Hypoglycemic 5-chromanyl, 2,3-dihydro-5-benzo[b]furanyl, 5-pyridyl, 5-quinolyl, 5-pyrrolyl, 5-indolyl, 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl and 5-isoxazolyl oxazolidine-2,4-diones and the pharmaceutically acceptable salts thereof; certain 3-acylated derivatives thereof; a method of treating hyperglycemic animals therewith; and intermediates useful in the preparation of said compounds.

BACKGROUND OF THE INVENTION 
The present invention relates to certain 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 
sulfonylureas ( 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 administration of an excess dose of insulin causes hypoglycemia, with 
effects ranging from mild abnormalities in blood glucose to coma, or even 
death. Where effective, a synthetic hypoglycemic agent is preferred over 
insulin, being more convenient to administer and less prone to cause 
severe hypoglycemic 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 by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, 
John Wiley and Sons, N.Y. (1979), pp. 1057-1080]. 
The oxazolidine-2,4-diones of the present invention 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, U.S. Pat. No. 
2,721,197), as an antidepressant agent (Plotnikoff, U.S. Pat. No. 
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. chim. France, pp. 1226-1230 (1961)], 
5-(4-methylphenyl)oxazolidine-2,4-dione [Reibsomer et al., J. Am. Chem. 
Soc. 61, pp. 3491-3493 (1939)], and 5-(4-aminophenyl)oxazolidine-2,4-dione 
(German Pat. No. 108,026); and 5-(2-pyrryl)oxazolidine-2,4-dione 
[Ciamacian and Silber, Gazz. chim. ital. 16, 357 (1886); Ber. 19, 
1708-1714 (1886)]. 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 (specifically, 
the 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, U.S. Pat. No. 2,961,377). We have 
determined 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 reductase inhibitors, thus finding utility in 
the treatment of certain complications of diabetes (Schnur, U.S. Pat. No. 
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 (Scholz, U.S. Pat. No. 4,220,787). The utility of these 
compounds is not specified. 
SUMMARY OF THE INVENTION 
The present invention is concerned with compounds of the formula 
##STR1## 
wherein 
R is hydrogen, (C.sub.1 -C.sub.4)-alkanoyl (e.g., formyl, acetyl, 
isobutyryl), benzoyl, (C.sub.2 -C.sub.4)-carbalkoxy (e.g., carbomethoxy, 
carbethoxy, carboisopropoxy), (C.sub.1 -C.sub.3)-alkylcarbamoyl (e.g., 
N-methylcarbamoyl, N-propylcarbamoyl), (C.sub.5 
-C.sub.7)-cycloalkylcarbamoyl (e.g., N-cyclohexylcarbamoyl) or di-(C.sub.1 
-C.sub.3)-dialkylcarbamoyl (e.g., N,N-dimethylcarbamoyl); and 
R.sup.1 is: 
##STR2## 
wherein R' is (C.sub.1 -C.sub.4)alkyl or phenyl, R" is hydrogen, (C.sub.1 
-C.sub.4)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; 
##STR3## 
wherein Y is hydrogen or (C.sub.1 -C.sub.3)alkoxy, Y' is hydrogen or 
(C.sub.1 -C.sub.3)alkyl and Y" is hydrogen or halo; 
##STR4## 
wherein Z' is hydrogen, halo or (C.sub.1 -C.sub.3)alkoxy and Z" is 
hydrogen or halo; 
##STR5## 
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; 
##STR6## 
wherein Q is sulfur or oxygen and V is hydrogen or (C.sub.1 
-C.sub.3)alkyl; or 
##STR7## 
wherein Q is sulfur or oxygen; and V is hydrogen or (C.sub.1 
-C.sub.3)alkyl; these formula are intended to encompass 3- , 4- and 
5-isothiazolyl and isoxazolyl derivatives; and pharmaceutically acceptable 
cationic salts thereof when R is hydrogen, as well as the pharmaceutically 
acceptable acid addition salts thereof when R.sup.1 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,N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, 
meglumine (N-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 blood glucose values to a normal range 
without danger of causing hypoglycemia. The compounds of the present 
invention are tested for hypoglycemic (anti-hyperglycemic) activity in 
rats, using the so-called glucose tolerance test, as described in greater 
detail hereinafter. 
Preferred 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-(5-chloro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione; 
5-(8-quinolyl)oxazolidine-2,4-dione; 
5-(7-methoxy-8-quinolyl)oxazolidine-2,4-dione; 
5-(6-chloro-8-quinolyl)oxazolidine-2,4-dione; 
5-(6-fluoro-8-quinolyl)oxazolidine-2,4-dione; 
5-(2-benzthiazolyl)oxazolidine-2,4-dione; 
5-(2-thiazolyl)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; and 
5-(3-methyl-5-isoxazolyl)oxazolidine-2,4-dione. 
DETAILS OF THE INVENTION 
The compounds of the present invention are prepared by a variety of 
methods, as summarized in Flowsheet I, wherein 
R.sup.1 is as defined above; 
R.sup.2 is lower alkyl (e.g. methyl or ethyl); 
R.sup.3 is hydrogen, lower alkyl or phenyl; and 
R.sup.4 is hydrogen, or acyl such as acetyl or benzoyl. 
A particularly convenient synthesis for compounds of the present invention 
is via carboximidate (3). The latter compound is reacted with phosgene in 
an inert solvent such as tetrahydrofuran in the presence of 2 to 2.3 
equivalents of a tertiary amine (e.g. triethylamine, N-methylmorpholine). 
A further equivalent of tertiary amine is used if the carboximidate is 
introduced as the acid addition salt (e.g. hydrochloride salt). The 
temperature of the reaction is not critical, but lower temperatures (e.g. 
-10.degree. to 10.degree. C.) are preferred during the initial stages of 
the reaction, particularly if it is desired to isolate the intermediate 
4-alkoxyoxazol-2-one (4). Isolation of this intermediate is carried out by 
simple evaporation of the reaction mixture to dryness. On further reaction 
at higher temperatures (e.g. 20.degree.-150.degree. C.) 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 (e.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. 
##STR8## 
The carboximidate (3) is conveniently prepared from the corresponding 
aldehyde by the sequence: 
##STR9## 
The aldehyde (11) is converted to the cyanohydrin (13) by standard 
procedures (e.g. via the bisulfite adduct, which is reacted with cyanide 
in a two phase, aqueous-organic solvent system). Alternatively, the 
aldehyde is converted to the trimethylsilyl cyanohydrin (12) by reaction 
with trimethylsilylcarbonitrile in the presence of a catalytic quantity of 
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.degree.-5.degree. C.) 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.degree. C.) in a two phase 
strong aqueous acid/organic solvent system. 
Either the cyanohydrin (13) or the trimethylsilyl ether (12) is converted 
to the carboximidate (3) by strong acid catalyzed alcoholysis (using 
strictly anhydrous 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.degree.-25.degree. C.) 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 specifically 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., J. Am. Chem. Soc. 68, p. 1156 (1946)]; a variety of the 
presently required aldehydes are further available by the Rosenmund 
reduction of the corresponding acid chlorides, 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-butoxide. 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 (6): 
##STR10## 
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.degree.-75.degree. C. 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 is 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 of 
1-acetyl-3-methylurea) in the presence of a basic catalyst such as sodium 
ethoxide (suitably 1 equivalent) in alcohol at a temperature of 
50.degree.-110.degree. C. The ester to be used for this purpose is by no 
means restricted to a simple lower alkyl ester, but can be any one of a 
broad variety of esters, e.g. phenyl, benzyl, etc. Furthermore, the ester 
can be replaced by a 1,3-dioxolan-4-one, an alpha-acyloxy ester or a 
thioester e.g., 
##STR11## 
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 of a co-solvent, such as a lower alcohol. The temperature of 
reaction is not critical, temperatures in the range 25.degree.-100.degree. 
C. being generally satisfactory. Other methods are usually preferred when 
R.sup.1 has an amine function, since competing oxidation at the nitrogen 
tends to reduce yields 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 alkylthio compounds (8) by simple acid or base catalyzed hydrolysis. 
Preferable conditions are aqueous hydrochloric acid in a temperature range 
of 0.degree.-50.degree. C. 
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.degree.-70.degree. C., following 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. 15-22 (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 precursor is the 2-imino-oxazolidine-4-one derivative 
(9), readily hydrolyzed to the oxazolidine-2,4-dione, preferably under 
aqueous 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 (R.sup.1 CHZCONHCONHR.sup.3 wherein Z is a halogen 
such as chloro or bromo), or by the condensation of the appropriate alkyl 
alpha-haloacetates (R.sup.1 CHZCOOR.sup.2) with urea or a substituted urea 
(R.sup.3 NHCONH.sub.2). 
Ammonolysis of the 4-alkoxy derivatives (4) yields 4-imino derivatives 
(isomeric with 9). The latter compounds are also readily hydrolyzed to 
oxazolidine-2,4-diones. The 4-alkoxy derivatives themselves are also 
prepared from the silver salt of the desired oxazolidine-2,4-dione. 
Also highly useful as precursors of the oxazolidine-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 suitable for the preparation of precursor 
dialuric acids (10) are shown in Flowsheet II, wherein the substituents 
R.sup.1, R.sup.2 and R.sup.4 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-2,4-diones of the present invention is from the malonic 
ester derivatives (14), 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 
R.sup.1 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. 
##STR12## 
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., 
##STR13## 
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 of alloxan 
(preferably in anhydrous form) with the appropriate organometal derivative 
(e.g., organolithium, Grignard reagent). For example: 
##STR14## 
Protection strategies are required when using this method for preparation 
of certain oxazolidine-2,4-diones wherein R.sup.1 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 R.sup.1 
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 R.sup.1 to another, depending upon such factors as 
availability of starting materials, yields, 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, sodium methoxide, sodium 
ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, 
calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, 
meglumine, benethamine, diethylamine, piperazine and tromethamine. Those 
salts which do not precipitate directly are isolated by concentration to 
dryness or by addition of a non-solvent. In some cases, salts can be 
prepared by mixing a solution of the acid with a solution of a different 
salt of the cation (sodium ethylhexanoate, magnesium oleate), employing a 
solvent in which the desired cationic salt precipitates, or can be 
otherwise 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 formed in situ by the 
addition of one equivalent of a tertiary amine such as triethylamine or 
N-methylmorpholine with an equivalent of the appropriate acid chloride or 
acid 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 methylene 
chloride. The temperature is not critical, and can be over a broad range 
(e.g. 0.degree.-150.degree. C.). It will be evident to those skilled in 
the art that such acylation will be complicated by competing or even 
selective sidechain (R.sup.1) 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 asymmetric and therefore capable of existing in two 
optically active enantiomeric forms. The racemic compounds of the present 
invention, being acids when R is H, form salts with organic amines. These 
racemic forms are therefore generally capable or 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 activity than the 
other. 
The reactions employed to prepare the compounds of this invention can 
generally be mentioned by standard tlc methods, employing commercially 
available plates. Suitable eluants are 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. Applying these methods, which are well known 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. 
The oxazolidine-2,4-diones of the present invention are readily adapted to 
clinical use as antidiabetic agents. The hypoglycemic activity required 
for 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 intraperitoneally 
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 
100 mg/kg). Blood glucose levels (mg/100 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 0.5 hour, 1 hour, 2 hours and 3 hours 
is calculated as: 
##EQU1## 
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 0.5 hour and 1 hour time points. A blood glucose lowering of 9% or 
greater generally reflects 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. 
TABLE I 
______________________________________ 
Hypoglycemic Activity of Oxazolidine-2,4-Diones 
in the Rat Glucose Tolerance Test 
##STR15## 
% Lowering 
Dose of Blood Glucose Level 
Ar (mg./kg.) 0.5 hr. 1 hr. 
______________________________________ 
8-Chromanyl -- -- -- 
6-Chloro- 10 -- 11 
6-Fluoro- 10 -- 9 
2,3-Dihydrobenzo- 
furanyl -- -- -- 
5-Chloro- 25 -- 23 (a) 
2-Pyrrolyl 100 11 8 
1-Methyl- 100 18 17 
1-Ethyl- 100 14 16 
1-(1-Butyl)- 100 4 13 
1-Phenyl 100 30 32 
3-Indolyl -- -- -- 
5-Bromo- 100 9 10 
1-Methyl- 100 11 8 
3-Pyridyl -- -- -- 
2-Methoxy- 10 -- 13 
2-Ethoxy- 25 -- 20 
2-Methoxy-5-chloro- 
25 22 17 
2-Ethoxy-5-chloro- 
10 -- 24 (a) 
5-Quinolyl -- -- -- 
6-Methoxy- 20 -- 7 (b) 
8-Quinolyl 18 19 16 
6-Chloro- 10 -- 16 
6-Fluoro- 10 -- 15 
7-Methoxy- 10 -- -- (c) 
2-Thiazolyl- 75 11 10 
2-Benzthiazolyl- 
50 8 10 
5-isoxazolyl -- -- -- 
3-Methyl- 100 4 7 (d) 
______________________________________ 
(a) At 0.75 hour. 
(b) 9 at 2 hours. 
(c) 12 at 3 hours. 
(d) 24 at 2 hours, 14 at 3 hours. 
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, generally smaller doses being administered 
initially and thereafter 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 pharmaceutically 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 form capsules, tablets, 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 administered 
intravenously, intraperitoneally, subcutaneously or intramuscularly, with 
intramuscular administration being preferred in man.

The present invention is illustrated by the following examples. However, it 
should be understood that the invention is not limited to the specific 
details of these examples. 
EXAMPLE 1 
Methyl 2-Methoxypyridine-3-carboxylate 
Thionyl chloride (50 ml.) was added to 2-methoxypyridine-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 hydrochloride was dissolved in excess methanol (50 ml.), stirred 
for 16 hours at room temperature, then evaporated an oil and taken up in 
chloroform. The chloroform 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/CDCl.sub.3 /delta (ppm): 3.9 and 4.1 (2s, 
6H), 6.9 (m, 1H), 8.2 (m, 2H)]. 
By the same procedure, 4-methylpyridine-3-carboxylic acid is converted to 
methyl 4-methylpyridine-3-carboxylate. 
EXAMPLE 2 
3-Methanesulfinylmethylcarbonyl-2-Methoxypyridine 
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 75.degree. C. 
for 45 minutes, by which time hydrogen evolution had ceased. The mixture 
was cooled in an ice-water bath and diluted with 30 ml. of dry 
tetrahydrofuran. Title compound of the preceding Example (4.63 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 
minutes, poured into 180 ml. of water, acidified to pH 4 with 1 N 
hydrochloric acid and extracted with three portions of chloroform. The 
combined organic layers were dried over magnesium sulfate, filtered and 
concentrated to yield title product as an oil [4.97 g.; pnmr/CDCl.sub.3 
/delta (ppm); 2.8 (s, 3H), 4.1 (s, 3H), 4.4 and 4.7 (2d, 2H), 7.0 (m, 
1H), 8.3 (m, 2H)]. 
By the same procedure the 4-methyl compound of the preceding Example is 
converted to 3-methanesulfinylmethylcarbonyl-4-methylpyridine. 
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.degree. for 16 hours. The mixture was cooled and evaporated 
to dryness 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. fractions. 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 (CH.sub.2 Cl.sub.2) 1748, 1686, 1582, 1460, 1205 cm.sup.-1 ]. 
By the same procedure the methyl compound of the preceding Example is 
converted to S-methyl 2-acetoxy-2-(4-methyl-3-pyridyl)thioacetate. 
EXAMPLE 4 
5-(2-Methoxy-3-pyridyl)oxazolidine-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 1 N 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.degree.-186.degree. C., Rf 0.32 (1:2 ethyl acetate:chloroform)]. 
By the same method, and methyl analog of the preceding Example is converted 
to 5-(4-methyl-3-pyridyl)oxazolidine-2,4-dione. 
EXAMPLE 5 
Ethyl 2-Ethoxypyridine-3-carboxylate 
2-Ethoxypyridine-3-carboxylic acid (4 g.) was converted to its acid 
chloride hydrochloride by refluxing 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 0.degree. C., then evaporated 
to solids, which were partitioned between toluene and 1 N 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/CDCl.sub.3 /delta (ppm) 1.6 (2s, 6H), 
4.4-5.0 (2q, 4H), 7.2 and 8.2 (m, 3H)]. 
EXAMPLE 6 
2-Ethoxy-3-methanesulfinylmethyl carbonylpyridine 
Using 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.degree.-91.degree. C.; 
pnmr/CDCl.sub.3 /delta (ppm), 1.5 (t, 3H), 2.8 (s, 3H), 4.2-4.8 (s and q, 
4H), 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 100.degree. C. and then 48 hours at 
room temperature, the procedure of Example 3 was employed to convert the 
product of the preceding Example (2.5 g.) 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 1 N 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 269]. 
EXAMPLE 8 
2-(2-Ethoxy-3-pyridyl)-2-hydroxyacetamide 
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 evaporated 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/CDCl.sub.3 /delta (ppm) 1.4 (t, 3H), 
4.5 (q, 2H), 5.4 (s, 1H), 6.2-8.2 (m, 5H)]. 
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 (1.08 g., 9.2 mmole) and then 
potassium 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 1 N 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, back-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.degree.-143.degree. C.; 
m/e 272). 
Anal. Calcd. for: C.sub.10 H.sub.10 O.sub.4 N.sub.2 : C, 54.05; H, 4.54; N, 
12.61. Found: C, 54.34; H, 4.85, N, 12.70. 
EXAMPLE 10 
Methyl 5-Chloro-2-methoxypyridine-3-carboxylate 
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.degree.-81.degree. C.; pnmr/CDCl.sub.3 /delta (ppm) 3.8 (s, 
3H), 4.1 (s, 3H), 8.1 (d, 1H), 8.3 (d, 1H)]. 
EXAMPLE 11 
5-Chloro-3-methanesulfinylmethylcarbonyl-2-methoxypyridine 
By the procedure of Example 2, the product of the preceding Example (9.7 
g., 0.045 mole) was converted to title product isolated as a viscous oil 
(10.3 g., m/e 249/247). 
EXAMPLE 12 
S-Methyl 2-Acetoxy-2-(5-chloro-2-methoxy-3-pyridyl)thioacetate 
Using a reaction time of 19 hours at 100.degree. C., 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/CDCl.sub.3 includes singlet at 6.4; m/e 
291/289). 
EXAMPLE 13 
2-(5-Chloro-2-methoxy-3-pyridyl)-2-hydroxyacetamide 
Methanol (125 ml.) was saturated with anhydrous ammonia at 
0.degree.-5.degree. C. The product of the preceding Example (8.8 g.) in 25 
ml. of methanol was added and the reaction 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 chloroform: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.degree.-113.degree. C.; m/e 218/216; ir(KBr) 3444, 3410, 1684 
cm.sup.-1 ]. 
EXAMPLE 14 
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 1 N hydrochloric acid. The 
mixture was then evaporated in vacuo to slightly gummy solids, which gave 
filterable, crude product on stirring with 25 ml. of water (1.09 g., m.p. 
199.degree.-204.degree. C. Recrystallization from 15 ml. of ethanol gave 
purified title product [470 mg.; m.p. 212.degree.-214.degree. C.; m/e 
244/242; ir(KBr) 3174, 3074, 2980, 1830, 1752 cm.sup.-1 ]. 
EXAMPLE 15 
2-(6-Chloro-8-quinolyl)-2-hydroxyacetamide 
Ethyl 2-(6-chloro-8-quinolyl)-2-hydroxyacetate (1.6 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 
concentrated to a volume of 100 ml., cooled slowly and a crop of title 
product (320 mg., m.p. 195.degree.-198.degree. C.) recovered by 
filtration. Additional product (145 mg). was recovered by concentration of 
the mother liquor to 50 ml. and extraction into three portions of ethyl 
acetate. The combined organic layers were washed with saturated sodium 
bicarbonate, 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-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)-2-hydroxyacetamide. 
EXAMPLE 16 
5-(6-Chloro-8-quinolyl)oxazolidine-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 1 N hydrochloric acid and diluted with 1 N 
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 1 N 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.degree.-210.degree. C.; ir(KBr) 1839, 
1825, 1740 cm.sup.-1 ]. 
By the same procedure the benzofuran analog of the preceding Example is 
converted to 
5-(6-chloro-2,3-dihydro-7-benzo[b]furanyl)oxazolidine-2,4-dione. 
EXAMPLE 17 
2-(6-Fluoro-8-quinolyl)-2-hydroxyacetamide 
Ethyl 2-(6-fluoro-8-quinolyl)-2-hydroxyacetate (1.1 g.) was refluxed for 10 
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.degree.-171.degree. C.). 
EXAMPLE 18 
5-(6-Fluoro-8-quinolyl)oxazolidine-2,4-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 16. In this case, a pH of 2 was used in the isolation without 
addition of excess 1 N hydrochloric acid and the crude product was 
recrystallized from toluene [120 mg., m.p. 202.degree.-204.degree. C.; m/e 
246; ir(KBr) 1819, 1743, 1363 cm.sup.-1 ]. 
EXAMPLE 19 
5-(8-Quinolyl)oxazolidin-4-one-2-thione 
Potassium thiocyanate (484 mg., 4.9 mmoles) and potassium cyanide (370 mg., 
5.7 mmoles) were combined in 5 ml. of water and cooled to 0.degree. C. 
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.degree. C., the 
reaction mixture was heated to 90.degree.-100.degree. C. for 25 minutes, 
cooled, quenched into crushed ice, adjusted to pH 8 with sodium 
bicarbonate and extracted with cloroform. The organic layer was dried over 
anhydrous magnesium sulfate, filtered and evaporated to dryness (163 mg.). 
The latter was partitioned between 1 N 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.; Rf 0.65 (ethyl acetate)] . The original, pH 8 
aqueous layer was salted and extracted with ethyl acetate to yield an 
additional crop (114 mg.). The last aqueous phase was acidified and 
extracted with ethyl acetate to yield a third crop (115 mg.). 
By the same method, 7-chloroquinoline-8-carbaldehyde is converted to 
5-(7-chloro-8-quinolyl)oxazolidin-4-one-2-thione. 
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 0.degree. C. 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 1 N 
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.). 
Crystallization from toluene-chloroform and recrystallization from toluene 
gave purified title product (40 mg., m/e 228). 
Anal. Calcd. for: C.sub.12 H.sub.8 O.sub.3 N.sub.2.0.33H.sub.2 O: C, 61.54; 
H, 3.70; N, 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. 
EXAMPLE 21 
5-(6-Methoxy-5-quinolyl)oxazolidin-4-one-2-thione 
By the procedure of Example 19, 6-methoxyquinoline-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 sulfate 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. 
EXAMPLE 22 
5-(6-Methoxy-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 (110 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 1 N sodium hydroxide, acidified to pH 4 with acetic acid and 
extracted with fresh ethyl acetate. The latter organic extracts were 
combined and evaporated to dryness. Trituration of the residue with ether, 
allowing the mixture to stand until crystallization was complete, gave 
title product (34 mg.; m.p. 144.degree.-146.degree. C.). 
EXAMPLE 23 
5-(7-Methoxy-8-quinolyl)oxazolidin-4-one-2-thione 
By the procedure of Example 19, but using adjustment to pH 7 with 
bicarbonate after quench and ethyl acetate for extraction, 
7-methoxyquinoline-8-carbaldehyde (2.0 g., 10.7 mmoles) was converted to 
title product [1.17 g.; Rf 0.7 (2:1 ethyl acetate:chloroform)]. 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. 207.degree.-208.degree. C.). 
Anal. Calcd. for C.sub.13 H.sub.9 N.sub.2 O.sub.3.1.2H.sub.2 O: C, 59.40; 
H, 4.34; N, 10.66. Found: C, 59.33; H, 4.01; N, 10.66. 
EXAMPLE 25 
5-Hydroxy-5-(1-methyl-2-pyrrolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione 
Alloxan hydrate (3.2 g., 0.02 mole) was dissolved in 50 ml. of ethanol by 
warming. 1-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-(1-Methyl-2-pyrrolyl)oxazolidine-2,4-dione 
Product of the preceding Example (2.8 g.) was combined with 25 ml. of 1 N 
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.). Recrystallization 
from methanol-ether afforded purified title product [0.70 g.; m.p. 108-114 
(dec); m/e 180]. 
Anal. Calcd. for C.sub.8 H.sub.8 O.sub.3 N.sub.2 : C, 53.33; H, 4.48; N, 
15.55. Found: C, 53.16; H, 4.72; N, 15.28. 
EXAMPLE 27 
5-Hydroxy-5-(1-ethyl-2-pyrrolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione 
Potassium pyrrole [J. Chem. Soc., p. 52 (1931); 1 g.; 0.01 mole] was 
slurried in 5 ml. of tetrahydrofuran. 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 
evaporated 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). 
EXAMPLE 28 
5-(1-Ethyl-2-pyrrolyl)oxazolidine-2,4-dione 
The procedure of the preceding Example was repeated on a three times scale. 
The initially isolated product gum (0.03 mole of the pyrimidinetrione) was 
stirred with 60 ml. of 1 N 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 (2.2 
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 
crystallized on standing. Trituration with water gave purified title 
product (170 mg.; m.p. 90.degree.-93.degree. C.; m/e 194). 
Anal. Calcd. for C.sub.9 H.sub.10 O.sub.3 N.sub.2.0.25H.sub.2 O: C, 54.40; 
H, 5.32; N, 14.10. Found: C, 54.37; H, 5.16; N, 13.76. 
EXAMPLE 29 
5-Hydroxy-5-[1-(1-butyl)-2-pyrrolyl]-2,4,6-(1H,3H,5H)pyrimidinetrione 
Potassium pyrrole (3.0 g., 0.03 mole), 1-iodobutane (9.2 g., 0.05 moles) 
and 10 ml. of tetrahydrofuran 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 
anhydrous alloxan (4.8 g., 0.03 mole) obtained by heating in 50 ml. of 
ethanol. The ether was distilled away, 6 N 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); m/e 265]. 
EXAMPLE 30 
5-[1-(1-Butyl)-2-furyl]oxazolidine-2,4-dione 
Product of the preceding Example (5.1 g., 0.019 mole) was combined with 1 N 
sodium hydroxide (38 ml., 0.038 mole) and stirred at room temperature for 
10 minutes. The reaction 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 C.sub.11 H.sub.14 O.sub.3 N.sub.2.0.5H.sub.2 O: C, 57.38; 
H, 6.57; N, 12.17. Found: C, 57.40; H, 6.35; N, 12.15. 
EXAMPLE 31 
Sodium 5-[1-(1-butyl)-2-furyl]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.degree.-126.degree. C. (dec); tlc mobility with 1:1 ethyl 
acetate:hexane/5% acetic acid as eluant identical with the free base 
form]. 
EXAMPLE 32 
5-Hydroxy-5-(1-phenyl-2-pyrrolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione 
1-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. 1 N 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 minutes, cooled 
and evaporated to dryness. Trituration of the residue with water gave 
title product [2.3 g.; m/e 285; m.p. 232.degree.-234.degree. C. (dec); Rf 
0.3 (1:1 ethyl acetate:hexane)]. 
Anal. Calcd. for C.sub.14 H.sub.11 O.sub.4 N.sub.3.0.25H.sub.2 O: C, 58.01; 
H, 4.00; N, 14.50. Found: C, 57.84; H, 4.05; N, 14.56. 
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 10 ml. of 1 N 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.degree.-132.degree. C.; m/e 242; Rf 0.47 (1:1 ethyl 
acetate:hexane)]. 
Anal. Calcd. for C.sub.13 H.sub.10 O.sub.3 N.sub.2 : C, 64.46; H, 4.16; N, 
11.57. Found: C, 64.40; H, 4.35; N, 11.56. 
EXAMPLE 34 
5-Hydroxy-5-(1-methyl-3-indolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione 
Alloxan hydrate (1.6 g., 0.01 mole) 1-methylindole (1.3 g., 0.01 mole) and 
ethanol (50 ml.) was combined and the mixture refluxed for 0.5 hour, then 
concentrated 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-(1-Methyl-3-indolyl)oxazolidine-2,4-dione 
Product of the preceding Example (2 g.) was heated on a steam bath for 15 
minutes with 35 ml. of 1 N 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 
clarified 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 combined and recrystallized from 
ethyl acetate/hexane to yield title product (0.33 g.; m.p. 
152.degree.-153.5.degree. C.). 
Anal. Calcd. for C.sub.12 H.sub.10 O.sub.3 N.sub.2.0.125H.sub.2 O: C, 
61.99; H, 4.45; N, 12.05. Found: C, 61.99; H, 4.45; N, 12.02. 
EXAMPLE 36 
5-Hydroxy-5-(5-bromo-3-indolyl)-2,4,6-(1H,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. 1 N Hydrochloric acid (10 ml.) was then added while maintaining 
the reaction near reflux. After 10 minutes, the reaction was concentrated 
to wet solids. Trituration of these wet solids with water gave the title 
product [3.17 g., m.p. &gt;250.degree. C.; 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-indolyl)oxazolidine-2,4-dione 
Product of the preceding Example (3.1 g.) was heated on a steam bath with 
50 ml. of 1 N sodium hydroxide for 15 minutes, then cooled and crude 
product (1.25 g.) precipitated by acidification with conc. hydrochloric 
acid. Chromatography on silica gel, using 1:1 ethyl acetate:hexane as 
eluant and tlc monitoring gave purified title product [0.41 g.; m.p. 
185.degree.-189.degree. C.; Rf 0.55 (1:5 ethyl acetate:hexane/5% acetic 
acid)]. 
Anal. Calcd. for C.sub.11 H.sub.7 O.sub.3 N.sub.2 Br: C, 44.76; H, 2.38; N, 
9.49. Found: C, 45.10; H, 2.68; N, 9.58. 
EXAMPLE 38 
5-Hydroxy-5-(2-thiazolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione 
Thiazole (1.7 g., 0.02 mole) was dissolved in tetrahydrofuran (35 ml.) and 
cooled to -60.degree. C. Butyllithium (9 ml. of 2.4 M in hexane, 0.0216 
mole) was added dropwise over 20 minutes, and the reaction mixture stirred 
for an additional 30 minutes at -60.degree. C. 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 -60.degree. C. The stirred reaction mixture was 
warmed to room temperature over 30 minutes, then recooled to 0.degree. C. 
1 N Hydrochloric acid (25 ml.) was added portion wise and the quenched 
reaction mixture extracted with 50 ml. of ethyl acetate. The ethyl acetate 
extract was back-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-(1H,3H,5H)pyrimidinetrione. 
EXAMPLE 39 
5-(2-Thiazolyl)oxazolidine-2,4-dione 
Title product of the preceding Example (1.37 g.) was stirred at room 
temperature with 24 ml. of 1 N 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 mg., 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.degree.-152.degree. C.). 
Anal. Calcd. for C.sub.6 H.sub.4 O.sub.3 N.sub.2 S: 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)oxazolidine-2,4-dione. 
EXAMPLE 40 
5-Hydroxy-5-(2-benzthiazolyl)-2,4,6-(1H,3H,5H)pyrimidinetrione 
By the procedure of Example 38, benzthiazole (2.7 g., 0.02 moles) was 
converted to its 2-lithio derivative and then reacted 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)]. 
EXAMPLE 41 
5-(2-Benzthiazolyl)oxazolidine-2,4-dione 
Product of the preceding Example 2.15 g.) was stirred with 30 ml. of 1 N 
sodium hydroxide for 30 minutes. The reaction mixture was extracted with 
ether and product (0.46 g.) precipitated by acidification of the aqueous 
layer with 6 N 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.degree.-216.degree. C. (dec)]. 
Anal. Calcd. for C.sub.10 H.sub.6 O.sub.3 N.sub.2 S: C, 51.29; H, 2.58; N, 
11.96 Found: C, 51.51; H, 2.99; N, 12.21. 
EXAMPLE 42 
2-(6-Chloro-8-chromanyl)-2-trimethylsiloxyethanenitrile 
6-Chlorochroman-8-carbaldehyde (7 g., 0.036 mole) in 70 ml. of methylene 
chloride was cooled to 0.degree.-5.degree. C. Zinc iodide (100 mg.) was 
added, followed by the dropwise 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(CH.sub.2 Cl.sub.2) 2857, 1479, 1215, 1190, 1060 cm.sup.-1 
]. 
EXAMPLE 43 
Ethyl 1-(6-Chloro-8-chromanyl)-1-hydroxymethanecarboximidate Hydrochloride 
To cold (0.degree.-5.degree. C.), 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 
10.degree. C. The mixture was stirred at 0.degree.-5.degree. C. for 35 
minutes and then evaporated to an oil. Crystallization from ethanolether 
gave title product [5.7 g.; m.p. 125.degree.-127.degree. (dec); m/e 
271/269]. 
EXAMPLE 44 
5-(6-Chloro-8-chromanyl)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 
(6.01 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 combined 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.degree.-172.degree. C., m/e 269/267). 
Anal. Calcd. for C.sub.12 H.sub.10 O.sub.4 NCl: 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-trimethylsiloxyethanenitrile 
By the procedure of 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 (CHCl.sub.2) 1498, 1205, 1066 cm.sup.-1 ]. 
EXAMPLE 46 
Ethyl 1-(6-Fluoro-8-chromanyl)-1-hydroxymethanecarboximidate Hydrochloride 
Using a reaction time of 1 hour at 0.degree.-5.degree. C., the 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.degree.-126.degree. C. (dec); m/e 
253]. 
EXAMPLE 47 
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 1 N sodium hydroxide and extracted with two portions of ether. 
Product was reprecipitated by adding the basic aqueous layer slowly to 
excess 3 N hydrochloric acid. Recrystallization from toluene gave purified 
title product [2.73 g.; m.p. 174.degree.-176.degree. C.; m/e 251]. 
Anal. Calcd. for C.sub.12 H.sub.10 O.sub.4 NF: C, 57.37; H, 4.01; N, 5.58. 
Found: C, 57.74; H, 3.91; N, 5.40. 
EXAMPLE 48 
2-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)-2-trimethylsiloxyethanenitrile 
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 
trimethylsilylcarbonitrile (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(CHCl.sub.2) 
1479, 1457, 1435, 1180, 866, 848 cm.sup.-1 ]. 
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-trimethylsiloxyethanenitrile. 
EXAMPLE 49 
Ethyl 
1-(5-Chloro-2,3-dihydro-7-benzo[b]-furanyl)-1-hydroxymethanecarboximidate 
Hydrochloride 
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.degree.-152.degree. C. (dec); m/e 257/255; ir(KBr) 3162, 2875, 1650, 
1524, 1458 cm.sup.-1 ]. 
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-hydroxymethanecarboximidate 
hydrochloride. 
EXAMPLE 50 
5-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)oxazolidine-2,4-dione 
By the procedure of Example 44, title compound of the preceding Example 
(1.1 g.) was converted to toluene recrystallized title product [630 mg.; 
m.p. 197.degree.-199.degree. C.; m/e 255/253; ir(KBr) 3084, 1833, 1810, 
1746 cm.sup.-1 ]. 
By the same procedure the fluoro analog of the preceding Example is 
converted to 
5-(5-fluoro-2,3-dihydro-7-benzo[b]furanyl)oxazolidine-2,4-dione. 
EXAMPLE 51 
2-(3-Methyl-5-isoxazolyl)-2-trimethylsilylethanenitrile 
By the 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-trimethylsilylethanenitrile 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 1-Hydroxy-1-(3-methyl-5-isoxazolyl)methanecarboximidate Hydrochloride 
Title product of the preceding Example (6.5 g.) was dissolved in cold, 
saturated ethanolic hydrogen chloride (50 ml.) and held at 5.degree. C. 
for 16 hours. Title product was recovered by filtration (3.3 g., m.p. 
119.degree.-121.degree. C.). 
By the same method, the other products of the preceding Example are 
converted to ethyl 1-hydroxy-1-(5-isothiazolyl)methanecarboximidate 
hydrochloride and ethyl 
1-hydroxy-1-(5-methyl-3-isoxazolyl)methanecarboximidate hydrochloride. 
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 1 N sodium hydroxide and 25 ml. of ether. 
The basic aqueous phase was separated, acidified with conc. hydrochloric 
acid and extracted 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.degree.-175.degree. C.). The ether triturate 
was evaporated to dryness and triturated with fresh ether (238 mg., m.p. 
175.degree.-177.degree. C.). 
By the same method, the other products of the preceding Example are 
converted to 5-(5-isothiazolyl)oxazolidine-2,4-dione and 
5-(5-methyl-3-isoxazolyl)oxazolidine-2,4-dione. 
EXAMPLE 54 
5-(5-Chloro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione 
5-(2-Ethoxy-3-pyridyl)oxazolidine-2,4-dione (125 mg.) was suspended in 100 
ml. of water and dissolved by warming to 56.degree. C. Chlorine was 
bubbled into the warm solution for 30 minutes, during which time the 
temperature slowly dropped to 34.degree. C. and a precipitate formed. The 
reaction mixture was flushed with nitrogen for 30 minutes and crude 
products recovered by filtration (101 mg., m.p. 119.degree.-124.degree. 
C.). Two recrystallizations from 2:1 ethanol:water gave purified title 
product [24 mg.; m.p. 145.degree.-147.degree. C.; 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. 
PREATION 1 
2-Ethoxy-3-pyridinecarboxylic 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 170.degree. C. 
for 6 hours. The vessel was cooled and the contents evaporated to dryness 
in vacuo. 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.degree.-88.degree. C.). 
PREATION 2 
2-Methoxy-3-pyridinecarboxylic Acid 
A stainless steel stirred autoclave was charged sequentially with methanol 
(2.8 l.), sodium methoxide (259 g.) (in portions, keeping the temperature 
less than 35.degree. C.), and 2-chloro-3-pyridinecarboxylic acid (190 g.). 
The autoclave was sealed and the reaction mixture heated at 110.degree. C. 
(50 psig) for 48 hours. The reaction mixture was cooled to 25.degree. C. 
and discharged from the autoclave. Solids were recovered by filtration. 
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 20.degree. C. The precipitated product was granulated for 30 minutes 
at 15.degree. C. and recovered by filtration (141 g.). Purified title 
product was obtained by recrystallization from ethyl acetate-hexane (120.5 
g., m.p. 148.degree.-150.degree. C.). 
PREATION 3 
Ethyl 2-(6-Chloro-8-quinolyl)-2-oxoacetate 
8-Bromo-6-chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g., 0.025 
mole] in 50 ml. of tetrahydrofuran was added dropwise over a 10 minute 
period to a mixture of butyl lithium (2.3 M in hexane, 12.2 ml., 0.028 
mole) and 40 ml. of tetrahydrofuran held at -70.degree. C. After an 
additional 30 minutes at this temperature, a cold (0.degree. C.) solution 
of diethyl oxalate (14.6 g., 0.10 mole) in 50 ml. of tetrahydrofuran was 
added dropwise. The reaction mixture was maintained at 0.degree. C. for 1 
hour, then quenched at 0.degree.-5.degree. C. with glacial acetic acid (17 
ml.) in 50 ml. of tetrahydrofuran. After warming to room temperature the 
quenched 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 fresh bicarbonate, 
dried over anhydrous magnesium sulfate, filtered, and evaporated to an 
oil. Trituration with two 100 ml. portions of hexane gave the title 
product (2.3 g., m.p. 107.degree.-110.degree. C.; m/e 265/263). 
PREATION 4 
Ethyl 2-(6-Chloro-8-quinolyl)-2-hydroxyacetate 
Sodium borohydride (2.5 g., 0.066 mole) was dissolved in 300 ml. of ethanol 
at 10.degree. C. and added in one portion to a 10.degree. C. solution of 
product of the preceding Preparation (2.0 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 anhydrous 
magnesium sulfate, filtered and evaporated to yield title product, 
initially an oil which crystallized on standing (1.87 g.; m.p 
121.degree.-124.degree. C., m/e 267/265). 
PREATION 5 
Ethyl 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.degree.-117.degree. C.). 
PREATION 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 converted to title product. The product, 
initially obtained as a turbid oil, was taken back up in ethyl acetate, 
washed with brine, dried, filtered and evaporated to an oil which rapidly 
crystallized (1.23 g., m.p. 84.degree.-87.degree. C.) 
PREATION 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 90.degree. C.) 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 product [2.5 g.; 
m.p 136.degree.-137.degree. C.; m/e 173; pnmr/CDCl.sub.3 shows aldehyde 
proton at 10.5 ppm and aromatic protons at 7.2-9.4 ppm.]. 
PREATION 8 
6-Methoxyquinoline-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 mixture stirred 
at room temperature for 16 hours. Additional potassium carbonate (0.34 g., 
2.5 mmole) and dimethyl sulfate (0.23 ml., 2.5 mmole) were added and the 
mixture stirred 4 more hours at room temperature and then 3 hours at 
60.degree. C. 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 1 
N 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/CDCl.sub.3 /delta (ppm): 
4.2 (s, 3H), 7.4-9.1 (m, 5H), 10.3 (s, 1H)]. 
PREATION 9 
7-Hydroxyquinoline-8-carbaldehyde 
By the procedure of the Preparation 7, 7-hydroxyquinoline (5 g.) was 
converted to title product (3.3 g., m.p. 127.degree.-130.degree. C.; m/e 
173; pnmr/CDCl.sub.3 shows aldehyde proton at 10.8 ppm, aromatic protons 
at 7.0-8.9 ppm. 
PREATION 10 
7-Methoxyquinoline-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/CDCl.sub.3 /delta (ppm): 4.1 (s, 3H), 7.5-9.0 (m, 5H), 11.2 (s, 1H)]. 
PREATION 11 
6-Chlorochroman 
Mossy zinc (75 g.), 7.5 g. of mercuric chloride, 125 ml. of water and 4 ml. 
of conc. hydrochloric 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 
refluxed 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 chromatographed on 400 g. of 
silica gel using 9:1 hexane:ether as eluant tlc monitoring and 15 ml. of 
fractions. Clean product fractions were combined and evaporated to yield 
title product as an oil [8.72 g.; pnmr/CDCl.sub.3 /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)]. 
PREATION 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, followed by the dropwise 
addition of 1,1-dichloromethyl methyl ether (6.2 g., 0.054 mole). The 
reaction mixture was stirred at 0.degree. 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.degree.-86.degree. C.; pnmr/CDCl.sub.3 /delta (ppm) 2.0 (m, 2H), 2.8 
(t, 2H), 4.2 (t, 2H), 7.1-7.5 (m, 2H), 10.2 (s, 1H), m/e 198/196]. 
PREATION 13 
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/CDCl.sub.3 
/delta (ppm) 2.0 (m, 2H), 3.8 (t, 2H), 4.1 (t, 2H), 6.8 (m, 3H); Rf 0.68 
(2:1 hexane:ether); m/e 152]. 
PREATION 14 
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.degree.-57.degree. C.; m/e 180). 
PREATION 15 
3-Methyl-5-isoxazolecarboxamide 
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, clarified by filtration and evaporated to an oil. The oil was 
multiply triturated with hot hexane, and the combined 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.degree.-182.degree. C.). 
PREATION 16 
3-Methyl-5-isoxazolecarbonitrile 
Product of the preceding Preparation (5 g.) was mixed thoroughly with 
phosphorous pentoxide (10 g.) and placed in an oil bath preheated to 
140.degree.. The bath temperature was increased to 200.degree. C. and 
title product recovered by distillation in vacuo [2.9 g., ir(film) nitrile 
band at 2220 cm.sup.1, no amide peak in the 1700 cm.sup.-1 region]. 
PREATION 17 
3-Methyl-5-isoxazolecarbaldehyde 
Product of the preceding Preparation (1.08 g., 0.01 mole) was dissolved in 
25 ml. of ether and cooled to -40.degree. C. Diisobutylaluminum hydride 
(12 ml. of 1 M in hexane, 0.012 mole) was added at -40.degree. C. over a 
15 minute period. The mixture was stirred at -30.degree. to -35.degree. C. 
for 10 minutes. Keeping the temperature at -20.degree. C., 60 ml. of ethyl 
acetate was added. Keeping the temperature at -25.degree. C., methanol (15 
ml.) was added dropwise, and keeping the temperature below -20.degree. C., 
3 ml. of 6 N hydrochloric acid was added. The reaction mixture was warmed 
to 5.degree. C. 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 combined and 
evaporated to yield title product (0.42 g.; m.p. 39.degree.-41.degree. 
C.). A small sample further purified by sublimation had m.p. 
43.degree.-45.degree. C. 
PREATION 18 
5-Chlorobenzo[b]furan-2-carboxylic Acid 
5-Chlorosalicylaldehyde (31.3 g., 0.2 mole) was dissolved in 200 ml. of 
2-butanone. Potassium carbonate (82.9 g., 0.6 mole) and then diethyl 
2-bromomalonate (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 6 N hydrochloric 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.degree.-262.degree. C., m/e 198/196). 
By the same procedure, 5-fluorosalicyaldehyde and 6-chlorosalicylaldehyde 
are converted, respectively, to 5-fluorobenzo[b]furan-2-carboxylic acid 
and 6-chlorobenzo[b]furan-2-carboxylic acid. 
PREATION 19 
5-Chlorobenzo[b]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 2 N hydrochloric acid and 
one of brine, dried over anhydrous magnesium sulfate and concentrated to 
an oil (6.2 g.). The oil was chromatographed 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-chlorobenzo[b]furan. 
PREATION 20 
5-Chloro-2,3-dihydrobenzo[b]furan 
Pd/C (5%, 12.2 g.) in 400 ml. of acetic acid was prehydrogenated at 
atmospheric pressure and 25.degree. C. 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 brine, dried over anhydrous magnesium sulfate, filtered and 
evaporated to an oil. The oil was chromatographed on 400 g. silica gel 
using hexane-3% ether as eluant, 15 ml. fractions 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 156/154]. 
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-dihydrobenzo[b]furan. 
PREATION 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.degree.-81.degree. C.; 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 compound 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. 
PREATION 22 
7-Chloroquinoline-8-carbaldehyde 
7-Chloro-8-methylquinoline (1 g.) [Bradford et al., J. Chem. Soc., p. 437 
(1947)] is dissolved in 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 isolated by 
evaporation. 
The bromo compound is solvolyzed to 7-chloro-8-(hydroxymethyl)quinoline by 
warming with excess alcoholic potassium hydroxide. To isolate the product, 
the reaction mixture is neutralized with hydrochloric acid, salts 
separated by filtration and the filtrate evaporated 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 condenser and occasional cooling in a cooling 
bath. The reaction mixture is diluted with ether, and the supernatant 
separated by decantation and filtration. The product is purified by 
filtration through a short magnesium silicate column with ether as eluant 
and isolated by removal of the solvent in vacuo.