-chromanyl)-2-trimethylsiloxy-
ethanenitrile
6-Chlorochroman-8-carbaldehyde (7 g., 0.036 mole)
in 70 ml. of methylene chloride was cooled to 0-5C.
Zinc iodide (100 mg.~ was added, followed by the drop-
wise addition of trimethylsilylcarbonitrile (4.26 g.,
0.043 mole). The reaction mixture was stirred at room
temperature for 64 hours, then washed in sequence with
three portions of saturated sodium bicarbonate and one
of brine, dried over anhydrous magnesium sulfate,
filtered and evaporated to yield title product as an
oil [9.5 g.; ir(CH2C12) 2857l 1479, 1215, 1190, 1060
-1~
EXAMPLE_43
Ethyl 1-(6-Chloro-8-chromanyl)-l-hydroxy-
methanecarb_ximidate Hydrochloride _
To cold (0-5C.), saturated ethanolic hydrogen
chloride (250 ml.) there was added, in a dropwise
manner, product of the preceding Example (9.29 g.) in
15 ml. of ethanol, keeping the temperature below 10C.
The mixture was stirred at 0-5C. ~or 35 minutes and
then evaporated to an oil. Crystallization from
ethanol-ether gave title product [5.7 g.; m.p. 125-
127 (dec); m/e 271/269].
~'`o
-63~ 3
EXAMPLE 44
5-(6-Chloro-8-chroman~ oxazolidine-2,4-dione
Product of the preceding Example (5.4 g., 18.6
mmoles~ was suspended in 250 ml. of tetrahydrofuran~
cooled in an ice-water bath, and triethylamine t6.01 g.,
0.06 mole~ added. The cold mixture was perfused with
phosgene for 30 minutes, stirred at room temperature
for 1 hour and then poured into 1 liter of crushed
ice. The quenched reaction mixture was extracted with
three portions of methylene chloride. The co~bined
extracts were washed with brine, dried over anhydrous
magnesium sulfate and evaporated to solids. The
residue was recrystallized from toluene to yield
purified title product (3.28 g., m.p. 170-172C., m/e
269/267).
Anal. Calcd. for C12H10O4NCl: C, 53.84; H, 3.77; N, 5.23.
Found: C, 53.73; H, 3.83; N, 5.48
EXAMPLE 45
2-(6-Fluoro-8~chromanyl)-2-trimethylsiloxy-
ethanenitrile;
By the procedure o~ Example 42, 6-fluorochroman-
8-carbaldehyde ~3.2 g., 0.0178 mole) was converted to
title product as an oil [4.51 g., m/e 279; ir (CHC12)
1498, 1205, 1066 cm~l]~
o
~64~ 3
EXAMPLE 46
Ethyl 1-(6-Fluoro-8-chromanyl)-1-hydroxy
_ methanecarboximidate Hydrochloride
Using a reaction time of 1 hour at 0-5C., the
5 procedure of Example 43 was employed to convert
product of the preceding Example (4.4 g.) to title
product [4.1 g.; m.p. 124-126C. (dec); m/e 253].
EXA~PLE 4 ?
5-[6-Fluoro-8-chromanyl)oxazolidine-2,4-dione
By the procedure of Example 44, product of the
preceding Example (3.9 g., 0.0134 mole) was converted
to crude title product. Crude solids were taken into
lN sodium hydroxide and extracted with two portions of
ether. Product was reprecipitated by adding the basic
aqueous layer slowly to excess 3N hydrochloric acid.
Recrystallization from toluene gave purified title
product [2.73 g.; m.p. 174-176C.; m/e 251].
Anal. Calcd. for C12H1004NF: Cy 57.37; H, 4.01; N, 5-58~
Found: C~ 57.74; H, 3.91; N, 5,40.
`` ` ~.~L&~ 3
-65-
EXAMPLE 48
~ . _
2-(5-Chloro-2,3 dihydro-7-benzorb]furanyl)-2-
trimethylsiloxyethanenitriIe
5-Chloro-2,3-dihydrobenzo[b]furan-7-carbaldehyde
(900 mg., 4.9 mmoles) was dissolved in 25 ml. of
ether Zinc iodide (20 mg.) and then trimethylsilyl-
carbonitrile (970 mg., 9.8 mmoles) were added and the
mixture stirred 16 hours at room temperature, then
diluted with 50 ml. ether, washed with three portions
of saturated sodium bicarbonate and one of brine,
dried over anhydrous magnesium sulfate, filtered and
evaporated to yield title product as an oil [1.4 g.;
m/e 283/281; ir(CHC12) 1479, 1457, 1435, 1180, 865,
848 cm~l].
By the same method 5-fluoro-2,3-dihydrobenzo[b]-
furan-7-carbaldehyde is converted to 2-(5-fluoro-2,3-
dihydro-7-benzo~b]furanyl)-2-trimethylsiloxyethane-
nitrile.
: \ -
`\ o ~.~
-66-
EXAMPLE 49
Ethyl 1 (5-Chloro-2,3-dihydro-7-benzo[b]-
furanyl)-l-hydroxymethanecarboximidate
By the procedure of Example 43~ title compound of
the preceding Example (1.37 g.) was converted to title
product. The initially isolated solids were repulped
twice in ether to obtain purified product [1.28 g.;
m.p. 149-152Co (dec); m/e 257/255; ir(KBr) 3162,
2875, 1650, 1524, 1458 cm~l].
By the same method the fluoro compound of the
preceding Example is converted to ethyl 1-(5-fluoro-
2,3-dihydro-7-benzo[b]furanyl)-1-hydroxymethanecarbox-
imidate hydrochloride.
EXAMPLE 50
5-(5-Chloro-2,3-dihydro-7-benzo~b]furanyl)-
oxazolidine-2,4-dione
By the procedure of Examp:Le 44, title compound of
the preceding Example (1.1 g.) was converted to toluene
recrystallized title product ~630 mg.; m.p. 197-
199C.; m/e 255/253; ir(KBr) 3084, 1833, 1810, 1746
-l]
By the same procedure the fluoro analog of the
preceding Example is converted to 5-~5-fluoro-2,3-
dihydro-7-benzo[b]furanyl)oxa~olidine-2,4-dione.
-67-
EXAMPLE SI
2-(3-Methyl-5-isoxazolyl)-2-trimethylsilyl-
ethanenitrile
_ _ _ _ _ _ _ _
By ~he procedure of Example 42, 3-methylisoxazole-
5-carbaldehyde (3.4 g., 0.032 mole) was converted to
title product, isolated as an oil (6.5 g., no aldehyde
proton by nmr).
By the same method, isothiazole-5-carbaldehyde is
converted to 2-(5-thiazolyl)-2-trimethylsilylethane-
nitrile and 5-methylisoxazole-3-carbaldehyde (Kane et
al., Japan 62/17,572) is converted to 2-(5-methyl-3-
isoxazolyl)-2-trimethylsilylethanenitrile.
EXAMPLE 52
Ethyl l-~ydroxy-1-(3-methyl-5-isoxazolyl)-
methanecarboximidate Hydrochloride_
Title product of the preceding Example ~6.5 g.)
was dissolved in cold, saturate~ ethanolic hydrogen
chloride (50 ml.) and held at 5"C. for 16 hours.
Title product was recovered by filtration t3.3 g.,
m.p. 119-121C.).
By the same method, the other products of the
preceding Example are converted to ethyl l-hydroxy-l-
(5-isothiazolyl)methanecarboximLdate hydrochloride and
ethyl l-hydroxy-1-(5-methyl-3-isoxazolyl)methan2carbox-
imidate hydrochloride~
-68-
ExAMpLE 53
5-~3-Methyl-5-isoxazolyl)oxazolidine-2,4-dione
By the procedure of Example 44, title product of
the preceding Example (2.2 g.), was converted to title
product. After quench into crushed ice, the product
was extracted into ether, the combined extracts dried
and evaporated to an oil (1.4 g.)~ Further extraction
with ethyl acetate and evaporation gave additional oil
(0.4 g.). The oils were combined and partitioned
between 25 ml. of lN sodium hydroxide and 25 ml. of
ether. The basic aqueous phase was separated, acidi-
fied with conc. hydrochloric acid and extraced with
25 ml. of ethyl acetate. The ethyl acetate extract
was back-washed with water, evaporated to dryness, the
residue triturated with ether (146 mg., m.p. 173-
175C.). The ether triturate was evaporated to
dryness and triturated with fresh ether (238 mg., m.p.
175-177C.).
By the same method, the ot:her products of the
preceding Example are convertecl to 5-(5-isothiazolyl)-
oxazolidine-2,4-dione and 5-(5-~methyl-3-isoxazolyl)-
oxazolidine-2,4-dione.
~ ~ 3
-69-
EXAMPLE 54
5-(S-Chloro-2-ethoxy-3-pyridyl)oxazolidine
2,4-dione
5-(2-Ethoxy-3-pyridyl)oxazolidine-2,4-dion~
(125 mg.) was suspended in 100 ml. of water and dis-
solved by warming to 56C. Chlorine was bubbled into
the warm solution for 30 minutes, during which time
the temperature slowly dropped to 34C. and a precipitate
formed. The reaction mixture was flushed with nitrogen
for 30 minutes and crude product recovered by filtration
(101 mg., m.p. 119-124C.). Two recrystallizations
from 2:1 ethanol:water gave purified title product
[24 mg.; m.p. 145-147C.; Rf 0.56 (1:1 ethyl acetate.
chloroform); m/e 256].
By the same procedure, substituting 10% fluorine
in nitrogen, 5-~2-ethoxy-3-pyridyl)oxazolidine-2,4-
dione is converted to 5-(5-fluoro-2-ethoxy-3-pyridyl)-
" oxazolidine-2,4-dione.
o
-70~ 3
EXAMPLE 55
2-(3-Fury~ 2-Trimeth~lsiloxyethanenitrile
To a mixture of 3-furaldehyde ~1.92 g., 20 mmoles)
and about 100 mg. of zinc iodide in 25 ml. of ether,
trimethylsilylcarbonitrile (4.74 g., 48 mmoles) was
added dropwise. The mixture was stirred about 16 hours
at room temperature. The reaction mixture was washed
sequentially with saturated sodium bicarbonate, water
and brine, dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo to yield 2-(3-furyl)-
2-trimethylsiloxyethanenitrile [2.2 g.; pnmr/CDC13/delta:
0.2 (s, 9H); 5.4 (s, lH); 6.4 (m, lH); 7.3 (m, lH);
7.5 (m, lH)].
EXAMPLE 56
Ethyl l-Hydroxy-1-(3-furyl)-
methanecarboximidate Hydrochloride
2-(3-Furyl)-2-trimethylsiloxyethanenitrile
(1.0 g.) was dissolved in 10 ml. of saturated ethanolic
hydrogen chloride at 0-5C. The resulting solution
was held at about 5C. for 16 hours. The reaction
mixture was concentrated to about half volume and
diluted with ether. Filtration, with ether wash, gave
ethyl l-hydroxy-l-~3-furyl)methanecarboximidate hydro-
chloride (746 mg.; m.p. 113-115C~; m/e 169).
EXAMPLE 57
5-(3-Fur~l)oxazolidine-2,4-dione
Ethyl l-hydroxy-1-(3-furyl)methanecarboximidate
hydrochloride ~1.5 g., 7.5 mmoles) was combined with
50 ml. of tetrahydrofuran and triethylamine (2.21 g.,
21.9 mmoles) and cooled to 10C. Phosgene was bubbled
through the cooled reaction mixture for 20 minutes.
After stirring the mixture for an additional 30 minutes,
nitrogen was flushed through the mixture for 10 minutes.
The reaction mixture was pour~d slowly into 100 g. of
crushed ice. The product was extracted into two
portions of ether and crude product isolated as an oil
by evaporation. The oil was taken up in 5 ml. of lN
sodium hydroxide and extracted with ether. The basic
aqueous phase was acidified and extracted with fresh
ether. Product was isolated as a gummy solid (600 mg.)
by evaporation of the latter ether extract. Trituration
with chloroform afforded purified S-(3~furyl)oxazolidine-
2,4-dione (109 mg.; m.p. 86-88C.; m/e 167). Addition
of hexane to the chloroform triturate gave a second
crop of product (66 mg.; m.p. 86-88C., m/e 167).
Analysis: Calcd. for C7H504N:
C, 50.31; H, 3.01; N, ~38.
Found:C, 49.97; H, 3.13; N, 8.37
EXAMPLE 58
2-(5-Chloro-2-furyl)-2-
trimethylsiloxY~thanenitrile
5-Chloro-2-furaldehyde (2.7 g., 21 mmoles) was
dissolved in 30 ml. of ether. Trimethylsilylcarbo-
nitrile (6.3 ml., 50 mmoles) and zinc iodide (about50 mg.) were added and the mixture stirred for 1.5 hours
at room temperature, at which time tlc (hexane:ethyl
acetate 8:1) indicated romplete reaction. Concentra-
tion to dryness afforded 2-~5-chloro-2-furyl)-2-
trimethylsiloxyethanenitrile as an oil (5.5 g.;pnmr/CDC13/delta: 0.3 (s, 9H); 5.4 (s, lH); 6.1 (d,
lH); 6.5 (d, lH)].
-72~
EXAMPLE 59
Ethyl 1-(5-chloro-2-furyl)-1-
hydroxymethanecarboximidate H~drochloride
2-(5-Chloro-2-furyl)-2-trimethylsiloxyethanenitrile
(2.3 g.) was dissolved in saturated ethanolic hydrogen
chloride (25 ml.) at 0C. The solution was held for
2.5 hours at about 5C. and then concentrated to oil.
Trituration with 20 ml. of ether afforded crystalline
ethyl l-(5-chloro-2-furyl)-1-hydroxymethanecarboximidate
hydrochloride (1.2 g~; m.p. 112-114C., m/e 203).
EXAMPLE 60
5-(5-Chloro-2-furyl)oxazolidine-2 4-dione
Ethyl 1-(5-chloro-2-furyl) l-hydroxymethanecarbox-
imidate hydrochloride (1.2 g., 5 mmoles) wa~ suspended
in 50 ml. of tetrahydrofuran and cooled in an ice
bath. Following the addition of riethylamine (2.1 ml.,
15 mmoles), phosgene was bubbled into the reaction
mixture for 20 minutes, maintaining the temperature at
10 to 20C, The mixture was flushed with nitrogen and
poured slowly into 100 ml. of crushed ice. The
quenched reaction mixture was extracted with 100 ml.
of ether, and the ether back-exl:racted with brine and
concentrated to an oil. The oil was taken up in
15 ml. of fresh ether, the solu1:ion clarified and
extracted with 10 ml. of lN sod:ium hydroxide. The
basic extract was acidified with concentrated hydro-
chloric acid and product extracted into ethyl acetate.
~fter back extracting with water, the ethyl acetate
layer was concentrated to an oil ~550 mg.). A portion
of this oil (500 mg.) was chromatographed on about
50 ml. of silica gel, with 5:1 hexane:ethyl acetate
containing 5% acetic acid as eluant. The column was
73-
monitored by tlc (same eluant). Late eluted, product
containing fractions were combined, evaporated to
dryness and triturated with hexane, affording 5-(5-
chloro-2-furyl)oxazolidine-2,4-dione [177 mg.; m.p.
112-114C.; m/e 201; Rf 0.25 (5:1 hexane:ethyl acetate
with 5% acetic acid)].
Analysis: Calcd. for C7H404NCl:
C, 41.71; H, 2.00; N, 6.95.
Found: C, 41.80; H, 2.21; N, 6.77.
EXAMPLE 61
2-(5-Bromo-2-furyl)-2-trimethylsiloxyethanenitrile
5-Bromo-2-furaldehyde (1.1 g., 6 mmsles) was
dissolved in 50 ml. of ether. A catalytic quantity
(about 50 mg.) of zinc iodide was added and then
trimethylsilylcarbonitrile (746 mg., 1.2 equiv.) was
added dropwise. The reaction was monitored by ir
(disappearance of typical carbonyl absorption) and
pnmr (disappearance of typical aldehyde proton peak).
After 60 minutes at room temperature, the reaction
mixture was washed with saturated sodium bicarbonate,
twice with water, and finally with brine, dried over
anhydrous sodium sulfate and evaporated to yield 2-(5-
bromo-2-furyl)-2-trimethylsiloxyethanenitrile as an
oil rl.2 g.; pnmr/CDC13/delta: 0.3 (s, 9H); 5.6 (s,
1ll); 6.4 (d, lH); 6.6 (d, lH~.
~61B ~3
--7~--
EXAMPLE 6 2
Ethyl 1-(5-Bromo-2-furyl)-1-
hydroxymethanecarb _imidate Hydrochloride
Following the procedure of Example 56, except that
the reaction mixture was not concentrated prior to
addition of ether, 2-(5-bromo-2-furyl~-2-trimethyl-
siloxyethanenitrile (1.2 g.) was converted to ethyl 1-
(5-bromo-2-furyl)-1-hydroxymethanecarboximidate
hydrochloride (480 mg., m.p. 120-122C., m/e 247,
249). A less pure second crop (235 mg., m.p. 104-106C.3
was recovered by evaporation of mother liquor and
trituration of the residue with ether.
EXAMPLE 6 3
5-(5-Bromo-2-furyl)oxazolidine-2,4 dione
Ethyl l-t5-bromo-2-furyl)-1-hydroxymethanecarbox-
imidate hydrochloride (982 mg~, 3.4 mmoles) was
converted to 5-(5-bromo-2-furyl)oxazolidine-2,4-dione
[126 mg., m.p. 126-129C., m/e 245, 247, Rf 0.2 (5:1
hexane:ethyl acetate with 5% acetic acid)] by the
procedure of Example 57
EXAMPL~S 64
2-(3-Bromo-2-furyl)-2-trimethYlsiloxyethanenitrile
By the procedure o~ Example 55, 3-bromo-2-furaldehyde
~1.75 g., 10 mmoles) in 50 ml. of ether was reacted
with trimethylsilylcarbonitrile (8.8 ml., 70 mmoles)
in the prasence of ahout 100 mg. of zinc iodide. At
the end of the 16 hour reaction period, the ether
supernatant was decantad from solids and evaporated to
dryness to yield 2-(3-bromo-2-furyl)-2-trimethylsiloxy-
ethanenitrile [3 g~, Rf 0.7 (3:1 hexane:ethyl acetate)].
- - \
`~J
-75-
EXAMPLE 65
Ethyl 1-(3-Bromo-2 furyl)-l-
hydroxymethanecarboximidate Hydrochloride
2-(3-Bromo-2-furyl)-2-trimethoxysilylethanenitrile
(6.8 g.) was dissolved in 70 ml. of saturated ethanolic
hydrogen chloride at 0C. and maintained at about 5C.
for 2 hours. Concentration to dryness and trituration
with acetone afforded ethyl 1-(3-bromo-2-furyl)=1-
hydroxymethanecarboximidate hydrochloride [4.4 g.,
m.p. 117-119 (dec.)].
EXAMPLE 66
5-(3-Bromo-2-furyl)oxazolidine-2,4-dione
By the procedures of Example 60, except that
phosgene was bubbled into the reaction mixture at 0 to
lS 10C., ethyl 1-(3-bromo-2-furyl)-1-hydroxymethane-
carboximidate hydrochloride (4.4 g.) was converted to
purified 5-~3-bromo-2-furyl)oxa~olidine-2,4-dione
~847 mg.; m.p. 128-130C.; Rf 0020 (5:1 hexane:ethyl
acetate containing 5% acetic acid~.
Ana~y_~ls: Calcd. for C7H~04NBr:
C, 34~16; H, 1.63; N, 5.69.
Found: C, 34.30; H, 1.8a; N, 5.67.
~6~ 3
-76-
EXAMPLE 67
2-(2-Furyl~-2-trimethylsiIoxyethane-nltr-ile
2-Furaldehyde (24 g., 0.25 mole) was cooled to
0-5C., zinc iodide (500 mg~) was added and the
mixture stirred. Trimethylsilylcarbonitrile (30 ml.)
was added dropwise. The mixture was allowed to warm
to room temperature and stirred for approximately
64 hours at room temperature. The reaction mixture
was diluted with methylene chloride, extracted twice
with saturated sodium bicarbonate, dried over anhydrous
magnesium sulfate, treated with activated carbon,
filtered and evaporated to yield 2-(2-furyl)-2-trimethyl-
siloxyethanenitrile as an oil [36 g., 74%; pnmr/CDC13/
delta: 0.2 (s, 9H); 5.6 (s, 1~); 6.4 (m, lH); 6.6 (m,
lH); 7.4 (d, lH)]~
EXAMPLE 68
Ethyl 1-(2-Furyl)-l-hydroxymethanecarboximidate
Following the procedure of Example 56, 2-(2-
furyl)-2-trimethylsiloxyethanenitrile (15 g.) was
reacted with saturated ethanolic hydrogen chloride,
except that a reaction time of about two hours was
employed. Crude product was isolated by evaporating
the reaction mixture to an oil. The oil was parti-
tioned in 400 ml. of chloroform and saturated sodium
bicarbonate. The chloroform was washed twice with
fresh saturated sodium bicarbonate, washed once with
brine, dried over anhydrous magnesium sulfate, fil-
tered and concentrated to yield ethyl l-(2-~uryl)-1-
hydroxymethanecarboximidate as an oil [10.6 g., 81%;
pnmr/CDC13/delta: 1.3 (t, 3H); 4.1 (q, 2H); 5.1 (s,
lH); 4.8-5.2 (m, lH~; 6.3 (m, 2H); 7.3 (d, lH)].
~7
-77~ 3
EXAMPLE 69
.
5-(2~Furyl)oxazolidine-2,4-dione
Ethyl 1-12-furyl)-1-hydroxymethanecarboximidate
(10.5 9., 6.2 mmoles) was dissolved in 125 ml. of
stirring tetrahydrofuran and cooled to 0-5C. Triethyl-
amine (12.5 g~, 0.124 mole) was added and the cold
solution then perfused with phosgene for 35 minutes,
warmed to room temperature and stirred for an additional
16 hours~ The reaction mixture was slowly poured into
1 liter of ice and water. The product was extracted
into 3 portions of ethyl acetate. The extracts were
combined and product extracted into 4 portions of lN
sodium hydroxide. The combined aqueous extracts were
acidified with 6N hydrochloric acid, and product
extracted into 4 portions of chloroform. The combined
chloroform extracts were dried over anhydrous magnesium
sulfate, treated with activated carbon, filtered and
evaporated to yield crude product as an oil (2.1 g.).
Column chromatography on 100 g. of silica gel with 2:1
chloroform:ethyl acetate as eluant in 10 ml. ~ractions,
monitored by tlc, gave, by evaporation of fractions
36-48, purified 5-(2-~uryl)oxazolidine-2,4-dione
(281 mg.; m.p. 99-102C.; m/e 167)~ Recrystallization
from toluene gave more highly purified product (235 mg.,
m.p. 101-103C.).
nalysis: Calcd. fox C7H504N:
C, 50.31; H, 3.02; N, 8~38.
Found: C, 50.41; H, 3.25; N, 8.28.
--78--
EXAMPLE 70
5-Hydroxy-5-(3-methoxy-2-furyl)-
2,4,6(1H,3H,5H)-pyrimidinetrione
3-Methoxyfuran (3.5 g., approximately 50~ pure
from Preparation 10), alloxan hydrate [5,5-dihydroxy-
2,4,6(lH,3H,5H)-pyrimidinetrione, 4.8 g.] and 75 ml.
of ethanol were combined and refluxed for 1 hour. The
reaction mixture was cooled to room temperature and
concentrated to dryness. Trituration of the residue
with 25 ml. of water afforded 5-hydroxy-5-(3~methoxy-
2-furyl)-2,4,6(1~,3H,5H)-pyrimidinetrione [1.9 g.,
m.p. 120-130 (dec.), m/e 240].
EXAMPLE 71
5-(3-Methoxy-2-furyl)oxaz_lid e-2,4-dione
5-Hydroxy 5-(3-methoxy-2-furyl)-2,4,6(1H,3H,5H)-
pyrimidinetrione (1.7 g.) was stirred with lN sodium
hydroxide (14 ml., 14 mmoles) for 20 minutes. The
reaction mixture was acidified with acetic acid and
product extracted into ethyl acetate and isolated in
crude form by evaporation to an oil. Chromatography
on ca. 100 ml. of silica gel, monitored by tlc,
afforded 5-~3-methoxy-2-furyl)Gxazolidine-2,4-dione
[470 mg., m.p. 102-104C., Rf 0.6 (1:1 hexane:ethyl
acetate with 5% acetic acid~].
EXAMPLE 72
2-(5-Phenyl-2-thienyl)-2-
trimethylsiloxyethanenitrile
5-Phenyl-2-thenaldehyde (0.9 9.) in 35 ml. of
ether was reacted with 1 ml. of trimethylsilylcarbo-
nitrile in the presence of about 50 mg. of zinc iodide.
After 1 hour of stirring at room temperatuxe, tlc
indicated reaction was complete. Evaporation to
dryness gave 2-(5-phenyl-2 thienyl)-2-trimethylsiloxy-
ethanenitrile [1.65 g., Rf 0.5 (5:1 hexane:ethyl
acetate with 5% acetic acid)].
-79~ 3
EXAMPLE 73
Ethyl l-Hydroxy-1-(5-phenyl-2-thienyl)-
methanecarboximidate HydrochIoride
2-(5-Phenyl-2-thienyl)-2-trimethylsiloxyethane-
nitrile (1.6 g.) was dissolved in 30 ml. of cold,
saturated ethanolic hydrogen chloride and maintained
at 0 to 5C. for about 17 hours. The reaction mixture
was evaporated to dryness and triturated with ethyl
acetate to yield ethyl l-hydroxy-l-(5-phenyl-2-thienyl3-
methanecarboximidate hydrochloride [0.9 g.; pnmr/DMSO/
delta: includes 1.1 (3H); 4.0 (2H); 5.2 (lH); 6.5
(lH)].
EXAMPLE 74
5-(5-Phenyl-2-thienyl)oxazolidine-2,4-dione
Ethyl l-hydroxy-1-(5-phenyl-2-thienyl)methane-
carboximidate hydrochloride (790 mg., 2.6 mmoles) and
triethylamine (1.4 ml., 10 mmoles) were reacted with
phosgene and product isolated according to the pro-
cedures of Example 12, except that the eluant in the
chromatography was 2:1 ethyl acetate:hexane, affording
5-(5-phenyl-2-thienyl)oxazolidine-2,4-dione (172 mg.,
m.p. 233-235C.).
Analysis: Calcd. for C13H9O3NS:
C, 60~23; H, 3.50; N, 5.40.
Found: C, 59.94; H, 3.65; N, 5.38.
EXAMPLE 7S
2-(2-Thienyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 67, 2-thenaldehyde
(56.1 g., 46.8 ml., 0.5 mole) was reacted for 16 hours
with trimethylsilylcarbonitrile (60 ml.) in the
presence of 2inc iodide (approximately 0.5 g.),
yielding 2-(2-thienyl)-2-trimethylsiloxyethanenitrile
as an oil [92 g.; m/e 211; pnmr/cDcl3/delta: 0.2 (s,
9H); 5.8 (s, lH); 6.9-7.5 (m, 3H)].
-80-
EXAMPLE 76
Ethyl l-Hydroxy-1-(2=thienyl)methanecarbo midate
2-(2-Thienyl)-2-trimethylsiloxyethanenitrile
(45 g.) was dissolved in 450 ml. of absolute ethanol.
The solution was cooled to 0-5C. and perfused with
hydrogen chloride for 40 minutes. The mixture was
kept at about 5C. for 16 hours and evaporated to
dryness. The residue was triturated with four 20Q ml,
portions of ether, and then partitioned between 400 ml.
of methylene chloride and saturated sodium bicarbonate.
The organic phase was washed twice with saturated
sodium bicarbonate, treated with activated carbon,
filtered and concentrated to yield ethyl l-hydroxy-l-
(2-thienyl~methanecarboximidate as an oil which
solidified on standing [10 g.; pnmr/CDC13/delta: 1.2
(t, 3H); 4.1 (q, 2H); 5.2 (s, lH), 5.9 (s, lH); 6.8-7.3
(m, 3H); 7.3-8.1 (s, lH)].
-81~ 3
EXAMPLE 77
5-(2-Thienyl)oxazolidine-2,4-dione
Ethyl l-hydroxy-1-(2-thienyl)methanecarboximidate
(10 g., 5.4 mmoles) and triethylamine ~1501 ml.,
10.8 mmoles) were dissolved in 100 ml. of tetrahydro-
furan. The solution was cooled to 0-5C. and perfused
with phosgene for 45 minutes. Stirring was continued
for an additional 5 hours at 0-5C. The reaction
mixture was poured slowly over 1500 ml. of crushed
ice. The product was extracted into 1.1 liter of
ethyl acetate in three portions. The combined ethyl
acetate extracts were then extracted twice with
saturat~d sodium bicarbonate and once with 1:1 saturated
sodium carbonate:water. The combined bicarbonate and
carbonate washes were acidified to pH 1-2 with 6N
hydrochloric acid and product extracted into several
portions of ether. The combined ether extracts were
washed with brine, dried over anhydrous magnesium
sulfate, treated with activated charcoal, ~iltered and
evaporated to yield product (3.0 g.). Recrystallization
from toluene afforded 5-~2-thienyl)oxazolidine-2,4
dione (1.8 g.; m.p. 138-140C., m/e 183).
: Calcd. ~or C7H5NO3S:
C, 45.89; H, 2.75 N, 7.65.
Found: C, 45.99; H, 2.87; N, 7.62.
` ~ -
-82-
EXAMPLE 78
Following the procedure of Example 67, 3-methyl-
2-thenaldehyde (31.6 g., 0.25 mole) was reacted with
trimethylsilylcarbonitrile (30 ml.) for 16 hours in
the presence of 500 mg. of zinc iodide. The reaction
mixture was diluted with 200 ml. of methylene chloride
and further isolated also according to Example 13,
afforaing 2-(3 methyl-2-thienyl)-2-trimethylsiloxy-
ethanenitrile [5~ gO, 93%; pnmr/CDC13/delta: 0.2 (s,
gH); 2.3 (s, 3H); 5.7 (s, lH); 6.8 (d, 1~); 7.25 (d,
lH)]-
EXAMPLE 79
Ethyl l-Hydroxy-1-(3-methyl-2-
thienyl)me~hanecarboximidate -
2-(3-Methyl-2-thienyl)-2-trimethylsiloxyethane-
nitrile (13 g.) was added dropwise to 100 ml. of cold
ethanol, saturated with hydrogen chloride, keeping the
temperature at 0-4C. After 1 hour at 0-4C., the
reaction mixture was evaporated to dryness. The
resi.due was triturated three times with 100 ml.
portions of ether, and then partitioned between 300 ml.
of methylene chloride and saturated sodium bicarbonate.
The separated methylene chloride layer was washed with
two additional portions of saturated sodium bicarbonate,
dried over anhydrous magnesium sulfate, filtered and
evaporated to yield ethyl l-hydroxy-l-~3-methyl-2-
thienyl)methanecarboximidate ~8.0 g., 69%; m.p. 73-76C.;
m/e 199).
-83-
EXAMPLE 80
5-(3-Me-hyI-2-thienyl)oxazoIidine-2~4-dione
Ethyl l-hydroxy 1-(3-methyl-2-thienyl)methane-
carboximidate (6.0 g., 0.03 mole) was dissolved in
75 ml. of tetrahydrofuran and cooled to 0-5Co Triethyl-
amine (6.07 g., 8.37 ml., 0.06 mole) was added, the
solution was perfused with phosgene for 35 minutes,
and poured slowly into 1 liter of ice and water. The
product was extracted into three portions of ethyl
acetate. The ethyl acetate extracts were combined and
product extracted into four portions of saturated
sodium bicarbonate. The combined aqueous extracts
were acidified with 6N hydrochloric acid and product
re~xtracted into 3 portions of fresh ethyl acetate.
The combined fresh organic extracts were dried over
anhydrous magnesium sulfate, filtered, and evaporated
to yield product as an oil (2.4 g., 41~), which
crystallized on scratching. Recrystallization from
toluene gave purified 5~~3-methyl-2-thienylloxazolidine-
2,4-diona (1.84 g., 31% overall; m.p. 119-121C., m/e
197).
Analys.is: Cal'cd. or C8H7O3NS:
C, 48.72; H, 3.58; N, 7.10.
Found: C, 48.65; H, 3.58; N, 7.01.
A second crop of product (0.63 9.) was obtained
by extraction of the initial ethyl acetate extracts
with 3 portions of lN sodium hydroxide, followed by
further isolation as above.
~,
-84-
EXAMPLE 81
2 (5-Methyl 2-thienyl3-
2-trimekhyfsiIoxyethanenitrile
5-Methyl-2-thanaldehyde (25 g., 0.2 mole), zinc
iodide (266 mg.) and 100 ml. of ether were combined
and stirred at room temperature. Trimethylsilylcarbo-
nitrile (23.5 g., 0.24 mole~ was added dropwise and
the reaction mixture stirred ~or an additional 2 hours~
The reaction mixture was diluted with 100 ml. of
ether, washed wtih two 50 ml. portions of 5% sodium
bicarbonate, washed with two 25 ml. portions of brine,
dried over anhydrous magnesium sulfate, filtered and
evaporated to dryness to produce 2-(5-methyl-2-thienyl)-
2-trimethylsiloxyethanenitrile [42 g.; pnmr/CDC13/delta:
0.2 (s, 9H); 2.2 (s, 3H); 5.6 ~s, lH); 6.6-7.4 (m,
2H)].
EXAMPLE 82
___
Ethyl l-Hydroxy-1-~5-methyl 2-thienyl)-
methanecarboximidate Hydrochloride
With cooling to 0-5C., et:hanol ~550 ml.) was
saturated with hydrogen chloricle. 2-(5-Methyl-2-
thienyl)-2-trimethylsiloxyethanenitrile ~42 g.) was
dissolved in portions and the solution maintained at
0C. for 2.5 hours. The reaction mixture was evaporated
to dryness and the residue triturated with diethyl
ether to provide ethyl l-hydroxy-1-(5-methyl-2-thienyl)-
methanecarboximidate hydrochloride [33 g.; m.p.
122-123C., pnmrlDMSO/delta: 1.1-1.6 ~3H); 2.S t3H);
4.6 (2H); 5.9 (lH); 6.6-72 (2H)].
-85- ~ 8L~3
EXAMPLE 83
5-(5-Methyl 2-thienyl)oxazolidine-2,4-dione
Ethyl l-hydroxy-1-(5-methyl-2-furyl)methane-
carboximidate hydrochloride (10 g., 0.042 mole) was
combined with triethylamine ~14.1 g., 0.14 mole) in
250 ml. of tetrahydrofuran and cooled to 0-5C. The
cold reaction mixture was perfused with phosgene for
30 minutes, warmed to room temperature and poured
portionwise onto about 275 ml. of crushed ice. The
product was extracted into two 200 ml. portions of
ethyl acetate. The ethyl acetate extracts were
combined and extracted with two 150 ml. portions of lN
sodium hydroxide. The combined aqueous extracts were
acidified with hydrochloric acid and then extracted
with two 250 ml. portions of fresh ethyl acetate. The
last, combined organic extracts were dried over
anhydrous magnesium sulfate, filtered and evaporated
to yield 5-(5-methyl-2-thienyl)oxazolidine-2,4-dione
(7.2 g.). Recrystallization from chloroform/hexane
gave purified product (910 mg.; m.p. 108-109C.; m/e
197).
-~6~ 3
EXAMPLE 84
2-(5-Chloro-2-thienyl)-2-trimethylsiloxyethanenitrile
5-Chlorothenaldehyde (5 g., 34 mmoles) was combined
with zinc iodide (50 mg.) and 30 ml. of diethyl ether
and cooled to 0C. Trimethylsilylcarbonitrile (4.04 g.,
40 mmoles) was added dropwise and the reaction mixture
warmed to room temperature and stirred for 4 hours.
Additional equal portions of trimethylsilylcarbonitrile
and zinc iodide were added and the reaction stirred an
additional 16 hours. The reaction mixture was diluted
with ether, washed with two 30 ml. portions of 5%-
sodium bicarbonate, washed once with 30 ml. of brine,
dried over anhydrous magnesium sulfate and evaporated
to yield 2-(5-chloro-2-thienyl)-2-trimethylsiloxyethane-
nitrile as an oil [4.0 g., pnmr/CDC13/delta: 0.3 (s,
9H); 5.7 (s, lH); 7.0 (q, 2H)].
By the same method, 3-fluoro-2-thenaldehyde, 4-
fluoro-2-thenaldehyde, 5-fluoro-2-thenaldehyde, 5-
fluoro-3-thenaldehye [Gronowitz and Rosen, Chem. Ser.
1, pp. 33-43 (1971); Chem. Abstracts 75, 20080c~, 4-
fluoro-3-thenaldehyde, 4-methoxy-3-thenaldehyde, and
4-methylthio-3-thenaldehyde are converted, respectively,
to 2-(3-fluoro-2-thienylt-2-trimethylsiloxyethanenitrile,
2-(4-fluoro-2-thienyl)-2-trimethylsiloxyethanenitrile,
2-(5-fluoro-2-thienyl)-2-trimethylsiloxyethanenitrile,
2-(5 fluoro-3-thienyl)-2-trimethylsiloxyethanenitrile,
2-(4-fluoro-3-thienyl)-2-trimethylsiloxyethanenitrile,
2-(4-methoxy-3-thienyl)-2-trimethylsiloxyethanenitrile r
2-~4-methylthio-3-thienyl)-2-trimethylsiloxyethanenitrile.
o
-87- ~ 3
EXAMPLE 85
Ethyl 1-(5-Chloro-2-thienyl)-1-
hydroxymethanecarboximidate Hydrochloride
2-(5-Chloro-2-thienyl)-2-trimethylsiloxyethane-
nitrile (4 g.) was dissolved in absolute ethanol
(lOO ml.). The solution was cooled to 0 5C. and
saturated with hydrogen chlorideO The reaction mixture
was held for 16 hours at 0C., evaporated to dryness
and triturated with ether to yield solid ethyl 1-(5-
chloro-2-thienyl)-1-hydroxymethanecarboximidate hydro-
chloride [3 9., pnmrtDMSO/delta: 1.2 (3H); 4.2 (2H);
5.3 (lH); 6.6 ~lH); 6.9 (lH); 7.4 (lH); 8.4 (lH)].
By the same method, the other nitriles of the
preceding Example are converted to ethyl 1-(3-fluoro~
2 thienyl)-l-hydroxymethanecarboximidate hydrochloride,
ethyl l-(4-fluoro-2 thienyl)-l-hydroxymethanecarbox-
imidate hydrochloxide, ethyl 1-(5-fluoro-2-thienyl)-1-
hydroxymethanecarboximidate hydrochloride, ethyl 1-(5-
fluoro-3-thienyl)-1-hydroxymethanecarboximida~e
hydrochloride, ethyl 1-(4-fluoro-3-thienyl)-1-hydroxy-
methanecarboximidate hydrochloride, ethyl l-hydroxy-l-
~4-methoxy-3-thienyl)methanecarboximidate hydrochloride
and l-hydroxy-1-(4-methylthio-3-thienylmethanecarbox-
imidate hydrochloride.
~o
-~8~ 3
EXAMPLE 86
5-(5-Chloro-2-thienyl)oxazolidine-2,4-dione
Ethyl 1-(5-chloro-2-thienyl)-1-hydroxymethane-
carboximidate hydrochloride (3.0 g., 12 mmoles) and
triethylamine ~4.0 g., 39 mmoles) were combined in
90 ml. of tetrahydrofuran and cooled to 0C. The
slurry was perfused with phosgene for 30 minutes,
warmed to room temperature and stirred for 16 hours.
The reaction mixture was poured slowly into 100 ml.
of crushed ice and product extracted into two 100 ml.
portions of ethyl acetate. The combined ethyl acetate
extracts were back-washed with two 50 ml. portions of
water and one 50 ml. portion of saturated sodium
chloride, dried over anhydrous magnesium sulfate,
filtered and evaporated to a semi-solid (2.5 g.).
Recrystallization from toluene provided purified 5-(5-
chloro-2~thienyl)oxazolidine~2 r 4-dione (0.6 g., m.p.
126-130C~).
~na~sis: Calcd. for C H O NClS:
7 4 3
C, 38.643 H, 1.84; N~ 6.44.
Found: C, 38.17; H, 2.07; N~ 6.91.
By the same method the other imino ethers of the
preaeding Example are converted to 5-~3-fluoro-2-
thienyl)oxazolidine-2,4-dione, 5-(4-fluoro-2-thienyl)-
oxazolidine-2,4-dione, 5-(5-fluoro-2-thienyl)oxazolidine-
2,4-dione, 5-(5-fluoro-3-thienyl)oxazolidine-2/4-
dione, 5-l4-fluoro-3-thienyl)oxazolidine-2,4-dione, 5-
(4-methoxy-3-thienyl)oxazolidine-2,4-dione and 5-(4-
methylthio-3-thienyl)oxazolidine-2,4-dione.
`o~
-89~ 3
EXAMPLE 87
2-(4-Bromo-3-thienyl)-2-trimethylsiloxyethanenitrile
4-Bromo-3-thenaldehyde (5.5 g., 29 mmoles) in
75 ml. of methylene chloride was cooled to 0-5C.
Zinc iodide (50 mg.) was added, followed by the
dropwise addition of trimethylsilylcarbonitrile
(3.47 g., 35 mmoles) over a 3 minute period. ~he
mixture was warmed to room temperature, stirred for
16 hours, washed twice with saturated sodium bicarbonate,
washed with brine, dried over anhydrous magnesium
sulfate, filtered and evaporated to yield 2-(4-bromo-
3-thienyl~-2-trimethylsiloxyethanenitrile as an oil
(7.6 g., 90%, m/e 291/289).
EXAMPLE 88
Ethyl 1-(4-Bromo-3-thienyl)-
l-hydroxymethanecarboximidate
2-(4-Bromo-3-thienyl)-2-trimethylsiloxyethanenitrile
(7.5 g.) in 200 ml. of ethanol, cooled in an ice bath,
~ was perfused with hydrogen chloride for 45 minutes.
After an additional 20 minutes at 0-5C. the reaction
mixture was evaporated to dryness and triturated with
ether to yield the hydrochloride salt of the product
as a hygroscopic solid~ The salt was taken up in a
mixture of methylene chloride and saturated sodium
2~ bicarbonate. The separated methylene chloride layer
was washed twice with saturated sodium bicarbonate,
washed with brine, dried over anhydrous magnesium
sulfate, filtered and evaporated to yield ethyl 1-(4-
bromo-3-thienyl)-1-hydroxymethanecarboximidate as an
oil 56.1 g~, 89%, m/e 265/263).
~6~3
9~
EXAMPLE 89
5-(4-Bromo-3-thienyl~oxazolidine-2,4-dione
Ethyl 1-(4-bromo-3-thienyl)-1-hydroxymethane-
carboximidate (6.0 g., 23 mmoles) and triethylamine
(5.15 g., 51 mmoles) were combined in 250 ml. of
tetrahydrofuran, cooled in an ice-water bath and
perfused with phosgene for 35 minutes. The reaction
mixture was warmed to room temperature, stirred for
1.5 hours, poured slowly ovex 1 liter of crushed ice,
and product extracted into 3 portions of methylene
chloride. The combined methylene chloride extracts
were evaporated to an oil, crystallized by the addition
of a small amount of ether and hexane, and triturated
in about 40 ml. of ether to yield 5-(4-bromo-3-thienyl)-
oxazolidine-3,4-dione (3.4 g., 56~; m.p. 158-161C.).
Recrystallization from 40 ml. of toluene afforded
purified product (2,51 g.; m.p. 164-166C.; m/e 263/261).
Alternatively, the ether solution of the lithium
derivative of 3,4-dibromothiophene is reacted with a
1.05 equivalent of alloxan according to the procedure
of Example 54, yielding 5-(4-bromo-3-thienyl)-5-
hydroxy-2,4,6(1H,3H,5H~-pyrimidinetrione. Following
the procedure of Example 55, the latter is convexted
to the desired 5-(4-bromo-3-thienyl)oxazolidine-2,4-
dione.
9~ 343
EXAMPLE 90
2-(3-Thienyl)-2-trimethylsiloxyethanenitrile
3-Thenaldehyde (10 9., 0.089 moles), zinc iodide
(120 mg.) and ether (60 ml.) were combined and stirred.
Trimethylsilylcarbonitrile (10.6 g., 0.107 mole~ was
added dropwise over 10 minutes and the reaction mixture
stirred for 16 hours, diluted with 60 ml. of ether,
washed with two 30 ml. portions of 5% sodium bicarbonate,
washed with 30 ml. of brine, dried over anhydrous
magnesium sulfate, filtered and evaporated to yield 2-
(3-thienyl)-2-trimethylsiloxyethanenitrile as an oil
[14.3 9., pnmr/CDC13/delta: 0.2 (9H); 5.6 (lH);
7.0-7.5 (3H)].
EXAMPLE 91
Ethyl l-Hydroxy~l-(3-thienyl)methanecarboximidate
At 0-5C., 2-(3-thienyl)~2-trimethylsiloxyethane-
nitrlle (14.3 g.) was dissolved portionwise in 500 ml.
of ethanol, previously saturated with hydrogen chloride
at 0-5C. The solution was held at 0C. for 16 hours,
and the product isolated as the hydrochloride salt by
evaporation of the reaction mixtuxe to dryness and
trituration o~ the residue with ether. The salt was
taken up in 400 ml. of chloroform and 100 ml. of
saturated sodium bicarbonate. ~he separated chloroform
layer was washed with an additional 100 ml. o~ saturated
sodium bicarbonate r washed with brine, dried over
magnesium sulfate, filtered and evaporated to yield
ethyl l-hydroxy-1-(3-thienyl)methanecarboximidate
[12.5 9., pnmr/CDC13/delta: 1.0-1.3 (3H): 4.8-5.3
(2H); 5.0 (lH); 6.9-7.2 (3H), 7.3-3.0 (lEI)].
-92-
EXAMPLE 92
Ethyl l-hydroxy-1-(3-thienyl)methanecarboximidate
(12.5 g., 0.067 mole) and triethylamine (16.1 g.,
0.159 mole) were combined in 600 ml. of tetrahydrofuran
and cooled to 0C. The mixture was perfused with
phosgene for 30 minutes, warmed to room temperature
and allowed to stand for 16 hours. The mixture was
poured slowly into 600 ml. of ice and water (foaming
of excess phosgene) r and extracted twice with 600 ml.
portions of ethyl acetate. The combined ex~racts were
washed with two 300 ml. portions of lN sodium hydroxide.
The combined basic extracts were acidified with hydro-
chloric acid and product re-extracted into two fresh
300 ml. portions of ethyl acetate. The combined fresh
extracts were dried over anhydrous magnesium sulfate,
filtered and evaporated to solids (8.0 g.). Recrystal-
lization from hot toluene gave purified 5-(3 thienyl)-
oxazolidine-2,4-dione (5.5 g., m.p. 133-136C.). A
second recrystallization, from ethyl acetate/hexane,
provided additional puri~ication (first crop: 2.352 g.;
m.p. 136-138C., m/e 183; ir (K}3r): 5.5, 5.8 microns).
o~
~6
-93-
EXAMPLE 93
Ethyl 2-Hydroxy-2-(3-thienyl)acetate
3-Thenaldehyde (10 g., 0.089 mole) and sodium
bisulfite (13.8 g., 0.133 mole) were heated at 50-60~C.,
in 152 ml. of water for 2 hours, forming the bisulfite
adduct in situ. The reaction mixture was cooled to
_
5~C., and 200 ml. of ethyl acetate was added. To the
stirred, two phase syst~m, potassium cyanide (17.4 g.,
0.267 mole) in 75 ml. of water was added dropwise over
30 minutes. The reaction mixture was warmed to 20C.
and held for 1 hour. Additional potassium cyanide
(5.7 g., 0.088 mole) was added and the mixture stirred
an additional 10 minutes at 20C. The layers were
separated and the aqueous layer washed with 50 ml. of
ethyl acetate. The combined ethyl acetate layers were
washed with saturated sodium chloride, providing a
clean solution of the cyanohydrin of 3-thenaldehyde in
ethyl acetate.
The solution of the cyanohydrin of 3-thenaldehyde
in ethyl acetate was stirred at room temperature and
charged with 41.6 g. (52.7 ml., 10 equiv.) of ethanol
and concentrated hydrochloric acid (15.2 ml., 0.182 mole)
and the mixture refluxed for 17 hours. The reaction
mixture was cooled to 25C., washed with 100 ml. of
water and then with saturated sodium bicarbonate to a
pH >7.0, dried over anhydrous magnesium sulfate,
treated with activated carbon, filtered and evaporated
to an oil (approximately 11.5 g.) which upon addition
of 46 ml. of 1:1 toluene/isooctane afforded crystalline
ethyl 2-hydroxy-2-(3-thienyl~acetate (7.4 g., 45%,
m.p. 55-57C.).
-94-
EXAMP~E 94
2-Hydroxy-2-(3-thienyl~acetamide
Ethyl 2-hydroxy-2-(3-thienyl)acetate (168 g.,
0.903 mole) was slurried in 15N ammonium hydroxide
(420 ml., 6.3 moles) and heated to reflux for 2.5 hours.
The resulting solution was cooled to 70C. and toluene
(840 ml.) was added. The stirred mixture was allowed
to cool to 20C. and granulated for 1 hour. Filtration,
with toluene wash, gave 2-hydroxy-2-(3-thienyljacetamide
(10509 g., 75%~ m.p. 120-126C.). A second crop
(10.3 9., m.p. 114-120C.) was obtained by evaporating
the aqueous layer of the filtrate to 50 ml. and granulat-
ing with 100 ml. of toluene. Recrystallization of the
first and second crops from ethyl acetate afforded a
77~79% recovery of purified product (m.p. 127-130C.).
EXAMPLE 9S
5-(3-Thienyl)oxazolidine-2,4-dione
At 25C., 2-hydroxy-2-(3-thienyl)acetamide
(10.0 g., 0.064 mole) was added to a solution of
sodium methoxide (10 g., 0.185 mole) and diethyl
carbonate (22.0 ml., 0.182 mole) in 200 ml. of
ethanol. The reaction mixture was heated to reflux
for 3 hours, cooled to 20C., and slowly dilu~ed with
100 ml. of water. Ethanol was removed by evaporation
and the aqueous residue treated with activated carbon
and filtered. The filtrate was layered with ethyl
acetate and the pH adjusted to 1.0 with concentrated
hydrochloric acid. The aqueous layer was separated
and washed with 100 ml~ of ethyl acetate. The combined
ethyl acetate layers were dried over anhydrous magnesiwn
sulfate. The ethyl acetate was removed by distillation
in vacuo with displacement by toluene to a final
volume of 150 ml. The resulting slurry was heated to
reflux (solution), cooled to 0C., and filtered to
yield 5-~3-thienyl)oxazolidine-2,4-dione (8.92 g.
76.5%, m.p. 135-138C.).
-95-
XAMPLE 96
Sodium 5 (3-Thienyl)oxazolidine-2,4-dione
5-(3-Thienyl)oxazolidine-2,4-dione (3.0 g.,
16.4 mmole~ was dissolved in 60 ml. of ethyl acetate
and treated with 300 mg. of activated carbon. After
stirring at 20C. for 10 minutes, the mixture was
filtered with ethyl acetate wash. Methanolic sodium
hydroxide (3.78N, 4.2 ml.~ was added and the sodium
salt was allowed to crystallize. After about 30 minutes,
0~3 ml. of water was added. The slurry was granulated
for 30 minutes at room temperature, then cooled to
5C. and granulated for an additional 30 minutes.
Filtration gave sodium 5-(3-thienyl)oxazolidine-2,4-
dione as the monohydrate (3.37 g., 95~, m.p. 208-210C.).
Analysis: Calcd. for C7H4O3NSNa.H2O:
C, 37.67; H, 2.71; N, 6.28: O, 28.67; S, 14.37;
Na, 10.30; H2O, 8.07.
Found: C, 37.35; H, 3.03; N, 6.24; O, 27.83; S, 14.33;
Na, 10.76; H2O, 8.30.
Sodium hydroxide is substituted with an equivalent
of potassium hydroxide, diethanolamine, meglumine or
piperazine to produce the corresponding salts. The
solvent is removed by evaporation or a non-solvent
such as ether or hexane is added as necessary to
facilitate precipitation of the product.
The same methods are employed to produce the
pharmaceutically acceptable salts of the other oxazo-
lidine-2,4-diones of the present in~ention.
-96-
EXAMPLE 97
2-(3-Bromo-2-thienyl)-2-trlmethyIsiIoxyethanenitrile
3-Bromo-2-thenaldehyde (6 g., 31 mmoles) and zinc
iodide ~50 mg.) were combined with 180 ml. of methylene
chloride. Trimethylsilylcarbonitrile (4.0 g., 5.2 ml.,
41 mmoles) were added dropwise. The reaction mixture
was stirred for 24 hours at room temperature, diluted
with 50 ml. of methylene chloride, washed with 60 ml.
of 5% sodium bicarbonate and then with 50 ml. of
brine, dried over anhydrous magnesium sulfate, filtered
and evaporated to yield 2-(3-bromo-2-thienyl)-2-
trimethylsiloxyethanenitrile (7.2 g., oil, m/e 291/289).
EXAMPLE 98
Ethyl 1-(3-Bromo-2-thienyl)-1-
hydroxymethanecarboximidate Hydrochloride
At 0C., 2-(3-bromo-2-thienyl)-2-trimethylsiloxy-
ethanenitrile (7.0 g., 24 moles) was dissolved in
210 ml. of ethanol saturated at 0C. with hydrogen
chloride. After stirring for 30 minutes at the same
temperature, the reaction mixture was evaporated to
dryness. Trituration o~ the solid residue with ether
af~oxded ethyl l-(3-bromo-2-thienyl)~l-hydroxymethane-
carboximidate hydrochloride (7.0 9., m.p. 120-122C.).
-97-
EXAMPLE 99
5-~3-Bromo-2-thienyl)oxazolidine-2,4-dione
Ethyl 1-(2-bromo-2-thienyl)-1-hydroxymethane-
carboximidate hydrochloride (6.8 g., 23 mmoles) and
triethylamine (7.6 g., 10.5 ml., 76 mmoles) were
combined in 250 ml. of tetrahydrofuran. The mixture
was cooled to 0-5C., perfused with phosgene for
30 minutes, warmed to room temperature, stirred for
16 hours, and poured slowly into 300 ml~ of crushed
ice. The quenched reaction mixture was extracted
twice with 200 ml. portions of chloroform. The
combined chloroform extracts were washed with 60 ml.
of brine, dried over anhydrous magnesium sulfate,
filtered and evaporated to an oil. ~ddition of hexane
and ether afforded crystalline product. Recrystalliza-
ti~on from toluene gave 5-(3-bromo-2-thienyl)oxazolidine-
2,4-diGne (2.25 g.; m.p. 138-139C.).
Analysis: Calcd. for C7H4O3NSBr:
C, 32.09; H, 1.59; N, 5.34; S, 12.21,
Found: C, 32.41; H, 1.75; N, 5.49; S, 12.61.
-98- ~ 3
EXAMPLE 100
5-(5-Bromo-2-thieny~)-2-thioxooxazolidin-4-one
Potassium cyanide t7.9 g., 0.123 mole) and
potassium ~hiocyanate tlO g., 0.104 mole) were combined
in 8.5 ml. of water and stirred at 0C. 5-Bromo-2-
thenaldehyde ~20 g., 0.104 mole) was added, yielding a
slurry. Hydrochloric acid (30%, 50.7 ml.) was added,
producing an oil ball. The reaction mixture was
diluted with 104 ml. of water and stirred for 48 hours,
by which time a granular solid had formed. Solids
were recovered by filtration and distributed between
chloroform and 5~ sodium bicarbonate. The mixture was
filtered, and the aqueous layer separatedl acidified
and the precipitated product recovered by filtration.
Recrystallization from toluene gave purified 5-(5-
bxomo-2-thienyl)-2-thioxooxazolidin-4-one (2.08 g.,
m.p. 119-120C., m/e 279/277).
Analysis: Calcd. for C7H4BrN02S2:
C, 30.23; H, 1.95; N, 5.04.
Found: C, 30.54; H, 1.72; N, 5.26.
O!
_99_
EXAMPLE 101
5-(5-Bromo-2-thieny~l)oxaz _idine-2,4-dione
5~(5-Bromo-2-thienyl)-2-thioxooxazolidin-4-one
(1.5 g.) was dissolved in 1:1 water:ethanol (10 ml.)
5 at 50C. Hydrogen peroxide (30%, 7.0 ml.) was added
to the stirred solution, which became somewhat turbid.
Turbidity was reduced by the addition of 1 ml. of
ethanol. The mixture was heated at 70~C. for 30 minutes,
cooled somewhat, diluted with 100 ml. water and extracted
with chloroform. The chloroform extract was washed
with two 50 ml. volumes of sodium bicarbonate. The
combined aqueous extxacts were clarified by filtration,
acidified with hydrochloric acid to pH 1.0, and filtered
to yield 5-(5-bromo-2-thienyl)oxazolidine-2,4-dione
(0.51 g., 36~; m.p. 139-139.5~C.; m/e 263/261).
Analysls: Calcd. for C7H4BrNO3S:
C, 32.08; H, 1.54; N, 5.34.
Found: C, 32.16; H, 1.69; N, 5.47.
EXAMPLE 102
5-Hydroxy-5-(3-methoxy-2-thienyl)-
2,4,6tlH!3H,5H)-pyrimidinetrione
3-Methoxythiophene ~2.4 g., crude material prepared
according to Arkiv. Kemi. 12, 239-246 ~1958); Chem.
Abstr. 52, 20115d~ and alloxan hydrate (3.2 g.) were
dissolved by heating in 25 ml. of ethanol. Hydrochloric
acid (lN, 3 ml., 3 mmoles) was added and the mixture
refluxed for 3 minutes. The mixture was cooled to
room temperature and diluted with 15 ml. of water to
induce further crystallization of product. Filtration
with 1:1 ethanol:water and then water wash gave 5-
hydroxy-5-(3-methoxy-2-thienyl)2,4,6tlH,3H,5H)-pyrimidine-
trione ~1.5 g , m.p~ lgO-210C. (dec.); Rf 0.3 (1:1
hexane:ethyl acetate with 5~ acetic acid); m/e 256].
o
-100-
EXAMPLE I03
5-(3-Methoxy-2-thienyl)oxazolldine-2,4-dione
5-Hydroxy-5 (3-methoxy 2 thienyl)-2~4,6(lH,3H,5H)-
pyrimidinetrione (1 g.) was dissolved in lN sodium
hydroxide (20 ml.) and stirred for 1 hour~ The mixture
was acidified, clarified, extracted twice with 50 ml.
portions of ethyl acetate. The combined ethyl acetate
extracts were back-washed with water and evaporated to
dryness tO.5 g. of solids). Chromatography on about
85 mlO of silica gel, monitored by tlc, afforded 5-(3-
methoxy-2-thienyl)oxazolidine-2,4-dione (300 mg., m.p.
156-158C.).
Analysis: Calcd. for C8H7O4NS:
C, 45.08; H, 3.31; N, 6.57.
Found:C, 45.21; H, 3.39; N, 6.47.
EXAMPLE 104
5-Hydroxy-5-(5-phenyl-2-furyl)-
2,4~6(1H,3H,5H)-pyr-mid-netrione
2-Phenylfuran (5.76 g., 40 mmoles) was combined
with 100 ml. of tetrahydrofuran and cooled to -30~C.
Butyl lithium in hexane (2.3M, 19.1 ml.) was added
dropwise over 5 minutes, keeping the temperature
betwean -20 and -30C. The reaction mixture was
allowed to warm to room temperature and then recooled
to -30C. Sublimed alloxan (5.96 g., 42 mmoles) in
40 ml. of tetrahydrofuran was added over S minutes,
again keeping the temperature -20 to -30C. The
reaction mixture was again allowed to warm to room
temperature, then recooled to 0C. and 50 ml. of lN
hydrochloric acid added portionwise over 2-3 minutes.
The quenched reaction mixture was extract~d with
100 ml. of ethyl acetate. The extract was filtered
through a bed of anhydrous magnesium sulfate, and
evaporated to yield 5-hydroxy-5~(5-phenyl-2-furyl)-
2,4,6(lH,3H,5H)pyrimidinetrione [9.4 g., gummy solid,
6~ 3
-101
Rf 0.75 (1:1 hexane ethyl acetate/5% acetic acid)]
contaminated with starting material (Rf 0.45).
EXAMPLE 105
5-~5-Phenyl-2-furyl)oxazolidine-2,4-dion_
5-Hydroxy-5-t5-phenyl-2-furyl)-2,4,6(1H~3H,5H)-
pyrimidinetrione (0.7 g.) was dissolved in 15 ml. of
lN sodium hydroxide, stirred at room temperature for
15 minutes, extracted with ethyl acetate, made slightly
acidic with about 1 ml. of glacial acetic acid, and
extracted with 25 ml. of ethyl acetate. The latter
ethyl acetate extract was back washed with about
6.5 ml. of water, filtered over a bed of anhydrous
magnesium sulfate and evaporated to yield solid 5-t5-
phenyl-2-furyl)oxazolidine-2,4-dione [100 mg.; m.p.
216-218C.; Rf 0.6 (1:1 hexane:ethyl acetate/5% acetic
acid)].
EXAMPLE 106
5-Hydroxy-5-(5-methyl-2-furyl)-
2,4,6(lH,3~,5~)eY_imidinetrione
2-Methylfuran (3~28 g., 3.58 ml., 40 mmoles) was
combined with 100 ml. o~ tetrahydrofuran. The reaction
mixture, flushed with nitrogen, wa~ cooled to -30C.
and butyl lithium (19.1 ml. of 2.3M in hexane) was
added over a period of 10 minutes, maintaininy the
temperature at -20 to -30C. The reaction mixture was
warmed to room temperature and then back to -30C.
Sublimed alloxan (5.96 g.) in 40 ml. of tetrahydro-
furan was added dropwise over 10 minutes, keeping the
temperature at -20 to -30C. The reaction mixture was
warmed to room temperature, cooled to 0C. and 50 ml.
o lN hydrochloric acid added portionwise, keeping the
temperature at 0 to 5C. The reaction mixture was
extracted with 100 ml. of ethyl acetate. The extract
was back washed with 25 ml. o water, filtered through
6~L8~
-lo~-
a bed of anhydrous magnesium sulfate and evaporated to
yield solid 5-hydroxy 5-(5-methyl-2-furyl)-2,4,6(lH,3H,5H)-
pyrimidinetrione (6.3 g.; m/e 224).
EXAMPLE 101
5~(5-MethyI-2-furyl)oxazoli- ne 4-dione
5-Hydroxy-5-(5-methyl-2-furyl~-2,4,6(1~,3H,5H)-
pyrimidinetrione (6.3 g.) was dissolved in 50 ml. of
lN sodium hydroxide and stirred at room temperature
for 15 minutes. The reaction mixture was extracted
with 50 ml. of ethyl acetate, and acidified with
glacial acetic acid. Product was then extracted into
fresh ethyl acetate (three 30 ml. portions). The
combined ethyl acetate extracts were filtered through
a bed of anhydrous magnesium sulfate and evaporated to
an oil~ The oil was chromatographed on 50 ml. of
silica gel, with 1:1 hexane:ethyl acetate/5~ acetic
acid as eluant. The column was monitored by tlc using
the same eluant. Clean product containing fractions
were combined, evaporated to dryness and triturated
with hexane (311 mg., m.p. 135-138C.~. Recrystalliza-
tion from methanol/water afEorded purified 5-(5-
methyl-2-furyl)oxazolidine-2,4-dione ~142 mg., m.p.
136.5-137.5C.).
Analysis: Calcd. for C8H7NO4:
C, 53.04; H, 3.90; ~, 7.73.
Found: C, 52.82; H, 4.03; N, 7.65.
~6~343
-103-
EXAMPLE 108
5-Hydroxy-5-(3-thienyl)-
2,4,6(1H,3H,5H)pyrimidlnetrione
Isopropyl ether (40 ml.) was cooled to -70C.
Bu~yl lithium in hexane (2.4M, 10 ml., 24 mmoles) was
added over 10 minutes, keeping the temperature -70
to -60C. 3-Bromothiophene (1.9 ml., 20 mmoles) was
added over 20 minutes, keeping the temperature -72
to -68C. The mixture was stirred for an additional
30 minutes at -72 to -70C. Sublimed alloxan ~3 g.,
21 mmoles) in 25 ml. of tetrahydrofuran was added over
40 minutes, keeping the temperature -70 to -65C.
Stirring at this temperature was continued for 15 minutes.
The cooling bath was removed and the reaction mixture
stirred ~or one hour at room temperature, then cooled
to 5C. Hydrochloric acid (lN, 40 ml.) was added
slowly, and the organic phase separated. The aqueous
phase was extracted with 35 ml. of ethyl acetate. The
combined organic phase/extract was washed with 10 ml.
of water, dried over anhydrous sodium sulfate and
concentrated to yield solid 5-hydroxy-5-(3-thienyl)-
2,4,6(lH,3H,5H)pyrimidinetrione (1.41 y., 31~; m/e
226).
When this reaction was carried out in tetrahydro-
furan with reverse addition of the 3-bromothiophene to
butyl lithium, with immediate addition of 0.5 equivalent
of alloxan hydrate in place of 1 equivalent of anhydrous
alloxan r the product was a mixture of the above trione
and 5-(3-bromo-2-thienyl)-5-hydroxy-2,4,6(1H,3H,5H)-
pyrimidinetrione, which in turn was converted to a
mixture of 5-(3-bromo-2-thienyl)oxazolidine-2,4-dione
and 5-(3-thienyl)oxazolidine-2,4-dione by the method
of Example 55.
-104-
EXAMPLE 109
5 (3-Thienyl)oxazolidine-2,4-dione
5-Hydroxy-5-(3-thienyl)-2,4,6(1H,3H,5H)pyrimidine-
trione (1.16 g~, 5.1 mmoles) was dissolved in lN
sodium hydroxide (11 ml., 11 mmoles) and allowed to
stand at room temperature for 15 minutes. The solution
was acidified with acetic acid, and product allowed to
crystallize over 35 minutes. Filtration gave 5-(3-
thienyl)oxazolidine-2,4-dione (480 mg., 51%; m.p.
133-135~C.). An additional crop of product was
obtained by extracting the mother liquor with ethyl
acetate. The extract was back washed with water, and
evaporated to dryness (80 mg., contaminated with
starting material)~
EXAMPLE 110
5-(3-Furyl)-5-hydroxy-
2,4,6(lH,3H,5H)pyrimidinetrione
The detailed procedure of Example 108, but substitut-
ing 3-bromofuran ~2.94 g., 1.8 ml., 20 mmoles) for the
3-bromothiophene, was employed to produce 5-(3-furyl)-
5-hydroxy-2,4,6(1H,3H,5H)pyrimidinetrione ~1.62 g.,
oil, m/e 210).
EXAMPLE 111
5-~3 Fury~)oxazolidine-2,4-dione
5-(3-Furyl)-S-hydroxy-2,4,6(1H,3H,5H)pyrimidine-
trione (1.62 g.) was dissolved in 15 ml. of lN sodium
hydroxide, and allowed to stand for lS minutes at room
temperature, and then extracted with 5 ml. of ethyl
acetate. The aqueous layer was acidified with glacial
acetic acid (about 1.5 ml.) and product extracted into
25 ml. o~ ethyl acetate. The extract was back washed
with 5 ml. of water, filtered through a bed of anhydrous
sodium sulfate, and evaporated to yield crude product
as an oil (470 mg., m/e 167). ~rystallization from
chloroform gave purified 5-(3-furyl)oxazolidine-2,4-
dione (129 mg., m.p. 88-90C., m/e 167). A second,
lower melting crop was obtained from mother liquor.
-105-
EXAMPLE I12
3-Thenaldehy~ Cyanoh~drin
Sodium bisulfite 130.2 g., 0.29 mole3 was dissolved
in 190 ml. of water and warmed to 50C. 3-Thenaldehyde
(25 g., 0.22 mole) was added and the reaction mixture
held at 50~55C. for 35 minutes, by which time all but
a small amount of gummy solids were in solution. The
mixture was cooled to 5C. and layered with 190 ml. of
isopropyl ether. With stirring, sodium cyanide
(24.8 g., 0.25 mole) in 190 ml. of water was added
dropwise over 20 minutes, keeping the temperature
below 10C. Stirring was continued at room temperature
for 1 hour. The organic layer was separated, and the
aqueous phase extracted with fresh isopropyl ether
(3Q0 ml.). The combined organic extracts we~e washed
with brine, dried over anhydrous magnesium sulfate,
filtered and concentrated to yield 3-thenaldehyde
cyanohydrin as an oil t28.3 g., 92~).
E MPLE 113
~ thienyl)acetamide
Formic acid (0.5 ml.) was cooled in an ice-water
bath. 3-Thenaldehyde cyanohydrin (1.0 g.) and then
concentrated hydrochloric acid (0.5 ml.) were added.
The reaction mixture was stirred at room temperature
for 1 hour, poured over crushed ice, and extracted
with three portions of ethyl acetate. The combined
extracts were washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated to an
oil, which partially crystallized on scratching.
Recrystallization from ethyl acetate gave 2-hydroxy-2-
(3-thienyl)acetamide 1389 ~g., 35~, m.p. 123-126C.,
m/e 157).
-106- ~6~4~
EXAMPLE_114
Mixed Methyl/Ethyl Esters of
2-Benzoyl-2-~3-thienyl ? malonic Acid
Commercially available mixed esters of 2-(3-
thienyl)malonic acid (47% diethyl, 43% methyl/ethyl,
10% dimethyl; 11.4 g.) were added portionwise to a
dispersion of sodium hydride in oil (50%, 2.4 g.)
slurried in 70 ml. of toluene. An exotherm was noted,
the temperature rising to 45C. The reaction mixture
was stirred for 3 hours at room temperature, and then
cooled in an ice-water bath. Benzoyl peroxide l8 g.)
in 100 ml. of toluene was added over a period of
1 hour, maintaining the temperature 10-20C. The
mixture was stirred for 30 minutes at room temperature,
dilut0d dropwise with 50 ml. of water (initial foaming
noted), and finally diluted with 50 ml. of ether. The
organic phase was separated, back washed with three
25 ml. portions of water, and evaporated to yield
mixed methyl/ethyl esters of 2-benzoyloxy-2-l3-thienyl)-
malonic acid as an oil (15.5 g. containing about1.2 g. of oil from the sodium hydride dispersion).
3L~"6~
-107-
EXAMPLE I15
5-t3-Thienyl)oxazolidine-2~4-dione
Sodium (0.46 g., 20 mmoles) was dissolved in
50 ml. o absolute ethanol. To the resulting warm
solution of sodium ethoxide (about 60C.), crude mixed
esters of 2-benzoyloxy-2-(3 thienyl)malonic acid
(7 g., approximately 20 mmoles, as prepared in Example 60)
were added, followed by urea (1.2 g., 20 mmoles)
dissolved in 20 ml. of hot ethanol. The reaction
mixture was heated in an oil bath at 105-110C. for
4.5 hours. The reaction mixture was cooled, acidified
with concentrated hydrochloric acid, and extracted
with ethyl acetate. The extract was back washed with
water and concentrated to an oil. Trituration with
20 ml. of 1:1 ether:hexane gave a mixture of 5-(3-
thienyl)oxa201idine-2,4-dione and intermediate 5-
benzoyloxy-5-(3-thienyl)2,4,6(1H,3H,5H)pyrimidinetrione
(0.8 g.). A portion of this mixture (0.3 g.) was
dissolved in lN sodium hydroxide (5 ml.) and allowed
to stand for 20 minutes at xoom temperature. The
reaction mixture was clarified by filtration, and
acidified with acetic acid to precipitate 5-(3-thienyl)-
oxazolidine-2,4-dione (100 mg., m.p. 136-138C.).
/ `~ -
~6~3
108-
EXAMPLE ll6
2-(3-Benzo[b]thienyl)-2-
trimethy~lsilo~yethanenitriIe
Benzo[b]thiophene-3-carbaldehyde [1.8 g., 11 mmoles,
J. Chem. Soc. C., pp. 339-340 (1969)] and about 100 mg.
of zinc iodide were combined in 35 ml. of ether.
Trimekhylsilylcarbonitrile (1.98 g.~ 20 mmoles) was
added dropwise. After approximately 1 hour, the
reaction mixture was washed in sequence with saturated
sodium bicarbonate, water and brine, dried over
anhydrous sodium sulfate, filtered and evaporated to
yield 2-(3-benzo[b]thienyl)-2-trimethylsiloxyethane
nitrile [2.5 g., oil, Rf 0.7 (1:2 ethyl acetate:hexane~3.
EXAMPLE 117
Ethyl 1-(3-Benzo[b]thienyl)-l-
hydroxymethanecarboximldate Hydrochloride
With cooling in an ice-water bath, 2-(3-benzo~b]-
thienyl)-2-trimethylsiloxyethanenitrile (2.3 g.) was
dissolved in 10 ml. of saturated ethanolic hydrogen
chloride, and held for 16 hours at about 5C. The
reaction mixture was evaporated to dryness and triturated
with ether to yield 1-~3-benzo~b]thienyl)-1-hydroxy-
methanecarboximidate hydrochloride (2.2 g., m.p.
128-131C., m/e 235).
(```~
L84~3
--109--
EXAMPLE I18
5~(3-Benzo[b]thien~l)oxazolidine-2,4-dione
Ethyl 1-(3-benzo[b]thienyl)-1-hydroxymethane-
carboximidate hydrochloride 12.36 g., 8.7 mmoles) and
triethylamine (2.64 g., 26 mmoles) were combined in
50 ml. of tetrahydrofuran and cooled to 10C. Phosgene
was bubbled through the cooled reaction mixture for
30 minutes, followed by a 10 minute flush with nitrogen.
The reaction mixture was slowly poured into 100 ml. of
ice and extracted twice with ether. The combined
ether extracts were back-washed with water and then
brine, dried over anhydrous sodium sulfate, filtered,
and evaporated to yield a gummy solid (1.7 g.). This
crude product was dissolved in lN sodium hydroxide,
washed twice with ether and acidified with 6N hydro-
chloric acid, affording purified 5-(3-benzo[b]thienyl)-
oxazolidine-2,4-dione (950 mg., m.p. 202-205C., m/e
233).
~ : Calcd. for Cl1H7~3NS:
C, 56.64; H, 3.02; N, 6.00.
Found:C, 56.74; H, 3.18; N, 5.69.
EXAMPLE 119
2-(7-Benzo[b]thienyl)-2-
trimethylsiIoxyethanenitriIe
Benzo[blthiophene-7-carbaldehyda [1.3 g., 8 mmoles,
J. Org. Chem. 39, 2829 (1974)3 was dissolved in 35 ml.
of ether. Trimethylsilylcarbonitrile (l.S ml.,
12 mmoles) and zinc iodide ~about 50 mg.) were added
and the mixture stirred for 1 hour at room temperature,
at which time tlc indicated conversion was complete.
The reaction mixture was evaporated to dryness, yielding
2-(7-benzo[b]thienyl)-2-trimethylsiloxyethanenitrile
[2.2 g., oil; R~ 0.6 (1:5 ethyl acetate:hexane/5%
acetic acid)].
--1 1 o--
EXAMPLE 120
Ethyl 1-(7-Benzo[b]thienyl)-l-
hydroxymethanècarboximidate Hydrochloride
By the procedure of Example 112, 2-(7-benzo[b]-
thienyl)-2-trimethylsiloxyethanenitrile (2.1 g.),
using 35 ml. of saturated ethanolic hydrogen chloride,
was converted to ethyl 1-(7-benzo[b]thienyl-l~hydroxy-
methanecarboximidate hydrochloride ~1.1 g , m.p.
120-122C.), after crystallization from acetone.
EXAMPLE I21
5-(7-Benzo[b]thienyl)oxazolidine-2,4 dione
Following the procedure of Example 118, ethyl 1-
(7-benzo[b]thienyl3-1-hydroxymethanecarboximidate
hydrochloride (1.1 g., 4 mmoles) and triethylamine
(1.7 ml., 12 mmoles) were reacted with phosgeneO The
crude product, isolated as an oil, was dissolved in
25 ml. ether and product extracted into 50 ml. of lN
sodium hydroxide. This agueous exkract was acidified
with concentrated hydrochloric acid and product
extracted into fresh ether, which was back washed with
water and evaporated in vacuo to a solid residue
(670 mg.). This residue was recrystallized to yield
5-(7-benzo~b]thienyl)oxazolidine-2,4-dione (0.45 9.,
m.p. 130-132C.~.5 Analysis: Calcd. for C H O NS:
11 7 3
C, 56.64; H, 3.02; N, 6.00.
Found: C, 56.42; H, 3.18; N, 5.91.
--111--
EXAMPLE I 2 2
5-Hydroxy-5-(5-methoxy-2-thienyl)-
2,4,6(lE,3H,5H3-~y~midinetrione
2-Methoxythiophene (2.3 g., 20 mmoles) was dis-
solved in 35 ml. of ether. With cooling, butyl
lithium in hexane (2.4M, 9 ml., 21.6 mmoles) was added
dropwise over 15 minutes, the temperature rising as
high as 35C. during this addition. The reaction
mixture was stirred for 1 hour at room temperature.
While maintaining the ~emperature between -20 and
-15C., sublimed alloxan (3 g., 21 mmoles) in 20 ml.
of tetrahydrofuran was added during 10 minutes. The
mixture was warmed to room temperature, stirred for
0.5 hourl cooled to 5C. and quenched by adding 35 ml.
of lN hydrochloric acid in portions. The organic
phase was separated and the aqueous phase extracted
with 25 ml. of ethyl acetate. The combined organic
phase and extract were back-washed with water, concen-
trated to dryness and triturated with hexane to yield
solid 5-hydroxy-5-(5-methoxy-2--thienyl)-2,4,6(1H,3H,SH)-
pyrimidinetrione (1.4 g., m/e 256).
EXAMPLE 123
-
5-(5-Methox~-2-thienyl~oxazolidine-2,4-dione
5-Hydroxy-5-(5-methoxy-2-thienyl)-2,4,6(~H,3H,5H)-
pyrimidinetrione (1.1 g.) was dissolved in 10 ml. of
1~ sodium hydroxide, allowed to stand for 1.5 hours at
room temperature~ extxacted with ether, acidified with
acetic acid, diluted with 15 ml. of water and filtered
to yield product ~567 mg., m.p. 144-146C. (decO)].
Recrystallization from acetone-hexane gave purified 5-
(5-methoxy-2-thienyl)oxazolidine-2,4-dione in two
crops ~487 mg., m.p. 147-148C. (dec.3].
,Analysis: Calcd. for C8H7O4NS:
C, 45.08; H, 3.31; N, 6.57.
Found: C, 45.08; H, 3.41; N, 6.39.
"~
-112-
EXAMPLE I24
,
5-[5-(2-phenyl-1,3-dioxolan-2-yl) 2-
thienyl]-2~4,6~lH,3H,5H)-~yrimidinetrione
At room temperature, 2-phenyl~2-thienyl)-1,3-
dioxolane (3.26 g., 14 mmoles) was dissolved in 35 ml.
of ether. Butyl lithium in hexane (2.4M, 6.25 ml.,
15 mmoles) was added dropwise over 15 minutes, the
temperature rising to 33~C. The mixture was stirred
for 75 minutes at room temperature and then cooled.
Maintaining the temperature between -15 and -20C.,
sublimed alloxan (2.13 g., 15 mmoles) in 20 ml. of
tetrahydrofuran was added dropwise over 10 minutes.
The reaction mixture was stirred at room temperature
for 30 minutes, cooled to 5C., quenched with 35 ml.
of lN hydrochloric acid, added in small portions, and
extracted with 25 ml. of ethyl acetate. The organic
layer was back washed with 15 ml. of water, filtered
through a bed of anhydrous sodium sulfate, and evaporated
to yield 5-[5-(2-phenyl-1,3-dioxolan-2-yl)thienyl]-
20 2,4,6(1H,3H,5H)-pyrimidinetrione [oil, Rf 0.25 (1:1
hexane:ethyl acetate/5% acetic acid)] contaminated
with starting material (Rf 0.8).
EXAMPLE 125
5-[5-(2-Phenyl-1,3-dioxolan-2-yl)-2-
~ zolidine-2, 4-dione
The entire crude product from the preceding
Example was taken into 35 ml. of lN sodium hydroxide
and allowed to stand for 30 minutesO After acidifica-
tion the product was extracted into isopropyl ether.
The extract was back washed with water and evaporated
to yield 5-~5-(2-phenyl-1,3-dioxolan-2-yl)thienyl~-
oxazolidine-2,4-dione [0.40 g., Rf 0.65 (1:1 ethyl
acetate:hexane15% acetic acid)].
-113-
EXAMPLE 126
5-(5-Benzoyl-2-thlenyl)oxazolidine-2,4-dlone
5-[5-(2-Phenyl-1,3-dioxolan-2-yl)-2-thienyl]-
oxazolidine-2,4-dione (0.40 g.) was dissolved in
30 ml. of ether and stirred with 10 ml. of 6N hydro-
chloric acid at room temperature for 1 hour. Ethyl
acetate ~10 ml.) was added, and the organic layer was
sepaxated and evaporated in vacuo to dryness (0.388 g~).
Chromatography on 50 ml. of silica gel, eluted with
1:1 hexane:ethyl acetate/5~ acetic acid and monitored
by tlc, gave in early fractions purified 5-(5-benzoyl-
2-thienyl)oxazolidine-2,4~dione (0.22 g., m.p. 153-155C.,
m/e 287).
~ : Calcd. for C14H904NS:
C, 58.52; H, 3.16; N, 4.87.
Found: C, 58.69; H, 3.50; N, 4.94.
EXAME~LE 127
5-(3-Thienyl)oxazolidine-2,4-dione CaPsules
The following ingredients were combined and
blended for 30 minutes:
Sodium 5-(3-thienyl)oxazolidine-2,4-dione
monohydrate 30.46*
~actose, anhydrous, U.S.P. 14.05 g.
Corn starch, dried, U~S.P. 5.00 g.
*Equivalent to 25 g. of active drug (unsolvated
free acid).
The mixture was milled (0.040 inch plate) and
blended for an additional 30 minutes. Magnesium
stearate, sodium lauryl sulfate, 90/10 blend (1.00 g.)
was added and the mixture blended for 20 minutes. The
blend was filled into #0 gelatin capsules (505 mg.
fill weight) so as to obtain capsules of 250 mg.
potency.
~ 34;~
-114-
Larger capsules are employed to prepare capsules
of higher potency.
The same procedure was employed to prepare
capsules of 100 mg. potency from the following ingre-
dients:
Sodium 5-(3-~hienyl)oxazolidine-2,4-dione
monohydrate 12.18 g.*
Lactose, anhydrous, U.S.P. 32.32 g.
Corn starch, dried, U.S.P. 5.00 g.
Magnesium stearate/lauryl sulfate
(90/10 blend) 0.50 g.
*Equivalent to 10 g. of activated ingredient
(unsolvated free acid).
A lower level of active ingredient in the blend
is used to prepare capsules of lower potency.
EXAMPLE 128
bIets
A tablet base is prepared by blending the follow-
ing ingredients in the proportion by weight indicated:
Sucrose, U.S~P. 8003
Tapioca starch 13.2
Magnesium stearate 6.5
Into this tablet base there is blended sufficient
sodium 5-(3-thienyl)oxazolidine-2,4-dione monohydrate
~5 to form tablets containing 50 mg~, 100 mg. or 250 mg.
of active drug ~weight equivalent to the free acid).
The portion of blend to active drug is within the
limits of 1-0.167 to 1-1, e.g., in the extremes,
60.2 mg. of sodium salt monohydrate arld 300 mg. of
blend in a 50 mg~ tablet or 304.6 mg. of sodium salt
monohydrate and 250 mg. of blend in a 250 mg. tablet.
-115- 13LG~3
EXAMPLE I29
In~ectable Preparation
Sterile ~odium 5-(3-thienyl)oxazolidine-2,4-dione
is dry filled into vials so as to contain 670~1 mg. of
the sodium salt monohydrate per vial (equivalent to
550 mg. of free acid). Prior to use, sterile water
for injection (11 ml.) is added, and the mixture
shaken to form a solution, containing 50 mg./ml. of
active drug, which is suitable for intravenous, intra-
muscular or subcutaneous injection.
Alternatively vials are filled by a freeze drying
procedure. Two ml. of a sterile, aqueous solution
containing 335 mg./ml. of sodium salt monohydrate is
introduced into each vial. The vials are freeze dried
on trays.
EXAMPLE 130
_
3-Ethoxycarbonyl-5-(3-
thi~y~L_____lldine-2,4-dione
Sodium 5-(3-thienyl)oxazolidine-2,4-dione mono-
~0 hydrate is stripped of water by drying in vacuo at
elevated temperature (50-70C~). The anhydrous salt
(2.05 g., 10 mmoles) is suspended in 35 ml. of 1,2-
dichloroethane. Ethyl chloroi-ormate (1.41 g., 10 mmoles)
is added and the mixture refluxed for about 2 hours.
The reaction mixture is cooled to room temperature, by-
product sodium chloride removed by filtration and the
filtrate concentrated to dryness to yield 3-ethoxy-
carbonyl-5-(3-thienyl)oxazolidin-2,4-dione.
Substitution of the ethyl chloroformate with an
equivalent quantity of acetyl chloride, isobutyryl
chloride, N,N-dimethylcarbamoyl chloride, or benzoyl
chloride produces, respectively, 3-acetyl-5-(3-thienyl)-
oxazolidine-2,4-dione, 3-isobutyroyl-5-(3-thienyl)-
oxazolidine-2,4-dione, 3-(N,N-dimethylcarbamoyl)-5-(3-
thienyl)oxazolidine-2,4-dione and 3-benzoyl-5-~3-
thienyl)oxazolidine-2,4-dione.
-116~ 8~3
EXAMPLE 13I
3-Acetyl-5-(3-thienyl)oxazolidine-2,4-dione
Method A
5-(3-Thienyl)oxazolidine-2,4-dione (1.83 g.,
10 mmoles) and triethylamine (0.14 ml., 10 mmoles) are
combined with 25 ml. of 1,2-dichloroethane at room
temperature. Acetyl chloride (0.72 ml., 10 mmoles) is
added dropwise over a few minutes and the reaction
mixture stirred for 3 hours. The reaction mixture is
evaporated to dryness and the residue distributed
between saturated sodium bicarbonate and chloroform.
The chloroform layer is washed with water, and then
brine, dried over anhydrous magnesium sulfate, filter-
ed and evaporated to yield 3-acetyl-5-(3-thienyl)-
oxazolidine-2,4-dione.
Method B
5-(3-Thienyl)oxazolidine-2,4-dione (1.83 g.,
10 mmoles) and acetic anhydride (1.14 ml., 12 mmoles)
are combined with 20 ml. of tetrahydrofuran and
stirred for 40 hours. The reaction mixture is evaporated
to dryness and 3-acetyl-5-(3-thienyl)oxazolidine-2,4-
dione further isolated as in Method A.
The same procedure, but substituting acetic
anhydride with an equivalent of acetoformic acid
reagent ~a solution of acetic-formic anhydride in
acetic acid; cf. Blackwood et al., J. ~m Chem. Soc.,
82, 5194 (1960)], propionic anhydride or benzoic
anhydride, allows formation of corresponding 3-formyl~-
5-(3-thienyl)oxazolidine-2,4-dione, 3-propionyl-5-~3-
thienyl)oxazolidine-2,4-dione and 3-benzoyl-5-(3-
thienyl)oxazolidine-2,4-dione.
117~ 6~
EXAMP:LE 132
3-(N-Methylcarbamoyl)-5-
(3-thienyl3oxazolldine-2,4-dione
5-(3-Thienyl)oxazolidine-2,4-dione (1.83 g.,
10 moles) and one drop of triethylamine are combined
in 35 ml. of 1,2-dichloroethane. Methyl isocyanate
(0.58 ml., 10 mmoles) is then added and the reaction
mixture stirred for 4 hours at room temperature. The
reaction is diluted with 35 ml. of 1,2-dichloroethane,
washed with saturated sodium bicarbonate and then
brine, dried over magnesium sul~ate, filtered and
concentrated to yield 3-lN-methyl)-5-(3-thienyl)
oxazolidine-2,4-dione.
~6~L8g~3
-118-
EXAMPLE 133
3-~4-Methoxy-3-thienyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 55, 4-methoxy-3-
thenaldehyde ~2.6 g., 18.3 mmole) and trimethylsilyl-
5 carbonitrile (2.15 g., 21.7 mmole) in 250 ml. of etherin the presence of 50 mg. of zinc iodide was converted
to title product as an oil (3.9 g., m/e 241).
XAMPLE I34
Methyl l-Hydroxy-1-(4-methoxy-3-thienyl)
methanecarboximidate Hydrochloride
Saturated methanolic hydrogen chloride (100 ml.)
was maintained at 0-5C. in an ice bath. Title product
of the pxeceding Example (3.9 g.) in 20 mlO of methanol
was added dropwise and the mixture held for 1 hour at
0-5C. The reaction mixture was concentrated to
solids and the residue triturated with ether to yield
the title product ~2.76 g., m.p. 94-99C. (dec.~].
Recrystallization from methano]-ether gave purified
title product [1.51 g.; m.p. 112-114 (dec.); m/e 201].
EXAMPI,E I35
5-~4-Methoxy-3-thienyI~oxazolidine-2~4-dione
_
By the procedure of Example 57, thP product of the
preceding Example (1.3 g., 5.5 mmoles) and trie~hylamine
~1.7 g., 17 mmoles) in 50 ml. of tetrahydrofuran were
reacted with phosgene for 30 minutes at 0-5C. The
reaction mixture was stirred overnight at room tempera-
ture. The reaction mixture was poured slowly into
500 ml. of crushed ice and extracted with three 50 ml.
portions of chloroform. The combined organic layers
were washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated to solids. Recrystal-
lization from toluene gave purified title product ~510 mg.;
m.p. 120-222C.; ir (KBr) 1377, 1732, 1767, 1808 cm 1].
Analysis: Calcd. for C H O NS:
8 7 4
C, 45.06; H, 3.31; N, 6~57.
Found: C, 45.31; H, 3.41; N, 6.85.
6~4;3~
--119--
EXAMPLE 136
3-(4~Ethoxy-3-thienyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 55, 4-ethoxy-3-then-
aldehyde (8.1 g., 0~052 mole) and trimethysilylcarbo-
nitrile (6.13 gO, 0.062 mole) in 300 ml. of ether, in
the presence of 50 mg. of zinc iodide, were converted
to title product (13 g.) as a viscous oil, pnmr
indicated absence of the aldehyde proton.
EXAMPLE 137
Ethyl l-Hydroxy-1-(4-ethoxy-3-thienyl)-
methanecarboximidate HydrochIoride
Using ethanol in place of methanol, but otherwise
tha procedure of Example 134, product of the preceding
Example (13 g.) was converted to title compound
[9.23 g., m.p. 126-128 (dec.)].
EXAMPLE 138
5-(4-Ethoxy-~-thienYI)oxazol;dine-2~4-dione
Using a phosgene perfusion time of 1 hour at
0-5C. and a further reaction time of 1 hour at room
temperature, product of the preceding Example (9.2 g.)
was converted to title product~ To isolate the product,
the reaction was poured in 1.5 1. of crushed ice and
extracted with three 200 ml. portions of chloroform.
The organic layers were combined and extracted with
three 150 ml. portions of lN sodium hydroxide. The
basic extracts were combined, back-washed with 200 ml.
of fresh chloroform, reacidified with 3N hydrochloric
acid and extracted with three 200 ml. portions o~
chloroform. The last three organic extracts were
combined, washed with brine, dried over magnesium
sulfate, filtered, evaporated to solids, and the
residue crystallized from toluene to yield title
compound [4.06 g., m.p. 144-146C., m/e 227; ir (KBr)
1822, 1737, 1568 cm 1].
843
-120-
Analysis: Calcd. for CgH904NS
C, 47~57; H, 3.99; N, 6.17
Found: C, 47.18; H, 4.04; N, 6.06.
The chloroform back-wash was reextracted with three
150 ml. portions of fresh lN sodium hydroxide. These
basic extracts were combined and additional product
~980 mg., m.p. 144-146C.) recovered in like manner.
EXAMPLE 139
.
2-[4-(n-Propoxy)-3-thienyl]-2-
trimethylsiloxyethanenitrile
By the procedure of Example 55, 4-(n-propoxy)-3-
thenaldehyde (3.1 g., 18 mmoles) and trimethylsilyl-
carbonitrile (2.28 g., 2.9 ml., 23 mmoles) in 250 ml.
of ether, in the presence of 50 mg. of zinc iodide,
were converted to title product as an oil [4.6 g.; m/e
269; ir (CH2C12) 2936, lS58 cm 1].
EXAMPLE l40
Ethyl l-Hydroxy-l-r4-~n-propoxy)-
3-thienyl~methanecarbox_ idate ~ydrochloride
Using a reaction time of 20 minutes after comple-
tion of the addition, the proc~3dure o~ Example 137 was
used to convert the product of the preceding Example
(4.5 g.) into title product of the present Example
[3.05 g., m.p. 127-129C. (dec.)].
XAMPLE 141
5-~4-(n-Propoxy)-3-thienyl-
oxazolidine-2,4-dione
By ~he procedure of Example 135, the product of
the preceding Example (2.8 g., 0.01 mole) was convertea
to toluene recrystallized 5-[4-(n-propoxy)-3-thienyl]-
oxazolidine-2,4-dione [1.63 g.; m.p. 134-136C.; m/e
241; ir (KBr) 1827, 1747, 1564 cm 1].
-121~ 3
EXAMPLE 142
2-(4-Methoxy-2-methyl-3-thienyl)-
2-trimethylsiIoxyethanenitrile
By the procedure of Example 55, 4-methoxy-2-
5methyl-3-thenaldehyde (5.2 g., 33.3 mmoles) and
trimethylsilylcarbonitrile (3.96 g., 40 mmoles) in
350 ml. of ether, in the presence of 50 mg. of zinc
iodide, were converted to title product, isolated as a
viscous oil [7.3 g.; m/e 255; ir (CH2C12) 1575, 1204,
101075 cm ].
EXAMPLE 143
Ethyl l-Hydroxy-1-(4-methoxy-2-methyl-3-
thieny~)methanecarboximidate Hydrochloride
The procedure of Example 137 was applied to the
15product of the preceding Example (7.2 g.) to produce
5.8 g. of a mixture of title compound and the corres-
ponding ethoxy ether (estimated by pnmr to be about
40% methyl ether and 60% ethyl ether; showing both m/e
243 and 229).
A portion of this mixture (2.5 g.) was taken into
100 ml. of methanol, cooled to 0-5C., and perfused
with hydrogen chloride for 1 hour. After 1 hour
additional stirring at 0C., the reaction mixture was
evaporated to a viscous oil. C'rystallization from
ether gave title product [2.1 g.; m.p. 123-125C.
(dec.); m/e 229].
The corresponding methyl imidate ester of the title
product is obtained by direc~ly reacting the product
of the preceding Example with methanolic hydrogen
chloride according to the procedure of Example 134.
4:~
-122-
EXAMPLE 144
Ethyl l-(Hydroxy)-1-(4-Ethoxy-2-methyl-3-
thien l)methanecarboximidate H drochloride
Y ~ Y
A portion of the mixed methyl and ethyl ethers of
the preceding Example (2.5 g.) was taken into 100 ml.
of ethanol and cooled to 0C. The cold solution was
perfused with hydrogen chloride for 1 hour, stirred
for an additional hour at 0C. and evaporated to an
oil. The oil was crystallized by trituration with
ether. Repulping in ether gave title product ~2.07 g.,
m.p. 105-107C. (dec.); m/e 243].
EXAMPLE I45
5-(4-Methoxy-2-methyI-3-thienyI~oxazolidine-_,4-dione
Using a reaction time of 3.5 hours at room tempera-
ture, but otherwise following the procedure of Example 57,
the product of Example 143 (2.0 g., 7.5 mmoles) was
converted to koluene recrystallized title product
[0.52 g., m.p. 179-181C.; m/e 227; ir (KBr) 1%20,
1750, 1727, 1583 cm~l~.
EXAMPLE 146
5-(4-Ethoxy-2-methyl-3-thienyI)oxazolidine-2,4-dione
__
By the procedure o~ the preceding Example, the
product o Example 144 (1.9 g.) was converted to title
product [245 rng., m.p. 136-138C.; m/e 241; ir (KBr)
1824, 1743 cm~l].
~ v
-123~
EXAMPLE 147
5-Hydroxy-(2,5-Dimethyl-3-furyl)-
2,4,6( IH, 3H,5H)pyrimidinetrlone
Isopropyl ether (35 ml.) was cooled to -68C.
Butyl lithium (5 ml. of 2.1M in hexane, 10.5 mmoles)
was added, allowing the temperature to rise to -60C.
2,5-Dimethyl-3-iodofuran [J. Am. Chem. Soc. 70, p. 739
(1948); 1.2 ml, 9 mmoles] was then added dropwise
keeping the temperature between -65 and -68C. After
stirring for 0.5 hour at -68C., anhydrous alloxan
(1.5 g., 10.6 mmoles) dissolved in 15 ml. of tetra-
hydrofuran was added dropwise over 30 minutes, keeping
the temperature -65 to -60~C. The stirred reaction
mixture was warmed over 15 minutes to 0C., lN hydro-
chloric acid (25 ml.) was added and the organic phase
separated. The aqueous phase was extracted with
20 ml. of ethyl acetate. The combined organic layers
were washed with 10 ml. of water and evaporated to
yield title product (1 g., Rf 0.05 (1:5 ethyl acetate:
hexane/5~ acetic acid)].
~ 3
-124-
EXAMPLE 148
5-(2,5-Dimethyl-3-furyl)oxazolidine-2,4-dione
Product of the preceding Example (1 g.) was taken
into 10 ml. of lN sodium hydroxide and held for
15 minutes~ The solution was extracted with 5 ml. of
ethyl acetate, acidified with acetic acid and extracted
with 25 ml. of ethyl acetate. The acidic extract was
back-washed with 5 ml. of water and evaporated to
solids (340 mg.), which were chromatographed on 50 ml.
of silica gel, using 1:1 ethyl acetate:hexane as
eluant and tlc monitoring. Clean fractions were
combined, evaporated to dryness and the residue
recyrstallized from ether-hexane to yield purified
title product [170 mg.; m.p. 144-145; m/e 195; Rf 0.3
(1:5 ethyl acetate:hexane/5% acetic acid~; Rf 0.55
(1:1 ethyl acetate:hexane)].
: Calcd. for C9H904N:
C, 55.38; H, 4.65; N, 7.18
Found: C, 55.15; ~, 4.76; N, 7.04.
-125~ 3
EXAMPLE 149
5-Hydroxy-5-(4-iodo-3-furyl)-
2,4,6(lH,3H,5H3pyrimidinetrione
3,4-Diiodofuran ~0.96 g., 3 mmoles) in 5 ml. of
ether was added slowly to a cold (-65C.) solution of
butyl lithium (2 ml. of 2.3M in hexane, 4.6 mmoles) in
15 ml. of ether. The mixture was stirred for 20 minutes
at -65C. Anhydrous alloxan (0.57 g., 4 mmoles) was
dissolved in 10 ml. of tetrahydrofuran and added
slowly to the 4-iodo-3-furyl lithium solution at -65C.
After 10 minutes at the same temperature, the reaction
mixture was warmed to 15C., acidified with 15 ml. of
lN hydrochloric acid and extracted with ether. The
ether extract was back-washed with 10 ml. of water,
concentrated to dryness and the residue triturated
with 2 ml. of hexane to yield title product [ios mg.;
m/e 336; Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic
acid)].
J
-126-
EXAMPLE 150
5-(4-Iodo-3-furyl)oxazolidine-2,4-dione
Product of the preceding Example (100 mg.) was
allowed to stand with 1 ml. of lN sodium hydroxide for
15 minutes at room temperature. The reaction mixture
was acidified with acetic acid and extracted with
3 ml. of ethyl acetate. The organic extract was back-
washed with 1 ml. of water and evaporated to a gum
(63 mg.). Crude material (120 mg.~ prepared in this
manner was chromatographed on 50 ml. of silica gel
using 1:1 ethyl acetate:hexane as eluant and tlc
monitoring. The first fractions from the column were
combined and evaporated to a gum (78 mg. which crystal-
lized from chloroform to yield purified title product
(45 mg.; m.p. 140-144C.).
Analysis: Calcd. for C7H404NI:
C, 28.69; H, 1.38; N, 4.78
Found: C, 28.37; H, 1.62; N, 4.74.
~6~ .3
-127-
EXAMPLE I 51
5-(5-Chloro-7-benzo~b]f uranYl ] oxazol idine-2 4-dione
Title produc~ of Example 50 (100 mg., 0~39 mmole)
was suspended in 6 ml. of chloroform and bis(trimethyl-
silyl~trifluoroacetamide (100 mg., 0.104 ml., 0.39 mmole)
added in one portion. After stirring for 1 minute, N-
bromosuccinimide t69 mg., 0.39 mmole) was added together
with a trace (a single crystal) of benzoyl peroxide.
The mixture was heated to reflux for 2 hours, cooled
to room temperature, filtered from insolubles and
evaporated to semisolids under a stream of nitrogen.
The residue was partitioned between lN sodium hydroxide
and ethyl acetate. The aqueous layer was separated,
washed with fresh ethyl acetate, acidified with lN
hydrochloric acid and extracted with three portions of
chloroform. The chloroform extracts were combined,
dried over anhydrous magnesium sulfate, filtered,
concentrated to an oil, and title product crystallized
from toluene (44 mg.; m.p. 154-157C.; mte 251.253).
By the same method the f]uoro analog of Example 50
is converted to 5-(5-fluoro-7-benzo[bJfuranyl]oxazolidine-
2,4-dione.
-128-
PREPARATION l
2-Ethoxy-3-pyridinecarbox~lic Acid
Sodium ethoxide was prepared by adding sodium
(1.4 g., 0.06 mole) portion wise to 50 ml. of anhydrous
ethanol. The solution was diluted with 20 ml. of
ethanol and 4.5 g. of 2-chloropyridine-3-carboxylic was
added. The reaction mixture was heated in a steel
pressure vessel at 170C. for 6 hours. The vessel was
~ cooled and the contents evaporated to dryness in vacuo.
10 ~ ~ The residue was taken up in 150 ml. of water and
acidified to constant pH 4.5. The water solution was
saturated with salt and extracted with four portions of
ethyl acetate. The combined ethyl acetate layers were
back washed with brine, dried over anhydrous magnesium
sulfate, filtered and evaporated to yield title product
(4.33 g., m.p. 85-88C.).
8~
-:L29-
PREPARATION 2
2-Methoxy-3~yridinecarboxylic Acid
A stainless steel stirred autoclave was charged
sequentially with methanol (2.8 1.), sodium methoxide
(259 g.) (in portions, keeping the temperature less
than 35C.), and 2-chloro-3-pyridinecarboxylic acid
(190 g.)~ The autoclave was sealed and the reaction
mixture heated at 110C. (50 psig) for 48 hours. The
reaction ~ixture was cooled to 25C. and discharged
from the autoclave. Solids were recovered by fil-
tration. Concentration of the filtrate gave a second
crop. These process steps were repeated until virtually
all of the methanol had been removed. The several
crops of solids were combined, taken up in 2.5 liters
of water and acidified with conc. hydrochloric acid to
pH 2.7 keeping the temperature below 20C. The pre-
cipitated product was granulated for 30 minutes at
15C. and recovered by filtration (141 g.). Purifi~d
title product was obtained by recrystallization from
ethyl acetate-hexane (120.5 g., m.p. 148-150C.).
.
~l~L6~3Lli3~3
--130--
PREPARATION 3
Ethyl 2- ( 6-Chloro-8-~uinolyl)-2-oxoacetate
8-Bromo-6-chloroquinoline [J. Het. Chem. 6,
pp. 243-245 (1969~; 6 g., 0.0~5 mole] in 50 ml. of
tetrahydrofuran was added dropwise over a 10 minute
period to a mixture of butyl lithium ( 2 . 3M in hexane,
12 . 2 ml., 0 . 028 mole) and 40 ml. of tetrahydrofuran held
at -70C. After an additional 30 minutes at this
temperature, a cold (0C.) solution of diethyl oxalate
(14.6 g., 0.10 mole) in 50 ml. of tetrahydrofuran was
added dropwise. The reaction mixture was maintained at
0C. for 1 hour, then quenched at 0-5C. with glacial
acetic acid (17 ml.) in 50 ml. of tetrahydrofuran.
After warming to room temperature the guenched mixture
was poured into 500 ml. of water and then diluted with
500 ml. of ethyl acetate and 500 ml. of saturated
sodium bicarbonate. The organic layer was separated,
washed with 500 ml. of ~resh bicarbonate, dried over
anh~drous magnesium sulfate, filtered, and evaporated
to an oil. Trituration with two 100 ml~ portions of
hexane gave the title product 1[2.3 g., m.p. 107-110C.;
m/e 265/263).
-131- ~6~843
PREPARATION 4
Ethyl 2-(6-Chloro-g-quinol~ 2-h_droxyacetate
Sodium borohydride (2.5 g., 0.066 mole) was dis-
solved in 300 ml. of ethanol at 10C. and added in one
portion to a 10C. solution of product of the preceding
Preparation t2.0 g., 0.0076 mole) in 200 ml. of ethanol.
After a few minutes, the reaction mixture was diluted
with 750 ml. of ethyl acetate and 750 ml. of water.
The aqueous layer was extracted with 250 ml. of fresh
ethyl acetate. The organic layers were combined, washed
with three 250 ml. portions of brine, dried over an-
hydrous magnesium sulfate, filtered and evaporated to
yield title product, initially an oil which crystallized
on standing (1.87 g.; m.p. 121-124C., m/e 267/265).
PREPARATION _
EthyI 2-(6-Fluoro-8-quinolyl)-2-oxoacetate
By the procedure of Preparation 3, 8-bromo-6-
fluoroquinoline [J. Het. Chem., 6, pp. 243-245 (1969);
4.5 g., 0.02 mole] was converted to hexane triturated
title product (1.6 g.; m.p. 114-117C.).
-132- ~ 43
PREPARATIO _6
Ethyl 2- 6-Fluoro-8-quinolyl~-2-hydroxyacetate
By the procedure of Preparation 4, product of the
preceding Preparation (1.5 g., 6.1 mmoles) was con~
verted to title product. The product, initially
obtained as a turbid oil, was taken back up in ethyl
acetate, washed with brine, dried, filtered and evapo-
rated to an oil which rapidly crystallized (1.23 g.,
m.p. 84-87C.).
PREPARATION 7
6-Hydroxyquinoline-5-carbaldehyde
Sodium hydroxide ~25 g~) was dissolved in 35 ml.
of water with cooling, 6-hydroxyquinoline (5 g.) in
15 ml. of chloroform was added and the reaction mixture
heated to reflux (about 90C.) for 12 hours, during
which two further 15 ml. portions of chloroform were
added - one after 2 hours and the other after 6 hours.
The reaction mixture was cooled and crude product
recovered by filtration. The crude was dissolved in
125 ml. of hot water treated with activated carbon,
filtered hot, cooled and acidified with acetic acid and
filtered to yield title produat [2.5 g.; m.p. 136-
137C.; m/e 173; pnmr/ CDC13 shows aldehyde proton at
10.5 ppm and aromatic protons at 7.2-9.4 ppm.].
34~
-133--
PREPARATION 8
6-MethoxygL_noline-5-carbaldehyde
Product of the preceding Preparation (1.7 g.,
9 . 8 mmoles) in 85 ml. of acetone was combined with
potassium carbonate ~1.21 g., 8.8 mmoles). Dimethyl
sulfate ( 0 . 83 ml., 8 . 8 mmoles) was added and the mix-,
ture stirred at room temperature for 16 hours. Ad-
ditional potassium carbonate (0.34 g., 2.5 mmole) and
dimethyl sulfate 10 . 23 ml., 2.5 mmole) were added and
the mixture stirred 4 more hours at room temperature
and then 3 hours at 60C. The reaction mixture was
cooled to room temperature, salts removed by filtration,
and the filtrate evaporated to dryness. The residue
was taken up in ethyl acetate, washed sequentially with
two portions of lN ammonium hydroxide, one of water and
one of brine, dried over anhydrous magnesium sulfate,
filtered and evaporated to yield title product ~0.78 g.;
Rf 0.35 (2:1 ethyl acetate:chloroform); pnmr/CDC13/delta
(ppm): 4.2 (s, 3H), 7.4-9.1 (m, 5H), 10.3 (s, lH)].
~.` '~f
. -134~ 43
PREPARATI ON_9
7-Hydroxy ~uinoline-8-carbaldehyde
By the procedure of the Preparation 7, 7-hydroxy-
~uinoline (S g.) was converted to title product (3.3 g.,
m.p. 127-130C.; m/e 173; pnmr/CDC13 shows aldehyde
proton at 10.8 ppm, aromatic protons at 7.0-8.9 ppm.
PREPARATION 1 0
7-Methoxy~uinoline-8-carbaldehyde
By the procedure of Preparation 8, the product of
the preceding Preparation (3.3 g., 19 mmoles) was
converted to title product [2.1 g., pnmr/CDC13/delta
(ppm): 4.1 (s, 3H), 7.5-9.0 (m, 5H), 11.2 (s, 1~)].
--13S~
PREPARATION 11
6-Chlorochroman
Mossy zinc (75 g.), 7.5 g. of mercuric chloride,
125 ml. of water and 4 ml. of conc. hydrochlori~ acid
were combined, shaken for 5 minutes, allowed to settle,
and liquids decanted from the resulting amalgamated
zinc. A mixture of 100 ml. of water and 126 ml. of
conc. hydrochloric acid and then 6-chloro-4-chomanone
(15 g.) were added to the metal, and the mixture re-
fluxed for 1.5 hours, cooled to room temperature,
decanted from the zinc and the decant extracted with
three portions of ether. The combined extracts were
dried over anhydrous magnesium sulfate, filtered and
concentrated to an oil ~14 g.). The oil was chroma-
tographed on 400 g. of silica gel using 9:1 hexane:
ether as eluant tlc monitoring and 15 ml. fractions.
Clean product fractions were combined and evaporated to
yield title product as an oil [8.72 g.; pnmr/CDC13/
delta (ppm~ 2.0 (m, 2H), 3.7 (t, 2H), 4.1 (t, 2H), 6.9
(m, 3H); m/e 170/168; Rf 0.88 (2:1 hexane: ether)].
-136- ~6~ 3
PREPARATION 12
6-Chlorochroman 8-carbaldehyde
Product of the preceding Preparation (8.6 g.,
0.051 mole) in 75 ml. of methylene chloride was cooled
in an ice-water bath. Titanium tetrachloride (19.34 g.
11.2 ml., 0.102 mole) was added, fol~owed by the drop-
wise addition of l,l-dichloromethyl methyl ether
(6.2 g., 0.054 mole). The reaction mixture was stirred
at 0 for 30 minutes, then slowly poured into 400 ml.
of saturated sodium bicarbonate. The aqueous phase was
extracted with three fresh portions of methylene
chloride. The combined organic layers were washed with
brine, dried over anhydrous magnesium sulfate, filtered
and evaporated to yield title product [7.9 g.; m.p. 83-
86C.; pnmr/CDC13/delta (ppm) 2.0 (m, 2H), 2.8 (t, 2~),
4.2 (t, 2H), 7.1-7.5 (m, 2H), 10.2 (s, lH), mle 198/
196].
~
-137- ~ L8~3
PREPARATION 1 3
6-Fluorochroman
By the procedures of Preparation 11, 6-fluoro-4-
chromanone (15 g.) was converted to chromatographed 6-
fluorochroman [5.7 g.; oil, pnmr/CDC13/delta tppm) 2.0
(m, 2H), 3.8 (t, 2H), 4. 1 (t, 2H), 6.8 (m, 3~); Rf 0.68
(2:1 hexane:ether); m/e 152].
6-Fluorochroman-8-carbaldehyde
By the procedures of Preparation 12, the product
of the preceding Preparation (5.5 g., 0 . 036 mole) was
converted to title product initially isolated as a
viscous oil which was crystallized from hexane (3.4 g.;
m.p. 54-57C.; m/e 180).
f~
~16~ 3
-138-
PRE PARATI ON~
3-Methyl-5-i oxazolecarboxamide
3-Methyl-5-isoxazolecarboxylic acid (20 g.) was
refluxed for 10 hours in 350 ml. of thionyl chloride,
then stirred at room temperature for 16 hours, clari-
fied by filtration and evaporated to an oil. The oil
was multiply triturated with hot hexane, and the com-
bined hexane triturates evaporated to yield acid
chloride (16.2 to 21 g.~ as a solid.
With stirring, acid chloride prepared in the
manner (35 g.) was added portionwise to 300 ml. of
conc. ammonium hydroxide at room temperature. After
granulating for 1 hour, title product was recovered by
filtration (24.2 g., m.p. 180-182C.).
PREPARATION 16
3-Methyl-5-isoxazolecarbonitrile
Product of the preceding Preparation (5 g.) was
mixed thoroughly with phosphoxous pentoxide (10 g.) and
placed in an oil bath preheated to 140. The bath
temperature was increased to ;200C. and title product
recovered by distillation in vacuo [2.9 g., ir(film)
nitrile band at 2220 cml, no amide peak in the 1700
cm 1 region].
f
-139- ~1618 ~3
PREPARATION 17
3-Methyl-5-isoxa-zolecarbaIdeh~-de
Product of the preceding Preparation (1~08 g.,
0.01 mole) was dissolved in 25 ml. of ether and cooled
to -40C. Diisobutylaluminum hydride (12 ml. of lM in
hexane, 0.012 mole) was added at -40C. over a 15
minute periodO The mixture was stirred at -30 to
-35C. for 10 minutes. Keeping the temperature at
-20C., 60 ml. of ethyl acetate was added. Keeping the
temperature at -25C., methanol (15 ml.) was added
dropwise, and keeping the temperature helow -20C.,
3 ml. of 6N hydrochloric acid was added. The reaction
mixture was warmed to 5C. and the organic phase washed
with 25 ml. of water and evaporated to ~an oil. The oil
was chromatographed on 50 ml. of silica gel using 1:1
ether:hexane as eluant. Product fractions were com-
bined and evaporated to yield title product (0.42 g.;
m.p. 39-41C.). A ~mall sample further purified by
sublimation had m.p. 43-45C.
J
~ 8 ~ 3
-140-
PREPARATION 18
5-Chlorobenzo[b]furan 2-_arboxylic Acid
5-Chlorosalicylaldehyde (31.3 g., 0.2 mole) was
dissolved in 200 ml. of 2-butanone. Potassium carbo-
nate (82.9 gO, 0.6 mole~ and then diethyl 2-bromo-
malonate (95.6 g., 0.4 mole) were added and the mixture
heated to reflux for five hours, then cooled, filtered
from salts, and concentrated to an oil. The oil was
partitioned between 500 ml. of 10~ sulfuric acid and
500 ml. of ether. The aqueous layer was extracted with
two 250 ml. portions of fresh ether. The combined
organic layers were washed with brine, dried over
anhydrous magnesium sulfate, filtered and concentrated
to a second oil. The second oil was dissolved in
400 ml. of 10% ethanolic potassium hydroxide,-heated at
reflux for 1 hour and concentrated to solids. The
solids were dissolved in 1500 ml. of water, filtered
from trace insoluble matter, acidified with 6N hydro-
chloric acid and precipitated solids recovered by
filtration. Purified title product was obtained by
repulping the solids in 1 liter of water (19 g., m.p.
259-262C., m/e 198tl96).
By the same procedure, 5-fluorosalicyaldehyde and
6-chlorosalicylaldehyde are converted, respectively, to
5-fluorobenzo[b]furan-2-carboxylic acid and 6-chloro-
benzo[b]furan-2-carboxylic acid
~ ~J ~L~
-141
PREPARATION 19
5-Chlorobenzolb]furan
Title compound of the preceding Preparation
(7.8 g.) was combined with copper powder (700 mg.) and
quinoline (50 ml.) and the mixture heated to reflux for
50 minutes, then cooled to room temperature and diluted
with 500 ml. of ether. Insolubles were removed by
filtration and the filtrate washed in sequence with
five 200 ml. portions of 2N hydrochloric acid and one
of brine, dried over anhydrous magnesium sulfate and
concentrated to an oil (6.2 g.). The oil was chroma-
tographed through 200 g. of silica gel using ether as
eluant and 300 ml. fractions. Fractions 1 and 2 were
combined and evaporated to yield title product as an
oil (6.1 g.).
By the same procedure the other benzofurancarboxylic
acids of the preceding Preparation are converted to 5-
fluorobenzo[b]furan and 6-chlorobenzolb~furan.
-142
PREPARATI ON 2 0
5-C l_ro-2,3-d~ydrobenzo[b]furan
Pd/C (5~, 12 . 2 g . ) in 400 ml. of acetic acid was
prehydrogenated at atmospheric pressure and 25C.
Title compound of the preceding Preparation (6.1 g.) in
100 ml. of acetic acid was added and hydrogenation
continued until slightly more than 1 equivalent of
hydrogen had been consumed. Catalyst was recovered by
filtration over diatomaceous earth. The filtrate was
neutralized with saturated potassium carbonate and
extracted with four 200 ml. portions of ether. The
combined extracts were washed with brinel dried over
anhydrous magnesium sulfate, filtered and evaporated to
an oil. The oil was chromatographed on 400 g. silica
gel u~ing hexane-3% ether as eluant, 15 ml. fractionæ
and tlc monitoring. Pure product fractions 70-90 were
combined and evaporated to yield title product [2.15 g.;
oil; Rf 0.32 (hexane); m/e 15G/154].
By the same procedure, the other benzofurans of
the preceding Preparation are converted to 5-fluoro-
2,3-dihydrobenzo[b]furan and 6-chloro-2,3-dihydro-
ben~o[b]furan.
~J ~ 4~
143-
PREPARATION 21
5-Chloro-2,3-dihydrobenzo~b]furan-7-carbaldehyde
By the procedure of Preparation 12, title compound
of the preceding Preparation (2.1 g.) was converted to
crude product contaminated with an isomeric aldehyde.
Purified title product was obtained by digesting the
crude product in 50 ml. of boiling hexane, filtering
and cooling the filtrate [0.93 g.; m.p. 79-81C.; Rf
0.55 (chloroform); m/e 184/182].
By the same method the 5-fluoro compound of the
preceding Preparation is converted to 5-fluoro-2,3-
dihydrobenzo[b]furan-7-carbaldehyde~
By the method of Preparation 3, the 6-chloro com-
pound is converted to ethyl 2-(6-chloro-2,3-dihydro-7-
benzo[b]furanyl)-2-oxoacetate; then by the method of
Preparation 4 to ethyl 2-(6-chloro-2,3-dihydro-7-benzo-
[b]furanyl)-2-hydroxyacetate.
~L6~ 3
-144--
PREPARATION 22
7-Chloroquinoline-8-carbaldehy~
7-Chloro-8-methylquinoline tl g.) [Bradford et
al., J. Chem. Soc., p. 437 (1947)] is dissolved in
5 20 ml. of benzene and brominated with one equivalent of
N-bromosuccinimide in the presence of catalytic amounts
of peroxide. The product, 7-chloro-8-(bromomethyl)-
quinoline is isolatad by evaporation.
The bromo compound is solvolyzed to 7-chloro-8-
(hydroxymethyl)quinoline by warming with excess alco-
holic potassium hydroxide. To isolate the product, the
reaction mixture is neutralized with hydrochloric acid,
salts separatad by filtration and the filtrate evapo-
rated to dryness.
The alcohol (1 g.) is dissolved in 10 ml. of
methylene chloride and added dropwise to a slurry of
1.5 equivalents of pyridinum chlorochromate in 20 ml.
of methylene chloride. The exothermic reaction is
controlled by rate of addition, use of a reflux con-
denser and occasional cooling in a cooling bath. ~he
reaction mixture is diluted with ether, and the super-
natant separated by decantation and filtration. The
product is purified by filtrat:ion through a short
magnesium silicate column with ether as eluant and
isolated by removal of the solvent ln vacuo.
~a6~3
--145--
PREPARAT I ON 2 3
3-Furaldehyde
3-Furylmethanol (19.6 g., 0.2 mole) in 50 ml. of
methylene chloride was added dropwise to a slurry of
pyridinium chlorochromate (64.5 g., 0.3 mole) in
450 ml. of methylene chloride. The exothermic reaction,
which led to vigorous reflux, was controlled by
occasional cooling with an ice-bath. By the end of
60 minutes, gummy solids had precipitated. The
reaction mixture was diluted with 600 ml. of ether and
the supernatant separated by a combination of decanta-
tion and filtration. The filtrate was passed through
Florisil (synthetic magnesium silicate) contained in a
short column, with ether as eluant. Collected fractions
were combined and evaporated to an oil. Distillation
of the oil provided 3-furaldehyde (7.6 g.; b.p.
68-72C./40-45 mm.).
Alternatively, this aldehyde is prepared by
Rosenmund reduction of 3-furoic acid chloride ~Hayes,
J. Am. Chem. Soc. 71, 2581 (1949)~.
PREPARaTION 24
2-(2-Furyl)-1,3-dioxolane
2~Furaldehyde (42 ml., 0.5 mole), ethyleneglycol
(50 ml., 0.9 moles) and p-toluenesulfonic acid (about
200 mg.) were combined in 150 ml. of toluene and the
mixture refluxed for 6 hours while collecting by-
product water in a Dean-Stark trap. The mixture was
cooled, diluted with 500 ml. of ether, and clarified
by filtration. The filtrate was washed with 200 ml.
of saturated sodium bicarbonate and the organic phase
again clarified by filtration. This second filtrate
was washed with 200 ml. of water, and the organic
layer concentrated to dryness, affording 2-(2-furyl)-
1,3-dioxolane as an oil (45 g.).
8~3
PREPARATI ON 25
2-(5-Chloro-2-furyl)-1,3-dioxolane
2-(2-Furyl)-1,3-dioxolane (14 g., 0.1 mole) was
dissolved in 100 ml. of tetrahydrofuran and the
solution cooled to -25 to -20C. Maintaining this
temperature range, butyl lithium in hexane (45 ml. of
2.2M, ~.l mole) was added over a period of lO minutes.
The mixture was allowed to warm to 0C. over 25
minutes and rechilled to -30C. While maintaining a
temperature range of -30 to -25C., hexachloroethane
(23.7 g., 0.1 mole) in 50 ml. of tetrahydrofuran was
added over 5 minutes. The reaction mixture was warmed
to room temperature, stirred for 1.5 hours, recooled
to 5C., and diluted slowly with 500 ml. of water.
Product was extracted into ether (2 x 500 ml.) and
recovered as an oil (15.8 g.) by evaporation to
dryness. The oil was chromatographed on a 200 ml
volume of silica gel, using 8:1 hexane:ethyl acetate
as eluant and monitoring by silica gel tlc with the
same eluant. The early, produc:t containing fractions
were combined and evaporated to yield purified 2-(5-
chloro-2-furyl)-1,3-dioxolane as an oil [5 g.; Rf 0.6
(8:1 hexane:ethyl acetate)].
PREPARATION 26
5-Chloro-2-furaldehyde
2-(5-Chloro-2-furyl)-1,3-dioxolane (4.8 g.~ was
dis~olved in 20 ml. of ether. 6N Hydrochloric acid
(lO ml.) was added and the two-phase mixture stirred
for l hour at room temperature. The ether phase was
separated, washed with water and evaporated to yield
5-chloro-2-furaldehyde as an oil (2.8 g.).
L1343
-147-
PREPARATION ~7
5-Bromo-2-fur~ carboxamide
5-Bromo-2-furoic acid (20 g.) was refluxed for
3 hours with 60 ml. of thionyl chloride, and the
corresponding acid chloride isolated as an oil by
concentration. The acid chloride was added dropwise
to 150 ml. of stirring, concentrated ammonium hydroxide.
Filtration afforded 5-bromo-2-furylcarboxamide (17.0 g.,
m.p. 140-143C.).
PREPARATION 28
5-Bromo-2-fu~y~arbonitrile
5-Bromo-2-furylcarboxamide ~10 g.) was combined
with 50 ml. of phosphorus oxychloride and refluxed for
24 hours. The mixture was poured onto ice, the
product extracted into ether, which on evaporation
gave 5-bromo-2-furylcarbonitrile as an oil (6.4 g.).
PREPARATION 29
5-Bromo-2-furaldehyde
5-Bromo-2-furylcarbonitrile (2.3 g., 13 mmoles)
was dissolved in 50 ml. of ether and cooled, under
nitrogen, to -10C. Diisobutylaluminum hydride
~1.9 g., 13 mmoles) as a 25% solution in toluene was
added dropwisa, maintaining the temperature near
-10C. The reaction was allowed to warm to room
temperature and allowed to stir about 6 hours. The
reaction mixture was cooled to 0 to 5C., dilutad
with 1 ml. of methanol, acidified with 3N hydrochloric
acid, washed with water, and evaporated to yield 5-
bromo-2-furaldehyde (1.2 g., m.p. 74-76C.).
~L61~3~3
-148--
PREPARATION 30
3-Bromo-2-furaldehyde
Phosphorus oxychloride (6.5 g., 70 mmoles) was
added to dimethylformamide (5.4 9., 70 mmoles) at 0
to 10C. The resulting slurry was diluted with 10 ml.
of ethylene dichloride. Maintaining the mixture near
10C., 3-bromofuran (9.2 g., 63 mmoles) was added.
The reaction mixture was then heated to 58-60C. for
1 hour and then recooled to 10C. Sodium acetate
trihydrate (15 g.) dissolved in 25 ml. of water was
added slowly, with good stirring, keeping the tempera-
ture 10 to 30C. The mixture was reheated to 68-72C.
for 20 minutes, cooled to room temperature, and
diluted with 20 ml. of water. Product was extracted
into 75 ml. of ether, and the ether back-washed with
water and concentrated to yield 3-bromo-2-furaldehyde
as an oil [0.9 g., Rf 0.65 (3:1 hexane:ethyl acetate)].
PREPARATION 31
3-Iodofuran
3-Bromofuran ~14.7 g., 0.1 mole) in 100 ml. of
ether was cooled to ~70C. ~utyl lithium (42 ml. of
2.4M, 0.1 mole) in hexane was added dropwise over
0.5 hour, maintaining the temperature from -70 to
-65C. Iodine (25 g., 0.1 mole) in 200 ml. of ether
was then added over 1 hour maintaining the same
temperature range. The reaction mixture was warmed to
room temperature and then back to 2C. Water (100 ml.
was added dropwise. The ether layer was separated,
washed with aqueous thiosulfate and then water, dried
over anhydrous sodium sulfate, evaporated to an oil
and distilled to yield 3-iodofuran (15.7 g., b.p.
48/28 mm.).
- 1 ~ 9-
PRE PARP.T I ON 3 2
3-Methoxyfu_an
Sodium metal ~5.6 g., 0.24 mole) was dissolved in
150 ml. of dry methanol. 3-Iodofuran (15.7 g.,
0.08 mole) and cuprous oxide (8 g., 0.1 mole) were
added and the mixture was refluxed with vigorous
stirring for 42 hours. The reaction mixture was
cooled to room temperature, diluted with 200 ml. of
water, and product extracted into 100 ml. of ether.
The ether extract was back-washed with 15 ml. of
water, dried over anhydrous sodium sulfate and eva-
porated to yield crude 3-methoxyfuran (approximately
3-4 g. of approximately 50% purity) suitable for
further processing.
PREP_RATION 33
5-PhenyI-2-thenaldehyde
l-Phenylthiophene [1O6 g., 0.01 mole, prepared
according to J. Am. Chem. Soc. 46, 2339 (192~)] was
dissolved in 20 ml. of tetrahydrofuran and cooled to
-40C~ Butyl lithium in hexane (4.5 ml. of 2.2M) was
added over 3 minutes, maintaining the temperature
-40 to -30C. The mixture w~s warmed to 0C. and
then cooled to -40C. Dimethylformamide (1.2 ml.,
lS mmole) was added, maintaining the temperature -40
to -30~C. The mixture was warmed to room temperature
and held for 0.5 hour, recooled to 0C., ~uenched with
6 ml. of 6N hydrochloric acid, diluted with 10 ml. of
water, and extracted with 20 ml. of ether. Evapora-
tion of the ether extract to dryness gave crude
product ~1.9 g.). Recrystallization from about 35 ml.
of hexane gave purified 5-phenyl-2-thenaldehyde
(0.9 g., m.p. 90-92C.).
-150--
PREPAPcATION 34
4-Bromo-3-thenaldehyde
3,4-Dibromothiophene [15 g., 0.062 mole, J. Org.
Chem. 36, 2690 t1971)] in 20 ml. of ether was cooled
to -70C. and butyl lithium in hexane (34.8 ml. of
2.lM, 0.073 mole) added dropwise over 5 minutes.
After stirring for 5 minutes at -70C., the solution
was transferred, via nylon tubing under nitrogen
pressure, to a solution of dimethylformamide (6.8 g.,
0.093 mole) in 35 ml. of ether. The resulting mixture
was heated to reflux for 2 hours, cooled to room
temperature, washed in sequence with two portions of
lN hydrochloric acid, one of saturated sodium bi-
carbonate and one of brine, dried over anhydrous
magnesium sulfate, filtered and concentrated to an
oil. The oil was twice distilled to yield 4-bromo-3-
thenaldehyde (5.7 g., b.p. 81-84C./0.8 mm., m/e
192/190).
-151-
PREPARATION 35
2 Phenylu-an
Aniline (46.5 g., 0.5 mole) was combined with
500 ml. of water and 100 ml. of concentrated hydro-
chloric acid and cooled to -5C. Sodium nitrite
(36.2 g., 0.525 mole) in 100 ml. of water was added
dropwise over 45 minutes, keeping the temperature -3
to -5C. After addition was complete, the mixture was
stirred for 30 minutes at -5C., and zinc chloride
(68 g.) was added. Maximal precipitation of the
diazonium salt was obtained by the addition of 100 g.
of sodium chloride. The mixture was stirred for
5 minutes, with the cooling bath removed and cautious-
ly filtered, without wash, and air dried for 2 hours.
(Previous vacuum drying of this product led to explosi~e
decomposition). The intermediate diazonium salt was
suspended in 750 ml. of Euran at 0C. With vigorous
stirring, powdered sodium hydroxide (5 g.) was added,
followed by anhydrous sodium acetate (10 9O)- The
reaction mixture was stirred for 5 hours at 0~C. and
then for 16 hours at room temperature. Solids were
removed by filtration and the Eiltrate evaporated to
crude product (25 ml. of oil). Distillation afforded
l-phenylfuran (9.2-9.6 g., b.p. 87-95/15 mm., b.p.
50/1 mm.).
_J
-152-
PREPARATION 36
2-Benzoylthiophene ~l9 g., 0.1 mole), ethylene
glycol (11 ml., 0.2 mole), toluene (150 ml.) and p-
toluenesulfonic acid (about 0.2 g.) were combined andrefluxed for 6 hours. By-product water was collected
in a Dean-Stark trap. Tlc (1:8 ethyl acetate:hexane)
indicated reaction to be about 40% complete. More
ethylene glycol (30 ml.) was added and reflux con-
tinued for 35 hours. Reaction was still incomplete.
The reaction mixture was diluted with 200 ml. of
ether, washed twice with 150 ml. portions of water and
concentrated to dryness. The residue was chromato
graphed on about 500 ml. of silica gel, with 1:8 ethyl
acetate:hexane as eluant, monitored by tlc. Faster
moving, product containing fractions were combined and
evaporated to yield 2-phenyl-2-(2-thienyl)-1,3-dioxolane
~8 g., oil, Rf 0.6 (1:8 ethyl acetate:hexane)J.
~L~6~L~343
--153-
PREPARATION 37
Methyl 4-Methoxy-3-thenoate
Methyl 4-acetoxy-3--thenoate (U.S. Patent 3,144,235;
10 g.~ was dissolved in 20 ml. of methanol and added
to 100 ml. of methanol containing 0.31 ml. of concen-
trated sulfuric acid. The mixture was refluxed for
4 days, then neutralized with 0.6 g. of sodium acetate
and solvent removed by evaporation. The residue was
taken up in 200 ml. of ether. The ether solution was
washed sequentially with two 50 ml. portions of
water, two 50 ml. portions of lN sodium hydroxide and
two 50 ml. portions of brine, dried over anhydrous
magnesium sulfate, filtered and evaporated to an oil
which crystallized on standing (4.35 g.; m.p. 64-66C).
When this reaction was worked up after only
1 day only a low yield of the desired product t2.2 g)
was isolated. The two lN sodium hydroxide extracts
were combined and acidified, precipitating methyl 4-
hydroxy-3-thenoate (5.13 g.). When this alcohol was
dissolved in 100 ml. of methanol containing 0.3 ml.
of concentrated sulfuric acid and refluxed for
3 days, the above work-up aorded title product
(2.10 g., m.p. 64-66C.).
L6~1343
--154--
PREPARATION 38
I-(4-Methoxy-3-thienyl~methanol
Me~hyl 4-methoxy-3-thenoate (U.S. Patent 4,144,235;
3.9 g., 23 mmoles) was dissolved in 50 ml. of toluene
and cooled in an acetone-dry ice bath. Diisobutyl
aluminum hydride (46 ml. of lM in hexane, 46 mmoles)
was added dropwise over 30 minutes. The mixture was
stirred for an additional 2 hours at the bath temperature
and then allowed to warm to room temperature. Keeping
the temperature below 30C., methanol (14.7 g.,
18.6 ml., 0.46 mole3 was slowly added. The mixture
was then stirred for 16 hours at room temperature, by
which time a granular precipitate had formed. The
mixture was filtered over diatomaceous earth with
methanol wash. The combined filtrate and washes were
concentrated to yield the title product as an oil
(2.8 g., m/e 144).
PREPARATION_39
4-Methoxy~_-thenaldehyde
Pyridinium chlorochromate (6.4 g., 29.7 mmoles)
was dissolved in 100 ml. of methylene chloride and
added in one portion to a solution of the product of
the preceding Example t2.8 g., 19.8 mmoles) also in
100 ml. of methylene chloride. The reaction mixture
was stirred at room temperature for three hours,
diluted with 200 ml. of ether and decanted from the
black precipitate. The precipitate was washed with
two 100 ml. portions of ether. The combined decant
and washes were filtered, washed in sequence with two
portions of lN hydrochloric acid, one portion of
water, two portions of lN sodium hydroxide and one
portion of brine, dried over anhydrous magnesium
sulfate, filtered and concentrated to yield title
product as an oil [2.6 g.; m/e 142; ir tcH2cl2)
1688, 1544 cm~l].
-155~ 3
PREPARATION 40
Ethyl 4-Ethoxy~3-thenoàte
Following the approximate procedure of U.S.
4,144,235, methyl 4-acetoxy-3-thenoate (20 g.) was
dissolved in 240 ml. of ethanol and 0.62 ml. of
concentrated sulfuric acid was added. The reaction
mixture was gently refluxed for 79 hours, then neutral-
ized with sodium acetate ~1.2 g.) and evaporated to
an oil. The latter was partitioned between 400 ml.
of ether and 50 ml. of water. The organic layer was
separated and washed in sequence with 75 ml. of
water, three 50 ml. portions of lN sodium hydroxide
and two 75 ml. portions of brine, dried over anhydrous
magnesium sulfate, filtered and evaporated to yield
title product as an oil [14.9 g., pnmr indicates
entirely ethyl ester, no methyl ester].
PREPARATION 41
l-l4--thox t3 ,hienyl?methanol
By the procedure of Preparation 38, the product
of the preceding Preparation (14 g.) was converted to
title product as an oil (9.15 g.).
PREPARATION 42
4-Ethoxy~3-thenaldehvde
By the procedure of Prep,aration 39, the product
of the preceding Preparation (9.15 g.) was converted
to the title product, initially isolated as an oil
which quickly crystallized on cooling [8.18 g.; m.p.
42-45C.; mle 156; ir (KBr) 3090, 2977, 1688 cm 1].
-
-156~
PREPARATIOE 43
n-Propyl 4-(n-Propoxy)-3-thenoate
By the procedure of Preparation 40, using a
reaction reflux time of 10 days, methyl 4-acetoxy-3-
thenoate (6 g.) in 750 ml. of l-propanol containing
0.19 ml. of concentrated sulfuric acid was converted
to title product as an oil l5.4 g.; m/e 228).
PREPARATION 44
1-[4-(n-Propoxy)-3-thienyl)methanol
By the procedure of Preparation 38, the product
of the preceding Preparation (5.4 g.) was reduced to
title compound, isolated as an oil (3.44 g.; m/e
172).
; PREPARATION 45
4-ln-Propoxy)-3-thenaldehyde)
By the procedure of Preparation 39, the product
of the preceding Preparation (3.34 g.) was converted
to title compound [3.19 g~; m/e 170; ir (CH2C12)
1689, 1539 cm~l],
2C PREP ATION 4~
Ethyl_4-Methoxy-,2-methyl-3-thenoate
Ethyl 4-hydroxy-2-methyl-3-thenoate ~Chem. Ber.
48, p. 593 (1915); 7.8 g.] was combined with 600 ml.
of methanol and 0.25 ml. concentrated sulfurlc acid
and refluxed for 21 hours. The reaction mixture was
evaporated to an oil, taken up in 500 ml. of ether,
washed with two 50 ml. portions of lN sodium hydroxide
and then one of brine, dried over anhydrous magnesium
sulfate, and evaporated to yield title product as an
oil (7.8 g.; m/e 200; pnmr/CDC13 includes singlet
OCH3 protons at 3.9 ppm). The product is contaminated
with a minor portion of the corresponding methyl
ester.
--1 ;7--
PREPARATION 47
~4-Methoxy-2-methyl-3-thienyl)methanol
The product of the preceding Preparation ~7.8 g.,
0.039 mole) was dissolved in 100 ml. of hexane and
75 ml. of toluene and cooled to -78C. Diisobutyl
aluminum hydride (78 ml. of lM in hexane, 0.078 mole)
was added dropwise over 40 minutes~ The mixture was
stirred for 2 hours at ~78C., warmed to room tempera-
ture and stirred for an additional 16 hours. Methanol
(25.0 g., 31.6 ml., 0.78 mole) was added dropwise to
the reaction mixture, keeping the temperature below
30C. After stirring 1.5 hours at room temperature,
the reaction mixture was clarified by filtration over
diatomaceous earth, with thorough methanol wash and
repulp of the cake and finally methylene chloride
wash. The combined filtrate and washes were dried
over anhydrous magnesium sulfate, filtered and
evaporated to yield title product as an oil (5.56 g.;
m/e 158; ir (CH2C12) 3598, 1582, 1708 cm 1)
PREpARATIoN 48
4-Methoxy-2-methyl-3-th naldehyde
By the procedure of Preparation 39, the product
of the preceding Preparation ~5.4 g., 0.034 mole) was
converted to title compound isolated as an oil
[5.23 g., Rf 0.36 (chloroform)].
