CA1323629C - Process for the preparation of 5-arylidene and alkylidene-substituted hydantoins - Google Patents

Process for the preparation of 5-arylidene and alkylidene-substituted hydantoins

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Publication number
CA1323629C
CA1323629C CA000548024A CA548024A CA1323629C CA 1323629 C CA1323629 C CA 1323629C CA 000548024 A CA000548024 A CA 000548024A CA 548024 A CA548024 A CA 548024A CA 1323629 C CA1323629 C CA 1323629C
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Prior art keywords
phosphonate
hydantoin
alkyl
methyl
hydrogen
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French (fr)
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John J. Wright
Nicholas A. Meanwell
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Abstract of the Disclosure There is disclosed a process for the preparation of C-5-ethylenically unsaturated hydantoin derivatives which are useful as intermediates in the synthesis of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones. The process comprises coupling an aliphatic or aromatic aldehyde or ketone or an alpha-dicarbonyl compound with a dialkyl 5-phosphonate hydantoin.

Description

~ 1 323629 .

; (MJ 638) Patent Application for .

AND ALXYLIDENE-SUBSTITUTED ~YDANTOINS

.

Back~round of the Invention This invention relates to an efficient and effective method for preparing C-5 unsaturated hydantoin derivatives useful as intermediates in the synthesis of 1,3-dihydro-2H-Lmidazo[4,5-b]quinolin-2-ones which are potent antithrom-botic agents.
The condensation of hydantoin (1) with aromatic alde-hydes (2) to afford C-5 unsa urated hydantoin derivatives (3) is described in the literature, E. Ware, Chemical Reviews, 1950, 46, pps. 403-470; H.L. Wheeler et al, Am.
Chem. J., 1911, 45, pps. 368-383, and U.S. Patent Nos.
4,345,042 and 4,582,903. This reaction is illustrated as follows:
,~ .

r,, ., . ~, ~ . ...

:, .
,. . . .
.

" .
" . , .

, .. . .
O H O

N ~ ~ CHO ~ /~ N
H R ~ H
R
(1) (2) (3) wherein R is hydrogen or a substituent. Adducts (3) are of synthetic utility as precursors to derivatives of phenylal-anine and phenylpyruvic acid. A variety of different cata-lysts and solvent systems have been described to effect this transformation. In general, the aldehyde, hydantoin and catalyst are heated in a suitable solvent system at tempera-tures ranging from 70-170C for periods of 0.5 to 24 hours.
Some of the more commonly employed conditions are in NaOAc/AcOH at 160-170C for three hours; in NH40Ac/AcOH at reflux for four hours; in NaOAc/Ac20 at reflux for one hour;
in piperidine at 130-140C for 0.5 hour; and in dimethyl-amine at 100C for 22 hours in a sealed vessel. These pro-cedures, however, are not entirely satisfactory. Thus, some aldehydes either fail to condense with hydantoin or form i adducts only in low yiel~. Simple ketones have not been reported to participate in this reaction.
The reaction of phosphonate carbanions with ketones and aldehydes is ~nown in the art, Wadsworth et al, J. Amer.
Chem. Soc., 1961, 83, pps. 1733-1738; Wadsworth, Orq.
Reactions, 1978, 25, 73-253.

summarY of the Invention This invention provides a process for the preparation of C-5 ethylenically unsaturated hydantoin derivatives which are useful as intermediates in the synthesis of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones as described in our co-pending applications Serial No. 726,869, filed April 25, 1985; Serial No. 832,212* filed February 26, 1986; Serial * (U. S . Patent 4, 668, 686) "
., .
, ~

,~

.
~ - 3 -* **
No. 866,813, filed May 23, 1986; and Se~ial No. 883,258, filed July 8, 1986. The 5-ethylenically unsaturated hydantoin derivatives prepared by the process of this inven-tion are also useful as intermediates in the preparation of other compounds, e.g., phenylalanine and phenylpyruvic acid.
Briefly, the process comprises coupling an aliphatic or aromatic aldehyde or ketone or an alpha-dicarbonyl compound with a dialkyl S-phosphonate hydantoin. The dialkyl 5-phosphonate hydantoin has the formula:

~' o IRl ^ R~ ~o . ( 3 )2 N

(I) ` wherein Rl and R2 are hydrogen, alkyl or aralkyl containing up to 10 carbon atoms, e.g., benzyl, phenethyl, phenylpropyl and R3 is lower alkyl, e.g., methyl, ethyl or propyl.
This invention also provides the novel compound, di-ethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate. The i corresponding diethyl 2,4-dioxoimidazolidine-5-phosphonate is described in the literature, Chem. Abstracts, 1985, 102, Item No. 204029a.

Detailed DescriPtion of the Invention The formula I phosphonates are prepared by brominating the appropriate Rl and R2-imidazolidine-2,4-dione in acetic acid to produce the corresponding 5-bromohydantoin and cou-pling the product with a trialkyl phosphite.
Any aliphatic or aromatic aldehyde or ketone or alpha-Z dicarbonyl compound may be used in the process of this in-vention. The aromatic aldehydes disclosed in U.S. Patent No. 4,345,072 and the aromatic and aliphatic aldehydes * U.S. Patent 4,775,674 ,~ ** U. S. Patent 4, 701, 459 ~' , ,: , , . :

~ ' ' ' -- 4 ~

disclosed in U.S. Patent No. 4,582,903, may be used in the process of this invention. Aromatic aldehydes disclosed in U.S. Patent 4,345,072 incl~de benzaldehyde, tolylaldehyde, 4-isopropylbenzaldehyde, 4-hydroxybenzalde-hyde, 3,4,5-trimethoxybenzaldehyde, 3-bromo-4-methoxybenzal-dehyde, 3,4-methylenedioxybenzaldehyde, 2-hydroxy-4-nitro-benzaldehyde, 4,5-dimethoxy-2-nitrobenzaldehyde, salicyalde-hyde, ~anillin, 4-phenylbenzaldehyde, 4-benzylbenzaldehyde, 4-fluorobenzaldehyde, 4-dimethylaminobenzaldehyde, 4-ace-toxybenzaldehyde, 4-acetaminobenzaldehyde, 4-methylthio-benzaldehyde, and 3,5-dichloro-4-hydroxybenzaldehyde. Addi-tional aldehydes disclosed in U.S. Patent 4,345,072 include p-tolylaldehyde, m-tolyaldehyde, 4-chlorobenzaldehyde, 4-hexylbenzaldehyde, 2-allylbenzaldehyde, 4-allylbenzaldehyde, 2-vinylbenzaldehyde, 3-vinylbenzaldehyde, 4-methallylbenzal-dehyde, 4-cr~tylbenzaldehyde, 2-nitrobenzaldehyde, 3-nitro-benzaldehyde, 4-nitrobenzaldehyde, 2-aminobenzaldehyde, 4-aminobenzaldehyde, 4-cyclopropylbenzaldehyde, 2-cyclopropyl-benzaldehyde, 4-cyclohexylbenzaldehyde, 2,6-dichlorobenzal-dehyde, anisaldehyde, 3-hydroxybenzaldehyde, 2-hydroxyben-zaldehyde, 2-hydroxy-4-methylbenzaldehyde, 2-hydroxy-3-meth-oxybenzaldehyde, veratraldehyde, 2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 4-cyclohexeneylbenzaldehyde, 4-cyclooctylbenzaldehyde, 4-piperidinylbenzaldehyde, 4-pyri-dinebenzaldehyde, 4-furylbenzaldehyde, 4-thienlbenzaldehyde, 4-phenylethylbenzaldehyde, 4-sec.butylbenzaldehyde, 4-mor-pholinobenzaldehyde, 4-isopropoxybenzaldehyde, 2-propoxyben-zaldehyde, 3-ethoxybenzaldehyde, 4-hexoxybenzaldehyde, 2-isopropylaminobenzaldehyde, 4-hexylaminobenzaldehyde, 4-diethylaminobenzaldehyde, 4-dipropylaminobenzaldehyde, 4-methylethylaminobenzaldehyde, 3,4-ethylenedioxybenzaldehyde, 4-acethiobenzaldehyde, 4-propionoxybenzaldehyde, 4-formoxy-benzaldehyde, 4-butyroxybenzaldehyde, 3,4-tetramethylene-benzaldehyde, 3,4-trimethylenebenzaldehyde. Aliphatic .

,~a ^' 1 323629 aldehydes disclosed in U.S. Patent 4,582,903 include butyral-dehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde, caproaldehyde, enanthaldehyde, nonaldehyde, cyclobutylalde-hyde, cyclopentylaldehyde, cyclohexylaldehyde, furfural, 2-thiophenealdehyde, 2-pyrrolealdehyde, imidazolealdehyde, oxazolealdehyde, 3-indolealdehyde, pyridylaldehyde, pyrimi-dylaldehyde, malonic acid half aldehyde and monoaldehyde derivatives of dicarboxylic acids. Aromatic aldehydes dis-closed in U.S. Patent 4,582,903 include benzaldehyde, tolyl-aldehyde, 4-isopropylbenzaldehyde, 4-hydroxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 3-bromo-4-methoxybenzaldehyde, 3,4-methylenedioxybenzaldehyde, 2-hydroxy-4-nitrobenzalde-hyde, 4,5-dimethoxy-2-nitrobenzaldehyde, salicylaldehyde, vanillin, 4-phenylbenzaldehyde, 4-benzylbenzaldehyde, 4-fluorobenzaldehyde, 4-dimethylaminobenzaldehyde, 4-acetoxy-benzaldehyde, 4-acetaminobenzaldehyde, 4-methylthiobenzalde-hyde, and 3,5-dichloro-4-hydroxybenzaldehyde. Additional aldehydes disclosed in U.S. Patent 4,582,903 include p-tolylaldehyde, m-tolylaldehyde, 4-chlorobenzaldehyde, 4-hexylbenzaldehyde, 2-allylbenzaldehyde, 4-allylbenzaldehyde, 2-vinylbenzaldehyde, 3-vinylbenzaldehyde, 4-methallylbenzal-dehyde, 4-crotylbenzaldehyde, 2-nitrobenzaldehyde, 3-nitro-benzaldehyde, 4-nitrobenzaldehyde, 2-aminobenzaldehyde, 4-aminobenzaldehyde, 4-cyclopropylbenzaldehyde, 2-cyclo-propylbenzaldehyde, 4-cyclohexylbenzaldehyde, 2,6-dichloro-benzaldehyde, anisaldehyde, 3-hydroxybenzaldehyde, 2-hy-droxybenzaldehyde, 2-hydroxy-4-methylbenzaldehyde, 2-hy-droxy-3-methoxybenzaldehyde, veratraldehyde, 2,4-dihydroxy-benzaldehyde, 2,5-dihydroxybenzaldehyde, 4-cyclohexenylben-zaldehyde, 4-cyclooctylbenzaldehyde, 4-piperidinylbenzalde-hyde, 4-pyridylbenzaldehyde, 4-furylbenzaldehyde, 4-thienyl-benzaldehyde, 4-phenylethylbenzaldehyde, 4-sec.butylbenzal-dehyde, 4-morpholinobenzaldehyde, 4-isopropoxybenzaldehyde, 2-propoxybenzaldehyde, 3-ethoxybenzaldehyde, 4-hexoxybenzal-dehyde, 2-isopropylaminobenzaldehyde, 4-hexylaminobenzalde-hyde, 4-diethylaminobenzaldehyde, 4-dipropylaminobenzalde-.
~ .
' -"

hyde, 4-methylethylaminobenzylaldehyde, 3,4-ethylenedioxy-benzaldehyde, 4-acetylthiobenzaldehyde, 4-propionoxybenzal-dehyde, 4-formyloxybenzaldehyde, 4-butyroxybenzaldehyde, 3,4-tetramethylenebenzaldehyde, 3,4-trimethylenebenzalde-hyde, 3,4-dihydroxybenzaldehyde, alpha-napthaldehyde, beta-napthaldehyde, and 3-indenecarboxaldehyde.
A large number of aliphatic and aromatic aldehydes and ketones and alpha-dicarbonyl compounds useful in the prac-tice of this invention are exemplified in the examples which follow. A preferred class of aldehydes are those having the formula RC~O wherein R is selected from the group consisting of (a) substituted or unsubstituted alkyl wherein the alkyl group contains from 2-6 carbon atoms, (b) substituted or unsubstituted alkenyl wherein the alkenyl group contains 3-5 carbon atoms, (c) substituted or unsubstituted phenyl where-in one or more substituents on the substituted phenyl is selected from the group consisting of halogen, hydroxy, alkoxy or substitued alkoxy wherein the alkoxy has from 1-6 carbon atoms, nitro, alkyl having from 1-6 carbon atoms and substituted or unsubstituted amino, 2-(2-methyldioxalano), l-piperidino, l-morpholino, l-pyrrolidino, or l-piperazino, ~d) thienyl, (e) pyridinyl, and (f) PhC(O)-. Substituents which may be present on an alkoxy group include mono- and dialkyl- amino groups containing from 1 to 6 carbon atoms, an aryl sulfonyl group containing from 6 to 10 carbon atoms, a carboxylic acid ester group containing from 2 to 6 carbon atoms, and a nitrogen containing heterocyclic group contain-ing from 1 to 4 nitrogen atoms which may itself be further substituted with a cycloalkyl group containing from 6 to 10 carbon atoms. Substituents which may be present on an amino group include mono- and dialkyl groups containing from 1 to 6 carbon atoms, alkyl carbonyl groups containing from 2 to 6 carbon atoms, and carboxylic acid ester groups containing from 2 to 6 carbon atoms. Substituents which may be present on a l-piperazine group include an aroyl group containing ~rom 6 to 10 carbon atoms which may itself be substituted r~~

with one or more alkoxy groups containing from 1 to 6 carbon atoms, and carboxylic acid ester groups containing from 2 to 6 car~on atoms. Substituents which may be present on a l-piperidino group include carboxylic acid ester groups containing from 2 to 6 carbon atoms, and an N-cycloalkyl, N-alkyl carboxamide group containing from 7 to 10 carbon atoms. Preferred ketones are selected from the group con-sisting of Cl 3 alkyl 2-ketophenylacetate, Cl 3 alkyl 2-keto Cl 5 alkyl acetate, substituted or unsubstituted C4 8 cyclo-~; alkyl wherein one or more substituents on the substituted cycloalkyl is selected from the group consisting of halogen, hydroxy, alkoxy or substituted alkoxy wherein the alkoxy has from 1-6 carbon atoms, and alkyl having from 1-6 carbon atoms, 1,2-dioxycyclohexane, substituted or unsubstituted C8 10 alkyl phenones wherein the substituted phenyl is se-lected from the group consisting of halogen, hydroxy, Cl 6 alkoxy or Cl 6 alkyl, 3-oxoindole, and N-Cl 4 alkyl-3-oxoin-dole. Although certain preferred classes of aldehydes and ketones have been defined, as previously noted, any ali-phatic or aromatic aldehyde or ketone or alpha-dicarbonyl compound may be used in the process of this invention.
Preferably, from about 0.5 to 1.5 moles of aliphatic or aromatic aldehyde or ketone or alpha dicarbonyl compound is reacted per mole of phosphonate at a temperature ranging from about 0C to about 50C under basic conditions for a period of from 15 minutes to 24 hours. More preferred re-action conditions are described following.
Addition of aromatic aldehydes to a slight excess of - phosphonates and sodium ethoxide in ethanol at room tempera-ture generally results in the rapid separation of the 5-benzylidine hydantoin derivatives in excellent yield. Since the starting phosphonates and the diethyl phosphate side product are water soluble, isolation of the products com-prise simply diluting with water or 2N hydrochloric acid solution and water followed by filtration. In some cases, prior removal of the solvent facilitates this process. The ~ .

.,. ~.

crude products isolated from the reaction mixture are gener-ally of high purity as judged by NMR spectral data, although a mixture of geometrical isomers is frequently obtained.
High ~ields are obtained regardless of the steric or elec-tronic nature of the aldehyde, although hindered and deacti-vated aldehydes react at a slightly lower rate. The mild reaction conditions are tolerant of a wide range of func-tional groups. The anhydrous conditions described above are not crucial for the success of the reaction. Aqueous sodium hydroxide or lithium hydroxide solutions in ethanol are e~ually effective and a 2-phase system comprising dichloro-methane and aqueous sodium hydroxide, with or without a phase transfer catalyst, also provide adducts in high yield.
Other suitable reaction conditions include triethylamine in acetonitrile; triethylamine and lithium bromide in aceto-nitrile; and lithium bromide in pyridine.
Aliphatic aldehydes react with hydantoin phosphonates to furnish S-alkylidene hydantoin derivatives in synthet-ically useful yields. Phenylacetaldehyde reacts exotherm-ically with phosphonates to produce adducts in excellent yield within 20 minutes, although phenylacetaldehyde and 4-methoxyphenylacetaldehyde have been reported in the litera-ture not to condense with hydantoin under a variety of con-ditions.
Alpha dicarbonyl compounds generally react exotherm-ically with hydantoin phosphonates under the standard con-ditions to provide adducts in high yield.
Cyclohexanone in the presence of lithium rather than sodium as the counter ion reacts with the hydantoin phospha-nates to provide high yields. The lithium salt of triethyl phosphonoacetate has been shown to be highly chelated and the lithium atom may play a similar role in the reaction of the hydantoin phosphonates with ketones. Although such a tightly bound lithium salt would be more stable and, thus, inherently less reactive, the increased stability of the salt may allow the coupling process to successfully compete with alternative reaction pathways of which proton transfer may be a major contributor~
The C-5 unsaturated hydantoin derivatives prepared by the instant process are, in some instances, isolated as a mixture of (Z) and (E) isomers as depicted below wherein R' --is a grouping derived from the aliphatic or aromatic alde-hydes and Rl and R2 are as described above.

~N ~ ~N

, R2 I R2 R' H
(Z) (E) That geometrical isomer in which R' i~ disposed cis to the N-R2 group of the hydantoin ring is designated (Z) where-as that in which R' is disposed trans to N-R2 is designated (E). When a vinyl proton is present, restonation at lower field in the NMR spectrum was usually predominant. When the proton of the double bond is replaced by another moiety as . in the case of a grouping derived from ketone or an alPha-dicarbonyl, then (E) or (Z) designation are made based on the Cahn-Wright-Prelog priority order. (See "Advanced Organic Chemistry', 2nd Ed., Jerry Merch, McGraw-Hill, 1977, i pages 113-117 and pages 99-101).
The following examples are given by way of illustration and are not to be construed as limiting the invention in any way inasmuch as many variations of the invention are possi-ble within the spirit of the invention. All temperatures are degrees centigrade and melting points taken with a Thomas Hoover capillary apparatus are uncorrected. Conven-tional abbreviations are employed in reporting Nuclear Mag-; netic Resonance (NMR) spectral data with tetramethylsilane ., .

.

; ' , .

' -` . 1 32362q as internal referenc~ and chemical shift data values in-parts per million. All new compounds reported gave satis-factory combustion analysis data and exhi~ited spectral characterisitcs which were consistent with their assignQd structures.

Example 1 Diethyl 2,4-dioxoimidazolidine-5-phosphonate. A mix-ture o~ imidazolidine-2,4-dione (20G g, 2 M) and acetic acid (800 ml) was heated to 85C in an oil bath. An addition funnel was charged with bromine (352 g, 112.8 mL, 2.2 M) and a small amount of bromine (~5 mL) introduced in to the reaction mixture with vigorous stirring. Once the orange color had dissipated, the remainder of the bromine was added rapidly over approximately seven minutes to afford a clear solution. After stirring at 85C for 30 minutes, the re-action mixture was cooled to 30C in an ice bath and tri-ethyl phosphite (465 g, 479 mL, 2.8 M) was introduced at such a rate that the internal temperature was maintained at 45-50C. After completing the addition, the ice bath was removed and the mixture stirred at ambient temperature for 90 minutes. The solvent was removed in vacuo and the resi-due diluted with diethyl ether (800 mL) with swirling to induce precipitation of a white solid. The mixture was poured into diethyl ether (2L) with vigorous stirring.
After 30 minutes, the solid was filtered off, washed with diethyl ether and air dried to give diethyl 2,4-dioxoimi-dazolidine-5-phosphonate (337.0 g, 71~) which was used with-out further purification. An analytical sample was prepared by recrystallization from ethanol and had mp 161-163C
H-NMR (DMSO-d6) ~ 1-25 (6H~ t, J = 7Hz, (OCH2CH3), 4.10 (4H, m, OCH2CH3), 4.76 (lH, d, J = 15Hz, P(O).CH.CO), 8.42 (lH, bs, NH) and 10.92 (lH, bs, NH). IR (KBr) 1035 (P-OEt), 1250 (P=0), 1720 (>C-0) and 1775 (>C=0) cm 1. m/e 237 (MH+). Anal. calcd. for C7H13N2O5P: C, 35.61; H, 5.55; N, 11.87. Found: C, 35.21; H, 5.60; N, 12.04.

. ~, .
.,,': .
, . .

.

...

: .

Example 2 Diethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate.
A mixture of l-methylimidazolidine-2,4-dione (202.5 g, 1.8 M) and glacial acetic acid (lL~ was heated to 90C in an oil bath. An addition funnel was charged with bromine (311.5 g, 100 mL, 1.95 M) and a small amount of bromine introduced into the reaction mixture. After dissipation of the orange color, the remainder of the bromine was added dropwise at such a rate that instant decolorization occurred. After completing the addition, the mixture was stirred at 90C for 60 minutes, cooled to room temperature and stirred over-night. The acetic acid was decanted from a white precipi-tate, concentrated in vacuo and the residue combined with the precipitate and suspended in diethyl ether (approxi-mately 2L). Triethyl phosphite (295 g, 320 mL, 1.8 M) was added portionwise with stirring. An exothermic reaction ensued which was controlled with tap water cooling of the reaction vessel. A solution resu~ted which, on continued stirring, yielded a white precipitate. After standing for 60 minutes, the mixture was poured into diethyl ether (4L) and allowed to stand overnight. Filtration afforded diethyl-l-methyl-2,4-dioxoimidazolidine-5-phosphonate (331.7 g, 75%) mp 95-96C. An analytical sample recrystallized from MeOH/Et2O had mp 95-96C. lH-NMR (CDCl3) ~ 1.26 (6H, m, OCH2CH3), 2.90 (3H, s, N-CH3), 4.12 (4H, m,, OCH2CH3), 4.72 (lH, d, J = 14Hz, P(O~.CH.CO3, and 11.06 (lH, bs, NH).
lR (KBr) 1025, 1050 (P-OC2H5), 1275, 1250 (P=O), 1725 (>C=O) and 1775 (>C=O) cm . m/e 251 (M ). Anal. calcd. for C8H15N2O5P: C, 38.41; H, 6.04; N, 11.20. Found: C, 38.22;
H, 6.07; N, 11.04.
The following 5-phosphonate hydantoin intermediates can be prepared analogously by substituting the appropriate imidazolidine-2,4-dione for 1-methylimidazolidine-2,4-dione in the above procedure:
diethyl 2,4-dioxoimidazolidine-5-phosphonate, m.p.
161-163C crystallized from ethanol, : .
~' , .

-~ ` 1 323629 .
~ - 12 -diethyl 1-ethyl-2,4-dioxoimidazolidine-5-phosphonate, diethyl l-propyl-2,4-dioxoimidazolidine-5-phosphonate, diethyl l-isopropyl-2,4-dioxoimidazolidine-5-phospho-~; nate, diethyl 1-butyl-2,4-dioxoimidazolidine-5-phosphonate, diethyl l-iso-butyl-2,4-dioxoimidazolidine-5-phospho-nate, diethyl l-tert-butyl-2,4-dioxoimidazolidine-5-phospho-nate.
The following seven examples illustrate the preparation of arylidene hydantoins of the formula . .~
Rl No2 H

Rl ~Y ~

, .
(II) ExamPle 3 5-~(2,3-DimethYl-6-nitrophenvl)methYlene]2,3-imidazoli-~ R1 R4 H, R2=R3=CH3). Sodium (0.41 g, 0 018 gatom) was dissolved in ethanol (40 mL) and diethyl 2,4-dioxo-imidazolidine-5-phosphonate (4.21 g, 18 mmol) added. After minutes, 2,3-dimethyl-6-nitrobenzaldehyda (2.66 g, 15 mmol) was added in one portion and the mixture stirred at room temperature for 90 minutes. The mixture was diluted with water, filtered and the solid washed with water and air dried gave 5-[(2,3-dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione as a single geometrical isomer (3.35 g, 86%). Analytical sample prepared by crystallization from methanol had m.p. 293-295C.
Anal. Calcd. for C12Hl1N3O4: C, 55.17; H, 4.24; N, 16.09. Found: C, 54.97; H, 4.27; N, 16.09.

., .

:"
~, .

. ~ .

. ~' . 1 323629 NMR (DMSO-d6~: ~ 2.20 (3H, s, CH3~, 2.37 (3H, s, CH3), 6.62 (lH, s, vinyl H), 7.39 (1~, d, J=9Hz, aromatic H) and 7.82 (lH, d, J=8Hz, aromatic H).
After standing overnight, a second crop consisting of a 1:1 mixture of geometrical isomers was collected from the aqueous layer (0.5 g, 12%), m.p. 267-270C (dec.).
NMR (DMSO-d6): ~ 2.20 (6H, s), 2.33 (3H, s), 2.37 (3H, s), 6.45 (lH, s, vinyl H trans to C=O), 6.62 (lH, s, vinyl H
cis to C=O), 7.31 (lH, d, J=8Hz), 7.38 (lH, d, J=8Hz), 7.73 (lH, d, J=8Hz), 7.81 (lH, d, J=8Hz).

Example 4 5-[(2-Methyl-6-nitrophenyl)methYlene]-2,4-imidazoli-1 2 R4 H; R3=CH3). Reaction of 2-methyl 6 nitrobenzaldehyde with diethyl 2,4-dioxoimidazolidine-5-phosphate according to the procedure of Example 3 provided the title compound as an 84:1 mixture of geometrical isomers, m.p. 238-239C (dec.) in 81% yield.
Anal. Calcd. for CllHgN3O4: C, 53.45; H, 3.67; N, 17.00. Found: C, 53.44; H, 3.66; N, 16.92.
.~
ExamPle 5 5-[(2,3-DimethYl-6-nitrophenyl)methylene]-1-methYl-2,4-imidazolidinedione (Rl=H; R2=R3=R4=CH3). Reaction of 2,3-dimethyl-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedure of Example 3 provided the title compound (partial hydrate) as a mixture of geometrical isomers, m.p. 195-198C in 88%
yield.
Anal. Calcd- for C13H13N34 l H2O
4.81; N, 15.17, H2O, 0.65. Found: C, 56.38; H, 4.87; N, 14.54, H2O, 0.16.
., Example 6 5-[(5-Methoxy-2-nitrophenyl)methylene]-1-methYl-2,4-imidazolidinedione (Rl=R3=H; R2=OCH3; R4=CH3). Reaction of ç~'';' ' ' ,~

~ 1 323629 3-methoxy -6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedure of Example 3 provided the title compound as a mixture of geometrical isomers, m.p. 257-260C in 93% yield.
Anal. Calcd. for C12HllN305: C, 51.99; H, 4.00; N, 15.16. Found: C, 51.87; H, 4.01; N, 14.90.

Example 7 l-MethYl-5-[(5-methy1-2-nitrophenYl)methYlene]-2,4-imidazolidinedione (Rl=R3=H; R2=R4=CH3). Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxo-imidazolidine-5-phosphonate according to the procedure o~
Example 3 provided the title compound (partial hydrate) as a mixture of geometrical isomers, m.p. 261-262C in 66% yield.
Anal. Calcd. for cl2HllN3o4. 0-1 H2O
4.29;-N, 15.97; H2O, 0.68. Found: C, 54.73; H, 4.30; N, 15.62; H2O, 0.24.

ExamPle 8 5-[4,5,6-~rimethoxy-2-nitroPhenYl)meth~lene]-2,4-imida-- zolidinedione (Rl=R2=R3=OCH3; R4=H). Reaction`of 2,3,4-trimethoxy-6-nitrobenzaldehyde with diethyl 2,4-dioxoimida-zolidine-5-phosphonate according to the procedure of Example 3 provided the title compound as a single geometrical isomer, m.p. 206-208C in 91% yield after crystallization from methanol.
- Anal. Calcd. for C13H13N3O7: C 48.30; H, 4.05; N, 13.00. Found: C, 48.38; H, 4.02; N, 13.00.

Example 9 l_Methvl_5_[(2-methyl-6-nitrophenyl)-methYlene]-2,4-imidazolidinedione (R =R =H; R =R =CH ). Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxo-imidazolidine-5-phosphonate according to the procedure of Example 3 provided the title compound as a mixture of geo-metrical isomers, m.p. 194-197C in 80% yield.

2$ - 15 -Anal. Calcd. for C12NllN3O4: C, 55.18; H, 4.25; N, 16.09. Found: C, 54.94; H, 4.24; N, 15.82.
.
The following examples 10 to 27 illustrate the prep~
aration of additional arylidene hydantoins.

~ ExamPle 10 ; Ethyl 4-[3-[(2,4-dioxoimidazolidin-5-yl-idene)methYl]-4-nitrophenoxy]butanoate. Sodium (4.92 g, 0.21 g atom) was dissolved in absolute ethanol (600 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (50.5 g, 0.21 mole) added.
After 10 minutes a solution of ethyl 4-(3-formyl-4-nitro-phenoxy)butanoate (50.0 g, 0.18 mole) in ethanol (I00 mL) was added in one portion. The mixture was stirred for two hours, concentrated in vacuo to about 250 mL and diluted with water. After 20 minutes, the precipitate was filtered .~ off. Two further crops were subsequently collected from mother liquors. Com~ined solids were dried ln vacuo over `3 P O to afford ethyl 4-[3]~(2,4-dioxoimidazolidin-5-ylidine)methyl]-4-nitrophenoxy]butanoate (61.3 g, 95%) which i by NMR was a 4:1 mixture of geometrical isomers. An ana-; lytical sample of the major isomer was obtained by crystal-lization from a~ueous ethanol and had m.p. 131-134C.
Anal. Calcd. for C16H17N3O7: C, 52.89; H, 4.72; N, 11.57. Found: C, 52.94; H, 4.71; N, 11.57.
~ . .
~' Example 11 EthYl [3-[(2,4-Dioxoimidazolidin-5-ylidene)methYl]-4-nitrophenoxY]acetate. Prepared from diethyl 2,4-dioxoimida-zolidine-5-phosphonate and ethyl 4-(3-formyl-4-nitrophen-oxy)acetate analogous to the procedure of Example 10, m.p.
268-270C.
.....
~ Anal. Calcd. for C14H13N3O7: C, 50.16; H, 3.91; N, - 12.54. Found: 50.06; H, 3.89; N, 12.51.
' , .

-. ~, Example 12 Ethyl 5-[3-[(2,4-Dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxY]Pentanoate. Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and ethyl 4-(3-formyl-4-nitrophenoxy)pentanoate analogous to the procedure of Example 10, m.p. 127-129C.
Anal. Calcd. for C17HlgN3O7: C, 54.11; H, 5.08; N, 11.14. Found: C, 54.28; H, 5.14; N, 11.29.

Example 13 EthYl 4-[3-[(1-MethYl-2,4-dioxoimidazolidin-5-Ylidene)-methyl-4-nitrophenoxy]butanoate. Prepared from diethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate and 4-(3-formyl-4-nitrophenoxy)butanoate analogous to the procedure of Example 10, m.p. 161-163C.
Anal- Calcd- for C17~19N37 C, 54-11; H~ 5-08; N~
11.14. Found: C, 54.01; H, 5.08; N, 11.12.

Example 14 EthYl 5-~3-[(1-MethYl-2,4-dioxoimidazolidin-5-Ylidene)-methvl-4-nitrophenoxy]pentanoatè. Prepared from diethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate and ethyl , 4-(3-formyl-4-nitrophenoxy)pentanoate analogous to the pro-cedure of Example 10, m.p. 121-123C.
Anal. Calcd. for C18H21N3O7: C, 55.24; H, 5.41; N, 10.74. Found: C, 55~22; H, 5.47; N, 10.80.

- ExamPle 15 N-CYclohexYl-N-methY1-4-[3-[(1-methyl-2,4-dioxoimida-zolidin-5-ylidene)methyl-4-nitroPhenoxy]butanamide. Sodium (0.079 g, 0.003 g atom) was dissolved in ethanol (20 mL) and diethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate (0.8~
g, 3.4 mmol) added. After 5 minutes, N-cyclohexyl-4-(3-formyl-4-nitrophenoxy))-N-methyl-butanamide (1 g, 2.9 mmol) was added and the mixture stirred at room temperature for 90 minutes. The solvent was evaporated and the residue diluted , -with water and extracted with dichloromethane to give a foam. Crystallization from hexane/dichloromethane afforded N-cyclohexyl-N-methyl-4-[3-[(1-methyl-2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]butanamide (0.96 g, 75% as a 3:1 mixture of geometrical isomers, m.p. 149-154C.
Anal. Calcd. for C22H28N4O6: C, 59.45; H, 6.36; N, 12.61. Found: C, 59.27; H, 6.29; N, 12.44.
., Example 16 5-[~5-[4-(1-CYclohexyl-lH-t_trazol-5-Yl)-butoxY]-2-nitrophenyl]methylene]-2,4-imidazolidinedione hydrate.
Sodium (1.38 g, 0.06 g atom) was dissolved in ethanol (250 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (14.22 g, 60 mmol) added. After 5 minutes, a solution of 5-[4-(1-cyclohexyl-lH-tetrazol-5-yl)butoxy]-2-nitrobenzaldehydé
(17.30 g, 46 mmol) obtained according to T. Nishi, et al., Chem. Pharm. Bull., 33, 1140-1147 (1985) in ethanol (50 mL) and dichloromethane (50 mL) was added in one portion. This mixture was stirred for 10 minutes, the solvent evaporated and the residue diluted with water and 2N hydrochloric acid solution. The yellow precipitate was filtered off, washed with water and dried in air to give S-[[5-[4-(1-cyclohexyl-lH-tetrazol-5-yl)butoxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (18.38 g, 87%). An analytical sample (asa partial hydrate) was prepared by crystallization from aqueous dimethylformamide and had m.p. indistinct.
Anal. Calcd. for C21H25N7O5Ø2H2O: C, 54.9S; H, 5.58;
N, 21.36; H O, 0.79. Found: C, 54.78; H, 5.74; N, 21.08;
H2O, 0.86.
ExamPle 17 5-[[2-Nitro-5-[4-(phenYlsulfonyl)butoxY]PhenYl]methyl-ene]-2,4-imidazolidinedione. Sodium (0.386 g, 0.017 g atom) was dissolved in ethanol (70 mL) and diethyl 2,4-dioxoimi-dazolidine-5-phosphonate (3.96 g, 17 mmol) added. After one hour, a solution of 2-nitro-5-[4-(phenylsulfonyl)butoxy]

: .
:- . , .,. , .~ .

- 18 - l 32 3 62~
, .
benzaldehyde (4.70 g, 13 mmol) (prepared by alkylating 5-hydroxy-2-nitrobenzaldehyde with 4-phenylsulfonylbutyl bro-mide) in ethanol and chloroform was added. After 20 minutes the solvent was evaporated and the residue extracted with chloroform to give a foamy solid which was dissolved in acetonitrile. Diethyl ether was added to the point of pre-cipitation and the mixture allowed to stand overnight. A
solid (0.86 g) was collected and further purified by crys-tallization from acetonitrile-diethyl ether to give 5-[[2-nitro-5-[4-(phenylsulfonyl)butoxy]phenyl]methylene]-2,4-imidazolidinedione (O.5 g). Concentration of the combinedmother liquors afforded 4.1 g of material that was used without further purification. Yield (4.6 g, 61~). Crystal-lized material had m.p. 150-152C.
Anal. Calcd. for C20HlgN3O7S C, 53.93; H, 4.30; N, 9.43. Found: C, 54.12; H, 4.31; N, 9.44.
:...
Example 18 5-l[5-[(2-Diethylamino)ethoxv]-2-nitrophenyl]methyl-ene]-2,4-imidazolidinedione. A mixture of 5-hydroxy-2-nitrobenzaldehyde (10 g, 60 mmol), 2-diethylaminoethyl chloride hydrochloride (13.4 g, 78 mmol), powdered potassium carbonate (24.8 g, 180 mmol) and dimethylformamide t200 mL) was heated at 100C in an oil bath. After two hours, the mixture was cooled, diluted with water and extracted with diethyl ether. The combined extracts were washed twice with water, dried, and the solvent evaporated to leave an oil (14.60 g, 92%) which was added, in one portion, to an ethanolic solution of the sodium salt of diethyl 2,4-dioxo-imidazolidine-5-phosphonate [prepared by dissolving sodiùm (1.46 g, 0.06 g atom) in ethanol (200 mL) and adding diethyl 2,4-dioxoimidazolidine-5-phosphonate (13.00 g, 49 mmol)].
After 30 minutes, the mixture was diluted with water, filtered, the solid washed with water and dried in air to afford 5-[[5-[(2-diethylamino)ethoxy]2-nitrophenyl]-'~

methylene]-2,4-imidazolidinedione (11.0 g, 65%~. An ana-lytical sample was prepared by crystallization from aqueous dimethylformamide and had m.p. 208-211C (dec).
Anal. Calcd. for C16H20N4O5: C, 55.17; H, 5.79; N, 16.09. Found: C, 55.12; H, 5.80; N, 15.98.

Example 19 5-[[5-[[[3-(1-Methylethyl)-2-oxooxazolidin-5-Yl]-methYl]oxY]-2-nitroPhenYl]methylene]-2,4-imidazolidinedione.
Step 1. 2-[2-Nitro-5-(oxiranYlmethoxy)ehen~l]-1,3-dioxo-lane. A mixture of 2-(2-nitro-5-hydroxyphenyl)-1,3-dioxo-lane (29.5 g, 0.14 mole), epibromohydrin (29.03 g, 18.15 mL, 0.21 mole), potassium carbonate (48.67 g, 0.35 mole) and dimethylformamide (250 mL) was heated with stirring at 100C. After 30 minutes, the mixture was cooled, diluted with water and extracted with diethyl ether. The combined organic extracts were washed with water (3x), dried over sodium sulfate and concentrated to afford a crystalline solid (34.50 g, 92~) which was used without further purifi-cation. An analytical sample was prepared by dissolution of 1 g in dichloromethane (15 mL). Addition of hexane (about 50 mL), precipitated a yellow solid which was removed by filtration. Further dilution with hexane precipitated 2-[2-nitro-5-(oxiranylmethoxy)phenyll-1,3-dioxolane (O.8 g) m.p. 78-79.5C.
Anal. Calcd. for C12H13NO6: C, 53.94; H, 4.91; N, 5.25. Found: C, 53.58; N, 4.82; H, 5.25.
SteP 2. 1-[3-1l~3-dioxolan-2-yl)-4-nitro~henyl]-3-[(l-methYlethyl)am-ino]-2-propanol. A mixture of 2-[2-nitro-5-(oxiranylmethoxy)phenyl]-1,3-dioxolane (2 g, 7.5 mmol) and isopropylamine (10 mL) was refluxed for 23 hours.
The isopropylamine was removed ~n vacuo and the residue dissolved in dichloromethane, washed with water, dried and concentrated to afford a solid. Purification was effected by dissolving in dichloromethane and filtering through a plug of silica gel using 10% methanol/chloroform as eluant.

~ .

~ 1 323629 , The solid isolated was dissolved in dichloromethane and diluted with hexane to furnish 1-[3-(1,3-dioxolan-2-yl)-4-nitrophenyl]-3-[(1-methylethyl)amino]-2-propanol (0.8 g, 32%), m.p. 97-99C.
Anal. Calcd. for C15H22~2O6: C, 55.20; H, 6.80; N, 8.59. Found: C, 54.80; H, 6.69; N, 8.54.
Step 3. 5-[t[3-(l-Methylethy-l)-2-oxooxazolldin-5-vl]
methyl]oxo]-2-nitrobenzaldehyde. Phosgene (11.12 g, 0.11 mole) in toluene (50 mL) was added dropwise to a stirred solution of 1-[3-(1,3-dioxolan-2-yl)-4-nitrophenyl]-3-[(1-methylethyl]amino]-2-propanol (14.65 g, 0.05 mole) and pyridine (8.88 g, 9.1 mL, 0.11 mole) in dichloromethane (150 mL) maintained at 0C in an ice bath. After completion of the addition, the ice bath was removed and the mixture warmed to room temperature and stirred for 15 minutes before being diluted with water. The mixture was extracted with dichloromethane, the combined extract dried and concentrated to afford an oil which was dissolved in tetrahydrofuran t300 mL). Dilute hydrochloric acid solution (75 mL) was added and the mixture heated to reflux. After 90 minutes, , ~ .
the tetrahydrofuran was evaporated and the residue extracted with dichloromethane. The combined extracts were dried over sodium sulfate and the solvent evaporated to leave an oil which crystallized to give a yellow solid (12.00 g, 86%).
An analytical sample was prepared by dissolving a portion (1 g) in dichloromethane and adding diethyl ether to pre-cipitate a tacky solid. After decanting, the solution was diluted with diethyl ether and then hexane to furnish 5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]2-nitrobenzaldehyde (0.7 g, 74%), m.p. 94-97C.
Anal. Calcd. for C14H16N2O6: C, 54.54; H, 5.23; N, 9.09. Found: C, 54.26; H, 5.21; N, 9.04.
SteP 4. 5-[[5-[[[3-(1-Methylethyl)-2-oxooxazolidin-5-Yl]methYl]oxY]-2-nitrophenYl]methYlene]-2,4-imidazolidine-dione. Sodium (0.9 g, 0.04 g atom) was dissolved in ethanol (150 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate :: , , . . .

.;'. .
(9.19 g, 40 mmol) added. After 30 minutes, solid 5-[[[3-(l-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitro-benzaldehyde (10.0 g, 32 mmol) was added and the mixturestirred vigorously. After 30 minutes, the mixture was di-luted with water (150 mL), filtered, and the solid washed with water and air dried to give 5-[[5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (9.80 g, 77~). An analytical sample was prepared by crystallization from dimethylformamide and water and had a m.p. of 285-287C (dec.).
Anal. Calcd. for C17H18N4O7: C, 52.31; H, 4.65; N, 14.35. Found: C, 51.84; H, 4.64; N, 14.25.
~, Example 20 ,.:.
5-~[5-[[3-(1,1-DimethylethYl)-2-oxooxazolidin-5-yl]-methoxy]-2-nitrophenYl]methYlene]imidazolidine-2,4-dione.
Prepared from 5-[[[3-(1,1-dimethylethyl)-2-oxooxazolidin-5-yl]methyl]oxo-2-nitrobenzaldehyde and diethyl 2,4-dioxo-imidazolidine-5-phosphonate analogous to the procedure of Example 19 (step 4), m.p. 273-275C (dec.).
Anal. Calcd. for C18H20N4O7: C, 53.46; H, 4.99; N, 13.86. Found: C, 53.35; H, 5.08; N, 13.86.

Example 21 5-[~[2-Nitro-5-[(3-tetrahydro-2H-pyran-2-Yl)-oxy]Pro-poxy]phenyl]methylene]-2,4-imidazolidinedione. A mixture of 5-hydroxy-2-nitrobenzaldehyde (8.18 g, 49 mmol), 1-bromo-3-(tetrahydro-2H-pyran-2-yl)oxypropane (11.50 g, 51 mmol), potassium carbonate (7.16 g, 51 mmol), potassium iodide (catalytic amount) and dimethylformamide (800 mL) was heated with stirring at 110C for 30 minutes. The mixture was cooled, diluted with water (150 mL) and extracted with di-chloromethane. The combined extracts were washed with water (3 times), dried over sodium sulfate and concentrated in vacuo to leave an oil which was dissolved in ethanol (15 mL) and added to a solution of sodium etho~ide (3.99 g, 58 mmol~

~ '.

. .

and diethyl 2,4-dioxoimidazolidine-5-phosphonate (13.87 g, 59 mmol) in ethanol (200 mL). After 90 minutes, the ethanol was evaporated, the residue diluted with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated ln vacuo to afford an oil which was dissolved in dichloromethane and filtered through a plug of silica gel using diethyl ether as eluant. Evapo-ration of the solvent left 5-[[2-nitro-5-~(3-tetrahydro-2H-pyran-2-yl]propoxy]phenyl]methylene]-2,4-imidazolidinedione as a viscous oil which was used without further purifica-tion. An analytical sample of the 2,4-imidazolidine as a partial hydrate was prepared by precipitation from dichloro-methane with hexane and had a m.p. 128-134C.
Anal. Calcd. for C18H21N3O7 O.O5H2O: C, 55.12; H, 5.43; N, 10.72; H2O, 0.23. Found: C, 54.80; H, 5.33; N, 10.85; H2O, 0.1.

- ExamPle 22 5[[5-(2-Ethoxvethoxv)-2-nitroPhenyl]-methylene]-2,4-imidazolidinedione. A mixture of 5-hydroxy-2-nitrobenzal-dehyde (1.00 g, 6 mmol), 2-bromoethyl ethyl ether (1.00 g, 0.74 mL, 6.5 mmol), powdered potassium carbonate (0.91 g, 6.5 mmol), potassium iodide (catalytic quantity) and di-methylformamide (10 mL) was heated with stirring at 110C.
After 30 minutes, the mixture was cooled, diluted with water and extxacted with dichloromethane (3 times). Combined extracts were washed with water (2 times), dried over sodium thiosulfate and concentrated ln vacuo to leave an oil which was dissolved in ethanol (3 mL) and added to a stirred solu-tion of sodium ethoxide (0.53 g, 78 mmol) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (1.83 g, 77 mmol) in eth-anol (15 mL). After 10 minutes, the mixture was diluted with 2N hydrochloric acid solution and the solid filtered off and dried in air to give 5-[[5-(2-ethoxyethoxy)-2-nitrophenyl]methylene]-2,4-imidazolidinedione as a partial hydrate (1.40 g, 73~), m.p. 228-233C (dec.).

, ': .

.

, .

~ 1 323629 Anal. Calcd. for C14H15N3O6 0.12H2O: C. 51.99; H, 4.75; H, 13.00; H2O, 0.67. Found: C, 51.59; H, 4.72; N, 12.82; H2O, 0.25. A second crop (0.2 g, 10~) was subse-quently collected.

Exam~le 23 5-[~5-[3-~2-Methvl-1,3-dioxolan-2-~1)-propoxy]-2-nitrophen~l]methvlene]-2,4-imidazolidinedione. A mixture of 5-hydroxy-2-nitrobenzaldehyde (20.00 g, 0.12 mole), 5-chloro-2-pentanone ethylene ketal (21.7 g, 0.132 mole), potassium carbonate (20.00 g, 0.14 mole), potassium iodide (0.5 g) and dimethylformamide (200 mL) was heated with stir-ring at 120C. After four hours, the mixture was cooled, diluted with water and extracted with diethyl ether. The combined ethereal extracts were washed with water, dried over magnesium sulfate and the solvent evaporated. The residual oil comprised of 5-[3-~2-methyl-1,3-dioxolan-2-yl)-propoxy]-2-nitrobenzaldehyde (used without purification) was dissolved in ethanol (200 mL) and added in one portion to a solution of sodium ethoxide (10.05 g, 0.15 mole) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (35.00 g, 0.15 mole) in ethanol, (300 mL). The mixture was stirred at room tempera-ture for 90 minutes, concentrated to a volume of approxi-mately 300 mL and diluted with water. The yellow precipi-tate was filtered off, washed with water and dried in vacuo at 70C to give 5-t[5-[3-(2-methyl-1,3-dioxolan-2-yl)-propoxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (38.17 g, 84%). An analytical sample was prepared by crys-tallization from ethanol and had a m.p. of 175-180C.
,, .
Anal. Calcd. for C17HlgN3O7: C, 54.11; H, 5.08; N, 11.14. Found: C, 54.34; H, 5.08; N, 10.85 Example 24 - 5-[[2-Nitro-5-[3-(Phenylsulfonyl)Propoxy]-Phenyl]-methvlene]2,4-imidazolidinedione. Prepared from 2-nitro-5-.
' , ' . .

. . .

'' ' :

, .. .

[3-(phenylsulfonyl)propoxy]benzaldehyde (obtained by alkyl-ating 5-hydroxy-2-nitrobenzaldehyde with 3-phenylsulfonyl-propyl bromide) and diethyl 2,4-dioxoimidazolidine-5-phos-phonate analogous to the procedure of Example 17, m.p.
125-157C.
Anal- Calcd- for ClgH17N3O7S C, 52.90; H, 3.97; N, 9.74. Found: C, 52.81; ~, 4.10; N, 9.71.

Example 25 l-Methyl-5-[[2-nitro-5-[3-(phenylsulfonYl)-proPoxY]-phenyl]methvlene]-2,4-imidazolidinedione. Prepared from 2-nitro-5-[3-(phenylsulfonyl)propoxy]benzaldehyde and di-ethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate analo-gous to the procedure of Example 17, m.p. 147-158C.
_nal. Calcd. for C20HlgN3O7S C 53.93: H, 4.30; N, 9.43. Found: C, 54.07; H, 4.50; N, 9.21.

ExæmPle 26 2-[3-[(2~4-Dioxoimidazolidin-5-ylidene)-methYl]-4-nitrophenoxvlethvl Acetate. Diethyl 2,4-dioxoimidazolidine-5-phosphonate was added to triethylamine (equimolar) in acetonitrile. After one hour, an equimolax amount of 4-[3-formyl-4-nitrophenoxy]ethyl acetate (obtained by alkylating 5-hydroxy-2-nitrobenzaldehyde with 2-bromoethyl acetate) was added and the mixture stirred for two hours. Isolation of the product according to the procedure of Example 10 pro-vided 2-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]ethyl acetate, m.p. indistinct.
Anal. Calcd. for C14H13N3O7: C, 50.16; H, 3.91; N, 12.54. Found: C, 49.90; H, 3.98; N, 12.68 Example 27 3-[3-[(2,4-Dioxoimidazolidin-5-vlidene)-methyl]-4-nitrophenoxY]proPyl Acetate. Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and ethyl 4-[3-formyl-4-nitrophenoxy]propyl acetate (obtained by alkylating 5-' ~ ' ' , --:. :

1 32362~

hydroxy-2-nitrobenzaldehyde with 3-bromopropyl acetate) analogous to the procedure of Example 26 m.p. 94-130C.
. C15H15N3O7: C, 51.58; H, 4.33; N, 12.03 Found: C, 51.56; H, 4.36; N, 12.27.

` Example 28 Additional substituted hydantoins of Formula III illus-tratd below may be prepared by following the procedures of Examples 10 to 27 employing appropriate 2-nitrobenzaldehydes and hydantoin-S-phosphonates.
.-.

(III) / 6 \ ~ ~ N
v" \ I
. O . R
`~ \ Alk-Y
, , R O-Alk-Y

EntrY Rl Position Radical Position Radical 28-1 H 6 Cl 5 o(cH2)3 2 29-2 H 3 Cl 5 O(CH2)3CO2 ~^ 28-3 H 4 Cl 5 O(CH2)3co2 28-4 H 3 F 5 o(CH2)3 2 2288-56 H 66 Me 5 o(CHH2)3Co2 28-7 H 5 F 6 o(cH2)3 2 28-8 H 3 Cl 6 o(CH2)3CO2 s 28-9 H 4 F 6 (CH2)3c2 28-10 H _ H 6 (CH2)3c2 28-11 H 4 Me 6 o(cH2)3co2 28-12 H 5 F 6 O(CH2)3 2 ; 28-13 H _ H 3 (CH2)3c2 28-14 H 5 Me 3 (CH2)3c2 28-15 H 5 F 4 o(CH2)3 2 ;~ 28-16 H 5 Cl 4 (CH2)3c2 28-17 H _ H 4 ( 2)3 o2 28-18 H 6 Me 4 o(CH2)3c 2 28-19 H 4 F 3 O(CH2)3CO2 28-20 H 4 Cl 3 O(CH2)3 28-21 H _ H 5 O(CH2)6CO2 28-22 H 6 Cl 5 O(CH2)6CO2 ;,.

. . .

;, - .
"
., ; - .
., .
.
. .
.- .. .............. . ..

` 1 323629 J
R2 O-Alk-Y
Entry R1Position Radical Position Radical 28-23 H 6 Me 5 O~CH2)6 2 28-24 H 3 Cl S O(CH2)6CO2Et 28-25 H _ H 6 O(CH2)6CO2Et 28-26 H 3 F 6 O(CH2)6CO2Et 28-27 H 4 Me 6 O(CH2)6CO2Et 28-28 H 4 C1 6 O(CH2)6CO2Et 28-29 H _ H 3 O(CH2)6CO2Et 28-30 H 6 F 3 O(CH2)6CO2 28-31 H 4 Cl 3 O(CH2)6CO2Et 28-32 H S Me 3 O(CH2)6CO2Et 28-33 H _ H 4 O(CH2)6CO2Et 28-34 H 6 Me 4 O(CH2)6CO2Et 28-35 H _ H 6 (CH2)4c2 28-36 H 3 Cl 6 O(CH2)4CO2Et 28-37 H 3 Me 6 O(CH2)4CO2Et 28-38 H 5 Me 6 O(CH2)4CO2Et 28-39 H 3 Cl 5 (CH2)4C2Et 28-40 H 6 Cl 5 (CH2)4C 2 28-41 H _ H 5 (CH2)4c2Et 28-42 H _ H 4 O(CH2)4co2Et 28-43 H 6 Me 4 (CH2)4c2 28-44 H 5 Cl 4 (CH2)4C2Et 28-45 H 4 Cl 5 (CH2)4c2 28-46 H _ H 3 (CH2)4c2Et 28-47 H 6 Me 3 (CH2)4c2Et 28-48 H 4 Cl 3 (CH2)4c2Et 28-49 H _ H 6 (CH2)5c2Et 28-50 H 3 Cl 6 O(CH2)5CO2Et 28-51 H 5 Cl 6 O(CH2)5CO2Et 28-52 H _ H 5 O(CH2)5Co2 28-53 H 4 Cl 5 O(CH2)5Co2 28-54 H 3 Me 5 O(C 2)5 2 28-55 H _ H 3 (CH2)5c2Et 28-56 H 4 F 3 O(C 2)5 2 28-57 H 5 Me 3 (CH2)5c2 28-58 H _ H 4 O~CH2)5CO2Et 28-59 H 5 Me 4 O(CH2)5C2Et 28-60 H 6 Cl 4 O(CH )5CO2 28-61 H 6 Cl 5 OCH2~O2Et 28-62 H _ H 5 OCH2CO2Et 28-63 H 3 C1 5 OCH2CO2Et 28-64 H 4 Cl 5 OCH2CO2Et 28-65 H 3 F 5 OCH2CO2Et 28-66 H _ H 5 OCH2CO2Et 28-67 H 4 Cl 5 OCH2CO2Et 28-68 CH3 - H 5 OCH~CO2Et 28-69 CH3 - H 5 O(CH2)2Co2 28-70 CH3 - H 5 ( 2 5 2 28-71 c~3 O~C~2~6CO2Et , .

, .

, R O-Alk-Y
EntrY RlPosition Radical PositionRadical 28-72 CH _ H 6O(CH2)3C~Et 28-73 CH3 H 3O(CH2)3CO2E
28-74 CH3 _ H 4 ( 2)3 2 28-75 (CH3)3CH - H 5(CH2)3c2Et 28076 C H C~ - H 5O(C~2)3CO2E
28-776 ~ 2 6 OMe 5 O(C 2)3 2 28-78 H 3 OMe 5O(CH2)3CO2E
28-79 H 4 OMe 5 O(C 2)3 2 28-80 H _ OCH(CH3)2 5 (CH2)3c2 ExamPle 29 The following additional substituted hydantoins may be prepared by following the procedures of Examples 10 to 27 ` employing appropriate 2-nitrobenzaldehydes and hydantoin-5-phosphonates:
~ 5-[[5-[3-[[(cyclohexyl)methylamino]-carbonyl~propoxy]-- 2-nitrophenyl]methylene]imidazolidine-2,4-dione; 4-[[4-nitro-3-[(2,4-dioxoimidazolidin-5-ylidine)methyl]phenyl]-' oxy]butanoic acid; 5-[[4-nitro-3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]phenyl]oxy]pentanoic acid; N-cyclohexyl-N-methyl-5-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]pentanamide; and N-cycloheptyl-N-methyl-5-[[4-nitro-3-(2,4-dioxoimidazolidin-5-yl)methylene]phenoxy]pent-anamide.
The following examples 30 to 42 illustrate the prepara-tion of additional arylidene hydantoins.

Example 30 5-[[2-Nitro-5-(1-piperidinyI)phenyl]-methvlene]-2,4-imidazolidinedione. Sodium (0.6 g, 0.026 g atom) was dis-solved in absolute ethanol (200 mL) and diethyl 2,4-dioxo-imidazolidine-5-phosphonate (6.0 g, 25 mmol) added. After 10 minutes, 2-nitro-5-(1-piperidinyl)benzaldehyde (5.0 g, 21 mmol) was added in one portion and the mixture stirred at room temperature for five hours. The yellow precipitate was ..

, , ~,., .. ...
., :

filtered off, washed with water and dried in air to give 5-~2-nitro-5-(1-piperidinyl)phenyl]methylene~-2,4-imidazol-idinedione 16.17 g, 92~), m.p. 273-276C. A sample dried ln vacuo at llO~C. had m.p. 280C. (dec.).
Anal. Calcd. for C15H16N4O4: C, 56.96; H, 5.10 N, 17.71. Found: C, 56.64; H, 5.06; N, 17.51 NMR (DMSO-d6): ~ 1.62 (6H, bs, CH2 of piperidine ring), 3.49 (4H, bs, NCH2), 6.67 and 6.78 (lH, 2 singlets, ratio 3:1, olefinic H), 6.80 to 7.00 ~2H, m, aromatic H
ortho to piperidino group) and 7.90 to 8.10 (lH, two doublets, J = 9Hz, aromatic H ortho to NO2).
., ExamPle 31 5-[[2-Nitro-5-(1-Pyrrolidinvl)Phenyl]-methYlene]-2,4-imidazolidinedione. Prepared from diethyl 2,4-dioxoimida-zolidine-5-phosphonate and 2- nitro-5-(1-pyrrolidinyl)benzal-dehyde analogous to the procedure of Example 30, m.p. 289C.
(dec.), crystallized from DMF-H2O.
~'~! Anal. Calcd. for C14H14N4O4: C, 55.63; H, 4.67; N, r`~ 18.53. Found: C, 55.73; H, 4.66; N, 18.51.

ExamPle 32 5-[[5-(Diethylamino)-2-nitro~henYl]-methYlene]-2,4-imidazolidinedione. Prepared as a partial hydrate from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-diethylaminobenzaldehyde analogous to the procedure of Example 30, m.p. 251-252C. (dec.), crystallized from ;' EtOH-H20.
Anal Calcd- for C14H16N44 2H2 N, 18.20; H2O; H2O, 1.17. Found: C, 54.62; H, 5.21; N, 17.92; H2O, 3.72*. (*Karl Fischer reagent reacted with compound and produced erroneous results.) Example 33 5-[~5-(4-Morpholinyl)-2-nitrophenYl]-methylene]-2,4-` imidazolidinedione. Prepared as a partial solvate/hydrate .'~ , , i .' ~ ' ', ~

, :
, , , from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(4-morpholinyl)benzaldehyde analogous to the pro-cedure of Exmaple 30, m.p. 278-280C., crystallized from ~ EtOEI--H20.
Anal. Calcd- for C14N14N4S 2C2H6 2 ~ 52.10; H, 4.77; N, 16.88; H2O, 1.36. Found: C, 51.74; H, r 4.67; N, 16.64; H2O, 0.99.
.~ .
ExamPle 34 ; Ethyl 1-[3-[(2,4-dioxoimidazolidin-5-~lidene)methvl]-4-nitrophenyl]-4-piperidinecarboxylate. Prepared from di-ethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(4-ethoxycarbonyl-1-piperidinyl)benzaldehyde analogous to the procedure of Example 30, m.p. 221-223C., crystallized from MeOH.
Anal. Calcd. for C18H20N4O6: C, 55.67; H, 5.19; N, 14.43 Found, 55.62; H, 5.28; H, 14.40.
. ~
Example 35 EthYl 4-[3-[(2,4-dioxoimidazolidin-5-Ylidene)methYl~-4-nitrophenyl]-1-piPerazinecarboxylate. Prepared as a partial hydrate from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[4-(ethoxycarbonyl)-1-pipera-zinyl)]benzaldehyde analogous to the procedure of Example 30, m.p. 274-275C., crystallized from EtOH-H2O.
Anal. Calcd. for C17HlgN506 0.25H20: C, 51.84; H, 4.99; N, 17.78; H2O, 1.14. Found: C, 51.94; H, 5.04; N, 17.41; H2O, 1.33.

ExamPle 36 l BenzoYl-4-[3-[(2,4-dioxoimidazolidin-5-Ylidene)-methyl]-4-nitrophenyl]piperazine. Prepared as a partial hydrate from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(4-benzoyl-1-piperazinyl)-benzaldehyde anal-ogous to the procedure of Example 30, m.p. 165-170C., crys-tallized from DMF-H20.

~ 1 323629 Anal. Calcd. for C21HlgN5O5 0.5H2O: C. 58-60; H, 4-68;
N, 16.27; H2O; 2.09. Found: C, 58.86; H, 4.98; N, 16.32;
H2O, 2.35.
.
Example 37 1-(3,4-Dimethoxybenzoyl)-4-[(2,4-dioxoimidazol_din-5-ylidene)methyl]-4-nitrophenyl]piperazine. Prepared as a partial hydrate from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[4-(3,4-dimethoxy-benzoyl)-pipera-zinyllbenzaldehyde analogous to the procedure of Example 30, m.p. 200-203C., crystallized from CH3CN.
Anal. Calcd- for C23H23Ns7 12H2 4.82; N, 14.55; H2O; 0.45. Found: C, 57.03; H, 4.77; N, 14.49; H2O, 0.44.

ExamPle 38 Ethyl 1-[3-~(2,4-dioxoimidazolidin-5-vlidene)methYl]-4-nitroPhenvl~-3-piperidinecarboxylate. Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[3-(ethoxycarbonyl)-1-piperidinyl)]benzaldehyde analogous to the procedure of Example 30, m.p. 223-225C.
Anal. Calcd. for C18H20N4O6: C, 55.67; H, 5.19; N, 14.43. Found: C, 55.50; H, 5.22; N, 14.26.
..... .
Example 39 N-CYclohexyl-l-[3-[(2~4-dioxoimidazolidin-5-ylidene) methyl]-4-nitrophenYl]-N-methyl-4-piperidinecarboxamide.
~repared as a partial hydrate from diethyl 2,4-dioxoimi-dazolidine-5-phosphonate and 2-nitro-5-[4-(N-methyl-N-cyclohexylcarbamoyl)-l-piperidinyl]benzaldehyde analogous to the procedure of Example 30, indistinct m.p. 162-170C., crystallized from MeOH-H2O.
Anal. Calcd. for C23H29N5O5 0.25H2O: C, 60.05; H, 6.46; N, 15.22; H2O, 0.98~ Found: C, 60.21; H, 6.41; N, 15.15; H2O, 1.07.
.
.

~ . - . .. .

,, .
.: ~ .

~ ~` . 1 323629 ' , - Example 40 N-CYclohexy1-1-[3-[(2,4-dioxoimidazolidin-5-ylidene)-~' methyl~-4-nitrophen~l]-N-methYl-4-piperidinecar~oxamide.
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[3-(N-methyl-N-cyclohexyl-carbamoyl)-piperi-dinyl~benzaldehyde analogous to the procedure of Example 30, m.p. 153-162C., crystallized from MeOH-H2O.
Anal. Calcd. for C23H29N5O5: C, 60.65; H, 6.42; N, - 15.37. Found: C, 60.62; H, 6.55; N, 14.97.

Example 41 1-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitro-Phenyl]-4-phenylpiperazine. Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[4-(phenyl)-l-piperazine]benzaldehyde analogous to the procedure of Example 30, m.p. 230-236C. (dec.), crystallized from EtOH.
~ ,.
Example 42 ~- By substituting the benzaldehydes: 2-nitro-5-dimethyl-` amino-6-chlorobenzaldehyde; 2-nitro-5-dimethylamino-6-~ chlorobenzaldehyde; 2-nitro-5-(1-pyrrolidinyl)-6-chloro-i~ benzaldehyde; 2-nitro-5-(1-piperidinyl)-6-chlorobenzal-dehyde; 2-nitro-5-dimethylamino-4-chlorobenzaldehyde;
~ 2-nitro-5-(1-piperidinyl)-4-chlorobenzaldehyde; 2-nitro-5--~ (1-morpholinyl)-4-chlorobenzaldehyde; 2-nitro-5-(1-piper-idinyl)-4-methylbenzaldehyde; 2-nitro-4-dimethylamino-6-chlorobenzaldehyde; 2-nitro-4-(1-piperidinyl)-6-chloro-benzaldehyde; 2-nitro-4-(1-piperidinyl)-5-methylbenzal-dehyde; 2-nitro-4-(1-piperidinyl)-5-methoxybenzaldehyde;
2-nitro-5-(4-phenyl-1-piperazinyl)-6-chlorobenzaldehyde; for 2-nitro-5-(1-piperidinyl)benzaldehyde in the procedure of '- Example 30, the following hydantoin intermediates of Formula IV wherein R1 is hydrogen are prepared.

':

- 32 - l 32 3 6 2q .

o (IV) R3-l R

la) 6-C1 5-dimethylamino (b) 6-C1 5-diethylamino (c) 6-C1 5~ pyrrolidinyl) (d) 4-C1 5-(1-piperidinyl) (e) 4-C1 5-dimethylamino (f) 4-Cl 5-(1-piperidinyl) (g) 4-C1 5-(1-morpholinyl) ; (h) 4-Me S-(l-piperidinyl) ~i) 6-C1 4-dimethylamino (j) 5-Me 4-(1-piperidinyl) J (k) 5-MeO 4-(1-piperidinyl~
(l) 6-C1 5-(4-phenyl-1-piperazinyl) -~The corresponding hydanotins wherein Rl is methyl are ,obtained by using the appropriate benzaldehyde and diethyl l-methyl-2,4-dioxoimidazolidine-5-phosphonate.
Examples 43 to 45 further illustrate the coupling of an aromatic aldehyde with a dialkyl 5-phosphonate hydantoin.
., .
Example 43 5-[(2-NitrophenYl)methYlene]-2,4-imidazolidinedione.
Lithium hydroxide monohydrate (0.334 g, 8 mmol) was dis-solved in water (10 mL) and the solution diluted with ethanol (20 mL). Diethyl-2,4-dioxoimidazolidine-5-phos-phonate (1.875 g, 8 mmol) was added and the mixture stirred for five minutes before adding solid 2-nitrobenzaldehyde (1 g, 6.6 mmol). Within a few minutes a heavy yellow precipi-tate formed. After 15 minutes, the mixture was diluted with lN hydrochloric acid solution filtered and the solid washed with water and air dried to give a 2.5:1 mixture of (Z) and (E) 5-[(2-nitrophenyl)methylene]-2,4-imidazolidinedione ,. . .
, ~ .

(1.48 g, 96% yield) mp 300-302C (dec). Anal. Calcd. for~- C10~7N3O4: C, 51.51; H, 3.03; N, 18.02. Found: C, 51.36;
H, 3.06; N, 18.29.

Example 44 ~, 5-(PhenylmethYlene)-2,4-imidazolidinedioine. Benzal-- dehyde (0.5 g, 5 mmol) in dichloromethane (10 mL) was added to a solution of diethyl 2,4-dioxoimidazolidine-5-phos-phonate (1.45 g, 6 mmol and 4N sodium hydroxide solution (0.15 mL) in water (10 mL). The mixture was stirred vigor-ously overnight, the solid filtered off, washed with water and air dried to give 5-(phenylmethylene)-2,4-imidazolidine-dione (0.73 g, 82%).
Repetition of the above reaction in the presence of ;, tetrabutylammonium hydrogen sulfate (spatula tip) resulted ~ in isolation of 5-(phenylmethylene)-2,4-imidazolidinedione `~ ~0.75 g, 84% yield).

Example 45 ; Reaction of the appropriate aromatic aldehyde with a dialkyl 5-phosphonate hydantoin yielded the following com-pounds:
(a) (Z)-l-methyl-5-[(2-nitrophenyl)methylene]-2,4-imi-dazolidinedione, m.p. 273-275C.
~; Anal. Calcd. for CllHgN3O4: C, 53.45; H, 3.67; N, 'i 17.00. Found: C, 53.68; H, 3.75; N, 16.94.
~b) (E)-l-methyl-5-[(2-nitrophenyl)methylene]-2,4-imi-dazolidinedione, m.p. 210-213C.
Anal. Calcd. for CllHgN3O4: C, 53.45; H, 3.67; N, f 17.00. Found: C, 53.61; H, 3.80; N, 16.80.
: (c) 5-[(2-nitro-5-hydroxyphenyl)methylene]-2,4-imida--~ zolidinedione hydrate, m.p. 285-286C.
s Anal. Calcd. for C H7N305Ø2H2O: C, 47.52; H, 2.95;
.. 10 N, 16.62. Found: C, 47.33; H, 2.93; N, 16.75.
(d) 5-[[4-(dimethylamino)phenyl]methylene]-2,4-imidazolidinedione, m.p. 272-277C.

:, .

,' ~ .

~ .
~., .

- r 1 3 2 3 6 ~ 9 ~ - 34 -, .
Anal. Calcd. for C12H13N3O2 C, 62.33; H, 5.67; N, 18.18. Found: C, 62.30; H, 5.71; N, 18.33.
(e) N-[2-[(2,4-dioxoimidazolidin-5-ylidine)methyl]-phenyllacetamide, m.p. 295-298C.
Anal. Calcd. for C12HllN3O3: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.58; H, 4.51; N, 17.07.
(f) 5-[(2,6-dichlorophenyl)methylene]-2,4-imidazoli-dinedione, m.p. 257-259C.
Anal, Calcd. for CloH6Cl2N2O2: , 10.90. Found: C, 46.80; H, 2.35; N, 10.87.
(g) 5-[(2,4,6-trLmethoxyphenyl)methylene]-2,4-imidazolidinedione hydrate, m.p. 258-260C.
Anal- Calcd- for C13H14N25 0 15H20 5.14; N, 9.90. Found: C, 55.19; H, 5.10; N, 9.69.
(h) 5-[(2-hydroxyphenyl)methylene]-2,4-imidazolidine-dione hydrate, m.p. 280-282C.
Anal. Calcd. for CloH8N2O3 0-05H2 . N, 13.66. Found: C, 58.38; H, 4.04; N, 13.51.
(i) N-[3,4-dimethoxy-2-[(2,4-dioxoimidazolidin-5-yli-dene)methyllphenyl~-2,2-dimethylpropanamide, m.p. 227-229C.
Anal. Calcd. for Cl7H21N3O5: C, 58.78; H, 6.03; N, - 12.10. Found: C, 58.53; H, 6.17; N, 11.91.
(j) 5-[[5-(2-methyl-1,3-dioxolan-2-yl)-2-nitrophenyl]-~! methylene~-2,4-imidazolidinedione, m.p. 202-203C.
` Anal. Calcd. for C14H13N3O6 13.17. Found: C, 52.37; H, 4.12; N, 12.95.
(k) Z-l,l-dimethylethyl [4-bromo-2-[(2,4-dioxoimi-dazolidin-5-ylidene)methyl]phenyl]carbamate, m.p. >315C.
Anal. Calcd. for C15H16BrN3O4: C, 47.14; H, 4.22; N, 11.00. Found: C, 47.25; H, 4.19; N, 10.78.
(1) E-l,l-dimethylethyl [4-bromo-2-[(2,4-dioxoimi-dazolidin-5-ylidene)methyl]phenyl]carbamate, m.p. 235-236C
(dec.).
- Anal. Calcd. for C H BrN O4: C, 47.14; H, 4.22; N, 11.00. Found: C, 47.18; H, 4.19; N, 10.84.

,, .

, ; - 35 -(m) 5-[(3-thienyl)methylene]-2,4-imidazolidinedione, m.p. 264-266C (dec.).
Anal. Calcd. for C8H6N2O2S: C, 49.48; H, 3.12; N, 14.43. Found: C, 49.28; H, 3.16; N, 14.20.
(n) 5-[(2-pyridinyl)methylene]-2,4-imidazolidinedione, m.p. 220-223C.
Anal. Calcd. for CgH7N3O2 C, 57.15; H, 3.74; N, .; 22.22. Found: C, 57.43; H, 3.76; N, 22.11.
i (o) N-[3,4-dimethoxy-2-[(1-methyl-2,4-dioxoimidazoli-din-5-ylidene)methyl]phenyl-2,2-dimethylpropanamide, m.p.
206-216C.
~ Anal. Calcd. for C18~23N3O5: C, 59-82; H~ 6-42; N~
,~A 11.63. Found: C, 60.07; H, 6.49; N, 11.47.
~!'; (p) 5-(1-phenyl-2,2,2-trifluoroethylidene)-2,4-~! imidazolidinedione hydrate, m.p. 170-180C.
Anal. Calcd. for CllH7F3N2O2 ~-05H2O C, 51-40; H~
2.79; N, 10.90. Found: C, 51.14; H, 2.87; N, 11.21.
,~, ,~ Examples 46 and 47 illustrate the coupling of an aliphatic aldehyde with a dialkyl 5-phosphonate hydantoin.
.~, ~., ;.~ Exam~le 46 .: .
5-(2-Phenylethvl_dene)-2,4-imidazolidinedione. Sodium (0.460 g, 0.02 atom) was dissolved in ethanol (30 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (4.72 g, 20 mmol) added. After five minutes, freshly distilled phenylacetaldehyde (2.0 g, 16 mmol) was added to give a slightly exothermic reaction. After 15 minutes, the reaction mixture was poured into lN hydrochloric acid solution (~J180 mL), the solid precipitate filtered off, washed with water and air dried to give 5-(2-phenylethyli-dene)-2,4-imidazolidinedione (2.74 g, 81%), mp 180-186C as a 2:1 mixture of (Z):(E) isomersr lH-NMR (DMSO-d6) ~ 3.54 (d, J = 8Hz PhCH2 of (Z) isomer), 3.98 (d, J = 8Hz, PhCH2 of (E) isomer), 5.57 (t, J = 8Hz, vinyl proton of (E) isomer), 5.67 (t, J = 8Hz, vinyl proton of (Z) isomer), 7.10 to 7.40 ,.

. . .
,", ' ' .

.

(m, aromatic H) 10.35 (bs, NH) and 10.97 (bs, NH~. IR (KBr) 1675 (>C=C<), 1725 and 1780 (>C=O) cm 1. m/e 203 (MH ).
Anal- calcd- for CllHlON202 C, 65-34; H~ 4.99; N~ 13-86-Fou~d: C, 65.32; H, 4.99; N, 13.75.

-~ Example 47 Reaction of the appropriate aliphatic aldehyde with a dialkyl 5-phosphonate hydantoin yielded the following compounds:
(a) 5-butylidene-2,4-imidazolidinedione hydrate, m.p.
-~ 125-130C.
Anal. Calcd. for C7HloN2O2 O.lH2O: C, 53-91; H, 6-60;
N, 17.97. Found: C, 54.09; H, 6.55; N, 17.65.
(b) 5-(3-phenyl-2-propeneylidene)-2,4-imidazolidine-~ dione hydrate, m.p. 256-274C.
;j Anal. Calcd. for C12HloN2O2 0.05H2O: C, 67.01; H, 4.74; N, 13.03. Found: C, 66.86; H, 4.69; N, 13.07.
f (c) l-methyl-5-(2-phenylethylidene)-2,4-imidazolidine-dione, m.p. indistinct.
Anal. Calcd. for C12H12N2O2: C, 66.66; H, 5.60; N, ~- 12.96. Found: C, 66.75; H, 5.58; N, 12.92.
(d) 5-ethylidene-2,4-imidazolidinedione, m.p. 274-276C.
Anal. Calcd. for C5H6N2O2: C, 47.63; H, 4.80; N, 22.22. Found: C, 47.34; H, 4.73; N, 22.16.
"
; Examples 48 and 49 illustrate the coup}ing of a ketone with a dialkyl 5-phosphonate hydantoin.
,i .
; ExamPle 48 . . .
` 5-[1-(PhenYlmethYl)-4-Piperidinylidene]-2,4-imida-zolidinedione. Lithium hydroxide monohydrate (0.288 g, 7 -~ mmol) was dissolved in water (10 mL). The solutlon was diluted with ethanol (20 mL) and diethyl 2,4-dioxoimida-zolidine-5-phosphonate (1.62 g, 7 mmol) added. After five - minutes, l-phenylmethyl-4-piperidone (1.00 g, 5 mmol) was "~

: , - .

~ . .

1 32362q , .
added and the mixture stirred at room temperature for 21 hours. The reaction mixture was diluted with water (~V30 mL) and acetic acid (rvlo mL), concentrated in vacuo and the mixture diluted with saturated sodium carbona~e `''3 solution to precipitate a white solid which was filtered -Ioff, air dried and recrystallized from aqueous methanol to afford 5-[1-(phenylmethyl)-4-piperidinylidene]-2,4-imida-zolidinedione (1.20 g 83%), mp 243-245C (dec). 1H-NMR
(DMSO-d6) ~ 2.30-2.45 (6H, m), 2.90-2.98 (2H, m), 3.48 (2H, s, N-CH~), 7.30 (5H, bs, aromatic H), 9.82 (lH, bs, NH) and 10.90 ( H, bs, NH). IR (KBr) 1660 (>C=C<), 1700 and 1725 (>C=O) cm 1. m/e 272 (MH ). Anal. calcd. for C15H17N3O2:
C, 66.41; H, 6.32; N, 15.49. Found: C, 66.48; H, 6.35; N, 15.51.

~; Example 49 .Reaction of the appropriate cyclic ketone with a dialkyl 5-phosphonate hydantoin gave the ~ollowing `~- compounds:
(a) 5-(cyclohexylidene)-2,4-imidazolidinedione, m.p.
253-255C.
Anal. Calcd. for CgH12N2O2: C, 59.99; H, 6.71; N, 15.55;. Found: C, 59.59; H, 6.73; N, 15.41.
(b) 5-(cyclopendylidene)-2,4-imidazolidinedione hydrate, m.p. 279-282C.
Anal. Calcd. for C8H1oN2O2 0.05H2O: C, 57.52: H, 6.10;
N, 16.77;. Found: C, 57.26; H, 6.07; N, 16.75.
~, Examples 50 and 51 illustrate the coupling of an alpha-dicarbonyl compound with a dialkyl 5-phosphonate hydantoin.

Example 50 5-(2-Oxo-2-phenvlethvlidene)-2,4-imidazolidinedione hYdrate (BMY K-21588-3). Sodium (0.393 g 0.017 g atom) was ' .

dissolved in ethanol (25 mL) and diethyl 2,4-dioxoimida-zolidine-5-phosphonate (4.04 g, 17 mmol) added. After five minutes, phenylglyoxal monohydrate (2 g, 13 mmol) was added as the solid in one portion. Almost immediately, a yellow precipitate separated. The mixture was stirred for 30 minutes, diluted with water, filtered, and the solid washed with water. Acidification of the mother liquor furnished a second crop which was combined with the first crop and air dried to give 5-(2-oxo-2-phenylethylidene)-2,4-imidazoli-dinedione hydrate t2.85 g, 100%), mp 264-266C (dec).
1H-NMR (DMSO-d6) ~ 6.85 (1~, s, vinyl H), 7.50 to 7.70 (4H, m, aromatic H) and 8.08 (lH, d, J=7.5Hz, aromatic H). lR
(KBr) 1675, 1740 and 1785 (C=O) cm 1 m/e 217 (MH ). Anal.
calcd. for CllH8N2O3 0.05H2O: C, 60.83; H, 3.77; N, 12.91;
H2O, 0.42. Found: C, 60.65; H, 3.65; N, 12.78; H2O, 0.11.
~, .
Example 51 Reaction of the appropriate alpha-dicarbonyl compound , with a dialkyl S-phosphonate hydantoin gave the following ,~! compounds:
(a) ethyl 2-(2,5-dioxo-4-imidazolidin-5-ylidene)propio-~i nate, m.p. 143-150C.
Anal. Calcd. for C8HloN2O4: C, 48.49; H, 5.09; N, 14.14;. Found: C, 48.09; H, 5.04; N, 13.30.
(b) 5-(2-oxocyclohexylidene~-2,4-imidazolidinedione, m.p. 223-226C.
Anal. Calcd. for CgHloN2O3: C, 55.67; H, 5.20; N, 14.43;. Found: C, 55.54; H, 5.14; N, 14.25.
(c) l-methyl-5-(2-oxo-2-phenylethylidene)-2,4-imidazolidinedione, m.p. 164-169C.
- Anal. Calcd. for C12HloN2O3: C, 62.61; H, 4.38; N, 12.17;. Found: C, 62.66; H, 4.36; N, 12.12.
- (d) Ethyl a-(2,4-dioxo-5-im~dazolidinylidene)benzene-acetate, m.p. 140-150C.
Anal. Calcd. for C13H12N2O4: C, 60.00; H, 4.65; N, 10.77;. Found: C, 59.75; H, 4.67; N, 10.74.

,, : .. ~ ; . ~." .

' . .

;^

1 32362~

(e) 5-(2,3-dihydro-1-methyl-2-oxo-lH-indol-3-ylidene)-2,4-imidazolidinedione, m.p. 308-310C.
Anal- Calcd- for C12H9N33 C~ 59-27; H~ 3-74; N~
17.28;. Found: C, 59.23; H, 3.78; N, 17.19.
(f) 5-(2,3-dihydro-2-oxo-lH-indol-3-ylidene)-2,4-i imidazolidinedione, m.p. >360C.
Anal. Calcd. for CllH7N303: C, 57.65; H, 3.08 N, 18.34:. Found: C, 57.61: d, 3.07: N, 18.35.

.
.

Claims (25)

1. A process for the preparation of C-5-ethylenically unsaturated hydantoin derivatives which comprises coupling an aliphatic or aromatic aldehyde or ketone or an alpha-dicarbonyl compound with a dialkyl 5-phosphonate hydantoin.
2. A process as defined in claim 1 wherein an ali-phatic aldehyde is coupled with said dialkyl 5-phosphonate hydantoin.
3. A process as defined in claim 1 wherein an aro-matic aldehyde is coupled with said dialkyl 5-phosphonate hydantoin.
4. A process as defined in claim 1 wherein a cyclic ketone coupled with said dialkyl 5-phosphonate hydantoin.
5. A process as defined in claim 1 wherein an alpha-dicarbonyl compound is coupled with said dialkyl 5-phospho-nate hydantoin.
6. A process as defined in claim 1 wherein said dialkyl 5-phosphonate hydantoin has the formula:

(I) wherein R1 and R2 are hydrogen, alkyl or aralkyl containing up to 10 carbon atoms.
7. A process as defined in claim 2 wherein said dialkyl 5-phosphonate hydantoin has the formula:

(I) wherein R1 and R2 are hydrogen, alkyl or aralkyl containing up to 10 carbon atoms.
8. A process as defined in claim 3 wherein said dialkyl 5-phosphonate hydantoin has the formula:

(I) wherein R1 and R2 are hydrogen, alkyl or aralkyl containing up to 10 carbon atoms.
9. A process as defined in claim 4 wherein said dialkyl 5-phosphonate hydantoin has the formula:

(I) wherein R1 and R2 are hydrogen, alkyl or aralkyl containing up to 10 carbon atoms.
10. A process as defined in claim 5 wherein said dialkyl 5-phosphonate hydantoin has the formula:

(I) wherein R1 and R2 are hydrogen, alkyl or aralkyl containing up to 10 carbon atoms.
11. A process as defined in claim 6 wherein R1 and R2 are each hydrogen and R3 is ethyl.
12. A process as defined in claim 7 wherein R1 and R2 are each hydrogen and R3 is ethyl.
13. A process as defined in claim 8 wherein R1 and R2 are each hydrogen and R3 is ethyl.
14. A process as defined in claim 9 wherein R1 and R2 are each hydrogen and R3 is ethyl.
15. A process as defined in claim 10 wherein R1 and R2 are each hydrogen and R3 is ethyl.
16. A process as defined in claim 6 wherein R1 is hydrogen, R2 is methyl, and R3 is ethyl.
17. A process as defined in claim 7 wherein R1 is hydrogen, R2 is methyl, and R3 is ethyl.
18. A process as defined in claim 8 wherein R1 is hydrogen, R2 is methyl, and R3 is ethyl.
19. A process as defined in claim 9 wherein R1 is hydrogen, R2 is methyl, and R3 is ethyl.
20. A process as defined in claim 10 wherein R1 is hydrogen, R2 is methyl, and R3 is ethyl.
21. A process as defined in claim 20 wherein from about 0.5 to 1.5 moles of aliphatic or aromatic aldehyde or ketone or alpha-dicarbonyl compound is reacted per mole of phosphonate at a temperature ranging from about 0°C to about 50°C under basic conditions for a period of from 15 minutes to 24 hours.
22. A process as defined in claim 1 wherein said alde-hyde has the formula RCHO wherein R is selected from the group consisting of (a) substituted or unsubstituted alkyl wherein the alkyl group contains from 2-6 carbon atoms, (b) substituted or unsubstituted alkenyl wherein the alkenyl group contains 3-5 carbon atoms, (c) substituted or unsub-stituted phenyl wherein one or more substituents on the substituted phenyl is selected from the group consisting of halogen, hydroxy, alkoxy or substituted alkoxy wherein the alkoxy has from 1-6 carbon atoms, nitro, alkyl having from 1-6 carbon atoms and substituted or unsubstituted amino, 2-(2-methyldioxalano), 1-piperidino, 1-morpholino, 1-pyr-rolidino, or 1-piperazino, (d) thienyl, (e) pyridinyl, and (f) PhC(O)-.
23. A process as defined in claim 1 wherein said ketone is selected from the group consisting of C1-3 alkyl 2-ketophenylacetate, C1-3 alkyl 2-keto C1-5 alkyl acetate, substituted or unsubstituted C4-8 cycloalkyl wherein one or more substituents on the substituted cycloalkyl is selected from the group consisting of halogen, hydroxy, alkoxy or substituted alkoxy wherein the alkoxy has from 1-6 carbon atoms, and alkyl having from 1-6 carbon atoms, and 1,2-dioxycyclohexane, substituted or unsubstituted C8-10 alkyl phenones wherein the substituted phenyl is selected from the group consisting of halogen, hydroxy, C1-6 alkoxy or C1-6 alkyl, 3-oxoindole, and N-C1-4 alkyl-3-oxoindole.
24. 1-Methyl-2,4-dioxoimidazolidine-5-phosphonate.
25. A method for preparing diethyl-2,4-dioxoimida-zolidine-5-phosphonates which comprises reacting a hydantoin selected from the group consisting of hydantoin and l-methyl hydantoin with bromine in acetic acid to produce the corres-ponding 5-bromo hydantoin and reacting said 5-bromo hydan-toin with triethyl phosphite.
CA000548024A 1986-09-29 1987-09-28 Process for the preparation of 5-arylidene and alkylidene-substituted hydantoins Expired - Fee Related CA1323629C (en)

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WO2011103289A2 (en) * 2010-02-17 2011-08-25 Jasco Pharmaceuticals, LLC Imidazole-2, 4-dione inhibitors of casein kinase 1
RU2781135C1 (en) * 2022-02-18 2022-10-06 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Benzylammonium salt of 4-ethoxycarbonyl-5-oxo-2-(2-oxo-2-phenylethylidene)-2,5-dihydro-1h-pyrrole-3-olate, showing antimicrobial activity

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DE59309402D1 (en) * 1992-07-31 1999-04-08 Hoechst Ag Process for the biotechnical production of L-thienylalanines in enantiomerically pure form from 2-hydroxy-3-thienyl-acrylic acids and their use
CN1636037A (en) 2002-02-21 2005-07-06 西巴特殊化学品控股有限公司 Lactam-based pigments and the use thereof in the production of coloured plastics or polymeric colour particles
EA200700117A1 (en) * 2004-06-24 2007-06-29 Инсайт Корпорейшн N-SUBSTITUTED PIPERIDINES AND THEIR APPLICATION AS PHARMACEUTICAL PREPARATIONS

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WO2011103289A2 (en) * 2010-02-17 2011-08-25 Jasco Pharmaceuticals, LLC Imidazole-2, 4-dione inhibitors of casein kinase 1
WO2011103289A3 (en) * 2010-02-17 2012-01-19 Jasco Pharmaceuticals, LLC Imidazole-2, 4-dione inhibitors of casein kinase 1
US9073903B2 (en) 2010-02-17 2015-07-07 Jasco Pharmaceuticals, LLC Imidazole-2,4-dione inhibitors of casein kinase 1
RU2781135C1 (en) * 2022-02-18 2022-10-06 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Benzylammonium salt of 4-ethoxycarbonyl-5-oxo-2-(2-oxo-2-phenylethylidene)-2,5-dihydro-1h-pyrrole-3-olate, showing antimicrobial activity

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